Friday October 10, 2014 (SW41 2014) NEWS WORLDWIDE EUROPEAN UNION

Transcription

Friday October 10, 2014 (SW41 2014)
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NEWS
WORLDWIDE
EUROPEAN UNION
FRANCE
EUROPE
RUSSIA & RELATED COUNTRIES
MIDDLE EAST
NORTH AMERICA
LATIN AMERICA
AUSTRALIA & NEW ZELAND
INDIA, PAKISTAN & ASIA
DISCOVERY - DESIGN – DEVELOPMENT
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Parmi les sujets sélectionnés dans ce numéro :
Sanofi says told U.S. about bribery claims in Africa, Mideast
p.2
Orphan drugs may be pricey, but payers are barely balking
p.6
ICH elemental impurities guideline expected to be finalized at end of
September
p.7
p.11
EU agency adopts plan to cut clinical trial secrecy
EMA releases revised guidance on EU Periodic-Safety-Update-Report
Single Assessment for Nationally Authorised Medicines
p.15
FRANCE - La base de données publique des médicaments a un an Point d'information
p.22
Hypocholestrolémiants et entente préalable: Le patron du service
médical de la CNAMTS s’explique
p.25
Médicaments: la HAS veut en finir avec le SMR (Service Médical
Rendu), et relance l’ITR (Index Thérapeutique Relatif)
p.31
Sovaldi may be cost-effective, but the U.K. can't afford it, documents
say
p.33
NICE - Medicines optimisation: guideline consultation
p.36
FDA’s New Roadmap for Progress: Strategic Priorities 2014-2018
p.41
p.50
Canada Wants to get Tough on Pay-to-Delay Deals
FDA warns of contaminated Chinese meds after toddler suffers lead
poisoning
p.54
Indian Industry Decries Smear Campaign Against its Pharma
Exporters
p.56
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© Adrien Tillet
«Beyond words, the world »
NEWS
 Accès au marché, prise en charge des médicaments: les difficultés
grandissent
En Europe, et particulièrement en France, les autorités de santé et les « payeurs » sont de plus en plus regardants
sur l’accès au marché et les conditions économiques de prise en charge.
Le Cabinet WHITE-TILLET, fort de sa longue expérience et de son expertise dans le domaine de l’évaluation clinique
des produits de santé, de la rédaction des dossiers de remboursement, du mode de fonctionnement des autorités de
tutelle, et de son taux historique de succès (> 90%) peut vous conseiller, vous assister, et contribuer au succès de
votre démarche. (Contact : M. Yves TILLET - Tel : 01 60 08 43 85)
 Sanofi says told U.S. about bribery claims in Africa, Mideast
French drugmaker Sanofi said it had informed U.S. authorities of allegations of improper payments by its
employees to healthcare professionals in East Africa and the Middle East, in the latest of a string of bribery
claims embarrassing the pharmaceutical industry.
Sanofi hired a law firm to investigate the claims after it received anonymous allegations that wrongdoing
occurred between 2007 and 2012, the Paris-listed company said in a statement late on Monday in reaction
to a Wall Street Journal report.
"The investigation is still ongoing and is expected to take some time given that the allegations date back
seven years. At this stage, it is too early to draw conclusions," Sanofi said, adding it was committed to
maintaining the highest ethical standards wherever it does business.
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Among the allegations are that Sanofi employees made improper payments to doctors in Kenya and other
East African countries by handing out perks encouraging doctors to prescribe Sanofi drugs, the WSJ
reported on its website, citing e-mails from a whistleblower.
Sanofi said it had notified the U.S. Department of Justice and the U.S. Securities and Exchange Commission
of the claims, that it took these seriously and that it would cooperate with any potential review.
The allegations follow a string of bribery claims over the past year in the industry that have mainly centred
on Britain's GlaxoSmithKline and its sales practices in China. … (Source: reuters)
 Needle-coated pill offers safe oral delivery of insulin, vaccines
A pill coated with tiny needles may help improve oral treatments, according to researchers at MIT and
Massachusetts General Hospital. When swallowed, the pill delivers large molecules such as insulin into the
lining of the stomach and does so more efficiently than an injection under the skin.
Oral insulin is a lofty goal for many companies that have looked for ways to deliver the large, fragile
molecule in a way that ensures it remains effective but also makes it through the gut. The researchers at
MIT and MGH tested their needled pill with insulin, and also think that it would be useful for antibody
cancer treatments and ones for autoimmune diseases like arthritis and Crohn's disease.
"This could be a way that the patient can circumvent the need to have an infusion or subcutaneous
administration of a drug," lead author Giovanni Traverso said in a statement.
The acrylic capsule is two centimeters long and one in diameter with a hollow reservoir, and has needles
just 5 millimeters long on its edge. With needles that size, the process would be both painless and safe,
according to previous studies. They tested it in pigs, finding no tissue damage during its weeklong voyage
through the digestive tract. … (Source: FierceDrugDelivery)
 Pfizer launches meds optimisation scratch card
Pfizer is launching a new scratch card for patients, as part of its ongoing campaign to raise awareness of
medicines optimisation.
The postcard-sized scratch card was launched at the Pharmacy Show in London on October 5 and will
become available to the public on October 20. It aims to improve medicines optimisation by increasing
public engagement with pharmacy teams and create opportunities to engage with pharmacy services such
as medicines use reviews and the new medicines service.
Developed in consultation with the National Pharmacy Association and supported by the Pharmaceutical
Services Negotiating Committee (PSNC), the Royal Pharmaceutical Society and Pharmacy Voice, the scratch
card’s public launch will be backed up by a series of awareness-raising events across England and Wales in
2014/15, plus posters to advertise its availability and a campaign guide for pharmacies.
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Listed on the card are five simple statements about medicines use. Individuals scratch a section to indicate
how strongly they agree or disagree with each statement and then return the card to a member of the
pharmacy team who will interpret the responses and provide appropriate advice and guidance.
Pharmacy leaders point out that millions of pounds are wasted every year on unused and untaken
medicines and that in many cases this is simply because people do not know enough about their medicines
or how to take them. And while initiatives such as the new medicines service (NMS) have been shown to
have a positive impact on patient adherence and offering savings to the NHS, public awareness of them is
low.
“The scratch cards are designed to capture public attention and I welcome any tool that creates
opportunities for pharmacy teams and the public to engage in meaningful conversations about medicines,”
said Ash Soni, president of the RPS. … (Source: PharmaTimes)

The Cabinet WHITE-TILLET is now established in CHINA
(Beijing) and can provide secure and reliable local audits
The CHINA Director of our new office is Alban TACQUET. Alban is master on quality management and
project management.
At 43 years old, he has worked twenty years in health industry in France and overseas. His expertise covers
the job positions and abilities that he has developed during his working experience: Quality Management,
Quality Control, Manufacturing, R&D, Project Management, audit and Training.
He is now established in China, where he lives since 7 years and is married with a Chinese wife.
He has been general manager for a foreign company in china during the previous 7 years and has a real and
practical knowledge about Chinese environment.
Considering his experience, Alban has ability to conduct audits in ccordance to the followed referentials:
GMP, ISO 9001, ISO 13485, ISO 22716, for active substances and drug products as well as for medical
devices and cosmetics. He can also perform consulting, outsourcing, and training on behalf of the Cabinet
WHITE-TILLET.
WORLDWIDE
Government and Regulatory Bodies
http://www.pharmweb.net/pwmirror/pwk/pharmwebk.html
http://www.who.int/en/
 Current projects (WHO)
New texts under review for medicines quality assurance
4
 Low-Global-Warming Propellant from Honeywell Powers New
Aerosol for Rash Treatment
Honeywell announced Oct. 2 that its low-global-warming propellant, Solstice® Propellant, is being used in a
new diaper rash aerosol treatment for infants, toddlers and adults.
Mission Pharmacal Co., a U.S. manufacturer of diaper rash ointments, is using Solstice Propellant in its new
line of Dr. Smith's®-brand diaper rash sprays. Solstice Propellant, which has a global warming potential
(GWP) of less than 1, enables the new product line to have a lower global warming impact than aerosols
using other propellants. The new products are some of the first low-GWP spray treatments for rashes on
the market today.
"Solstice Propellant provides Mission Pharmacal and its customers with the best of both worlds - the
performance of today's propellants with greatly reduced environmental impact," said David Cooper, global
business director for Honeywell's Fluorine Products business. "Because it complies with major
environmental regulations around the world, Solstice Propellant is being steadily adopted by companies
seeking to sell their products in multiple markets."
In addition to personal care products, Solstice Propellant is used in aerosols for automotive, electronics and
industrial applications, including air horns, dusters and cleaning sprays. Honeywell announced in July 2011
that it was investing $33 million in its Baton Rouge, La. manufacturing facility to supply Solstice Propellant
to aerosol manufacturers globally. … (Source: PMPnews)
 Industry Groups, Providers Comment on Physician Payment Website
Reaction to the launch of CMS' online Open Payments System has been mixed, with some doctors and
industry groups raising concerns about usability and data errors and others commending the increased
transparency, Politico reports (Wheaton, Politico, 9/30).
Background
Yesterday, CMS launched its Open Payments System, which is required under the Affordable Care Act's
Sunshine Act and aims to boost transparency by making public what payments health care providers have
received from drugmakers and medical device manufactures (iHealthBeat, 9/30).
In addition, to medical doctors, the disclosure rules under the Sunshine Act apply to chiropractors, dentists,
podiatrists and optometrists (Thomas et al., "Business Day," New York Times, 9/30).
Physicians whose data are listed in the online database had until Sept. 25 to review and dispute payments,
though many providers reported issues registering and accessing the data (iHealthBeat, 8/29).
CMS officials say just 26,000 of the 546,000 health care professionals, and 400 of the 1,360 teaching
hospitals listed in the database registered to verify their data before they were released (Politico, 9/30). …
(Source: IhealthBeat)
 Hundreds of firms join global hunt for copycat biotech drugs
Hundreds of companies around the world are chasing an emerging market for cheaper copies of costly
biotech drugs, with more than 700 so-called biosimilars now in development or already approved,
according to a major study of the sector.
Biotech medicines - made from proteins and other large molecules - account for six of the 10 biggest-selling
drugs in the world today, led by AbbVie's $12 billion-a-year rheumatoid arthritis injection Humira.
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The total market for such biological medicines could exceed $250 billion by 2020 but many of today's topsellers, such as Roche's cancer drugs Rituxan and Herceptin, are now losing patent protection or will do so
in the next few years.
That has opened up an opportunity for companies with the technical ability to make copycat versions something that is easier said than done, since such drugs are produced in living cells and imitations can only
ever be similar, not identical.
Despite the hurdles, a total of 245 companies in different countries have now jumped on the bandwagon as
developers, manufacturers and suppliers of biosimilars or follow-on biologics, the study compiled by
Thomson Reuters BioWorld found.
Major companies involved in the emerging biosimilars sector include leading generics players such as
Novartis's Sandoz unit and Teva; innovative pharmaceutical groups like Pfizer and Amgen; and scores of
smaller drugmakers and regional businesses.
In all, biosimilars are expected to account for approximately one quarter of the $100 billion worth of sales
stemming from off-patent biological drugs by the end of the decade, the study said.
South Korea and Brazil stand out as pioneers of biosimilar drug development, with India's large
pharmaceutical sector also anticipating a thriving market for such products.
While biosimilars could slash the cost of treating diseases like cancer and rheumatoid arthritis in much the
same way that generics have curbed spending on traditional medicines, the impact is likely to be more
gradual for several reasons.
In the first place, such copycat medicines are typically offered at a 20 to 30 percent discount to innovator
brands - rather than the 90 percent or so seen with conventional generics - and many doctors are cautious
about their use as they may vary slightly from the original product.
What is more, the regulations surrounding biosimilars have, until recently, been unclear. Europe approved
the first biosimilar drug in 2006 but the United States is only now considering the first applications. …
(Source: Reuters)
 Orphan drugs may be pricey, but payers are barely balking
Some orphan drugs to treat rare diseases can cost as much as $400,000 a year. Those hefty price tags have
sparked a lively debate in recent years about whether the American health care system can shoulder the
burden of treating rare diseases over the long term.
A new report from analysts at Leerink suggests that the debate is overshadowing the reality of the
situation: Most insurers are willing to pay high prices for orphan disease treatments.
A Leerink survey of 34 insurance companies, which together cover more than 90 million American patients,
revealed that policies allowing access to orphan drugs are unlikely to change much over the next five years,
according to The Wall Street Journal blog Pharmalot. The analysts determined that the probability of
policies becoming more restrictive starts at 17% by 2016 and rises to just 35% by 2020.
By contrast, the same survey a year ago found a 30% probability that orphan drug coverage would tighten
in the short term and a 43% chance of that happening over the long term.
What changed? According to the survey, insurers cited strong clinical trial results, availability of alternative
treatments, and safety as more important than price in making coverage decisions. Only three of the 34
companies expected to review orphan drugs more comprehensively going forward, with many saying they
would merely "tweak" their policies, by placing greater scrutiny on orphan cancer drugs, for example.
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Leerink's analysts suggest that insurance companies may have become numb to pricey orphan drugs
because of high prices on some non-orphan drugs--most notably Gilead's $84,000 hepatitis C treatment
Sovaldi and Biogen Idec's $55,000-per-year Tecfidera for multiple sclerosis. … (Source: FiercePharma)
http://www.ipec-europe.org
http://www.ich.org/
http://www.picscheme.org/
International Network of Agencies for Health Technology Assessment
(INAHTA)
 IPEC (International Pharmaceutical Excipients Council)
IPEC e-newsletter - Excipients Insight July 2014
 APIC (Active Pharmaceutical Ingredients Committee)
eCTD How to do Document
 ICH elemental impurities guideline expected to be finalized at end of
September
After much discussion and some confusion , the ICH’s (International Conference on Harmonization) Q3D
guideline , which will govern elemental impurities in final drug products, is expected to be finalized at the
end of this month. … (Source: In-Pharma)
 ICH Steering Committee - Meeting report - June 2014
5. M7 EWG: Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit
Potential Carcinogenic Risk
The Rapporteur reported to the SC on the outcome of the M7 EWG meeting held in Minneapolis on 2 – 5
June 2014.
The SC noted that the EWG reached agreement on the addressing of all public comments received from
regional consultation. The regulatory M7 experts signed-off the Step 4 M7 Guideline. The SC noted that
implementation of ICH M7 was encouraged after publication, however because of the complexity of the
Guideline; application of M7 is not expected prior to 18 months after ICH publication. Once the revision is
published and required, companies would not be required to go back and test 1) marketed products and 2)
products in P2b/P3 that had already been tested under previous expectations. The SC noted that the EWG
would continue to review and discuss the proposed Addendum to ICH M7 which would contain
the acceptable limits of known mutagenic impurities and supporting monographs. The group would work
on the Addendum by teleconferences and expect to reach Step 2 in December 2014 after which the draft
Addendum would be submitted for public comments under Step 3 of the ICH process.
SC Decisions/Actions:
7
Ø The SC supported the proposed implementation plan for the M7 Guideline;
Ø The regulatory members of the SC signed-off Step 4 of the M7 Guideline;
Ø The ICH Secretariat will organise a webinar on the ICH M7 Guideline in Q3/Q42014;
Ø The SC noted the proposed timeframe for the M7 Addendum to reach Step 2 of the ICH process.
6. E6(R2) EWG: Good Clinical Practices
The Rapporteur reported to the SC on the outcome of the first meeting of the E6(R2) EWG held in
Minneapolis on 2 – 5 June, 2014 and progress made in the development of an
Addendum to the existing ICH E6 Guideline and recommendations to facilitate innovative approaches to
Good Clinical Practices (GCP) to better ensure data quality and human subject protection in an environment
of highly complex multinational trials.The SC noted that prior to the initiation of its work as a formal the
EWG, the group hadfinalised its Concept Paper and Business Plan and following which the formal
EWG progressed the development of the Addendum structure, concepts and preliminary text on quality
management, risk management and risk-based monitoring. It was noted that the
E6(R2) EWG was anticipating to reach Step 2 in June 2015 and Step 4 in November 2016.SC
Decisions/Actions:
Ø The SC endorsed the revised ICH E6(R2) Concept Paper and its Business Plan, dated 2 June 2014;
Ø The SC supported the work plan of the E6(R2) EWG for activities to be undertaken between the
Minneapolis meeting and the next meeting in Lisbon Portugal in
November 2014.
7. Q3D EWG: Guideline for Elemental Impurities
The Rapporteur reported to the SC on the outcome of the Q3D EWG meeting held in Minneapolis on 31
May – 5 June, 2014 and progress made towards reaching Step 4.
The SC noted the work undertaken by the EWG to address public comments received during the
consultation period (Step3) which ended on 31 December, 2013. The SC also noted the progress made by
the EWG in Minneapolis to complete the review of monographs for all elements (revision of some
Permitted Daily Exposures (PDEs) and alignment of USP/ICH PDEs), to develop a process to establish a PDE
for additional routes of administration and to provide guidance on justification of levels higher than the
established PDEs. The SC noted that the EWG would continue to work by teleconference to discuss a
few implementation challenges remaining on: the harmonised implementation and interpretationof the
Guideline (e.g., its application to existing marketed products; its consistent compendial and regulatory
compliance) and on large volume parenterals. The group also suggested developing some case studies and
training materials to help facilitate the understanding and implementation of the Q3D Guideline at Step 5
of the ICH process.
It is expected that the Q3D Guideline will reach Step 4 by the end of September 2014.
Ø The SC supported the work plan of the Q3D EWG for activity to be undertaken to reach Step 4 by the end
of September 2014;
Ø The EWG will report on progress achieved at the autumn SC webconference and whether they would
request the establishment of an IWG and a face-to-face meeting
to finalise a training package.
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8. Q7 IWG: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
The Rapporteur reported to the SC on the outcome of the Q7 IWG meeting held in Minneapolis on 2 – 5
June, 2014 and progress made in the development of the ICH Q7 Q&A
document. The SC noted that the IWG collected comments from constituencies on the first set of 23 Q&As
and anticipated to review the feedback received after the Minneapolis meeting. The first set of draft Q&As
is expected to be finalised by the end of September 2014. Depending on the feedback received and its
complexity, the Q7 IWG might request to meet in Lisbon, Portugal in November 2014. A second set of draft
Q&As would be reviewed by the constituencies of each party by the end of June 2014 during four
months.Based on feedback received, the group proposed to the SC that the Q&As could go directly to Step
4 without the need of regional consultation. It was noted that the group was expecting to finalise its work
on the ICH Q&As by the end of June 2015.SC Decision/Action:
Ø The SC supported the work plan of the Q7 IWG for activity to be undertaken between the Minneapolis
meeting and the next meeting in Lisbon Portugal in November 2014.
9. M2: Electronic Standards for the Transfer of Regulatory Information
The Rapporteur reported to the SC on the outcome of the M2 EWG meeting held in Minneapolis on 2 – 4
June, 2014. The responsibility of the M2 EWG is to consider the
technical ‘bigger picture’ with respect to ICH work, ensure ICH awareness, and enabletechnical
harmonisation.
The report included an update on progress made in:
· Continuing SDO monitoring activities;
· Monitoring Technology Watch activities that capture key aspects of the evolving technology and
information standards landscape and their impact relevant to ICH;
· Providing an information repository to ICH EWGs/IWGs;
· Proceeding with the Electronic Standards for the Transfer of Regulatory Information –(ESTRI) PDF/A
recommendation on an additional file format standard that may be accepted by all regions.
The SC noted the updated leadership of the M2 EWG. A work plan was also proposed for major activities to
be undertaken between the Minneapolis meeting and the next meeting inLisbon, in November 2014. This
included: drafting of M2 strategic framework of guiding principles and process to assess emerging
standards and technologies; performing initial assessment of technology activity impacts and opportunities
for ICH topics; working with the ICH Secretariat on how to manage potential maintenance impact of broad
adoption of ICH standards; advancing ESTRI activities for DOCX testing, evaluating the “current state”
of redaction in each region to identify commonalities and potential for harmonised principles
or approaches.
Ø The SC endorsed the new Rapporteurship and Regulatory Chairmanship of the M2 EWG;
Ø The SC supported the recommendation of the M2 EWG on the PDF/A file format
for ESTRI;
Ø The SC approved the work plan and major activities between the Minneapolis meeting and the next
meeting in Lisbon Portugal in November 2014;
Ø The SC agreed for HL7 to have a liaison to ICH as a primary point of contact;
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Ø The SC noted the recommendations of the EWG regarding the technology watch activities.
10. M8 EWG/IWG: The Electronic Common Technical Document: eCTD
The Rapporteur reported to the SC on the outcome of the M8 EWG/IWG meeting held in Minneapolis on 31
May – 5 June, 2014.The report included an update on the:
· Work to complete Step 2 for Testing for eCTD v4.0.Preparation for Step 2 of the eCTD Implementation
Guide, including progress in addressing outstanding issues;
· Review of sample eCTD instances provided by the eCTD Tool Providers;
· Review of eCTD Change Requests / update of Q&A document.The M8 EWG also presented to the SC its
work plan for Step 2 for Testing activities between Minneapolis and Lisbon. The SC noted that the group
aimed to reach Step 2 of the ICH eCTD Implementation Guide (eCTD v4.0) in November 2014.
Ø The regulatory SC members signed-off Step 4 of Version 1.26 of the eCTD Change Request/Q&A
document;
Ø The SC endorsed the test schedule and milestones to reach Step 2 of eCTD version 4.0 in November 2014
and Step 4 in November 2015;
Ø The SC endorsed the work plan of the M8 EWG/IWG for work to be undertaken between the Minneapolis
meeting and the next meeting in Lisbon Portugal in November 2014.
11. M1 PtC WG: MedDRA Points to Consider Working Group
The Rapporteur reported to the SC on the outcome of the M1 PtC WG meeting held in Minneapolis.The SC
noted that the PtC WG worked to update the two PtC documents for consistent use of MedDRA. Updates
would include the addition of a new coding section for abuse/misuse and addiction; addition of a new
coding section for occupational exposure; additional examples for coding of medication errors to align with
European regulation and other exposures; and expanded coding guidance on indications, overdoses and off
label use. It was mentioned that some time was needed to confirm the influence on Japanese Regulation
and whether the medication errors concept contradicts internal policy. Further input will be provided
afterinternal consultation.
Both the Term Selection and the Data Retrieval and Presentation PtC documents which are updated with
each MedDRA version (twice a year) should be completed and released together with release of MedDRA
version 17.1 on 1 September 2014.
SC Decision/Action:
Ø The SC endorsed the work plan of the M1 PtC WG for work to be undertaken between the Minneapolis
and Lisbon meetings.
ICH Steering Committee - Meeting report - June 2014.pdf
EUROPEAN UNION
10
 EFPIA: 'we did not lobby for EU pharma policy change'
Europe’s research-based pharmaceutical industry association has said that it did not lobby for the new
European Commission to remove responsibility for medicines from the Directorate-General for Health and
Consumers and give it back to DG Enterprise.
Commission President-elect Jean-Claude Juncker’s controversial plan to take responsibility for medicines including the European Medicines Agency (EMA) - from DG SANCO, which it had held since 2009, and give it
back to DG Enterprise, has been roundly condemned by health activists. The European Public Health
Alliance (EPHA) has urged Members of the European Parliament (MEPs) to make a reversal of the decision a
requirement of their endorsing the new Commissioners-designate when questioning them this week.
However, Richard Bergstrom, director-general of the European Federation of Pharmaceutical Industries and
Associations (EFPIA), has said that “having everything for pharmaceutical companies in one unit makes a lot
of sense.” … (Source: PharmaTimes)
 EU agency adopts plan to cut clinical trial secrecy
Europe's medicines regulator has endorsed a scheme to publish detailed clinical reports underpinning new
drug approvals from next year, though campaigners for full transparency said they were concerned some
data would still be missing.
The London-based European Medicines Agency (EMA) has been at the center of a row about divulging trials
data for the past two years, following concerns over undisclosed data for certain drugs such as Roche's flu
pill Tamiflu.
Critics of the pharmaceuticals industry argue that free access to such data is essential, so that independent
experts can test claims made about prescription drugs. But some companies have fought to keep the
information private.
The EMA -- Europe's equivalent of the U.S. Food and Drug Administration -- said on Thursday its
management board had unanimously adopted a policy to publish all clinical reports for new drugs from
2015.
Importantly, outside researchers will be free to download and save the information, allowing them to
reassess large data sets -- something the EMA had at one stage been reluctant to permit.
Tracey Brown, managing director of the group Sense About Science, which has campaigned against clinical
trials secrecy, said she was pleased the EMA had reversed a "ridiculous" proposal that would have meant
researchers could only see information from clinical trials on-screen in a sealed room.
"However, it is still the case that trial sponsors (drug companies) can cut out any information they don't
want others to see," she said.
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The agency's new policy states that "in limited instances", information that may be considered
commercially confidential will be redacted from the clinical reports. … (Source: Reuters)
 European doctors want more drug info
New research shows that 72% of EU doctors surveyed believe new drugs and treatments will significantly
improve the outlook for their patients in the next three years, according to findings by M3 Europe.
The research by the global provider of technology services in healthcare also found that the majority of
European doctors also want to keep up-to-date with developments on new drugs.
These are just two findings from the survey of EU doctors conducted by M3 Europe. More results will be
announced during a free webinar, in conjunction with PharmaTimes, on Wednesday 8 October (1pm UK,
2pm Europe).
The hour-long webinar will also discuss doctors’ digital behaviour, their optimism for the future, their
attitude to pharma and what influences their treatment of patients, and how this will affect the future of
healthcare and pharma’s place in it. This webinar will ultimately give insights on how pharma can capitalise
on engaging with doctors. … (Source: PharmaTimes)
European Medicines Agency
http://www.ema.europa.eu/ema/
Human medicines: Regulatory
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/landing/human_medicines_regulatory.js
p&mid=WC0b01ac058001ff89
 EMA Management Board: highlights of October 2014 meeting
Focus on publication of clinical reports, medicines for rare diseases and patient involvement
EMA’s policy on publication of clinical reports adopted
The European Medicines Agency’s (EMA) Management Board unanimously adopted a new policy on the
publication of clinical reports that underpin the decision-making on medicines. The policy will enter into
force on 1 January 2015 and will apply to clinical reports supporting all applications for centralised
marketing authorisations submitted after that date. Please see separate press release for further
information.
Mid-year report: supporting the development of innovative medicines
The Management Board discussed the Agency’s mid-year report for 2014.
Innovative medicines hold the potential to bring significant benefits to patients. Supporting the
development of such medicines is a priority for the Agency. In the first half of 2014, interaction and
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dialogue with medicines developers increased. The number of requests for scientific advice and protocol
assistance increased by 16% compared to the same period last year. This is in line with the continuous
increase in requests seen in the past four years. When followed by applicants, scientific advice has been
proven to increase the success rate of marketing authorisation applications.
The Board was updated on the progress of two ongoing pilot projects which aim to facilitate timely access
to medicines for patients.
The number of requests for joint scientific advice with health technology assessment (HTA) bodies has
considerably increased (six in the first half of 2014 compared with one in the first half of 2013). HTA bodies
provide recommendations on medicines that can be paid for or reimbursed by the healthcare system in a
particular Member State. Joint early dialogue between EMA, HTA bodies and medicines developers aims to
facilitate agreement on a development plan and enable new medicines to reach patients in a timely
manner.
The Board also heard that the EMA has selected eight development programmes for in-depth discussion
with the applicant as part of its adaptive licensing pilot project, which was launched in March 2014. The
project is intended to explore the progressive licensing of medicines, a prospectively planned process,
which starts with an early authorisation in a restricted patient population, followed by iterative phases of
evidence gathering and adaptations of the marketing authorisation to expand access to the medicine for
increasingly broader patient populations.
In the first half of 2014, the overall number of applications for marketing authorisation remained stable.
Steady increase in medicines for rare diseases
Bruno Sepodes, the Chair of the EMA’s Committee for Orphan Medicinal Products (COMP), highlighted the
steady increase in the number of medicines authorised for the treatment of rare diseases. So far, 93
medicines are available for patients.
The number of requests for the orphan designation of medicines for rare diseases, a status which offers a
range of incentives to companies developing these medicines, is also increasing. In 2014, the COMP expects
more than 300 requests for orphan medicines designations, a 50% increase compared to 2013 and the
highest figure since the creation of the Committee.
The Chair stressed the importance of supporting companies during the early stages of development of their
medicines. With more and more applications for orphan designation expected, scientific advice is essential
to increase the chances for these developments to lead to new medicines for patients.
Involving patients and healthcare professionals in EMA activities
The Board received the 2013 annual report on the Agency’s interaction with patients, consumers and
healthcare professionals.
The overall number of patients and consumers involved in EMA activities has increased significantly since
2007. In 2013 more than 550 patients contributed to the work of the EMA. Patients and healthcare
professionals now provide their views during the development, evaluation and safety monitoring of
medicines. In addition, there has been growing collaboration on topics of common interest such as
shortages of medicines, medication errors, and antimicrobial resistance.
In September 2014, the EMA started a pilot project to involve patients in the assessment of the benefits
and risks of medicines in the EMA’s Committee for Medicinal Products for Human Use (CHMP).
Since 2013, a formal Healthcare Professionals’ Working Party (HCPWP) has supported the participation of
doctors, pharmacists and other healthcare professionals in the work of the EMA.
13
Continued focus on replacement, reduction and refinement of animal testing
The Management Board renewed for the second time the mandate of the joint ad hoc expert group on the
application of the so-called 3Rs principles. This group aims to promote best practice in relation to the
replacement, reduction and refinement of the use of animals in the tests required by regulatory
authorities. The group comprises experts from working parties of both the Committee for Medicinal
Products for Veterinary Use (CVMP) and the CHMP.
Among other activities, the group has worked on opening up a route for the approval of alternative testing
methods by the EMA. A guideline describing this route and the key principles underlying regulatory
acceptance was adopted by the CHMP and the CVMP in September 2014 and is available on the EMA
website.
EMA Management Board: highlights of October 2014 meeting
 Publication of clinical reports
EMA adopts landmark policy to take effect on 1 January 2015
The European Medicines Agency (EMA) has decided to publish the clinical reports that underpin the
decision-making on medicines. Following extensive consultations held by the Agency with patients,
healthcare professionals, academia, industry and other European entities over the past 18 months, the
EMA Management Board unanimously adopted the new policy at its meeting on 2 October 2014. The policy
will enter into force on 1 January 2015. It will apply to clinical reports contained in all applications for
centralised marketing authorisations submitted after that date. The reports will be released as soon as a
decision on the application has been taken.
“The adoption of this policy sets a new standard for transparency in public health and pharmaceutical
research and development,” said Guido Rasi, EMA Executive Director. “This unprecedented level of access
to clinical reports will benefit patients, healthcare professionals, academia and industry.”
The new EMA policy will serve as a useful complementary tool ahead of the implementation of the new EU
Clinical Trials Regulation that will come into force not before May 2016. EMA expects the new policy to
increase trust in its regulatory work as it will allow the general public to better understand the Agency’s
decision-making. In addition, academics and researchers will be able to re-assess data sets. The publication
of clinical reports will also help to avoid duplication of clinical trials, foster innovation and encourage
development of new medicines.
According to the policy’s terms of use, the public can either browse or search the data on screen, or
download, print and save the information. The reports cannot be used for commercial purposes. In general,
the clinical reports do not contain commercially confidential information. Information that, in limited
instances, may be considered commercially confidential will be redacted. The redaction will be made in
accordance with principles outlined in the policy’s annexes. The decision on such redactions lies with the
Agency.
The policy will be implemented in phases. The first phase starts on 1 January 2015. Once a medicine has
received a marketing authorisation, EMA will publish the clinical reports supporting applications for
authorisation of medicines submitted after the policy’s entry into force. For line extensions and extensions
of indications of already approved medicines, the Agency will give access to clinical reports for applications
submitted as of 1 July 2015 after a decision has been taken.
In future, EMA plans to also make available individual patient data. To address the various legal and
technical issues linked with the access to patient data, the Agency will first consult patients, healthcare
14
professionals, academia and industry. It is critically important for EMA that the privacy of patients is
adequately protected before their data are released.
The policy does not replace the existing EMA policy on access to documents. It will be reviewed in June
2016 at the latest. … (Source: EMA)
 EMA releases revised guidance on EU Periodic-Safety-Update-Report
Single Assessment for Nationally Authorised Medicines
The revised procedural guidance European Medicines Agency Post-Authorisation Procedural Advice for
Users of the Centralised Procedure is intended “to ensure thatMarketing-Authorization Holders (MAHs)
are prepared for the submission of Periodic Safety Update Reports (PSURs) for nationally authorized
medicines subject to European Union single assessment.”
PSURs provide a comprehensive and critical analysis of the risk-benefit balance of a medicinal product,
submitted by MAHs at defined time points during the post-authorization phase. The single assessment of
nationally authorized medicines “aims to harmonize and strengthen the review of the benefits and risks of
all medicines across the EU.” The Pharmacovigilance Risk Assessment Committee (PRAC) issues a
recommendation for all EU PSUR single assessments (PSUSA).
The following information briefly outlines the procedures and responsibilities of MAHs with nationally
authorized medicines subject to EU single assessment:

They must submit PSURs to the EMA and all Member States where their medicine is authorized. This
applies to all medicines with data lock points falling on or after September 1, 2014.

These PSURs will be assessed by the PRAC or a Member State appointed by the CMDh, and one single
assessment report will be generated. This report is then shared amongst all MAHs whose medicinal products
are part of the PSUSA procedure.

The dates and frequency of submission of the PSUR have been listed in the EU reference dates (EURDs).

“For all EU PSUSA procedures starting October 2014, the procedure number will be published in advance in
the EURD list. MAHs should therefore include their procedure number when preparing their submission.”

“MAHs of nationally authorized products should also complete Annex I of the formatted table template of the
cover letter.”

“The PSUR timetable has also been integrated with the PSUR single-assessment procedures containing
nationally authorized medicinal products.”

MAHs have to pay a fee for assessment of PSURs as of August 26, 2014.
Pages 142 through 158 of the revised guidance further clarifies the procedures concerning the
submission of PSURs and outlines the responsibilities of all parties involved in the process.
The EMA guidance press release can be accessed here:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/08/news_detail_002
160.jsp&mid=WC0b01ac058004d5c1
15
The full revised guidance can be accessed here:
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10
/WC500003981.pdf
(Source: regxia)
 Information on suspected side effects of nationally authorised
medicines now available through a single website
EMA encourages patients to report suspected side effects
As of today, European citizens can obtain information on suspected side effects, also known as suspected
adverse drug reactions, of an additional 1,700 active substances contained in medicines approved in the
European Union (EU) through a website maintained by the European Medicines Agency
(EMA).
The website launched in 2012 previously only contained information on suspected side effects reported
with centrally authorised medicines. Its expansion now also allows the public to access the relevant
information for medicines approved by national authorities in the EU.
Suspected side effects are reported by patients, consumers and healthcare professionals. These reports are
suspected but not necessarily established side effects. They may not be related to or caused by the
medicine.
National medicines regulatory authorities or pharmaceutical companies that hold the marketing
authorisation for the medicine concerned are obliged to transmit these reports electronically to
EudraVigilance, the European database of suspected side effects reported with medicines authorised in the
European Economic Area (EEA). The information made available through the public website comes directly
from EudraVigilance.
Spontaneous reports of suspected side effects provide regulatory authorities with important information
which is used to monitor the safety of a medicine. Throughout a medicine’s lifecycle, regulatory authorities
analyse all reports together with all other available information on the medicines, to make sure that their
benefits remain greater than their risks and to optimise their safe and effective use. Each report available
on the public website pulls together the total number of individual suspected side effects reports submitted
to EudraVigilance. These aggregated data can be viewed by age group, sex, type of suspected side effect
and outcome. (Source: EMA)
Information on suspected side effects of nationally authorised medicines now available through a single
website
 Meeting highlights from the Pharmacovigilance Risk Assessment
Committee (PRAC) 6-9 October 2014
European Medicines Agency updates on key outcomes of the meeting
The Pharmacovigilance Risk Assessment Committee (PRAC) concluded three safety reviews at its October
meeting.
PRAC recommends strengthening the restrictions on the use of valproate in women and girls
The Committee has recommended further restrictions on the use of valproate medicines due to the risk of
malformations and developmental problems in children exposed to valproate in the womb. The PRAC also
16
recommended that doctors who prescribe valproate provide women with full information to ensure that
they understand the risks and to support their treatment decisions.
Valproate is used to treat epilepsy and bipolar disorder. Some valproate medicines have also been used in
certain EU Member States to prevent migraine attacks.
More information is available in the table below.
PRAC review does not confirm increase in heart problems with testosterone medicines
The PRAC review did not find consistent evidence that the use of testosterone in its authorised indication in
men who do not produce enough testosterone (a condition known as hypogonadism) increases the risk of
heart problems. The Committee considered that the benefits of testosterone continue to outweigh its risks
but recommended that testosterone-containing medicines should only be used where lack of testosterone
has been confirmed by signs and symptoms as well as laboratory tests.
PRAC recommends further measures to minimise risk of blood vessel blockage with Iclusig
The Committee completed its review of the cancer medicine Iclusig (ponatinib), which aimed to examine
the risk of blood clots or blockage of the arteries or veins and to assess whether further measures were
needed to minimise this risk.
The PRAC considered that the benefits of Iclusig continue to outweigh its risks; however, it recommended
that the product information for patients and healthcare professionals should be updated with
strengthened warnings, particularly about the risk of blood clots and blockages of the arteries.
Five days left to respond to the consultation on public hearings
The EMA has launched a public consultation on draft rules of procedures for public hearings to be held by
the PRAC. Comments are invited until 15 October 2014 and should be sent to [email protected] using the comments submission form.
The rules of procedures describe the process and practical arrangements for the preparation, conduct and
follow-up of public hearings.
Public hearings are a new tool for the EMA to engage EU citizens in the regulatory process of the
supervision of medicines and to listen to their views and experiences. The contributions made by the public
during a public hearing will be considered by the PRAC and will inform the Committee’s decision-making.
 PRAC recommends further measures to minimise risk of blood vessel
blockage with Iclusig
PRAC recommendations to be considered by CHMP for final opinion
The EMA’s Pharmacovigilance Risk Assessment committee (PRAC) has completed a review of the benefits
and risks of Iclusig (ponatinib), a medicine used for the treatment of leukaemia (cancer of the white blood
cells). The aim of this review was to examine the risk of blood clots or blockage of the arteries or veins and
to assess whether further measures were needed to minimise this risk.
Iclusig is authorised for use in patients with chronic myeloid leukaemia (CML) and acute lymphoblastic
leukaemia (ALL) who cannot take or tolerate several other medicines of the same class (known as ‘tyrosinekinase inhibitors’). The PRAC considered that the benefits of Iclusig continue to outweigh its risks; however,
the Committee recommended that the product information for patients and healthcare professionals
17
should be updated with strengthened warnings, particularly about the risk of blood clots and blockages in
the arteries.
The PRAC assessed the available data on the nature, frequency and severity of blood clots or blockage of
the arteries or veins. Although the Committee noted that this risk is likely to be dose-related, there are
insufficient data to formally recommend the use of lower doses of Iclusig, and there is a risk that lower
doses might not be as effective in all patients and in long-term treatment. The PRAC therefore considered
that the recommended starting dose of Iclusig should remain 45 mg once a day. However, updates to the
product information are recommended to provide healthcare professionals with the latest evidence, in
case they wish to consider reducing the dose in patients with ‘chronic phase’ CML who are responding well
to treatment, and who might be at particular risk of blood vessel blockage. In addition, healthcare
professionals should stop Iclusig if there has been no response after three months of treatment, and
monitor patients for high blood pressure or signs of heart problems.
A new study on the safety and benefits of Iclusig is planned to help clarify if lower doses of the medicine
carry a lower risk of blood clots or blockages of the blood vessels while still having a beneficial effect in
patients with chronic phase CML.
The PRAC recommendation will now be forwarded to the Committee for Medicinal Products for Human Use
(CHMP), which will adopt the EMA’s final opinion. … (Source: EMA)
PRAC recommends further measures to minimise risk of blood vessel blockage with Iclusig
 PRAC review does not confirm increase in heart problems with
testosterone medicines
Committee recommends medicines can continue to be given for their authorised uses
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed an EU-wide review of
testosterone-containing medicines following concerns over serious side effects on the heart and blood
vessels, including heart attack. The PRAC review did not find consistent evidence that the use of
testosterone in men who do not produce enough testosterone (a condition known as hypogonadism)
increases the risk of heart problems. The committee considered that the benefits of testosterone continue
to outweigh its risks but recommended that testosterone-containing medicines should only be used where
lack of testosterone has been confirmed by signs and symptoms as well as laboratory tests.
The evidence about the risks of serious side effects on the heart of these medicines is inconsistent. While
some studies including three recently published studies1,2,3 did suggest an increased risk of heart problems
in men using testosterone compared with men not taking it, these studies had some limitations and others
did not confirm this risk4,5. The PRAC also noted that the lack of testosterone itself could increase the risk of
heart problems. The PRAC therefore recommended that testosterone-containing medicines should only be
used if the lack of testosterone has been confirmed by signs and symptoms as well as laboratory tests. The
EU product information for all testosterone-containing medicines should be updated to include this
recommendation as well as warnings against use in men suffering from severe heart, liver or kidney
problems. The limited data on safety and effectiveness in patients over 65 years of age as well as the fact
that testosterone levels decrease with age and that age-specific testosterone reference values do not exist
will be highlighted in the product information.
The safety of testosterone medicines should continue to be monitored. In particular, a number of studies
are still ongoing and their results will be considered in future regular benefit-risk assessments for these
medicines.
18
The PRAC recommendation will now be forwarded to the Coordination Group for Mutual Recognition and
Decentralised Procedures – Human (CMDh) which will adopt a final position. … (Source: EMA)
 PRAC recommends strengthening the restrictions on the use of
valproate in women and girls
Women to be better informed of the risks of valproate use during pregnancy
The PRAC has recommended strengthening the restrictions on the use of valproate medicines due to the
risk of malformations and developmental problems in children exposed to valproate in the womb.
Valproate should not be used to treat epilepsy or bipolar disorder in girls and in women who are pregnant
or who can become pregnant unless other treatments are ineffective or not tolerated. Women for whom
valproate is the only option after trying other treatments, should use effective contraception and
treatment should be started and supervised by a doctor experienced in treating these conditions.
Women who have been prescribed valproate should not stop taking their medicine without first consulting
their doctor.
In countries where valproate medicines are authorised for the prevention of migraine, women must not
use valproate for preventing migraine when they are pregnant. Pregnancy should be excluded before
starting treatment for migraine, and women should use effective contraception.
The PRAC also recommended that doctors who prescribe valproate provide women with full information to
ensure understanding of the risks and to support their decisions.
These recommendations follow a review of available data on the effects of valproate exposure during
pregnancy. During the review the PRAC also consulted representatives of patients and families who have
been affected as well as a group of experts and specialists. While valproate remains an option for patients
where other treatments have failed or are not tolerated, the Committee concluded that women and
healthcare professionals need to be better informed about the risks of valproate exposure in the womb and
of the need for effective contraception.
Recent studies have shown a risk of developmental problems of up to 30 to 40% in pre-school children
exposed to valproate in the womb, including delayed walking and talking, memory problems, difficulty with
speech and language and lower intellectual ability.
In addition, data show that children exposed to valproate in the womb are at an approximately 11% risk of
malformations at birth (such as neural tube defects and cleft palate) compared to a 2 to 3% risk for children
in the general population. Available data also show that children exposed to valproate in the womb are at
increased risk of autistic spectrum disorder (around 3 times higher than in the general population) and
childhood autism (5 times higher than in the general population). There are also limited data suggesting
that children exposed to valproate in the womb may be more likely to develop symptoms of attention
deficit hyperactivity disorder (ADHD).
The PRAC recommended that educational materials should be provided to all healthcare professionals in
the EU and to women prescribed valproate to inform them of these risks. Doctors will be required to review
the treatment of girls and women on a regular basis, including at puberty and when a woman plans to
become pregnant. The PRAC emphasised that women should not stop taking valproate without first
consulting their doctor.
The EU product information for healthcare professionals and patients is to be updated with the latest
information and recommendations.
19
The recommendations of the PRAC will now be sent the Co-ordination Group for Mutual Recognition and
Decentralised Procedures – Human (CMDh), which will adopt a final position. In the meantime, women
currently taking valproate who have any questions about their treatment should speak with their doctor. …
(Source: EMA)
 Human Medicines

CHMP

PDCO

COMP

HMPC

CAT

PRAC
 Human Medicines – Regulatory and Referal Procedures
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_00
0150.jsp&mid=WC0b01ac0580024e98
 Human Medicines – Orphan Drugs
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp
 Human Medicines – Herbals
22/07/2014 - Arnica, Arnicae flos, Arnica montana L.
(Final Community herbal monograph, Opinion of the HMPC on a Community herbal monograph, Final
assessment report, Final list of references supporting the assessment, Overview of comments received on
Community herbal monograph)
15/07/2014 - 24/07/2014 - Call for scientific data for use in HMPC assessment work:
Artemisia absinthium L., herba
Centaurium, Centaurii herba, Centaurium erythraea Rafn
Curcuma, Curcumae longae rhizoma, Curcuma longa L.
Equisetum, Equiseti herba, Equisetum arvense L.
Gentiana, Gentianae radix, Gentiana lutea L.
Juniperus, Juniperi summitates, Juniperus communis L.
Myroxylon balsamum, Balsamum peruvianum, Myroxylon balsamum (L.) Harms var. perierae (Royle) Harms
 Human Medicines – Advanced Therapies
20
http://www.hma.eu/cmdh.html
WHAT’S NEW: http://www.hma.eu/186.html

NEW - Applications submitted in Mutual Recognition and Decentralised Procedures

NEW - Timetables 2015 for requests to CMDh for a recommendation on classification of an
unforseen variation - Article 5

NEW - Timetables 2015 for CMDh referrals

NEW - Recommendations on submission dates for Applicants of the DCP

NEW - Recommendations on submission dates for Applications of the Mutual Recognition
Procedure

UPDATE - Procedural advice: Automatic validation of MR/Repeat-use/DC Procedures

UPDATE - Non Clinical / Clinical AR for Generics - MRP & DCP ( 2014 September) - to be used for
procedures started (day 0) after October 1, 2014

UPDATE - CMDh Best Practice Guide for the Public Assessment Report and Summary Public
Assessment Report in MRP/DCP

UPDATE - CMDh Best Practice Guide on the compilation of the dossier for New Applications
submitted in MRP/DCP

UPDATE - Information on applications referred to CMDh in accordance with Article 29(1) of
Directive 2001/83/EC

UPDATE - Information on Applications referred in accordance with Art. 30(2) of Directive
2001/83/EC

UPDATE - List of substances under PSUR Worksharing scheme and other substances contained in
Nationally Authorised Products with DLP synchronised

UPDATE - List of active substances for which data has been submitted in accordance with Article 45
of the Paediatric Regulation

NEW
Summary
PSUR
Assessment
Reports
for
brotizolam,
candesartan/candesartan+hydrochlorothiazide,
estradiol+norethisterone,
methylphenidate
hydrochloride, modafinil and valsartan

NEW - 2014 - Statistics for New Applications (MRP/DCP), Variations and referrals - the first two
quarters of 2014

NEW - Article 45 of the Paediatric Regulation
Bisoprolol+hydrochlorothiazide, Nimodipine and Fluarix

NEW - Article 46 of the Paediatric Regulation - Public Assessment Reports for Asmanex Twishaler
(mometasone furoate), Menitorix (haemophilus influenzae type b conjugate, neisseria meningitidis
capsular polysaccharide C, Tetanus toxoid conjugates) and Palexia and associated names
(tapentadol hydrochloride)

NEW - CMDh Recommendation for implementation of Commission Decisions or CMDh agreements
following Union referral procedures where the marketing authorisation is maintained or varied
21
- Public
Assessment Reports
for

UPDATE - Mandate for the Working Party on Paediatric Regulation

UPDATE - Final List of products for SmPC Harmonisation - 2014

UPDATE - Q&As on Variations

UPDATE - CMDh Recommendation for classification of unforeseen variations according to Article 5
of Commission Regulation (EC) 1234/2008

UPDATE - Mandate for the Working Party on Variation Regulation
.
http://www.edqm.eu/en/edqm-homepage-628.html
 New webpage for the Certification Division
Just published: Volume 19 of the Newsletter Transplant 2014
Updated application forms available for immediate use
European Pharmacopoeia
A new document is available: Comments concerning revised texts published in Supplement 8.4
Control of Medicines
Human OCABR
A document was recently updated: Annex III List of contacts (02/10/14)
 Certification Monthly Report of Activities
The last monthly activity report for the Certification of Substances Division (DCEP) is now available:
September 2014 Certification Monthly Report. … (Source: EDQM)
FRANCE
 La base de données publique des médicaments a un an - Point
d'information
La base de données publique des médicaments a été mise à disposition le 1er octobre 2013. Depuis son
ouverture, plus de 7 millions de pages ont déjà été consultées. La base de données s’est depuis enrichie de
nouveaux contenus et de nouvelles fonctionnalités. Elle permet ainsi d’accéder à des documents de bon
usage publiés par la Haute Autorité de Santé, de télécharger les informations contenues dans la base et
d’accéder à des indications remboursables dont le libellé a été simplifié. Elle permet de surcroît, grâce à
l’application « medicaments.gouv », de scanner les codes figurant sur la boîte des médicaments pour
accéder directement à la fiche d’information correspondante du médicament dans la base de données.
La base de données publique des médicaments a été ouverte le 1er octobre 2013 dans le cadre de
l’application de l’article 8 de la Loi du 29 décembre 2011[1] . La mise en œuvre de ce projet a été confiée à
22
l’Agence nationale de sécurité du médicament et des produits de santé (ANSM) en partenariat avec la
Haute autorité de santé (HAS) et l’Union nationale des caisses d’assurance maladie (UNCAM), et sous
l’égide du Ministère des affaires sociales et de la santé.
Accessible depuis un portail d’information générale sur le médicament « medicaments.gouv.fr » du site
Internet du ministère des affaires sociales, de la santé et des droits des femmes, cette base permet au
grand public et aux professionnels de santé d’accéder, en un même espace, aux informations émanant des
différentes institutions de santé, en lien avec les missions dont elles ont la charge, sur les médicaments
commercialisés ou dont l’arrêt de commercialisation date de moins de trois ans.
Garante d’une information publique de référence sur plus de 12 000 médicaments, elle donne notamment
accès à des données de référence issues de l’ANSM, de la HAS, du CEPS et de l’UNCAM, dont en particulier :


des données issues de l’autorisation de mise sur le marché : Résumé des caractéristiques des
produits, notice et indications thérapeutiques
des informations réglementaires comme les conditions de prescription et de délivrance, la
procédure d’autorisation

l’appartenance à un groupe générique

des informations de sécurité sanitaire

des documents de bon usage

le Service Médical Rendu et l’Amélioration du Service Médical Rendu

des informations médico-économiques comme le prix, le taux de remboursement, l’agrément aux
collectivités
Dans le cadre de la dématérialisation de la vignette, la base de données constitue un site de référence
officiel permettant aux patients de consulter librement et gratuitement les informations relatives aux prix
et taux de remboursement des médicaments remboursables. L’application de flash « medicaments.gouv »
permet d’en faciliter l’accès en scannant le code-barres (flashcode) présent sur la boîte du médicament à
partir d’un smartphone.
Une enquête de satisfaction auprès des professionnels de santé et du public est actuellement menée et
permettra de recueillir leurs avis et attentes concernant les évolutions souhaitées. Ces éléments seront pris
en compte dans la réflexion que mènent actuellement les institutions pour faire évoluer cette base en
adéquation avec les besoins des utilisateurs. … (Source: Basededonnéespubliquedesmédicaments)
 Opération Transparence dans la pharmacie: le bilan, un an après
Un an après la mise en place du décret Transparence, visant à lever le voile sur les liens d’intérêt entre
médecins et laboratoires pharmaceutiques, où en est-on ? L’Usine Nouvelle fait le point avec Bruno
Moreau, directeur associé de l’agence Market iT et Sébastien Pradeau, avocat spécialisé en droit de la
santé, membres du think-tank "Loi Bertrand", surnom de la réforme du système du médicament adoptée
suite à l’affaire Mediator.
L'Usine Nouvelle - Globalement, les industriels ont-ils joué le jeu de la transparence?
Sébastien Pradeau - Tant les laboratoires pharmaceutiques que les fabricants de dispositifs médicaux ont
bien joué le jeu. Les process sont en place. Ils ont adapté leurs contrats, informé les médecins et les
pharmaciens, formé leurs visiteurs médicaux.
23
Bruno Moreau - La mise en place de ces procédures est longue et difficile pour les laboratoires qui ont
beaucoup de filiales, ou ceux - une majorité d’entre eux - qui sont des filiales de sociétés étrangères et dont
la maison-mère n’est pas soumise à ce décret. Il y a 230 laboratoires en France, or si on regarde les autres
entreprises qui ont réalisé des déclarations, on a l’impression que le compte n’y est pas, si l'on se réfère à
ce que disait François Rousselot, le président de la commission Relations médecins-industries au Conseil
National de l’Ordre des Médecins. La très grande majorité des entreprises de la santé ont joué le jeu, mais
pas celles de la cosmétique.
Sébastien Pradeau - Je ne suis pas d’accord avec M. Rousselot. D’après ce que je vois, les industriels l’ont
vraiment fait : c’est leur crédibilité qui est en jeu. Ils ont investi du temps et de l’argent pour que toutes les
publications soient à jour.
Le dispositif s’est-il révélé coûteux à mettre en place ?
Bruno Moreau - Pour un grand laboratoire comme Pfizer, la mise en place a coûté 1,5 million d’euros, pour
une PME comme Astellas, 300 000 euros. Malheureusement le coût n’est pas directement proportionnel au
chiffre d'affaires : il y a un seuil plancher… Et il ne prend pas en compte le coût de fonctionnement.
Quel impact cela a-t-il eu sur les relations avec les médecins ?
Sébastien Pradeau - Des clauses particulières concernant la transparence ont été ajoutées dans les
contrats. Lorsque des délégués médicaux invitent à déjeuner des professionnels de santé, ils doivent leur
rappeler que des informations vont être publiées. Certains médecins, après avoir vu leur nom publié sur les
sites Internet, ont même renvoyé aux laboratoires le montant du déjeuner par chèque, mais les entreprises
ne peuvent pas l’encaisser si facilement !
Un certain nombre de médecins, qui travaillaient ponctuellement comme experts pour l’autorité sanitaire
(ANSM), n’ont pas voulu révéler leurs liens d’intérêt et ont préféré démissionner. Résultat, alors que
l’ANSM avait pu bâtir un réseau d’expertises publiques et privées, elle a perdu des compétences de gens
très pointus.
Quel a été le succès du site public lancé en juin par le gouvernement pour recenser toutes ces
déclarations ?
Sébastien Pradeau - Son objectif est de faciliter les contrôles, car il suffit d’aller sur ce site pour voir auprès
de qui et de quels avantages a bénéficié un médecin. Le site est très bien fait, cela a vraiment été un travail
de partenariat entre le ministère de la Santé et les industriels pour définir une grille de publication.
On a beaucoup reproché à ce texte de ne pas inclure les montants et l’objet des principaux contrats…
Sébastien Pradeau - Tout ce qui considéré comme un avantage, principalement des repas ou des frais de
transport, est rendu public. Quant aux contrats, il a fallu trouver un équilibre entre ce que l'opinion
publique attend et la confidentialité que requiert le secret des affaires. Imaginez si l'on publiait que telle
entreprise mène des recherches sur telle molécule avec telle action pour telle indication !
Bruno Moreau - Ces arguments du syndicat de l'industrie pharmaceutique (Leem) ont permis d’enlever
cette partie du décret : on est loin de l’esprit de la Loi Xavier Bertrand. Pourtant, on aurait pu s’inspirer du
Sunshine Act américain. Aux Etats-Unis, les montants des contrats de recherche clinique sont déclarés à
l’administration, mais ne sont pas rendus publics tant que la molécule n’est pas mise sur le marché, ce qui
garantit une certaine confidentialité.
Où en est l’application de la Transparence à l’échelle européenne ?
Bruno Moreau - Le syndicat européen de l’industrie pharmaceutique (EFPIA) demande aux laboratoires de
33 pays de déclarer à partir de 2016 les liens noués en 2015. Il faudra publier également les montants.
24
Sébastien Pradeau - Mais les entreprises françaises auront pris trois ans d’avance sur leurs concurrents
européens, en développant une expertise que les autres n’ont pas.
Bruno Moreau - On le voit déjà : pour certains groupes dont la maison-mère est à l’étranger, ces projets
sont en partie pilotés par la filiale France. … (Source: UsineNouvelle)
 Hypocholestrolémiants et entente préalable: Le patron du service
médical de la CNAMTS s’explique
Le Pr Luc Barret revient pour la première fois sur la mise sous entente préalable de deux statines Il appuie
cette décision récente de la cnamts sur les recommandations en vigueur. Pour lui, elle ne porte pas atteinte
à la liberté de prescription des médecins. Et le médecin conseil national assure qu’à l’heure des
téléservices, elle ne devrait pas leur compliquer la vie.
Le patron du service médical de la CNAMTS s’explique - 1
L’annonce il y a quelques jours par la CNAMTS de l’obligation d’entente préalable pour la rosuvastatine et
l’ézétimibe a suscité une vive polémique. Le Pr Luc Barret, médecin conseil national de la CNAMTS revient
pour legeneraliste.fr sur les raisons qui ont motivé cette décision.
Pourquoi une telle mesure ?
Ces mesures s’inscrivent dans la continuité des actions mises en place pour la promotion du bon usage des
hypolipémiants, et la prescription plus efficiente des statines. Elles s’expliquent par leur caractère
particulièrement coûteux pour l’Assurance Maladie.
Quels sont les objectifs de cette mesure ?
Notre ambition est de privilégier des traitements plus efficients cela permet de garantir à tous les patients
un traitement sûr et efficace, pris en charge par l’Assurance Maladie.
Pourquoi spécifiquement ces molécules et pas d’autres ? Le fait que le Crestor et l’Inegy figurent parmi
les médicaments les plus vendus n’a-t-il pas joué un rôle dans cette décision ?
En 2013, CRESTOR® (rosuvastatine) et INEGY® (ézetimibe/simvastatine) faisaient partie des 10
médicaments de ville les plus remboursés par l’Assurance Maladie, occupant respectivement la 3ème place
avec 342,8 millions d’euros (+ 1,4% par rapport à 2012) et la 9ème place avec 179,0 millions d’euros (+ 4,4%
par rapport à 2012). La consommation de rosuvastatine en France est singulière par rapport à ses voisins
européens ; elle représente 30,1% des statines en 2013 (en volume) alors que c’est seulement 0,5% en
Allemagne, 3,9% au Royaume-Uni et en moyenne 7,8% dans 7 pays européens.
En quoi les recommandations de la HAS ne sont-elles pas suivies concernant les médicaments en
question ?
La HAS recommande d’utiliser l’ézétimibe, en cas de contre-indication et/ou d’intolérance aux statines et,
de l’associer à une statine si l’objectif thérapeutique n’est pas atteint. Les données de consommation
25
montrent que dans la majorité des cas les traitements initiés par ézétimibe se font aujourd’hui seuls et sans
antécédent de prescription de statine, hors des recommandations de l’AMM. Concernant la rosuvastatine,
conformément aux recommandations, une alternative thérapeutique plus efficiente est disponible.
N’est-ce pas la première fois qu’une demande d’entente préalable touche un médicament ? Jusqu’ici ces
demandes étaient réservées à des actes de kinésithérapie, aux traitements d’orthodontie faciale, à
certains appareillages médicaux, à certaines pathologies inhabituelles, à certains examens et analyses de
laboratoire.
Jusqu’à présent la demande d’entente préalable ne concernait que certaines prestations comme
l’oxygénothérapie, certains produits de LPP… Il existait des procédures d'information du service médical
pour les médicaments d'exception, mais les conditions diffèrent. Il s'agit de la première application de la
procédure de demande d'accord préalable fondée sur l'article L.315-2 du CSS.
N’est ce pas une sorte de révolution dans l’exercice de la médecine difficilement acceptable par les
médecins puisque cela réduit leur droit de prescription ? N’est-elle pas une sorte de sanction
administrative pour le médecin accusé de ne pas respecter les recommandations de la HAS pour la
prescription de ces produits ?
Cette décision ne porte pas sur le droit de prescription, mais sur sa prise en charge de la molécule prescrite,
qui relève du ressort de l’Assurance Maladie. Elle s’inscrit dans la promotion du bon usage du médicament
et s’appuie sur une évaluation de l’efficience des traitements disponibles sur le marché.
A t-il fallu changer le cadre administratif de l’entente préalable pour l’adapter à un médicament ?
Une décision du collège de l'Uncam fixant le cadre général de la procédure de demande d'accord préalable
fondée sur l'article L.315-2 du CSS a été publiée le 9 septembre 2014. Elle précise les conditions
d’application des règles relatives à la procédure d’accord préalable au remboursement pour certaines
prestations.
Ce type de mesure n’ouvre–t-elle pas la porte à d’autres obligations à venir d’entente préalable
concernant d’autres médicaments ?
La décision du collège de l'Uncam fixant le cadre général de la procédure de demande d'accord préalable,
publiée le 9 septembre, encadre les conditions dans lesquelles ce type de mesure peut être mise en œuvre
si le besoin est identifié sur d’autres prestations.
Ce type de mesure ne va-t-il pas poser des problèmes sur le plan médical ?
De manière générale, le code de déontologie médicale précise à l’article 8 que le médecin doit limiter ses
prescriptions et ses actes à ce qui est nécessaire à la qualité, à la sécurité et à l’efficacité des soins. Cette
mesure repose sur les AMM et les recommandations en vigueur, notamment les fiches de bon usage des
médicaments. Concernant la rosuvastatine, il y a conformément aux recommandations une alternative
thérapeutique plus efficiente et pour l’ézétimibe cette mesure incite à mieux respecter les
recommandations.
Ne va t-elle pas trop compliquer les prescriptions de ce type de médicaments ?
Avec le téléservice, la procédure est simplifiée au maximum. Lors de la consultation, les médecins ont la
possibilité de soumettre la demande d’accord préalable et d’obtenir la réponse en direct. Si la réponse est
positive le traitement sera pris en charge. Si la réponse est négative, le médecin peut proposer un autre
traitement pris en charge par l’Assurance Maladie.
Le risque n’est-il pas de voir les praticiens pour éviter cette entente préalable substituer dans leur
prescription d’autres statines à celles concernées ?
26
L’ambition de cette mesure est bien de privilégier des traitements plus efficients. L’existence d’alternatives
thérapeutiques à la rosuvastatine présentant une efficacité équivalente dans les mêmes indications et le
respect des bonnes conditions de prescriptions de l’ézétimibe, permet en effet de garantir à tous les
patients un traitement sûr et efficace, pris en charge par l’Assurance Maladie.
Propos recueillis par le Dr Alain Dorra
Source : Legeneraliste.fr
Quand les applications électroniques (e-apps) sont-elles des Dispositifs Médicaux ?
Le Cabinet WHITE-TILLET est spécialiste de la question et peut vous aider à y répondre ; le cas échéant,
nous pouvons vous assister pour le marquage CE de votre application.
http://ansm.sante.fr/
 Les 1ères Rencontres de l’ANSM sous le signe de l’innovation et de la
surveillance
L’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a tenu le 26 septembre
2014 ses 1ères Rencontres sur le thème " Produits de santé : les nouveaux défis de l’innovation et de la
surveillance", en présence de plus de 600 participants, chercheurs, professionnels de santé, institutionnels,
industriels, représentants des patients. L’occasion pour l’Agence d’affirmer son ouverture sur son
environnement et son engagement scientifique pour stimuler et accompagner la mise à disposition de
l’innovation.
Ouvertes par Agnès Jeannet, présidente du Conseil d’administration de l’ANSM, Françoise Weber, directrice
générale adjointe de la Santé et Dominique Martin, directeur général de l’ANSM, ces rencontres se sont
organisées autour de quatre temps forts qui correspondent à des axes stratégiques de l’Agence :

l’innovation en santé

régulation des produits de santé et progrès scientifiques

progrès technologiques : maîtriser les nouveaux risques

de la vigilance à la surveillance
Les 1ères Rencontres de l’ANSM sous le signe de l’innovation et de la surveillance - Point d'information
(08/10/2014)
(57 ko)
Consulter le dossier participants, les enregistrements vidéos et les interventions des 1ères rencontres de
l'ANSM
(Source: ANSM)
27
 Contraception d’urgence hormonale: rapport bénéfice / risque jugé
favorable par la Commission européenne quel que soit le poids de la
femme
La contraception d’urgence désigne les méthodes contraceptives qu’une femme peut utiliser pour prévenir
la survenue d’une grossesse non prévue après un rapport non ou mal protégé. Les méthodes utilisables
dans la contraception d’urgence sont hormonale (lévonorgestrel per os[1] ou ulipristal per os ) ou non
hormonale (dispositif intra-utérin au cuivre).
Dans le cadre d’un arbitrage européen, le Comité des médicaments à usage humain (CHMP) de l’Agence
européenne des médicaments (EMA) a analysé l’effet du poids de la femme sur l’efficacité de la
contraception d’urgence hormonale. Ce comité a ainsi conclu que le rapport bénéfice risque de ces
spécialités restait favorable quel que soit le poids de la femme.
Le 30 septembre 2014, la Commission européenne a décidé de suivre cet avis du CHMP.
L’Agence nationale de sécurité du médicament et des produit de santé (ANSM) rappelle que la
contraception d’urgence hormonale doit être administrée le plus rapidement possible après un rapport non
ou mal protégé et que le recours à cette méthode dite « de rattrapage » doit rester exceptionnel
notamment en raison du risque d’échec plus élevé que les contraceptions régulières. Ce point a également
été rappelé lors de l’arbitrage européen. … (Source: ANSM)
 L’ANSM publie une RTU concernant la spécialité Rémicade
(infliximab) dans la maladie de Takayasu
RTU REMICADE 100 mg, poudre pour solution à diluer pour perfusion
Le dispositif des recommandations temporaires d’utilisation (RTU ) est destiné à sécuriser l’accès à des
traitements dans des indications ou des conditions d’utilisation différentes de celles de leur autorisation de
mise sur le marché (AMM). La deuxième RTU concernant une maladie rare, est publiée aujourd’hui sur le
site internet de l’Agence. Elle concerne la spécialité Rémicade du laboratoire MSD dans l’indication
"traitement de la maladie de Takayasu réfractaire aux traitements conventionnels".
La spécialité Rémicade est autorisée au niveau européen depuis août 2009, commercialisée en France
depuis janvier 2000 et indiquée pour le traitement :

de la polyarthrite rhumatoïde

la maladie de Crohn,

la rectocolite hémorragique

la spondylarthrite ankylosante

le rhumatisme psoriasique

et le psoriasis.
Dans ce cadre, cette spécialité fait l’objet d’un plan de gestion des risques européen et est réservée à
l’usage hospitalier et à certains spécialistes.
La maladie de Takayasu est une maladie qui touche prioritairement les femmes jeunes (15-40 ans).Cette
maladie est une artérite inflammatoire des vaisseaux de gros calibre qui atteint avec prédilection l'aorte et
ses principales branches. Il s’agit d’une maladie rare dont la prévalence est estimée selon Orphanet à
0.6/100 00 personnes soit une centaine de patients potentiellement concernés par cette RTU. Plusieurs
28
études sont en faveur d’un rapport bénéfice/risque présumé favorable de Remicade dans la maladie de
Takayasu réfractaire aux traitements conventionnels.
L’utilisation de cette spécialité dans le cadre de la RTU est soumise à un protocole de suivi qui définit les
modalités pratiques de prescription, de délivrance, d’administration du médicament et de suivi des
patients. Il précise également le rôle des différents acteurs notamment de l’ANSM, du laboratoire MSD et
des prescripteurs.
Le protocole mentionne également les éléments scientifiques qui ont fondé la décision d’octroi de cette
RTU, les informations destinées aux professionnels de santé et aux patients dans le cadre de la RTU, ainsi
que les différentes fiches de suivi médical (initiation, suivi, formulaires de déclaration d’effet indésirable
par les professionnels et les patients, arrêt du traitement). … (Source: ANSM)
 Mise à disposition de la spécialité Symmetrel 100 mg, gélule pour
pallier l’indisponibilité de Mantadix 100 mg, capsule - Point
d'information
Des tensions d’approvisionnement du médicament Mantadix 100 mg, capsule (chlorhydrate d’amantadine)
ont été observées en France depuis le mois de mars 2014. Ce médicament est indispensable pour certains
patients dans la maladie de Parkinson, notamment dans les dyskinésies induites par la L-Dopa. Dans ce
contexte, le laboratoire Bristol Myers Squibb met en place, en accord avec l’Agence nationale du
médicament et des produits de santé (ANSM), à titre exceptionnel et transitoire, l’importation d’une
spécialité comparable Symmetrel 100 mg, gélule (chlorhydrate d’amantadine). Cette spécialité sera
distribuée à partir du 8 octobre 2014 auprès des officines et des pharmacies hospitalières à titre gracieux. …
(Source: ANSM)
Le Cabinet WHITE-TILLET s’est entouré de juristes de haut niveau pour vous aider
à valider la publicité et la promotion de vos médicaments. Leur expertise se
combine à notre expérience réglementaire et à notre maîtrise de la
méthodologie clinique. Contactez-nous pour le reviewing de vos documents
publicitaires ou promotionnels!
 Directions et comités
Direction de l’évaluation
Direction de la surveillance
Direction de l’inspection
Organigramme – nominatif
Groupes de travail
Comités techniques
Commissions
 Procédures
Soumission électronique à l’ANSM via le CESP - Phase pilote - Avis aux demandeurs d’AMM de
médicaments à usage humain - Janvier 2014 (version 2.1)
29
ANSM : Formulaire de soumission électronique structurée (e-CTD ou NeeS)
ANSM : Fiche de déclaration de rupture de stock ou de risque de rupture de stock de médicament dont
l’indisponibilité transitoire, totale ou partielle, est susceptible d’entraîner un problème de santé publique
11/07/2014 - Recommandations relatives à la rédaction des projets d’annexes de l’AMM (modèle / feuille
de style) (version 3.0)
11/07/2014 - Feuille de style (version 2.0)
11/07/2014 - Conseils pour l’élaboration des notices destinées aux patients et la conduite des tests de
lisibilité
18/07/2014 - Modalités de dépôt des demandes de modification d’AMM en vue d’une mise en accès
direct des médicaments de prescription médicale facultative
 Pharmacovigilance
Vigilances - Bulletin n° 62 (11/07/2014)
 Etablissements Pharmaceutiques
ANSM : Dossier : Etat des établissements pharmaceutiques visés à l’article R. 5124-2, 1° à 15° du code de
la santé publique
ANSM : Dossier technique à tenir à disposition en cas de demande de l’inspection
 Matières premières à usage pharmaceutique
ANSM : Autorisation et déclaration des activités de fabrication, d’importation et de distribution de
matières premières à usage pharmaceutique (MPUP) - Questions/Réponses
ANSM : Guide utilisateur - Portail de télé-enregistrement des activités de fabrication, d’importation et de
distribution de matières premières à usage pharmaceutique
Le Cabinet WHITE-TILLET a plus de 20 ans d’expérience et d’expertise dans le
domaine des dossiers d’AMM. Nous maîtrisons l’eCTD. Par notre structure et notre
réseau (cabinet associé au UK, réseau international), nous maîtrisons les
procédures et assurons un suivi efficace. Confiez-nous vos dossiers d’AMM ou de
variations!
http://www.has-sante.fr/portail/jcms/j_5/accueil
30
 Médicaments: la HAS veut en finir avec le SMR (Service Médical
Rendu), et relance l’ITR (Index Thérapeutique Relatif)
L’évaluation des produits de santé doit évoluer, juge la Haute Autorité de santé (HAS). Lors d’une
conférence de presse ce lundi, son président, le Pr Jean-Luc Harousseau, a assuré que cette évaluation
« nécessite une adaptation des méthodes et du cadre juridique actuels ».
La HAS a mis au point un nouvel indicateur baptisé « index therapeutique relatif » (ITR), appelé à
remplacer les notions de service médical rendu (SMR) et amélioration du service médical rendu (ASMR).
« Les innovations thérapeutiques coûteuses que l’on voit apparaître rendent une évaluation comparative et
une clarification des critères indispensables », souligne la HAS. Pour le Pr Harousseau, « le SMR est devenu
obsolète ».
La HAS attend toujours le feu vert des autorités pour utiliser enfin l’index thérapeutique relatif. Regrettant
que le passage du SMR et de l’ASMR à ce nouvel outil d’évaluation comparative ne soit pas inscrit dans le
projet de loi de santé de Marisol Touraine, la HAS milite pour son inscription dans le projet de loi de
financement de la Sécurité sociale (PLFSS) 2015.
Avis d’efficience plus rapides
Le Pr Harousseau s’est payé le luxe de faire la leçon au gouvernement. Revenant sur la décision de
l’assurance-maladie subordonnant à son accord préalable toute initiation de traitement à la
rosuvastatine (Crestor), le Pr Harousseau a rappelé que la HAS avait réalisé une analyse médicoéconomique de cette molécule dès 2010. « Nous avions dit que la prescription de Crestor n’était pas
nécessaire ni efficiente dans la grande majorité des cas, vu son prix. Ça n’a pas été suivi d’effet ».
Aujourd’hui, le Pr Harousseau relève que la décision soudaine de mise sous accord préalable est « très mal
vécue par les médecins qui considèrent que c’est une atteinte à leur liberté de prescription ».
Le président de la HAS a par ailleurs souhaité que les avis d’efficience de la commission d’évaluation
économique et de santé publique (CEESP) « puissent être publiés plus rapidement ». 12 avis d’évaluation
médicoéconomique ont déjà été rédigés depuis que la HAS est en charge de cette mission (octobre 2013), a
précisé le Pr Harousseau. … (Source: Le Quotidien du Médecin)
 SYNTHÈSES D'AVIS SUR LES MÉDICAMENTS

PALEXIA LP (tapentadol), antalgique opioïde

TIVICAY 50 mg (dolutégravir), inhibiteur de l'intégrase

IMNOVID (pomalidomide), immunomodulateur

LANTUS (insuline glargine), antidiabétique injectable

MABELIO (ceftobiprole), autres céphalosporines

PREZISTA (darunavir), inhibiteur de protéase

VELCADE (bortézomib), inhibiteur de protéasome
31

ERIVEDGE (vismodegib), antinéoplasique

SOVALDI (sofosbuvir), antiviral à action directe

CARMYNE (indigotine ou carmin d'indigo)

IXIARO, vaccin contre l'encéphalite japonaise

TYBOST (cobicistat), potentialisateur d'antirétroviral

VONCENTO (facteur VIII de coagulation humain + facteur von Willebrand), facteurs de coagulation
CEPS
http://www.sante.gouv.fr/comite-economique-des-produits-de-sante-ceps.html
 France uses tax to put pressure on hepatitis C drug prices
France will tax drugmakers whose costly hepatitis C drugs threaten to throw off course its healthcare
budget, the government has said, heaping pressure on pharmaceutical companies like Gilead Sciences to
cut their prices.
The Socialist government said it had designed a "progressive contribution scheme" ensuring all patients can
access new and more effective treatments against the liver-destroying virus, while limiting the burden of
these drugs on state finances.
The government will selectively tax drugmakers when the total cost to the state from their hepatitis C drugs
exceeds a certain amount each year, Health Minister Marisol Touraine said, as she unveiled the country's
2015 social security budget bill on Monday.
If social security spending on hepatitis C drugs exceeds 450 million euros ($567 million) in 2014, the makers
of those drugs will be taxed based on the revenue they had reaped in excess of that cap, the ministry said
in a presentation.
In 2015, the tax will apply beyond a 700 million euro cap, it added.
Details of the new tax should be presented to lawmakers in October and a vote on the budget is due by the
end of the year.
Some 200,000 people in France are infected with hepatitis C and treatments for the virus could cost the
state-run healthcare system as much as 1 billion euros this year, according to reports in newspapers Le
Monde and Les Echos.
The ministry declined to comment on any estimates. … (Source: Reuters)
Le Cabinet WHITE-TILLET a près de 30 ans d’expérience et d’expertise dans le
domaine du remboursement des médicaments, incluant la maîtrise de la
méthodologie clinique. La rédaction de ces dossiers est un art complexe. Les
conséquences pour les firmes peuvent être cruciales. Confiez-nous vos dossiers de
remboursement !
32
EUROPE
http://www.mhra.gov.uk/
 Sovaldi may be cost-effective, but the U.K. can't afford it, documents
say
Gilead Sciences' hepatitis C drug Sovaldi may be worth the sticker price. But it's too expensive for the U.K.'s
health system to bear. That's the assessment in some National Health Service documents obtained by the
Health Service Journal.
Last month, the notoriously nit-picky National Institute for Health and Care Excellence (NICE) backed
Sovaldi for use by the NHS. Gilead had offered a price break on the drug--its cost to the service is estimated
at £35,000--but it's still no penny-pincher. NICE weighed the evidence, totted up the long-term benefits of
curing thousands of hep C patients outright--and determined that Sovaldi was cheap at the price.
Apparently, behind closed doors at the health service, there's some doubt about that. According to the
journal, cited in Pharmafile, offering Sovaldi via the NHS would put 20,000 patients in line for treatment.
That's where the problem lies. It's not a price problem, but a cost-burden problem.
The aggregate cost of treating those patients? Some £1 billion. And that's 'prohibitive,' the NHS briefing
documents say (as cited by Pharmafile).
The NHS has come to the same conclusion as many payers in the U.S. The cost of treating hepatitis C
patients in the States is staggering. The potential pool of patients is large--about 3 million. Multiply that by
Sovaldi's higher U.S. price--$84,000--and add on the companion treatments? By some calculations,
spending on Sovaldi would top the cost of treating all other patients with all other drugs, combined.
That's why insurers and pharmacy benefits managers have been trying to limit access to Sovaldi and its
cocktail partners. Pharmacy benefits managers such as CVS Caremark and Express Scripts have begged
doctors to hold off on treating early-stage patients until competing drugs hit the market. State Medicaid
programs are limiting Sovaldi to only the sickest patients. Some aren't paying for it at all, saying they're still
"assessing" the drug. … (Source: FiercePharma)
 Advertising - Blue guide - Updated edition
Medicines regulatory news
From 1 October 2014, companies marketing over-the-counter (OTC) medicines will be able to use a short
form of advertisement when promoting their products to prescribers and suppliers of medicines.
This responds to a Red Tape Challenge proposal from the Proprietary Association of Great Britain, the OTC
trade association. It is designed to reduce the number of times advertisements need to be updated when
changes are made to the Summary of Product Characteristics (SPC).
A linked change will allow a link to the SPC to be provided in an advertisement, instead of a summary of this
33
information. The changes are made by regulations 24 and 29 of the Human Medicines (Amendment No. 2)
Regulations 2014.
MHRA Blue Guide
(549Kb), Advertising and promotion of medicines in the UK, has been updated to
reflect these changes. Detailed advice on information requirements for advertising to prescribers and
suppliers is available in sections 6.4 and 6.5. Self-regulatory codes of practice are also being amended to
reflect these changes.
MHRA has also taken the opportunity to make additional updates to the Blue Guide as follows:
• Updated guidance for providers offering medicinal treatment services, with new advice on advertising in
social media (section 7.3 and appendix 6)
• Additional advice on prohibited gifts and benefits (section 6.14)
• Updated information about adverse drug reaction reporting (section 7.6)
• Additional clarification concerning advertising of medicines for use in pregnancy (Appendix 3)
• Updates to contact details for MHRA staff and information about NICE, ABPI and PMCPA
Any questions about these changes should be sent to the Advertising Standards Unit at
[email protected].
Further information:
Consultation proposal, MLX 384 (external link)
Outcome of consultation (external link)
Human Medicines (Amendment No. 2) Regulations 2014, SI 2014/1878 (external link)
MHRA - Updated - Blue Guide - Advertising.pdf
 UK alliance to accelerate development of advanced therapies
University College London has linked arms with The National Institute for Biological Standards and Control,
a centre of the Medicines and Healthcare products Regulatory Agency, in a pact to accelerate the
development of advanced therapies in the country.
The groups plan to maximise and further promote scientific collaboration in the field of advanced
therapies, so that the UK can develop its standing as a centre for research and manufacture in gene
therapy, stem cell therapy and tissue engineering.
A memorandum of understanding has been signed recognising the great promise such therapies hold in
preventing and treating diseases such as Alzheimer's, cancer or muscular dystrophy.
As part of the agreement NIBSC and UCL will collaborate and share knowledge and resources to help
support the development of safe and effective advanced therapies.
“Advanced therapies such as stem cell treatments have huge potential in directly targeting and treating a
range of conditions,” said Professor Mary Collins head of the Advanced Therapies unit at NIBS, noting that
“closer working with University College London will greatly help to take forward studies that focus on
therapeutic areas of gene and cell therapies”. … (Source: PharmaTimes)
34
 MHRA responds to European Medicines Agency recommendations on
the use of valproate medicines
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has
recommended strengthening the restrictions on the use of valproate medicines due to an increased risk of
birth defects and developmental problems in children exposed to valproate in the womb.
It is being recommended that valproate medicines should not be used to treat epilepsy and bipolar disorder
in girls, women who can become pregnant or pregnant women unless other treatments are ineffective or
not tolerated.
The recommendations will now be sent to the Co-ordination Group for Mutual Recognition and
Decentralised Procedures – Human (CMDh) for a final opinion.
We will provide further information to patients and healthcare professionals once a final opinion is
reached.
Dr. Sarah Branch, Deputy Director of MHRA’s Vigilance and Risk Management of Medicines division said:
“There are already strong warnings contained in product information for patients and prescribers on the
potential for birth defects and developmental disorders in children born to women taking valproate during
pregnancy. It is now being recommended that this information is strengthened further.
“It is important that anyone taking valproate should not stop their treatment without first discussing it with
their doctor.
“If anyone has any questions they should speak with their GP or pharmacist.” … (Source: MHRA)
 Information sent to healthcare professionals in September about the
safety of medicines
(Source: MHRA)
 Landmark UK patent law change will boost clinical research
A major amendment to UK patent law has taken effect today (October 1) could help to attract drug
research back to the UK.
The amendment will remove the risk of infringement claims and allow companies to use a patented
product when carrying out clinical trials. The change is an addition to the existing ‘Bolar Exemption’, a
European Union directive which only protected generic drugmakers from the risk of infringement lawsuits if
they conducted trials on a patented product.
The new change now removes intellectual property barriers to the research-based pharmaceutical industry
carrying out clinical trials in the UK, putting the country on the same level as other EU countries and with
generics players.
Stephen Bennett, a partner in Hogan Lovells London IP practice, told PharmaTimes “one of the issues that
drives location for clinical trials is whether that work will escape the risk of patent infringement claims,
injunctions stopping trials part way through or ‘stop-go’ injunctions and damages imposed after the event”.
This is now “a much more straightforward exercise to clear trials in the UK for patent purposes”, giving
research-based companies “more certainty in the planning stage and removes one of the tricky issues from
the matrix of factors that need to be addressed to get trials off the ground”.
35
He added that “although this is a move that the innovator industry will welcome, it is not clear what effect
it will have when the new Unitary Patent Court comes into effect”, slated for 2015. Mr Bennett went on to
say that the legislation which sets up that system “has its own Bolar provision that is squarely aimed only at
trials to generate data for generic authorisation. Given that existing patents end up in this new system by
default, there is potential for the revised Bolar to have a short life”. … (Source: PharmaTimes)
 UK bioscience now leading Europe for capital raised, R&D: report
The UK leads Europe for the amount of bioscience innovation capital raised in first-half 2014, and it remains
Europe’s largest bioscience cluster, with more than 450 product candidates developed in 2013, says a new
report.
The UK bioscience sector raised a total of £734 million in innovation capital during the first six months of
this year, and also had Europe’s largest number of financing rounds (36) during the period, according to the
new State of the National report, produced by the BioIndustry Association (BIA) and Ernst & Young (EY) and
published at the BIA’s UK Bioscience Forum in London today (October 7).
2014 is set to be a banner year, as the total for first-half 2014 has already surpassed the £483 million total
innovation capital raised in the UK for the whole of 2013, says the report. Moreover, European life sciences
funding in first-half 2014 has already surpassed the £2.1 billion raised in 2013, it adds.
“2014 has been a strong a confident year for UK life science companies. This year, for the first time in many
years, we’ve seen IPOs [initial public offerings] return to the sector. Companies large and small, academia,
research charities, new institutions and the NHS now mix together in our ecosystem to make it one of the
most vibrant and dynamic in the world,” said the BIA’s CEO, Steve Bates.
“It’s an exciting time as the UK develops the therapies of the future. That’s why we are seeing global
investment in the UK in genetic diagnostics, new approaches to cancer treatment, therapies for stratified
and rare diseases as well as cutting-edge regenerative medicines and cell therapies,” he said. … (Source:
PharmaTimes)
http://www.nice.org.uk/
 Medicines optimisation: guideline consultation
A clinical practice guideline on medicines optimisation is being developed for use in the NHS in England,
Wales and Northern Ireland. Registered stakeholders for this guideline are invited to comment on the
provisional recommendations. Individuals and organisations not registered as stakeholders are not able
to comment. We recommend that you register as a stakeholder or contact the registered stakeholder
organisation that most closely represents your interests and pass your comments to them.
Note that the provisional recommendations presented here do not constitute the Institute's formal
guidance on this topic. The recommendations are provisional and may change after consultation.
An embargoed version of the final guideline will be available to stakeholder organisations that comment
during this consultation. Stakeholders must respond to the consultation in order to receive a confidentiality
form to sign. The response needn’t be formal comments, an email to say ‘no comment’ will suffice.
Respondents will receive a confidentiality form after the consultation closes.
The embargoed version will be released two weeks before the official publication and will be subject to the
signing of the confidentiality form. Only stakeholder organisations that return a signed confidentiality form
36
(signed by hand, not electronically) returned either by email or post will receive the embargoed guideline 2
weeks before the official publication.
Consultation dates: 10 October - 7 November 2014
Consultation documents:
Full version
Appendix 1
Appendix 2
Comments proforma
(Source: NICE)
 Leukaemia (chronic lymphocytic) - obinutuzumab (with chlorambucil,
1st line) [ID650]
The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to
produce guidance on using obinutuzumab in the NHS in England. The Appraisal Committee has considered
the evidence submitted by the company and the views of non-company consultees and commentators,
clinical experts and patient experts.
This document has been prepared for consultation with the consultees. It summarises the evidence and
views that have been considered, and sets out the draft recommendations made by the Committee. NICE
invites comments from the consultees and commentators for this appraisal (see section 9) and the public.
This document should be read along with the evidence base (the committee papers). … (Source: NICE)
 Alcohol dependence - nalmefene [ID660]
Anticipated publication date: November 2014
Nalmefene for reducing alcohol consumption in people with alcohol dependence. … (Source: NICE)
 Lundbeck's alcohol consumption pill gets NHS green light
Up to 600,000 patients with alcohol dependency in England will from today have ‘routine’ access to a new
treatment approach after cost regulators endorsed National Health Service use of Lundbeck’s Selincro
(nalmefene).
Following draft guidelines in July, the National Institute for Health and Care Excellence has this morning
(Thursday) published final guidance recommending the drug as an option for cutting alcohol consumption
in adult patients with alcohol dependence, in those without physical withdrawal symptoms and who do not
require immediate detoxification.
The decision means that, for the first time, patients will have access to a pill to reduce alcohol intake rather
than stop it altogether, which some experts believe is a more realistic treatment aim.
Lundbeck notes that, along with counselling, Selincro could help more than halve the amount of alcohol
consumed - by an average of 61% after six months, which equates to around 28 fewer bottles of wine per
person over one month.
37
But the drug should only be initiated in patients who continue to have a WHO high drinking risk level two
weeks after initial assessment, meaning men who cannot cut down to below 7.5 units per day or women
who can’t cut down to less than 5 units a day, NICE has stipulated. … (Source: PharmaTimes)
http://www.hpra.ie/
http://www.fagg-afmps.be/fr/
http://www.bfarm.de/DE/Home/home_node.html
http://www.agenziafarmaco.gov.it/en
http://www.aemps.gob.es/en/home.htm
http://www.legemiddelverket.no/English/Sider/default.aspx
http://www.lakemedelsverket.se/english/
http://www.eum.hu/about-us/the-ministry/ministry-of-health
http://www.swissmedic.ch/index.html?lang=fr
Les Bonnes Pratiques de Fabrication (GMP) et les Bonnes Pratiques
Cliniques (GCP) sont au cœur de nos préoccupations et dans notre
champ de compétence. N’hésitez pas à venir vers nous pour réaliser vos
audits. Nous avons un réseau de des correspondants locaux en Asie et
aux Etats-Unis.
38
Ministry of Health of Ukraine
http://www.kmu.gov.ua/control/en/publish/article?art_id=88456
RUSSIA & RELATED COUNTRIES
Ministry of Healthcare of the Russian Federation
http://government.ru/eng/power/23/
MIDDLE EAST
 Cedars-Sinai Heart Institute launches stem cell therapy
research clinic for cardiac patients
The Cedars-Sinai Heart Institute has announced the opening of a research clinic for evaluation of patients
with heart and vascular disease as participants in stem cell therapy studies.
The Heart Institute Regenerative Medicine Clinic, will evaluate the potential benefits of stem cells for the
repair of diseased or damaged CV tissue and match patients with appropriate clinical trials. The clinic is the
first of its kind within a major US academic medical center, according to a press release. Eduardo Marbán,
MD, PhD, director of the Heart Institute, and Timothy Henry, MD, director of the Institute’s cardiology
division, will lead the new facility.
“Our goal is to help make stem cells a regular treatment option for heart disease,” Henry said in the
release. “Right now, many patients with advanced heart disease have limited treatment options. Stem cells
offer not only hope but a real chance of a game-changing treatment.”
The clinic offers consulting services for potential investigative stem cell therapy patients with heart or
vascular disease. Physicians will assess patients willing to participate in stem cell trials at Cedars-Sinai, as
well as those willing to travel to other facilities nationwide, according to the release. In cases where
patients travel to other institutions, Cedars-Sinai will work with the investigators to expedite referrals and
transfer of medical records.
“Patients who have battled HF, heart attacks and severe hypertension for years might not be aware of new
options that could improve their health and quality of life,” Marbán said in the release. “Not every patient
will find a suitable stem cell clinical trial, but we are focused on finding each patient the most advanced
treatment for their disease.” … (Source: Healio)
39
 Cipla works with partner to build a manufacturing plant
in Iran
Sri Lanka, Yemen, Iran. India's Cipla is aggressively moving into markets that Western drugmakers often
take a very long time to evaluate. It is using partners it already has to put together manufacturing deals
that provide it ownership in local production.
The drugmaker reported this week to the Bombay Stock Exchange that it had struck a deal with "its existing
Iranian distributor for setting up a manufacturing facility in Iran." There were no details, but Cipla reported
it will contribute machinery, equipment and technical know-how over the next three years, an investment
it values at about 225 crore ($36.5 million). For that, it said it will get a 75% ownership in the new
operation.
Cipla said that its proposed investment is subject to completion of certain conditions and getting all of the
applicable regulatory approvals.
Western sanctions do allow drugs to be sold in Iran, and relations have eased some this year, but Iran
remains a tricky market. Germany-based Merck KGaA said late last year it was looking for a partner to
produce its diabetes drug Glucophage and its high-blood-pressure treatment Concor in Iran. France-based
Sanofi, which licenses some cancer meds in Iran and maintains a staff of 170 there, has indicated it intends
to expand in the country.
Iran does have some domestic production. In June, the Fars News Agency (FNA) in Iran said that officials
there had inaugurated the first phase of the Bayer Aflak plant near the western city of Azna in the Lorestan
province, and that it would initially produce veterinary drugs, but that a second phase was being slated to
make human products, including cancer drugs. A spokesperson for Bayer HealthCare made clear that the
German company has no facilities in Iran and that Bayer Aflak is not related to Bayer HealthCare. According
to FNA, government officials have said the country expects to produce up to a dozen biologic drugs in the
next two to three years.
Iran is not the only emerging market on Cipla's list. In July, the drugmaker announced its intent to invest
$21 million for a 51% stake in a pharma manufacturing and distribution operation in Yemen. The company
declined at the time to identify the company or seller, but Cipla spokesperson Jaisingh Krishnan said its
partner had one manufacturing facility which was expected to come online shortly and that would
manufacture tablets and capsules. Earlier it said it would spend $14 million to buy a 60% stake in a
company in Sri Lanka that would distribute its products there. … (Source: FiercePharmaManufacturing)
NORTH AMERICA
http://www.fda.gov/
40
 FDA’s New Roadmap for Progress: Strategic Priorities 2014-2018
The U.S. Food and Drug Administration regulates products that represent about 20 cents of every dollar
American consumers spend on products. This includes the safety and effectiveness of drugs, medical
devices, and vaccines, the safety of blood supply to food supply, cosmetics, dietary supplements, products
that emit radiation, and more recently, tobacco. This fact can be easy to gloss over, but if one pauses for a
moment to reflect on this fact, it is clear that the FDA’s regulatory role is large and truly meaningful to all of
our everyday lives.
When the FDA was first established, our regulated industries were predominantly local, the volume of
imported products was low, and even the movement of goods across country was minimal. But times have
changed, and so have the strategies we employ to address those changes. Over the last five years alone,
the FDA’s regulatory portfolio has increased to now include regulating tobacco products, developing a new
global system for protecting food safety, and addressing challenges created by the global expansion of
research, commerce and trade.
In fact, more often than not today, a drug or medical product that ends up on the shelves of an American
drugstore or in our hospitals will come, at least in part, from some foreign source. Nearly 40 percent of
finished medicines that Americans now take are made elsewhere, as are about 50 percent of all medical
devices. Approximately 80 percent of the manufacturers of active pharmaceutical ingredients used in the
United States are located outside our borders.
These and other new challenges and transformative developments in global science, technology and trade
are rapidly altering the environment in which we work to fulfill our broad public health mission. In order to
continue to carry out that mission, we need a set of clearly defined priorities and goals, as well as the
strategies for reaching them. Therefore, I am pleased to announce the release of a revised set of FDA
Strategic Priorities which will guide the agency in how we continue to promote and protect the health of
the American public.
The new Strategic Priorities document sets the path for our Agency over the next four years. It establishes a
framework for integrating our five strategic priorities – regulatory science, globalization, safety and quality,
smart regulation, and stewardship.
Although each priority is significant in and of itself, the priorities are also interconnected and must not be
addressed in isolation. In addition, this new roadmap sets forth FDA’s core mission goals and objectives,
such as improving and safeguarding access to the products FDA regulates – and promoting better informed
decisions about their use.
The Strategic Plan has been in development for more than a year and was created by a hard-working team
of talented and knowledgeable FDA employees representing programs from across the agency. While this
team drove the Plan’s creation, it is backed by the commitment of all of us at the FDA. My hope is that
these priorities, which will be repeatedly cited in our speeches, policies and writings, will serve as our
foundational guidepost, providing the strategic direction to help the agency continue to provide the level of
service and protection the American people deserve. … (Source: FDA)
 FDA Panel to Review New Watchman Data Wednesday
The Watchman left atrial appendage closure device (Boston Scientific) is making its third trip to
Gaithersburg, MD, Wednesday. Once again, the FDA's Circulatory System Devices Panel will review the
evidence supporting the safety and efficacy of the investigational device and make recommendations to
the agency as to whether it should be approved for the prevention of thromboembolism in patients with
nonvalvular atrial fibrillation.
41
It's been more than five years since the FDA's panel first reviewed the Watchman, as reported by heartwire
, voting 7 to 5 in favor of approval. The FDA then requested an additional study from the sponsor, Boston
Scientific, and that led to the PREVAIL study, which subsequently faced its own share of controversy. In
December 2013 an advisory panel review that included the PREVAIL data led to a vote of 13 to 1 in favor of
approval. Once again, however, the FDA held off on a decision, most notably because just 28% of the 18month data from PREVAIL were ready for review.
Briefing documents for the panel posted online today make it clear that the panel is being asked to
consider the updated follow-up data provided to the FDA following the December 2013 review and in
particular the updated total number of ischemic strokes in the PREVAIL data set.
As recently reported by heartwire , Watchman investigators presented some of these data at last month's
TCT 2014 meeting, including the fact that eight new ischemic strokes have occurred in the Watchmantreated patients in PREVAIL and zero in the comparator group.
The briefing document does note that advisory panel members review the "totality of data" when deciding
whether it supports the safety and efficacy of the device and whether the probable benefits outweigh the
risks. … (Source: Medscape)
 North Carolina drugmaker gets FDA approval to provide experimental
treatment to Ebola patients
A North Carolina drugmaker says it is providing an experimental antiviral drug for patients with Ebola, an
emergency step authorized by the Food and Drug Administration.
Chimerix Inc. says physicians sought federal permission to use company's drug, called brincidofovir, which
is in late-stage testing for other types of viruses. The company did not identify the physicians making the
request.
Last Tuesday doctors in Dallas diagnosed the first U.S. case of Ebola in a man who recently arrived from
Liberia.
Brincidofovir is an oral antiviral drug being tested to fight more common viruses, including one that infects
patients undergoing bone marrow transplants. Laboratory tests suggested it might also fight Ebola.
Two other experimental drugs developed specifically for Ebola have been used in American patients. None
have been approved by the FDA. … (Source: FoxBusiness)
 FDA Grants Orphan Drug Designation To DNAtrix's DNX-2401 For The
Treatment Of Malignant Glioma
DNAtrix, experts in oncolytic virus development, today announced that the U.S. Food and Drug
Administration (FDA) has granted Orphan Drug Designation for DNX-2401, a conditionally-replicative
oncolytic adenovirus for malignant glioma. Glioma is the most common form of primary brain cancer, the
treatment of which remains a significant unmet medical need. Under the designation, companies are
provided with development and commercial incentives for designated compounds. The company's DNX2401 program has already been granted fast track status.
The FDA's orphan drug program designates a special status to drugs and biologics intended to treat,
diagnose, or prevent diseases and disorders that affect fewer than 200,000 people in the U.S. It can be
easier to gain marketing approval for drugs with orphan status, and orphan drugs typically also enjoy
extended marketing exclusivity periods.
42
"We are pleased to have been granted Orphan Drug designation for our lead glioma oncolytic virus
therapy," said Dr. Frank Tufaro, president and chief executive officer of DNAtrix. "Results from our clinical
trials with DNX-2401 continue to indicate that the drug may be an important treatment option for the
disease."
Oncolytic virus therapy is based on the concept of using live viruses to selectively infect and replicate in
cancer cells, with minimal destruction of normal tissue. Virus replication amplifies the input dose of the
oncolytic virus and helps spread the agent to adjacent tumor cells. Moreover, there is evidence for a longlasting anti-glioma immune effect that can lead to durable tumor destruction and long-term survival in
some patients. DNX-2401, which has been engineered to be highly potent and selective for killing tumors, is
currently being evaluated in clinical studies in the United States and Europe. … (Source: PMPnews)
 FDA grants aldoxorubicin orphan drug status
CytRx Corp. announced that the FDA granted multiple orphan drug designation to aldoxorubicin for the
treatment of patients with glioblastoma multiforme, small cell lung cancer and ovarian cancer.
Aldoxorubicin is a modified version of the chemotherapeutic agent doxorubicin, combined with a novel
single-molecule linker that binds directly and specifically to circulating albumin. This combination allows
patients to receive higher doses of doxorubicin while reducing its toxic side effects.
“The FDA’s decision to grant Orphan Drug designation for aldoxorubicin in these three new indications is a
key milestone for the aldoxorubicin clinical development program and a clear reflection of the high unmet
medical need for new treatments in these cancer types,” Steven A. Kriegsman, president and CEO of CytRx,
said in a press release. “These designations are also a testament to the team’s regulatory and development
expertise and part of our core strategy to bring aldoxorubicin to patients worldwide as rapidly as possible.
We look forward to reporting top-line results from both our phase 2 [glioblastoma multiforme] trial and our
phase 2 Kaposi’s sarcoma trial in the first half of 2015.”
Aldoxorubicin is being evaluated in a global phase 3 clinical trial, examining its safety and efficacy as a
second-line treatment for patients with soft tissue sarcoma under a special protocol assessment with the
FDA.
In addition, CytRx has initiated two phase 2 clinical trials, assessing aldoxorubicin treatment for patients
with late-stage glioblastoma multiforme and HIV-related Kaposi’s sarcoma. CytRx also plans to launch a
global phase 2b trial in patients with relapsed small cell lung cancer, as well as a phase 1b combination
study of aldoxorubicin plus gemcitabine as a potential precursor to a trial in patients with relapsed ovarian
cancer.
The FDA Office of Orphan Products Development grants orphan drug designation to novel drugs and
biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or
disorders that affect fewer than 200,000 people in the United States. … (Source: Healio)
 Maker of highly criticized painkiller asks FDA to approve new, harderto-abuse version
The maker of the much-debated painkiller Zohydro is seeking approval of a harder-to-abuse version of its
drug which, if approved, could replace the currently marketed version of the pill by next spring.
San Diego-based Zogenix said Wednesday it submitted a Food and Drug Administration application for the
new Zohydro formulation that is designed to be more difficult to snort or inject — two common methods
43
for abusing painkillers. Zogenix expects approval in the first quarter of 2015, which would allow the
drugmaker to replace the older version of Zohydro in the second quarter.
Zohydro has been criticized by health advocates, politicians and law enforcement officials since it became
the first single-ingredient hydrocodone drug ever approved for U.S. patients last fall. … (Source:
FoxBusiness)
 Otsuka & Lundbeck’s Abilify Maintena Gets FDA Nod for New
Formulation
The FDA has signed off on a new formulation of Otsuka and Lundbeck’s collaborative anti-psychotic Abilify
Maintena to be delivered via pre-filled dual chamber syringe.
Otsuka and Lundbeck said FDA approved the new Abilify Maintena (aripiprazole) syringe this week, calling it
the first of several planned enhancements for the product that was first approved February 2013 and is
prescribed for the treatment of schizophrenia.
The new syringe, which allows for a once-a-month injection in either a 300 mg or 400 mg dose, should be
available in the U.S. in January, the companies said.
Abilify Maintena is an atypical antipsychotic based off the tablet version of oral Abilify, which was first
approved in 2002. The syringe-version is so far the only injectable dopamine D2 partial agonist approved by
the FDA.
The new dual-chamber product proved its efficacy in a placebo-controlled, randomized-withdrawal
maintenance trial conducted in patients living with schizophrenia, Otsuka and Lundbeck said.
The companies cautioned that Abilify Maintena is not indicated for patients with dementia-related
psychosis and carries increased risk in elderly patients with such a disease. … (Source: FDAnews)
 Ariad Pharma's lung cancer drug gets breakthrough therapy status
Ariad Pharmaceuticals Inc said its experimental lung cancer drug was granted "breakthrough therapy"
status by the U.S. Food and Drug Administration and it expected to file for marketing approval in early
2016.
The designation hastens the development and review of a drug that shows evidence of providing
improvement over existing treatment for patients with serious diseases.
The drug, AP26113, which is in a mid-stage trial is designed to treat non-small cell lung cancer (NSCLC) with
a specific gene mutation.
About 1.5 million cases of NSCLC, the most common form of lung cancer, are diagnosed every year, Ariad
said. The company said about 3-8 percent of NSCLC patients have the gene mutation.
The company said it was not looking to partner with any one for the development of the drug. … (Source:
Reuters)
 FDA grants fast track designation to NKTT120 for sickle cell disease
The FDA granted fast track designation to NKTT120 as a potential treatment for patients with sickle cell
disease, the drug’s manufacturer announced.
44
NKTT120 (NKT Therapeutics) is a humanized monoclonal antibody that specifically depletes invariant
natural killer T cells, which have been demonstrated to be key mediators of organ damage in preclinical
models of sickle cell disease.
“We look forward to working with the FDA on the design of our efficacy trials for NKTT120,” Robert
Mashal, CEO of NKT Therapeutics, said in a company release. “Fast track status will help us reach our goal
of bringing this new therapy to patients as rapidly as possible.”
The FDA based its decision on interim results from an ongoing phase 1 safety and dose escalation study of
NKTT120 in adults with stable sickle cell disease. … (Source: Healio)
 Zogenix races to FDA with abuse-deterrent version of maligned pain
pill Zohydro
Ever since the FDA approved Zogenix's all-hydrocodone painkiller Zohydro last year, both the agency and
the company have faced a storm of criticism. The powerful pill, without tamper-resistant features, was
destined to be abused, they claimed.
Zogenix wasted little time responding to the outcry, applying for FDA approval on Wednesday for a new,
modified version of the drug--a capsule formulation designed to make it difficult for addicts to abuse it by
snorting or injecting it.
Zogenix expects the FDA to hand down a decision in the first quarter of 2015, according to a press release
from the company. If that decision is positive, Zogenix plans to transition patients from the currently
marketed version of the drug to the abuse-deterrent capsules.
The news comes just one week after 15 anti-addiction advocacy groups sent a letter to the U.S. Department
of Health and Human Services demanding that FDA Commissioner Margaret Hamburg be forced to resign
over the agency's decision to approve Zohydro. Hamburg had been under fire all year--first from 28 state
attorneys general demanding the FDA withdraw the approval, then from U.S. Sen. Joe Manchin (D-WV),
who introduced a bill to try to force the FDA to pull the plug on the product.
Hamburg, for her part, has continued to defend Zohydro's approval, insisting that the drug fills an
important niche for treating patients with chronic pain. The FDA has approved some pain pills with abusedeterrent characteristics, though Hamburg has acknowledged that such features do little to discourage the
most serious of addicts.
Zogenix, nevertheless, is under extreme pressure from legislators seeking to stem the rise of drug
addiction. In the spring, Massachusetts Gov. Deval Patrick tried to ban Zohydro, prompting a lawsuit from
Zogenix that the company won. Still, the incident got nationwide attention, providing Zogenix with plenty
of negative PR.
Then there's the competitive pressure. Purdue Pharmaceuticals, Teva and Pfizer are all working on pain pills
with abuse-deterrent features. … (Source: FiercePharma)
 FDA approves expanded indication for Ozurdex implant
The U.S. Food and Drug Administration has approved Ozurdex for the general patient population being
treated for diabetic macular edema, Allergan announced in a press release.
In June, the FDA approved Ozurdex (dexamethasone intravitreal implant 0.7 mg) for the treatment of DME
in pseudophakic adult patients or patients who were scheduled for cataract surgery.
45
The FDA’s initial approval of Ozurdex was based on results from the MEAD study, which comprised two
multi-center, sham-controlled, randomized clinical studies. The primary outcome measure was the
proportion of patients who had a 15-letter or greater improvement in best corrected visual acuity.
The most common adverse events related to treatment were cataracts and elevated IOP. In most cases, IOP
returned to baseline values between treatment cycles, according to the release.
Ozurdex is also indicated for the treatment of macular edema secondary to branch retinal vein occlusion
and central retinal vein occlusion, as well as for the treatment of non-infectious uveitis in the posterior
segment of the eye. … (Source: Healio)
 FDA Okays Methylnaltrexone (Relistor) for Opioid Constipation
The US Food and Drug Administration (FDA) has approved methylnaltrexone bromide (Relistor, Salix
Pharmaceuticals/Progenics Pharmaceuticals) subcutaneous injection 12 mg/0.6 mL for the treatment of
opioid-induced constipation (OIC) in patients taking opioids for noncancer pain.
The drug was approved in the United States in 2008 for the treatment of OIC in patients with advanced
illness receiving palliative care, when the response to laxative therapy has not been sufficient.
It is currently the only available peripherally acting mu-opioid receptor antagonist approved for treating
OIC by blocking the constipating effects of opioids in the gastrointestinal tract without crossing the bloodbrain barrier and interfering with the analgesic effects of opioids, the companies note in a joint statement.
The drug was declined approval for this indication in July of 2012. In the complete response letter, the FDA
asked for more data to support the application.
Approval is based on results of a randomized, double-blind, placebo-controlled trial including a total of 312
patients with a history of noncancer pain who were taking opioids for at least 1 month prior to study entry.
All had confirmed constipation, defined as less than 3 spontaneous bowel movements per week during the
screening period.
Constipation due to opioid use had to be associated with 1 of more of the following, the statement notes: a
Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements; straining during, or a
sensation of incomplete evacuation after at least 25% of the bowel movements.
The median duration of constipation at baseline was 59 months, the statement notes. The median daily
baseline oral morphine equivalent dose was 161 mg. Patients were randomized to receive
methylnaltrexone 12 mg or placebo once daily for 4 weeks, followed by an 8-week open-label phase where
patients could take medications as needed.
Study results showed that a significantly great proportion of patients taking methylnaltrexone reported
having 3 or more spontaneous bowel movements during the 4-week double-blind period vs placebo (59%
vs 38%).
After the first dose, 33% of treated patients reported having a spontaneous bowel movement within 4
hours, and approximately 50% had a bowel movement prior to the second dose.
Treatment was well tolerated, and adverse events were consistent with those seen with other studies of
the drug in an advanced illness population, the statement adds. The most common side effects were
abdominal pain (21%), diarrhea (6%), nausea (9%), and hyperhidrosis (6%). Hot flush, tremor, and chills
were also seen.
Methylnaltrexone is contraindicated in patients with known or suspected gastrointestinal (GI) obstruction
and those at increased risk of recurrent obstruction, due to the potential for GI perforation, the statement
46
warns. Cases of perforation have been reported in patients with advanced illness in conditions that may be
associated with localized or diffuse reduction in the structural integrity of the GI tract, such as peptic ulcer
disease, Ogilvie syndrome, diverticular disease, infiltrative GI tract malignancies, or peritoneal metastases.
"Take into account the overall risk-benefit profile when using Relistor in patients with these conditions or
other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's
disease)," the statement adds. "Monitor for the development of severe, persistent, or worsening
abdominal pain; discontinue Relistor in patients who develop this symptom. If severe or persistent diarrhea
occurs during treatment, advise patients to discontinue therapy with Relistor and consult their physician."
… (Source: Medscape)
 FDA grants orphan drug designation to PEGPH20 for pancreatic
cancer
The FDA has granted orphan drug designation to pegylated recombinant human hyaluronidase for the
treatment of pancreatic cancer, according to a press release.
Pegylated recombinant human hyaluronidase (PEGPH20, Halozyme Therapeutics) is an investigational drug
being developed for the systemic treatment of hyaluronan-accumulating tumors, the release said.
“This designation follows the fast track designation and allows us to collaborate more closely with the FDA
to facilitate development of PEGPH20 and is part of our core strategy to bring this therapy to patients as
rapidly as possible,” Helen Torley, MB, ChB, president and CEO of Halozyme, said in the release. “Receiving
orphan drug designation is an important milestone for this clinical development program.”
A phase 2 study of PEGPH20 in combination with gemcitabine (Gemzar, Eli Lilly) and nab-paclitaxel
(Abraxane, Celgene) for metastatic pancreatic cancer treatment is currently under way, the release said. …
(Source: Healio)
 FDA seeks permanent injunction against Pharmaceutical Innovations,
Inc.
The U.S. Food and Drug Administration is seeking a permanent injunction to stop Pharmaceutical
Innovations Inc., and its principal officer, Gilbert Buchalter, from manufacturing, marketing, selling, and
distributing medical products until they come into compliance with all applicable FDA requirements.
The Newark, New Jersey company's products include ultrasound, mammography, and electrocardiogram
gels, and scanning pads. These products are medical devices used for diagnostic purposes in health care
settings.
The complaint alleges that the defendants did not manufacture their devices in conformity with the current
good manufacturing practice requirements of the Federal Food, Drug, and Cosmetic Act, and that they
distributed their products nationwide without required premarket approval or clearance.
The complaint also details that U.S. marshals, acting at the request of the FDA, seized certain lots of OtherSonic Generic Ultrasound Transmission Gel from the company in April 2012. The seizure took place after
FDA laboratories found in those lots significant amounts of Pseudomonas aeruginosa and Klebsiella oxytoca
- bacteria that pose serious risks of infection, such as pneumonia, to people exposed to the product. The
FDA is aware of people who were infected with Pseudomonas aeruginosa after having undergone a surgical
procedure at a Michigan hospital involving Other Sonic Generic Ultrasound Transmission Gel. On April 18,
2012, FDA issued a safety alert to health care professionals and facilities to stop using the contaminated
product. … (Source: PMPnews)
47
USA
 'Parity' Laws for Costly Oral Cancer Drugs Not a Solution
The much-lauded legislation to protect patients in the United States from the ruinously high cost of oral
cancer drugs should not be whole-heartedly cheered, suggest a trio of experts in a Viewpoint essay
published online September 22 in JAMA Internal Medicine.
The so-called "oral chemotherapy parity laws" — passed in 34 states plus the District of Columbia —
require health insurers to cover oral chemotherapeutic agents under "no less favorable" terms than
intravenous (IV) chemotherapy. The latter tends to be comprised of old drugs and is much less expensive.
In short, the laws, which have been praised by law makers, physicians, and patient advocates, make oral
cancer drugs "more affordable and accessible to patients," write Bo Wang, PharmD, and Aaron Kesselheim,
MD, JD, MPH, both from Harvard Medical School in Boston, and Steven Joffee, MD, from the University of
Pennsylvania in Philadelphia.
So why do these distinguished analysts also say that the laws are "an inadequate response"?
They explain that the laws "merely shift the responsibility" for the cost of the drugs to insurers, who in turn
will inevitably pass the additional costs on to all policy holders.
In other words, some cancer patients might be spared the potential financial ruin resulting from the
exorbitant cost of oral agents, such as imatinib (Gleevec, Novartis) and pertuzumab (Perjeta, Roche), but all
Americans who have health insurance will ultimately pay more for coverage to compensate.
It's a shell game, they suggest.
One thing stays the same under the new laws — the high cost of cancer drugs is not challenged or changed
for the United States as a whole, the essayists report. And the cost of cancer medications will continue to
go up, they predict.
Indeed, one prominent American oncologist recently pointed out that the prices appear to be set at
whatever the market will bear, and noted that recently launched oral cancer drugs are costing more than
$100,000 per year.
In their Viewpoint, the essayists assert that the parity laws are weakened by the fact that they "only apply
to the limited number of private insurance plans," which have "large" discrepancies in cost-sharing
arrangements for oral and IV chemotherapy.
"It is unclear how many patients will actually benefit," they state, adding that the continuing legislative
focus on these "well meaning" laws "misses the mark." … (Source: Medscape)
 Potential liver repair drug CF102 issued US patent
Can-Fite BioPharma received a US patent for CF102, a drug under development to repair liver cells and
function in patients with hepatocellular carcinoma, according to a news release.
CF102, an oral molecular bioavailable drug, acts as an agonist at the A3 adenosine receptor and has
demonstrated antitumor effects in multiple phase 1 and 2 clinical trials, resulting in liver cancer cell death,
according to Can-Fite.
48
“The treatment of postsurgery liver function is an indication that would complement our current portfolio
of indications in clinical trials,” Pnina Fishman, PhD, chief executive officer at Can-Fite, said in the release.
“CF102 may offer important healing benefits for the liver not only to cancer patients, but also for patients
who have other diseases or injuries of the liver.”
Can-Fite received orphan drug designation from the FDA for CF102 and a patent from the European Union
earlier this year. A phase 2 clinical study is under way in the US, Europe and Israel with 78 participants
dosed with placebo or CF102 as a second-line treatment for advanced HCC in patients who have failed
treatment with sorafenib. The study will investigate the safety and efficacy of CF102 compared with
placebo. … (Source: Healio)
 Forest, Otsuka and J&J spend the most on fees and food for doctors
The Sunshine Act data's been out in the open for a couple of days now (well--most of it), and despite the
database's clunkiness, the number crunching is well underway. The Wall Street Journal, for one, has broken
down which pharma companies topped the doc-paying list in a variety of different spending categories.
The overall highest roller? Genentech, which doled out $122.5 million of the $302.5 million the industry as
a whole spent on royalties and licenses between Aug. 1 and Dec. 31 of last year. Forest Labs took the cake
on promotional speakers, throwing down $12.5 million in fees to physicians. Otsuka America forked over
$9.5 million to docs in consulting fees, while Johnson & Johnson's ($JNJ) Janssen plowed $4.2 million into
wining and dining.
But as the WSJ points out, those totals don't necessarily signal a conflict of interest. In fact, some of the
physicians who took home the biggest payments last year received them for purposes that had nothing to
do with patient care. Several doctors who no longer even practice medicine scored large sums for serving
on corporate boards or writing software used in laser-surgery machines, for example.
It's just another reason some docs and drug companies haven't been too fond of the idea of full disclosure.
The numbers paint an incomplete picture--literally, with CMS for now holding back chunks of payment data
thanks to coding problems--and, in some cases, a flawed one, medical professionals say.
Take Michigan doc James VanderLugt, listed as one of the top-paid in the nation in the "nonconsulting
compensation" category. In the 5-month period the database covers, he supposedly pocketed $570,000
from Boehringer Ingelheim-owned Roxane Laboratories for leading clinical research as medical director of
Jasper Clinical. … (Source: FiercePharma)
http://www.pcori.org/
http://www.ahrq.gov/
49
http://www.iom.edu/
SANTE/HEALTH CANADA
http://www.hc-sc.gc.ca/index-fra.php#tabs1_3
 Canada Wants to get Tough on Pay-to-Delay Deals
In a speech last week, Canada’s chief anti-trust regulator sought to dispel the notion that the country is soft
on preventing potentially anticompetitive deals that would delay generic drugs from reaching consumers as
soon as possible. Specifically, the Canadian Competition Bureau plans to take a tougher approach on socalled pay-to-delay settlements that have generated substantial controversy.
In such agreements, brand-name drug makers reach a deal with a generic rival in exchange for ending
patent litigation and launching a lower-cost version of a medicine at a future date. The pharmaceutical
industry contends the deals are not only legal, but actually allow lower-cost generic medicines to reach
consumers faster than if litigation continued.
But regulators argue the deals are anti-competitive and cost consumers lots of money. How so? The generic
drug makers settle litigation by agreeing to delay the sale of lower-cost copycat versions and, in return, the
brand-name drug may make a cash payment or agree not to sell its own authorized generic. Meanwhile,
though, regulators say consumers are unable to purchase lower-cost generics.
In fact, regulators in the U.S. and Europe have regularly investigated many deals and either initiated
lawsuits or issued fines. The U.S. Supreme Court ruled last year that settlements can be subject to greater
anti-trust scrutiny. And so, John Pecman, the commissioner of the Canadian Competition Bureau, wants
you to know that Canada is equally interested in getting tough.
In remarks at a conference on pharmaceutical industry issues at George Mason University, Pecman told the
crowd the bureau will review agreements under both criminal and civil laws. He noted a criminal conspiracy
would be pursued for pay-to-delay agreements between competitors to fix prices, allocate markets or
restrict output that constitute “naked restraints,” or general restraints, on competition.
He would pursue criminal violations under two scenarios. One would involve a settlement that includes
terms of a deal beyond the focus of the patent litigation, such as fixing an entry date for the launch of a
generic drug beyond the date when the patent expires.
“By way of example,” he said, “if there was a settlement in which a generic agreed to enter beyond the
expected [patent expiration] date in exchange for a payment, we would likely interpret this as a clear
payment for delayed entry… and it would be examined under the criminal conspiracy provision.”
He continued that if evidence suggested a payment was made by a brand-name drug maker to a generic
rival strictly to delay or prevent entry of a lower-cost copycat medicine, this would also potentially be
examined under the criminal provision of the law. He added that even when criminal conspiracies are not
50
pursued because general restraint of competition is not found, the bureau may investigate violations of civil
regulations (and here is a newly issued white paper on bureau views).
Pecman pointed out that, unlike the U.S., there is no requirement in Canada that potential pay-for-delay
settlements must be reported. This system has made it possible for the U.S. Federal Trade Commission to
track deals. Pecman argues that a similar approach in Canada would equip his bureau with the needed tools
to protect consumers.
Right now, the bureau is unaware when – or even if – pay-for-delay settlements are occurring, he
explained, “and this lack of insight challenges our determination to ensure that competition is open and
transparent.” He vowed to “advocate for better information on patent settlements and the need to explore
approaches that could be adapted to Canada’s regulatory framework.”
Pecman raised another point: There is no Canadian equivalent to the Hatch-Waxman Act, the 1984 law that
ushered in the modern-day model for generic competition and, specifically, provides 180 days of market
exclusivity to the first generic drug maker to challenge a brand-name patent. But he disagreed that the
absence of such an incentive has resulted in lax scrutiny of deals.
Another nugget: the Canadian Institute for Health Information estimates that total health care spending
accounts for 11.2% of the Canadian economy and prescription drugs accounted for the second-largest
component, estimated at 16.3% last year, according to Pecman. And while generics represent two-thirds of
retail prescriptions, they accounted for less than a quarter of total prescription drug expenditures. …
(Source: WSJ)
LATIN AMERICA
SSA http://www.salud.gob.mx/
http://portal.anvisa.gov.br/wps/portal/anvisa/home
 Brazil clarifies bioavailability studies necessary for approval of fixed
dose generics
Brazil's regulatory agency, Anvisa, has issued a Technical Note clarifying the bioavailability studies needed
to demonstrate pharmacokinetic interaction for the marketing approval of a fixed dose generic drug. The
agency also republished guidance concerning therapeutic equivalency that was first released on May 17,
2014. The guidance documents are intended to further national policy in support of generic drugs, given
the country's ongoing commitment to reduce the financial burden on the national health insurance system.
AUSTRALIA – NEW ZELAND
51
http://tga.gov.au/
 TGA international engagement strategy 2013-2015
Updated Annex 1 and Annex 2. … (Source: TGA)
 Electronic funds transfer agreement
Updated fax number and bank details on EFT forms… (Source: TGA)
 Payment options
Updated payment option details… (Source: TGA)
 New FDA concerns arise for Hospira plant in Australia
Hospira has been dealing with FDA concerns for years for plants in the U.S. and more recently in India. But
despite being told more than a year ago that it should have a "global corrective action plan" for both its
foreign and U.S. plants, new issues have surfaced, this time for a plant in Australia that makes specialty
injectable drugs.
The most current letter, for a plant in Mulgrave, Victoria, was concerned about the company's failure to get
to the root cause of out-of-specification results for multiples batches of the injectable cancer drug
mitoxantrone. There was also a particularly long delay between when it first got word of particles
appearing in the chemo drug carboplatin, in May 2012, and when it finally confirmed the issue, in
December 2013. Then it was another three months before Hospira gave providers a heads up that they
should be watching for particles and should use a filter before administering it.
In an SEC filing last week, Hospira acknowledged the newest warning letter and said it took the issues very
seriously. It said it was working to get them resolved. That is a common refrain for the drugmaker, which
has spent years of work and tens of millions of dollars in investments to get on top of manufacturing
problems with its drug manufacturing plants in the U.S.
Even as it has indicated those problems were mostly resolved, it has had a series of failings for plants in
India in the last couple of years. A facility in Irungattukottai was tagged with a warning letter in May 2013
and then received another 23 observations in a follow-up inspection last December. Earlier this year,
Hospira CEO F. Michael Ball told analysts that after a preapproval inspection of a plant it is building in Vizag,
India, the FDA issued a Form 483 with 10 observations. … (Source: FiercePharmaManufacturing)
 Documents released under Section 11C of the Freedom of
Information Act 1982
Added FOI 302-1314 documents… (Source: TGA)
 ACSOM meeting statement, Meeting 21, 7 March 2014
Advisory Committee on the Safety of Medicines meeting statement. … (Source: TGA)
52
 Non-steroidal anti-inflammatory drugs and diclofenac reviews
TGA has completed a review of the cardiovascular risks associated with the use of the non-steroidal antiinflammatory drugs (NSAIDs)
ANZTPA http://www.anztpa.org/
INDIA - PAKISTAN & ASIA
China SFDA | Hong Kong MDCO & PSDH | India CDSCO | Japan MHLW | Korea KFDA | Malaysia MOH |
Philippines DOH | Singapore HSA | Taiwan TFDA | Thailand FDA | Vietnam MOH
http://www.pmda.go.jp/english/
http://eng.sfda.gov.cn/WS03/CL0755/
 La R&D de Sanofi s'installe à Shanghai
Le 25 septembre, le groupe pharmaceutique Sanofi a annoncé l'ouverture d'un pôle de recherche et
développement à Shanghai (Chine), qui permettra au fabricant d'avoir "une plus grande flexibilité pour
répondre à l'évolution des besoins" en Asie-Pacifique.
Malgré les incertitudes qui pèsent sur les marchés émergents, tant sur le plan économique que sur celui de
l'exigence de transparence, le groupe pharmaceutique Sanofi a annoncé, le 25 septembre, l'ouverture d'un
centre de R&D à Shanghai, en Chine.
53
Lors d'une conférence relatée par l'AFP, le groupe français a précisé que l'effectif de ce nouveau pôle
tournera autour de 1 400 employés, qui assureront la R&D pour onze pays en plus de la Chine. … (Source:
UsineNouvelle)
 Pfizer, Kyowa Hakko Kirin Partner to Evaluate Anticancer mAb Combo
Therapy
Pfizer and Kyowa Hakko Kirin (KHK) are teaming up to explore how well the combination of Pfizer’s
investigational monoclonal antibody (mAb) PF-05082566 with KHK's anti-CCR4 antibody mogamulizumab
works in a Phase Ib study in patients with solid tumors. Per the agreement, Pfizer will conduct the study,
which will establish a dose regimen and assess the combination's safety and efficacy, and both firms will cofund it. The companies are planning to begin the study in 2015.
PF-05082566 is a fully humanized mAb that Pfizer says can stimulate signaling through 4-1BB (CD-137), a
protein involved in regulation of immune cell activation, proliferation, and survival. Mogamulizumab, KHK
says, can suppress some of the immune cells that shield the tumor from the immune system.
Both companies believe the immuno-oncology combination of mogamulizumab with the 4-1BB
agonist holds great promise for treating patients with cancer. "We believe that combination therapy in
immuno-oncology holds great promise to improve outcomes for patients with cancer and provides an
exciting opportunity for Pfizer to maximize the potential of our emerging immuno-oncology
portfolio," Mace Rothenberg, M.D., svp of Clinical Development and Medical Affairs and CMO for Pfizer
Oncology, said in a statement.
Pfizer is also currently in a cancer combination therapy collaboration with Merck & Co.; the firms recently
announced plans for a Phase Ib study combining Pfizer’s Xalkori® (crizotinib) with Merck’s investigational
drug pembrolizumab (MK-3475) in patients with anaplastic lymphoma kinase-positive advanced or
metastatic non-small cell lung cancer. The study is set to start next year. … (Source: Gen)
 FDA warns of contaminated Chinese meds after toddler suffers lead
poisoning
The problem of contaminated cold remedies has once again surfaced in the U.S. More than 7 years after
diethylene glycol put authorities on high alert, a toddler in New York has suffered from lead poisoning after
taking a Chinese cold remedy.
The FDA put out an alert about the product that is suspected to have caused the problems--Bo Ying
compound, allegedly made by Eu Yan Sang--late last week. As Forbes contributor David Kroll notes, Eu Yan
Sang is an established manufacturer of Chinese medicines, with sales of $293 million in the last financial
year and a website that boasts of its manufacturing practices.
54
The company claims to only source ingredients from reputable suppliers and have GMP-standard plants in
Hong Kong and Malaysia. Eu Yan Sang is investigating whether another company manufactured the
product--which is marketed for treating influenza, fever and sneezing in infants and children--and used its
brand name. The Bo Ying sold direct from Eu Yan Sang has different packaging than the product
investigated by the FDA.
New York City officials reportedly found high levels of lead in the samples of Bo Ying compound they tested
and passed on the information to the FDA. The regulator has also received one adverse-event report
relating to an 18-month-old child who suffered from lead poisoning after being given the product. …
(Source: FiercePharmaManufacturing)
Food and Drug Administration - Department of Health
http://www.taiwan.gov.tw/ct.asp?xItem=25613&ctNode=1970&mp=1001
MFDS
http://www.mfds.go.kr/eng/index.do;jsessionid=qciHSjRkQKTKw4WNZ1WnOhp4yqR9HwaML5QHjUrGctpVtwPtqyJUamREbNSCgy5c
HSA
http://www.hsa.gov.sg/publish/hsaportal/en/home.html#page=tab1
CDSCO
http://www.cdsco.nic.in/
 Modi pressed to address intellectual property reforms
Indian Prime Minister Narendra Modi has declared that his nation is “open for business,” but some U.S.
industry leaders remain troubled by India’s policy toward intellectual property rights and question whether
the new leader, making his first visit to Washington this week, will follow through on his promise to address
the problem.
Mr. Modi, who took power in May, had a private dinner with President Obama Monday night, though the
White House wouldn’t say whether intellectual property was on the agenda.
In advance of Mr. Modi’s stop in Washington, leaders from a variety of powerful U.S. industries pressed the
president to raise intellectual property issues with his Indian counterpart.
55
“Since [Modi] has taken office, he and his team have certainly said positive things,” said Chris Moore, senior
director of international business policy at the National Association of Manufacturers. “But thus far we
haven’t really seen any actions from this government on intellectual property. … We are pressing our
government but also the Indian leadership to really deliver concrete progress and real results.”
Mr. Modi has raised expectations of an economic rebound for India, based in part on his success promoting
jobs and investment as head of the state of Gujarat and in part on a new “Make in India” liberalizing
agenda he unveiled in New Delhi shortly before leaving last week for New York.
The National Association of Manufacturers is a member of the Alliance for Fair Trade With India, which last
week sent a letter to Mr. Obama urging him to push Mr. Modi to follow through on his goal of reforming
the Indian intellectual property system.
The group also counts among its members the Pharmaceutical Research and Manufacturers of America, the
Motion Picture Association of America, the U.S. Chamber of Commerce and other groups from virtually all
sectors of the U.S. economy. … (Source: WashingtonTimes)
 Indian Industry Decries Smear Campaign Against its Pharma
Exporters
The India Brand Equity Foundation (IBEF), on behalf of the Government of India, has taken strong objection
to a smear campaign being orchestrated by the Washington-based American Enterprise Institute (AEI)
against the whole Indian pharmaceutical industry. It seems that the effort is to tarnish the image of the
Indian pharma industry which it has painstakingly developed over the years and is often recognised as
“Pharmacy of the World”.
In the latest instance, AEI has published the findings of a 'study' as a working paper in the National Bureau
of Economic Research (NBER) Working Paper series. The study has not been reviewed by any of the
authors’ peers as is the gold standard in serious academic publishing. The study cites anecdotal evidence
and hearsay, quoted earlier in the author’s other publications, as facts with established academic
provenance. Cleverly, the Board of NBER distances itself from the contents of the report; yet parts are
being reproduced under NBER’s name to give it credibility which is completely being otherwise.
The study claims to assess “the quality of 1470 antibiotic and tuberculosis drug samples that claim to be
made in India and were sold in Africa, India, and five mid-income non-African countries” based on samples
“from pharmacies in 22 cities of 18 low- to mid-income countries between 2009 and 2012.” The
conclusions of the study are disputed not only for methodology and ethics, but also for the poor treatment
of data sampling used.
“Quality is one of the major focus for pharmaceutical exports from India. Indian companies meet the
quality requirements of all our importing countries. India looks at healthcare as a holistic issue rather than
just commercial business,” said Mr Sudhanshu Pandey, Joint Secretary, Department of Commerce,
Government of India. … (Source: CPhI)
 CDSCO upgrades manpower to
manufacturing facilities in the country
implement
GMP
across
The Central Drug Standards Control Organization (CDSCO) has started deputing drug inspectors as
observers to carry out joint inspections on an event of inspection from an international regulator. The
exercise done in coordination with state drug regulators is meant to monitor manufacturing plants on
56
GMPs and equip drug inspectors on enforcing its compliance across the country. Following which, around
80 drug inspectors have been recruited at the CDSCO in the past one year.
A total of additional 1195 posts have been sanctioned for the upgradation of manpower and labs under the
12th five year plan. Central Government has allocated Rs. 900 crore for enhancing manpower and
capacities of minilabs at port offices and mobile labs at CDSCO level.
Informs Dr K Bangarurajan, deputy drugs controller, DDC(I), CDSCO, "We expect to double the manpower
and enhance the lab infrastructure both at the centre and states by the end of 2017. CDSCO has also
conducted 17 training programmes to train drug inspectors on carrying out GMP inspections in the year
2013-14 to ensure quality of drugs supplied to over 200 countries from India." Talking about the increasing
global requirement for evolving regulatory compliance in regulated and unregulated markets, he stressed
on the need for uniformity of GMP inspections for supplying quality drugs globally.
"The practice of deputing drug inspectors as observers through joint inspections has been able to help draw
suggestions and feedback from our global regulatory counterparts on continuing good manufacturing
practices. It will help manufacturers in adopting global practices followed in other countries where our
medicines are consumed. Similar kind of inspections have also been carried from India to other importing
countries for the sake of ensuring quality and consistency. Countries globally are concerned about safe and
efficacious medicines to be supplied for the sake of patient safety," he added.
He further said that US FDA's workshops on GMP and CGMP compliance for the first time in four cities of
India in partnership with Central Drugs Standard Control Organisation (CDSCO) earlier this year has been
well received as over 60 pharma companies participated in the workshop. … (Source: PharmaBiz)
 India’s draft rules on patenting drugs draw mixed response
India’s latest draft rules on patenting drugs that say modifications of existing medicines can be patented
only if they show increased therapeutic value has drawn sharp reaction from international pharma
companies.
In 2006, the Madras high court had ruled that the term efficacy in Section 3(d) of India’s patent law meant
therapeutic efficacy, while rejecting a Novartis AG petition. The Swiss firm had claimed patent for its cancer
drug Glivec, which was a modified version of a previously known anti-cancer molecule called imatinib
mesylate.
Novartis lost the appeal in the Supreme Court as well, after which the patent office in August issued
guidelines enshrining therapeutic efficacy as a patent criterion for such claims.
The guidelines do not provide guidance on scope and application of Section 3(d), as it merely reiterates
existing Indian case law, according to the International Federation of Pharmaceutical Manufacturers
Association (IFPMA), a global lobby of firms that relies on drugs research.
“Therapeutic efficacy profiles are rarely available at the time of invention because these are determined
once the clinical trials are conducted,” IFPMA said in its response to the guidelines. “Therefore, such an
obligation is difficult to meet at the time of patent application.”
“The fact that ‘efficacy’ is to be construed only as ‘therapeutic efficacy’ is still problematic because it
incorporates further limitations into Section 3(d) that may be more difficult to establish,” Pharmaceutical
Research and Manufacturers of America commented.
However, Access Campaign, an initiative of non-profit Medecins Sans Frontieres that provides medical
humanitarian services, has welcomed the new criterion of efficacy but objects to the way proposed to
check for previous patents.
57
Before any patent is granted, the examiner must search and establish that the claimed invention is
unknown and no patents existed for this prior to 1995. To eliminate patent applications for pre-1995
molecules, the new guidelines direct the patent examiner to rely on the drug’s so-called international nonproprietary name (INN), which is the generic name of a drug given by the World Health Organization (WHO)
to identify the unique nature of the drug’s ingredients as the key words for online search.
“We welcome the development that revised draft guidelines on the examination of patent applications
clearly recognizes that prior art searches by examiners on compounds should also be based on the INN of
the medicine. However, the burden seems to be on the examiner and not on the applicant,” the global nonprofit organization said in its response to the latest rules. “The burden of providing INNs to which a
particular patent application relates should be shifted to those who are in the best possible position to
provide this information—the patent applicants.” … (Source: LiveMint)
 MSF urges Indian PM to stand firm against Big Pharma's patent
lobbying
As Indian Prime Minister Narendra Modi travels to the U.S. to meet with officials, Doctors Without Borders
(MSF) has one message for him: Don't back down on drug patents.
The way the medical charity sees it, India's patent-busting policies are critical to keeping med prices down.
But that's an unpopular goal with Big Pharma, which has been frustrated time and again by sales-hurting
moves in a region it's tabbed for serious growth. And MSF warned Modi that U.S. officials would try to
lobby him over those very moves.
"India's patent law and practices are favorable to public health, were put in place through a democratic
legislative process, and are in line with international trade and intellectual property rules," MSF's Meena
Narula Ahamed and Unni Karunakara wrote in an op-ed in Foreign Policy. "Every country has the right to set
policies that balance private business interests with public health needs."
But from pharma's point of view, some of India's recent patent moves have been out of line. Drugmakers
have taken issue with compulsory licenses, which allow generics producers to get to work making copies of
meds Indians can't afford--regardless of their patent status. India granted the first such license, on Bayer's
Nexavar, to Natco Pharma back in 2012, a move the German company said "damages the international
patent system and endangers pharmaceutical research."
And more could be on the way. In March, Reuters reported that an Indian committee was reviewing up to a
dozen on-patent therapies to see whether additional compulsory licenses could be issued. Ranjit Shahani,
vice chairman and managing director of Novartis' India unit, told the news service at the time that "the
constant threat of compulsory licenses hangs like a Damocles sword over patent-holders." … (Source:
FiercePharma)
DISCOVERY - DESIGN - DEVELOPMENT
 Chemists recruit anthrax to deliver cancer drugs
Bacillus anthracis bacteria have very efficient machinery for injecting toxic proteins into cells, leading to the
potentially deadly infection known as anthrax. A team of MIT researchers has now hijacked that delivery
system for a different purpose: administering cancer drugs.
“Anthrax toxin is a professional at delivering large enzymes into cells,” says Bradley Pentelute, the PfizerLaubauch Career Development Assistant Professor of Chemistry at MIT. “We wondered if we could render
anthrax toxin nontoxic, and use it as a platform to deliver antibody drugs into cells.”
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In a paper appearing in the journal ChemBioChem, Pentelute and colleagues showed that they could use
this disarmed version of the anthrax toxin to deliver two proteins known as antibody mimics, which can kill
cancer cells by disrupting specific proteins inside the cells. This is the first demonstration of effective
delivery of antibody mimics into cells, which could allow researchers to develop new drugs for cancer and
many other diseases, says Pentelute, the senior author of the paper. … (Source: MIT)
 Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a
model for peptidase activation by AAA+ partner binding and substrate
delivery
Schmitz K et Al. doi: 10.1073/pnas.1417120111
Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases
associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although
many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small
peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that
require a AAA+ partner and protein–substrate delivery or a peptide agonist to stabilize assembly of the
active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides
synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine
the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly
and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to
one ring but appear to open the axial pores of both rings, provide a foundation for rational drug
development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family
proteolysis. … (Source: PNAS)
 Global profiling of co- and post-translationally N-myristoylated
proteomes in human cells
Thinon E et Al. Nature Communications 5, Article number: 4919 doi:10.1038/ncomms5919
Protein N-myristoylation is a ubiquitous co- and post-translational modification that has been implicated in
the development and progression of a range of human diseases. Here, we report the global Nmyristoylated proteome in human cells determined using quantitative chemical proteomics combined with
potent and specific human N-myristoyltransferase (NMT) inhibition. Global quantification of Nmyristoylation during normal growth or apoptosis allowed the identification of >100 N-myristoylated
proteins, >95% of which are identified for the first time at endogenous levels. Furthermore, quantitative
59
dose response for inhibition of N-myristoylation is determined for >70 substrates simultaneously across the
proteome. Small-molecule inhibition through a conserved substrate-binding pocket is also demonstrated by
solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand
the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the
pharmacological inhibition of NMT in living cells. … (Source: Nature)
 Portola Pharma drug reverses effect of anti-clotting drugs in study
Portola Pharmaceuticals Inc said its drug met the main goal of reversing the effect of anti-coagulant drugs
in a late-stage study.
Data showed that an intravenous shot of the drug, andexanet alfa, immediately reversed the effect of
Eliquis, an anti-clotting drug by Bristol-Myers Squibb Co and Pfizer Inc.
Andexanet alfa is also being tested against Xarelto, a drug made by Bayer Healthcare and Johnson &
Johnson's unit Janssen, Portola said in a statement. … (Source: Reuters)
 Zafgen begins late-stage study of obesity drug in rare-disease
patients
A late-stage trial of a potential drug to treat obesity by Zafgen will enroll 84 adolescents and adults across
the U.S. with a rare disease known as Prader-Willi syndrome.
The trial, which kicked off today, will test the Boston-based biotech firm’s lead drug, called beloranib. CEO
Thomas Hughes explained recently that the drug works by rebalancing the ways the body packages and
uses fat, and in the process slows the mechanism by which a person feels hungry. He plans to first seek
approval in people with the generic disease called Prader-Willi, but eventually hopes to seek approval in all
people with severe obesity as an alternative to bariatric surgery.
The blinded study will randomize the patients so that some receive a placebo, while others get either 1.8
milligram or 2.4 milligram injections twice a week for a period of six months. Patients will be evaluated on
food-related behaviors, total body fat mass, and safety, and all patients who complete the study will have
the option to enter a six-month open label extension study where all participants will get beloranib. Results
are expected sometime next year. … (Source: BioFlash)
 All over for tabalumab as Lilly drug now fails for lupus
Eli Lilly is giving up on tabalumab after the drug failed in two late-stage trials, this time for lupus.
The company notes that in the ILLUMINATE 1 study, tabalumab did not achieve the primary endpoint of
statistically significant improvement on SRI-5 (a measurement of lupus disease activity and response),
compared to standard of care therapy. However, in ILLUMINATE 2, a higher dose met this endpoint, “the
first time a lupus study has achieved this efficacy measure as a primary endpoint in a Phase III trial”, Lilly
said.
Nevertheless, collectively, the data from these studies “did not meet expectations for efficacy in the
context of existing treatments”, the company noted. As such, it will not move forward with regulatory
submissions to global regulators. … (Source: PharmaTimes)
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 New wave of HER2 meds to fuel huge leap in breast cancer market
HER2-positive breast cancer treatments already do pretty well for themselves, with Roche's ($RHHBY)
Herceptin taking the No. 8 spot last year on the world's list of best-selling drugs. But according to a new
report, their sales are about to jump--big time.
As research and consulting firm GlobalData sees it, the U.S. treatment market for HER2-positive drugs is set
to leap threefold by 2023, surging from $2.41 billion last year to $7.95 billion.
"The rising incidence of HER2-positive breast cancer in the U.S., along with the significant use of premiumpriced HER2-targeting therapies in all stages of the disease, particularly the neoadjuvant and adjuvant
settings, has boosted sales of these drugs in the country," GD analyst Jamie Mallinson said in a statement.
Among the premium-priced new treatments is Roche's HER2-drug Perjeta, which recently won approval to
treat patients before surgery--that is, in the neoadjuvant setting. That was a landmark decision by the FDA,
and likely to boost its sales. Another potential sales boost: Earlier this week, new data showed that the
drug, combined with Herceptin and chemo, helped women with advanced disease live 15.7 months longer
than those treated with Herceptin and chemo alone. … (Source: FiercePharma)
 Little Esperion eyes big rivals as its cholesterol drug clears mid-stage
hurdle
Esperion Therapeutics has taken another big stride along the clinical path for its cholesterol drug. The
biotech reports that its drug ETC-1002 slashed levels of the bad cholesterol LDL, particularly when it was
combined with Merck's Zetia, in a Phase IIb trial. And now that the mid-stage program is complete, the Ann
Arbor, MI-based biotech finds itself at the threshold of a late-stage program with a drug the company feels
can thread the market needle between cheap generics and a looming wave of rival biologics.
Investors were in a cheerful mood after they saw the data, sending the company's stock up 27% in
premarket trading. They were responding to some impressive numbers. ETC-1002 by itself cut LDL levels by
up to 30%. Two doses combined with Zetia spurred a 43% and 48% plunge in LDL, with the response
typically seen in the first two weeks of treatment. And investigators tracked a reduction in C-reactive
protein, a biomarker for inflammation in coronary disease.
It's been mostly clear sailing for Esperion ever since its top executives managed to regain control of a
portfolio of molecules that had been sold to Pfizer in 2004 for $1.3 billion. It pulled off a successful IPO last
year and now has reported on two promising mid-stage studies.
Cholesterol drugs, though, have had a long and troubled history complicated by the fact that late-stage
programs require huge patient populations to prove to regulators that the drugs not only work, but that
they're safe for the huge markets they hope to cater to--making Phase III trials enormously expensive to
complete. One possible red flag: Esperion's drug has also been tapped as a potential PPAR inhibitor,
prompting the FDA to limit the dose allowed in trials and require rodent carcinogenicity studies ahead of
Phase III, according to the biotech's filings with the SEC.
While Esperion has been steadily completing a round of mid-stage efforts, rival teams from
Sanofi/Regeneron and Amgen have been racing to the FDA with positive late-stage data on their impressive
PCSK9 programs. And all of them have been touting the potential of these drugs for treatment-resistant
patients suffering from hypercholesterolemia.
That can be a tough position for a small biotech with a market cap of $376 million. … (Source:
FierceBiotech)
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 Intarcia's annual diabetes treatment aces two Phase III trials
Well-funded biotech Intarcia Therapeutics is rolling along with its ambitious plans to develop a diabetes
treatment without Big Pharma's help, posting positive results from two late-stage studies on its once-a-year
drug-device combo.
Intarcia's product, ITCA 650, is an under-the-skin minipump armed with the GLP-1 receptor agonist
exenatide--also known as AstraZeneca's Bydureon--for up to one year.
In its first Phase III trial, Intarcia enrolled 460 patients with Type 2 diabetes and blood glucose levels
between 7.5% and 10%. After 39 weeks, ITCA 650 met its primary endpoint of significantly beating out
placebo in reducing blood sugar and cleared secondary goals of weight loss and percentage of patients who
reached their goal glucose levels of under 7%. In a second, open-label study on patients with blood glucose
levels over 10%, ITCA got 25% of participants down below the 7% threshold and charted a sustained 3.4%
reduction at 9 months.
Intarcia is calling that a major victory. Current GLP-1 therapies, led by Novo Nordisk's blockbuster Victoza,
require daily or weekly injections to get diabetes down to their target blood sugar concentrations. If ITCA
650 can match its rivals on efficacy, its promise of a once-a-year procedure could disrupt the stillgrowing GLP-1 market.
The new clinical data spell a huge milestone for Intarcia, which closed a $200 million funding round in April
and has steadfastly refused to seek a partner for its top prospect. Now, according to CEO Kurt Graves, that
commitment is looking prudent.
"Many thought an emerging biotech company could never innovate enough, finance enough or execute
well enough to bring a transformational therapy through Phase III in a major disease area like Type 2
diabetes," Graves said in a statement. "But we've proven it can be done, and done well." … (Source:
FierceBiotech)
 Oncologists hail the beauty of CLEOPATRA
Research oncologists are not given to hyperbole, so when the words, “extraordinary” and “unprecedented”
are used during a scientific presentation you need to pay attention.
At the recently-concluded European Society of Medical Oncology meeting in Madrid, this is exactly how the
results for the CLEOPATRA breast cancer study on Roche’s Perjeta (pertuzumab) were described.
“Many of us work our whole career to have this kind of data,” said Sandra Swain, medical director of the
Washington Cancer Institute, and lead investigator of the CLEOPATRA study. “I’ve been doing this for about
30 years and I have to say, this is very exciting for me, and the patients I treat.”
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The purpose of CLEOPATRA was to look at combining one of the most successful cancer drugs ever created,
Roche’s HER2 receptor-targeting antibody Herceptin (trastuzumab), with Perjeta in a population of HER2positive, metastatic breast cancer patients.
“Pertuzumab binds at a different site on the HER2 receptor than trastuzumab,” said Dr Swain at a press
conference discussion on CLEOPATRA. “And both the preclinical, and then early clinical data supported the
idea of using the two together rather than sequentially.”
Over 800 patients at 204 medical centres in 25 countries participated in CLEOPATRA. Patients were
randomized in a blinded fashion to treatment with either pertuzumab plus trastuzumab and docetaxel, or
the same regimen with placebo replacing the pertuzumab.
Patients remained on therapy until their disease progressed and after a median follow up of 50 months,
data for overall survival were analyzsed.
As reported by Dr Swain, these analyses showed an improvement of 15.7 months in survival for the
monoclonal combination as compared to using just trastuzumab alone.
“The median survival for trastuzumab is already very good at 40.8 months, and that alone really changed
things for patients for HER2-positive breast cancer,” said Dr. Swain. “Adding pertuzumab increased it by
15.7 months – so to me that’s incredible. I’ve never seen that in any other trial in metastatic breast cancer.”
… (Source: PharmaTimes)
 Sanofi-Regeneron drug has positive trial results in chronic sinusitis
An experimental drug from Sanofi and Regeneron significantly reduced congestion in a mid-stage trial on
patients with chronic sinusitis with nasal polyps, a condition poorly controlled by existing drugs, the
companies said on Tuesday.
In a Phase IIa trial of dupilumab in patients who did not respond to intranasal corticosteroids, the injectable
drug brought a statistically significant reduction in the size of nasal polyps and improved other symptoms
such as congestion and sleep disruption, Sanofi said.
Dupilumab is also being tested by the drugmakers against two other allergic conditions - atopic dermatitis
and asthma. The drug was named "clinical advance of the year" in 2013 by industry publication Scrip
Intelligence, and some analysts say it could capture annual sales of up to $2 billion if approved.
Chronic sinusitis with nasal polyps causes inflammation of the mucosa and polyps in the nasal cavity and
sinuses, resulting in congestion, a reduced sense of smell and facial pain.
Patients gain limited relief from intranasal corticosteroids, the only therapy currently available. Dupilumab
works through a new approach, by blocking two proteins linked to inflammation, interleukin-4 (IL-4) and
interleukin-13 (IL-13)
Sanofi said the findings of the trial on 60 adults with moderate-to-severe disease, combined with previous
encouraging Phase II data for dupilumab in asthma and atopic dermatitis, supported evidence that these
conditions may result from a core allergic inflammatory process driven by the IL-4/IL-13 pathway.
About 30 percent of patients with chronic sinusitis with nasal polyps also have asthma, and in an
exploratory analysis, dupilumab-treated patients with both conditions also experienced significant
improvement in asthma control, Sanofi noted.
The drug's main side effects were injection site reactions, common cold, sore throat, nosebleed, headache
and dizziness. … (Source: Yahoo)
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 Experimental Cervical Cancer Vaccine Looks Promising in Trial
An experimental vaccine meant to protect against nine types of human papillomavirus (HPV) could prevent
90 percent of all cervical cancers, a new study suggests.
Researchers examined data from more than 2,500 women with precancerous cervical lesions and found
that nearly all were caused by the nine types of HPV targeted by the vaccine being developed by Merck and
Co.
The new vaccine, currently undergoing clinical trials, protects against more types of HPV than current
vaccines, according to the study published Oct. 1 in the journal Cancer Epidemiology, Biomarkers &
Prevention.
"We wanted to study how many cervical precancers could potentially be prevented by an investigational
nine-valent HPV vaccine that provides protection against the HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58,"
Dr. Elmar Joura, an associate professor of gynecology at the Medical University of Vienna in Austria, said in
a journal news release.
"Given the high vaccine efficacy that was observed in a large phase III clinical trial testing the nine-valent
HPV vaccine, if vaccination programs with this new-generation vaccine are effectively implemented,
approximately 90 percent of invasive cervical cancer cases worldwide could be prevented, in addition to
the majority of precancerous lesions," he said.
Of the women aged 15 to 26 with precancers, about one-third were infected with more than one HPV type,
the researchers said. Of women aged 24 to 45 with precancers, nearly one in five was infected with more
than one HPV type, the investigators found.
HPV, which is spread through sexual contact, not only can lead to cervical cancer, but also cancers of the
vulva, vagina and anus in women. In men, it can lead to cancers of the anus and penis.
The study was funded by Merck. Joura has received grant support to his institution, as well as advisory
board and lecture fees from Merck and other drug companies.
Joura noted that even though current HPV vaccines (Gardasil and Cervarix) are known to be safe, their use
in the United States and other wealthy nations has been "inadequate." He said the use of HPV vaccines
must increase if their full potential to reduce cervical cancer is to be achieved. … (Source: Drugs)
 Multiple Sclerosis Patients Successfully Replace Damaged Cells With
New Healthy Stem Cells; First Treatment With Placenta
Multiple sclerosis is a chronic, life-altering incurable disease, but an unprecedented treatment may have
opened doors up for a successful treatment using cells from human placenta tissues. Researchers from
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Mount Sinai designed the treatment and have found patients were able to handle the treatment, and
published their results in the journal Multiple Sclerosis and Related Disorders.
"This is the first time placenta-derived cells have been tested as a possible therapy for multiple sclerosis,"
the study’s lead author Fred Lublin, Director of the Corinne Goldsmith Dickinson Center for Multiple
Sclerosis, said in a press release. "The next step will be to study larger numbers of MS patients to assess
efficacy of the cells, but we could be looking at a new frontier in treatment for the disease."
When a patient is diagnosed with MS, an autoimmune disease that causes the body’s immune system to
attack itself and disrupt the flow of information between the brain and the rest of the body, according to
the National Multiple Sclerosis Society. More than 2.3 million please are affected by MS and while
symptoms are unpredictable and can vary greatly in severity from one person to another, it always worsens
overtime. The damaged nerve cells were repaired and tolerated by the MS person’s body successfully with
PDA-001, a group of cultured placenta cells that resemble the connective tissue found in bone marrow. A
placenta is a organ that encases the fetus inside a pregnant woman's womb, rich in oxygen and nutritents.
By using cells cultured from placentas, researchers were able to extract significantly more of these cellrepairing cells from one donor, so they could supply many patients at a time.
Researchers examined the treatment in 16 patients with MS, some had relapsing-remitting multiple
sclerosis (RRMS) and others had the more evolved version of the chronic and more debilitating condition
called secondary progressive multiple sclerosis (SPMS). Patients were between the ages of 18 and 65 and
one group was given a high dose of PDA-001, another were given a low dosage, and a third group was given
a placebo. While there is always a risk for MS to worsen once the immune system is experimented with in
cell transplants, over the six-month treatment the majority of the patients who were treated with PDA-001
had stabilized or showed improvement. … (Source: MedicalDaily)
 Regeneron's would-be blockbuster completes the allergic circle with
Phase II success
Regeneron and partner Sanofi have notched another midstage milestone with their in-development allergy
drug, a victory that affirms the hypothesis behind a treatment the companies believe could bring in billions.
The drug, dupilumab, works by blocking interleukin-4 and interleukin-13, proteins tied to inflammation. In a
Phase IIa proof-of-concept study, the injected treatment met its primary endpoint of reducing the size of
nasal polyps and hit its secondary goals of improving sinusitis, nasal air flow and patient-reported
symptoms, Regeneron said, also tamping down asthma in patients with that comorbidity.
Those results build on a previous Phase IIb in which dupilumab significantly cleared the skin of patients with
severe eczema (atopic dermatitis) and another midstage trial in which the drug substantially relieved
asthma symptoms. The string of success supports Regeneron's unified theory of dupilumab: that each of
the three diseases carries an underlying inflammatory link, and that blocking IL-4 and IL-13 can treat them
all at once, Vice President Neil Graham said.
"There is growing recognition that patients suffering from one type of allergic disease often have additional
allergic conditions" Graham said in a statement. "For example, many patients with chronic sinusitis with
nasal polyps also have asthma or atopic dermatitis and vice versa. The new data reported today, together
with prior Phase II data with dupilumab in asthma and atopic dermatitis, support the growing body of
scientific evidence that these conditions may result from a core allergic inflammatory process driven by the
IL-4/IL-13 pathway."
65
Now Regeneron and Sanofi are mounting an ambitious Phase III effort, starting with eczema before moving
on to asthma and, in light of the new Phase II results, chronic sinusitis with nasal polyps. … (Source:
FierceBiotech)
 Catalyst soars as its controversial rare disease drug aces Phase III
Catalyst Pharmaceutical Partners is heralding positive late-stage results for its lead drug, planning to make
its case to the FDA in hopes of winning approval for a much-scrutinized orphan treatment.
The drug, Firdapse, is designed to treat Lambert-Eaton myasthenic syndrome (LEMS), a rare neuromuscular
disease that gradually robs patients of their mobility. In a Phase III trial on 38 LEMS sufferers, the treatment
met its co-primary endpoints of improving physician-rated and patient-reported symptoms of the disease,
Catalyst said, significantly beating out placebo while proving safe and well-tolerated.
Now Catalyst is requesting a pre-NDA meeting with the FDA, planning to kick off a rolling submission for
Firdapse in early 2015. Last year, the biotech picked up the agency's coveted breakthrough-therapy
designation for the drug, which promises to shorten its time under review.
The news sent the biotech up as much as 20% on Monday evening, reaching a 6-year high. And, if all goes
according to plan, Firdapse would become the only FDA-approved treatment for LEMS.
However, whether that's entirely good news for LEMS patients has been the subject of some controversy.
As TheStreet's Adam Feuerstein reported last year, a family-owned outfit called Jacobus Pharmaceuticals
has been giving away doses of 3,4-Dap, a treatment similar to Firdapse, for more than 20 years. That drug
has never secured FDA approval and thus can't be sold legally in the U.S. Firdapse, if approved, could thus
demand an orphan price tag just to replace an effective treatment that's currently free, leading Jacobus to
accuse Catalyst of disguising a business opportunity as an unmet medical need.
But Catalyst CEO Patrick McEnany contends that winning approval for and launching Firdapse will
ultimately benefit the largest number of people. Jacobus' compassionate use system can't cover the
entirety of LEMS patients--Catalyst wouldn't have been able to enroll a Phase III study if it could--and,
unlike 3,4-Dap, his company's drug would have gone through the rigors of FDA review, he told Feuerstein in
October 2013. … (Source: FierceBiotech)
 No benefit for TKI use after lung cancer progression
Results of IMPRESS, a lung cancer study presented at the European Society of Medical Oncology in Madrid
last week, suggest that the common practice of continuing treatment with epidermal growth factor
receptor tyrosine kinase inhibitors (TKIs) beyond disease progression is misguided, and needlessly
expensive.
“IMPRESS is not so impressive,” reported study investigator Tony Mok of the Chinese University, Hong
Kong. At first glance, the idea of continuing TKIs beyond progression is counter intuitive; after all, disease
66
progression indicates that the patient has developed resistance to the therapy. “Almost all patients with an
initial response to an EGFR TKI eventually develop acquired resistance,” said Dr Mok.
However, as a number of past investigations have suggested, stopping these targeted agents after disease
progression can actually make matters worse due to the so-called, flare phenomenon, whereby the tumor
comes roaring back to life after treatment discontinuation, rather than continuing to exhibit the indolent
growth of treatment-resistant tumor cells.
In order to establish a treatment standard in this setting, IMPRESS recruited 265 patients with non-small
cell lung cancer who were experiencing disease progression after treatment with AstraZeneca’s TKI Iressa
(gefitinib). Patients were randomised to treatment with gefitinib plus cisplatin and pemetrexed, or the
doublet alone. … (Source: PharmaTimes)
 Positive PhIII PONV study brings little Acacia to a crossroads
Acacia Pharma says it gleaned positive results from a Phase III study of its experimental therapy designed to
prevent postoperative nausea and vomiting (PONV). And now it's brought in the investment banker J.P.
Morgan Cazenove to advise the board on what its next steps should be as it tries to position the treatment
for regulatory approval and commercialization.
In the study, the Cambridge, U.K.-based biotech says it tracked a 19.4% risk reduction in PONV, a sharp
plunge from the results seen in earlier, and much smaller, studies sponsored by Acacia. CEO Julian Gilbert,
though, says he wasn't surprised by the drop, which reflects similar fluctuations in related late-stage trials.
There are already a couple of different remedies available for these patients, he adds, but high-risk patients
in danger of failing those treatments are in need of a third option--which is where Acacia sees an
opportunity. And rather than shoot for a quick regulatory OK, with its primary focus on the U.S. market,
Gilbert wants to pursue some additional trial work ahead of a filing in order to get some information in the
label that will help position the drug.
"We will be doing a study looking at the efficacy of our drug in combination with current anti-emetics, and
one or two looking at our drug as a rescue treatment following failure of a prophylactic," says Gilbert, who
counts himself as quite pleased by the fact that Acacia got through Phase III on its own while pushing a
pipeline with 4 programs.
But first, the company--which has a lean-and-mean virtual staff of three full-timers and several part-time
workers--has to make some decisions on funding.
"We don't have the money to take those programs through to the market," says the CEO, "but we do have
supportive investors. We have started working with strategic advisers on which route we want to go
down."
Just about everything is on the table right now, he adds. They could sell the company, perhaps file an IPO,
raise more cash or execute a licensing pact. … (Source: FierceBiotech)
 Exploiting CRISPR-Cas nucleases to produce sequence-specific
antimicrobials
Bichard D et Al. Nature Biotechnology (2014) doi:10.1038/nbt.3043
Antibiotics target conserved bacterial cellular pathways or growth functions and therefore cannot
selectively kill specific members of a complex microbial population. Here, we develop programmable,
sequence-specific antimicrobials using the RNA-guided nuclease Cas9 (refs.1,2) delivered by a
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bacteriophage. We show that Cas9, reprogrammed to target virulence genes, kills virulent, but not
avirulent, Staphylococcus aureus. Reprogramming the nuclease to target antibiotic resistance genes
destroys staphylococcal plasmids that harbor antibiotic resistance genes3, 4 and immunizes avirulent
staphylococci to prevent the spread of plasmid-borne resistance genes. We also show that CRISPR-Cas9
antimicrobials function in vivo to kill S. aureus in a mouse skin colonization model. This technology creates
opportunities to manipulate complex bacterial populations in a sequence-specific manner. … (Source:
Nature)
 Alcobra says its ADHD drug works--as long as you don't compare it to
placebo
Alcobra is touting the benefits of its in-development ADHD treatment, saying the drug provided a
statistically significant benefit over placebo--but only after the company removed data from four "extreme"
responders from its analysis. Investors were unconvinced by the modified results, however, sending the
biotech's shares down nearly 50% on Monday morning.
The company's lead drug is metadoxine (MDX), a nonstimulant GABA modulator the company bills as free
of the abuse potential that plagues other treatments for ADHD. In a Phase III trial on 300 adult patients, the
drug improved symptoms of the disorder among patients in the treatment arm, but whether it can be said
to have significantly topped placebo is the subject of some controversy.
In full results from all 300 patients, MDX "yielded a positive trend" versus placebo, notching a p value of
0.15--well short of the industry standard 0.05 threshold for statistical significance. However, if you remove
four placebo patients who fared particularly well in the trial--as Alcobra did in a post hoc analysis--the p
value comes down to a healthy 0.03, and the company is confident the results from its modified intent-totreat (mITT) population best reflect MDX's true potential.
"We conducted the mITT analysis after observing the disproportional effect of a few extremely large
placebo responses which were inconsistent with what has been reported in previous ADHD trials of MDX or
other agents," Alcobra Chief Medical Officer Jonathan Rubin said in a statement. "We plan to take the
complete findings of this and other MDX studies to the FDA to determine the next steps on the path to
potential regulatory approval for MDX." … (Source: FierceBiotech)
 Seattle Genetics and Takeda's cancer drug meets main trial goal
Seattle Genetics Inc and Takeda Pharmaceutical Co Ltd said their approved cancer drug was successfully
used as a consolidation therapy in a late-stage trial for patients with a type of lymphatic cancer.
Consolidation therapy kills any cancer cells that may be left in the body after initial therapy.
Patients who received the drug, Adcetris, immediately after a stem cell transplant, lived significantly longer
without the disease progressing than those who were given a placebo, the companies said in a joint
statement.
The late stage trial compared Adcetris to a placebo in patients at risk of relapse of Hodgkin lymphoma.
Seattle Genetics said it expected to submit a marketing application to FDA for the drug's supplemental use
in 2015.
The late-stage trial is currently being conducted in the United States, Eastern and Western Europe and
Russia.
Seattle Genetics holds the marketing rights for Adcetris in the United States and Canada, while Takeda will
market the drug in the rest of the world.
68
Adcetris is currently approved in 45 countries for the treatment of relapsed Hodgkin lymphoma and
systemic anaplastic large cell lymphoma, another type of cancer. … (Source: Reuters)
69
Le Cabinet WHITE-TILLET est enregistré pour la formation et agréé
pour le Crédit Impôt Recherche (lorsque les prestations le justifient)
70
Experience & Expertise
Associate Consultants & Experts
Tel : + 33 1 600 843 85
E-mail : [email protected]
Website: www.white-tillet.com
Pour abonner vos ami(e)s écrire à : [email protected]
Pour vous désabonner écrire à : [email protected]
71

Friday October 10, 2014 (SW41 2014) NEWS WORLDWIDE EUROPEAN UNION

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