International Drug Safety Landscape: Challenge and an Opportunity

International Drug Safety Landscape:
Challenge and an Opportunity for Change
An industry overview and update on recent
developments
Rebecca Wang MD
MD, FRCP
FRCP, FACC
FACC,
Head, Regional Center, Asia Pacific, Shanghai, China
Pharma Development, Drug Safety Operation, Roche
N E O S
New Er a of Safet y
Industry Under Fire
Over Product Safety Concerns
Exanta
Zyprexa
yp
Accomplia
Avandia
N E O S
New Er a of Safet y
Accutane Torcetrapib
Ketek
Baychol
Tysabri
Galvus Vioxx
Zelnorm
Palladone PlasugrelGalida Oxycontin
Epogen
2/22
Presentation Outline
• Factors and forces driving a paradigm shift and
conceptual change
– Internal pressure by threats to commercial success of Pharma products
– External pressures by consumers and health authorities
• Opportunities for Industry Response
change
to the challenge of
– Overview of strategic & regulatory developments impacting drug safety in
– USA and European Union
– Risk management plan (RMP)
– Personalized health care
– Collaboration for advances in DS management across industry
• Roche Action PlanPlan New Era of Safety (NEOS)
N •EConclusions
O S
New Er a of Safet y
3/22
Increased Pressure by Threats to
C mm r i l Su
Commercial
Success off Ph
Pharma
rm
Medicines
The number of drug withdrawals
has been increasing . . .
. . . each of which results in significant revenue
loss
Annual number of drug withdrawals
Major drug withdrawal events in recent years
in U.S./E.U.
14
Company
Drug name
Estimated revenue loss
11
10
Merck
Vioxx
Pfizer
Bextra
2,5001
1,300
800
Pfizer
6
6
5
1
2002 03
04
05
06
1 Only 2003 revenue loss estimation
07 2008
Rezulin
Zomax, Suprofen,
J&J
Hismanal,
NNovartis
i Propulsid
Z l
Zelnorm
Seldane
Aventis
(Hoechst)
Bayer
Baycol
Pondimin, Redux
AHP
(Wyeth), Duract
450
290
241
233
Financial analysts are increasingly becoming
sensitive to news of product safety issues and drug
withdrawal
N SOURCE:
E O
S
FDA website; EMEA website; IMS Midas Dataview; Literature search; team analysis
New Er a of Safet y
667
4/22
Increased Pressures
f
from
Global
Gl b l Health
H l h Authorities
A h i i
Post marketing safety requirements
Post-marketing
have grown . . .
. . . as have black box label changes
Percent of NMEs approved with post-marketing
Number of safety label changes
commitments (PMC)
involving a boxed warning
91
In addition, the
size and cost of a
typical PMC program
h grown
has
dramatically
73
77
77
62
66
54
48
33
25
1970 1985 1987 1993 2003 2006
1984S 1986 1993 2003 2005 2007
O
20
2003
2004
N SOURCE:
E Tufts Center for the Study of Drug Development (2004); FDA MedWatch; The RPM Report; Parexel
New Er a of Safet y
2005
2006
2007
5/22
Stringency of
Gl b l HHealth
Global
l h AAuthorities
h i i
• U.S. regulatory environment is more stringent with
greater pre and post-marketing requirements, higher
hurdles for approval and increasing risk management
requirements.
i
• E.U.
E U regulatory environment is also evolving with
more stringent regulation of pediatric products,
increasing focus on risk management and move toward
greater transparency
N E O S
New Er a of Safet y
6/22
External Pressures on
Gl b l HHealth
Global
l h AAuthorities
h i i
Public
Patient
advocacy
groups
Media
Government/
legislation
KOLs/
prescribers
Payors
Health
authorities
N E O S
New Er a of Safet y
7/22
Collaboration of HA
GMP inspections
i
i
Clinical trial oversight
Anti counterfeit initiati
• Global communication increasing,
especially on safety issues and
labeling
• Control beyond geographical boundaries
on clinical trial oversight and GMP
inspections; FDA offices in multiple
N SOURCE:
E O
S
EMEA website; Food & Drug Letter, September 26, 2008; USTR website
New Er a of Safet y
countries
8/22
Paradigm Shift
i Safety
in
S f
MManagement
• From Reactive to Proactive and anticipatory (detecting
risks, to predicting risks)
• Integrate the potential and identified risks and
cumulative safety knowledge from preclinical and
clinical studies
• Apply the learnings and safety expertise from
postmarketing safety to early development safety
• Move from regular re-assessment of benefit / risk for
drugs already on the market to identification of drugs
with acceptable benefit/risk prior to their introduction
on the
th market.
k t
N E O S
New Er a of Safet y
9/22
A Major Conceptual Change
N E O S
New Er a of Safet y
10/22
Recent and Future US
Legislation
• Recent US Legislation
– FDAAA passed in 2007 and effective in 2008
– The most comprehensive revision bringing sweeping safety
reforms
f
with
ith emphasis
h i on Risk
Ri k evaluation
l ti andd mitigation
iti ti
strategy (REMS)
• Future US Legislation
g
– Food and Drug Globalization Act
– Would require sponsors to pay for FDA inspections
– Addresses
Add
counterfeiting
t f iti
– Comparative Effectiveness
• Would require review of evidence and production of new
information to determine which treatments and products
achieve the best clinical outcomes for patients
N E O S
New Er a of Safet y
11/22
Recent and Future EU
Legislation
• Recent EU Legislation
– RMP :
• Introduced in 2005 to ensure that the benefits of a particular
medicine exceed the risks.
– Pediatric Investigation Plan (PIP)
• Introduced in 2007; Development
p
pplan to assess the safety
y and
efficacy of pharmaceuticals in pediatric patients
– Penalties Regulation 2008
• Fines for non
non-compliance
compliance with conditions of marketing
authorisation, including commitments
• Future EU Legislation
g
– EU Pharmaceutical Package
• A communication and 3 legislative proposals (Patient Information,
Pharmacovigilance and Counterfeit Medicines) adopted in 2008
N E O S
New Er a of Safet y
12/22
RMP throughout
Product life cycle (1)
• Limitations
Li it ti
of
f clinical
li i l ttrial
i l ddata
t
– Selected population (demographics, co-morbidities, concomitant
medications)
– Limited sample size and duration of follow up
– Educated investigators, informed patients, rigorous monitoring in a
studyy environment
• RMP with rigorous pharmacovigilance program for earlier
detection of safety signal and institution of appropriate
action to protect patient safety
– Rare, idiosyncratic SADRs from spontaneous AE reporting after extensive
market
k exposure e.g. acute liver
l
failure
l
withh Rezulin
l
– Complex SADRs from post-marketing pharmacoepidemiology study/clinical
observational studies or clinical trials e.g. Increase in CV events
which are common in the target population with Vioxx & Avandia
N E O S
New Er a of Safet y
13/22
RMP throughout
product life cycle (2)
• Although submitted usually during approval, RMP is to be
developed early in clinical development and throughout
the product cycle to protect patient safety, with the
following essential components:
– A pharmacovigilance
h
i il
plan
l
ffor early
l ddetection
t ti of
f new risk
i k
(potential risk and missing information) or change in the
severity & frequency of known risk
– A risk mitigation plan to minimize all known and potential risks
associated with the use of the drug
– Ongoing assessment of the effectiveness of the risk mitigation
plan with modifications if required
– FDA REMS for a drug or biologic must include: a timetable for
submission
b
of assessments – annually
ll for the
h first 3 years,
N E Owith
S overall assessment at 7 years & failure to comply leads to
14/22
New Er a of Safet
y
misbranded
product/penalty
Maximizing Industry/Regulatory
Agencies Collaboration on RMP
Product knowledge resides within the pharmaceutical company
(a full function team of scientists/physicians)
Regulatory
g
y agencies
g
have unique
q access into confidential safety
y
information, both developmental and postmarketing safety data, of
similar class of drugs not available to the public and therefore can
provide
id valuable
l bl advice
d i to the
h d
development
l
off RMP and
d critical
ii l
review of the post marketing pharmacovigilance program
Close collaboration between regulatory agencies and
pharmaceutical
p
a aceut ca co
companies
pa es is
s mandatory
a dato y in de
development
e op e t o
of a
an
appropriate RMP
N E O S
New Er a of Safet y
15/22
The benefit risk ratio and expanded
capabilities are driving further
changes
Healthcare Pressures:
Economic Pressures:
New Technologies:
g
Benefit-Risk Ratio
Benefit-Cost Ratio
Expanded Capabilities
N E O S
New Er a of Safet y
16/22
Industry Opportunity:
Developing Safer and More
Effective Drugs
g
Drug Response Rate in percentage
Analgesics
Efficacy
80
Safety
GSK
Sanofi Aventis
60
Novartis
Cancer
40
Bayer
20
Novartis
0
N 1 Spears
E etOal.,STrends Mol Med, 2001; 2 Lazarou et al., JAMA, 1998
New Er a of Safet y
17/22
Industryy Opportunity:
pp
y Improve
p
B
/R through use of Molecular
Genomics Proteomics
G
Genomics
i
P
i
DNA
Target
• Wh
What
t information
i f
ti iis stored
t
d iin a
biological system?
SNPs
(Single nucleotide
polymorphisms)
Proteins
• Wh
What
t pieces
i
of
f stored
t
d iinformation
f
ti
are being expressed at a given
timepoint?
DSPs
vs.
(Disease-specific proteins)
• Predisposition
p
• Small changes in a persons DNA
(SNPs) can predict onset of
disease
• Which proteins are present in
present
health and which ones are p
in disease
• Patient stratification (e.g.,
AmpliChip CYP450)
• How effectively will a drug be
N E
O S ?
metabolized
New Er a of Safet y
18/22
Industryy Opportunity:
pp
y Developp
highly Differentiated Medicines
Healthcare Pressures:
Economic Pressures:
New Technologies:
Benefit-Risk Ratio
Benefit-Cost Ratio
Expanded Capabilities
Need for highly differentiated medicine
that impact positively public health
Payors will reward innovation
N E O S
New Er a of Safet y
19/22
Personalized Healthcare
C d l
Co-development
off companion
i diagnostic
di
i
tools
Marker /
Replace(d)
Drug
Indication
Technology
MDM2
GA201
N E O S
New Er a of Safet y
Gastric Cancer
Breast Cancer
HER2 FISH & IHC
NSCLC
EGFR FISH
EGFR IHC
EGFR Mutation PCR
Hepatitis B
qHBsAg -ELISA
Advanced Solid
Tumors
MDM2 FISH
Advanced
M li
Malignant
EGFR+ Solid
Tumors
EGFR IHC
KRAS – Mutation
PCR
Test/Assay
20/22
Identifying Patient
Subgroups at Risk: SAEC)
• An International Industrial Biomedical Consortium
Creating an Understanding of the Genetic Basis of
Related SAE
T
o
p
57
S
Drug
A
Es
S
E pD
U aIL
Extern
Dal niI
R sG
Collabo
A
rators/
hE
G DN
Contrib
E IL
utors
N I
E
• Quote from Janet Woodcock Director of the FDA’s CDER
– Drug induced serious adverse events are the major cause of
failure of both new drugs underdevelopment and approved drugs
which are withdrawn from the market
market. Any effort to improve
pharmaceutical company productivity must reckon head on with
this reality”
• The SAEC will identify and validate DNA-variants useful
in predicting the risk of drug induced serious adverse
events. All data will be made available to researchers
N Efree
O S
of charge and IP constraints.
New Er a of Safet y
21/22
SAEC’s Membership
Spanish DILI
EUDRAGENE
DILIGEN
Top 5-7
5 7 SAEs
External Collaborators/Contributors
N E O S
New Er a of Safet y
22/22
How is Roche leading in this
environment
New Er a of Saf et y
N E O S
New Er a of Safet y
23/22
Mission of NEOS
We enhance healthcare for patients by
understanding
d t di andd communicating
i ti th
the safety
f t
profile of our medicines to optimise their
b fit risk
benefit
i k profile
fil
1. Understanding our drugs from a benefit-risk
perspective at the individual patient level
2. Communicatingg with all stakeholders on the benefitrisk profile of our medicines throughout the life
cycle
3. Protecting patients, their health care providers, and
the company
NN EE O
O S
S
New
aa ofof Saf
et yy
NewErEr
Safet
24/22
Safety Tools and Processes
Understand
Communicate
Protect
B
Benefit/Risk
fit/Ri k
Integrated
safety risk
management
Signal detection
Single case &
aggregate
reporting
Integrated Safety Management Plan (ISMP)
NN EE O
O S
S
New
aa ofof Saf
et yy
NewErEr
Safet
25/22
B/R Statement based on MOA
B/R data-driven: qualitative
B/R data-driven:
d
d i
quantitative
i
i
EiGLPtox
B
R*
Target
Selection
Approval
EIM
B
R*
Pre-Clinical
Development
B
R*
Clinical
Development
Phase I
B
R*
B
R*
Clinical
Development
Phase II
Clinical
Development
Phase III
PostApproval
Phase IV
Mature
Products
L b l
Label
Target Product Profile
Key Claims
CDS
IB
*: Milestones for formal
B/R review
Patient Informed Consent
Protocols and CSRs
Regulatory documents
with B/R section
(Clinical Study Reports)
ISMP
Core RMP
RMP / REMS
NDA
License Renewals
SUSARs , SAEs , Drug Safety Reports
, PSUR
,
,ASR, QSR
Signal detection
N E EO O
N
S
S
NewEr aErofa Saf
ofet ySafet y
New
26
26/22
Benefit/Risk Decision ?
• Collaborative effort among Clinical &
Regulatory
Safety &
• Data (comprehensive) – driven
• Qualitative & quantitative
•T
To be
b started
t t d ASAP (phase
( h
II) as it will
ill
influence the design, sample & endpoints of
phase III
NN EE O
O S
S
New
aa ofof Saf
et yy
NewErEr
Safet
27
27/22
Drug Safety Science Review
N E O S
New Er a of Safet y
28/22
Drugg Safetyy Committee:
Single Company Voice
• Corporate Governance role
• Medical
M di l expertise
ti
prevails
il over ffunctional
ti
l
representation & status
• From everywhere in the organization
• Organ-system safety expert groups: represented in
DSC, associated with external expert group,
recommendations,
d i
may bbe consulted
l d bby teams
NN EE O
O S
S
New
aa ofof Safety
NewErEr
Safet y
29
29/22
Drug Safety Decision-Making
C t li d via
Centralized
i Drug
D
Safety
S f t
Committee
6.
Expert Oncology
7.
Expert Hepatology
8.
Experts CVS
9.
Expert Renal
10.
Expert
p
Immunology
gy
11.
Escalation
RRT
DSC
LCT/DBA
/
Other
HA
Affiliates
New
Er a
Safety
New
Er of
a of
Safet y
2.
Head
d Safety Riskk
Management & EEA QPPV
3.
Global Head Regulatory
4.
Gl l Head
Gloal
d DSC
SC OOffice
i
Urgent Safety
Issues & Crises
Non-urgent
safety issues
1
CMO/ Global Head
Development
PEC
Non-clinical
Safety Experts
NN EE OO SS
1.
RRT: Rapid Response Team
2
LCT:
Drug Safety
Units
LifeCycle Team; DBA: Disease Biology Areas
30/22
Achieving a stable balance
Safety Science
Safety Operations
BENEFIT/RISK
ASSESSMENT &
COMMUNICATION
DISCIPLINE IN
AFFILIATE DRIVEN
STUDIES
RISK MITIGATION
REGULATED DOCUMENTS
& SOPs
SIGNAL DETECTION
REGULATORY REPORTING
MEDICAL EVALUATION
ADVERSE EVENT PROCESSING
N E O S
New Er a of Safet y
31/22
Conclusion- Response to change
and many others……….
• Safety science combines a growing understanding of the disease and its
origins at the molecular level with an understanding of adverse events
resulting from treatment.
• NNew methods
h d of
f signal
i
l ddetection,
i
ddata mining
i i
and
d analysis
l i will
ill enable
bl
researchers to generate hypotheses about, and confirm the existence and
causal factors for, safety risks for patients.
• Personalized medicine will focus on the generation of information about
the unique genetic and biologic features of individuals (or defined
subgroups)
b
) th
that
t will
ill hhelp
l iin ffuture
t
tto bbetter
tt
predict
di t th
their
i response tto
and risks of treatment.
• Great strides have been made in developing and implementing electronic
standards and new systems for managing health information that will
allow multiple collaborators to create and share the successes of
Safety Sciences in the future
future.
N• Improving
E O S benefit/risk analysis is one of the most important facets of
the Safety Sciences that urgently requires additional development.
New Er a of Safet y
32/22
Conclusion- Personalised Healthcare
E
Every
goodd therapy
th
starts
t t with
ith a goodd
diagnosis
Personalised Healthcare: Use of new molecular insights and molecular
diagnostic tests to better tailor medicines and better manage a
patient’s disease
Molecular diagnosis
Still today, almost all patients are
treated
in a few similar ways
• Only 25-80 % of patients receive effective
treatment1
• >100.000 deaths / yr from adverse drug
Nreactions
E O inS US2
New Er a of Safet y
Increasingly, treatment will
be tailored to selected
patient groups defined by
molecular markers
33/22
Conclusion - Drug Safety
Sciences
• Drug Safety Scientists need to be an integral partner in
the development process from bench to bedside and back
• Th
The knowledge
kn l d
and
nd understanding
und r t ndin off Drug
Dru Safety
S f t Sciences
S i n
(e.g., Epidemiology, Signal Detection, and Risk Management)
must be firmly embedded into product lifecycle management
• Information resources will need to be expanded to address
the needs of the new development paradigm
– Integration of data from a variety of sources, currently non-compatible
data types
– Integration of genetic, genomic and metabolomic data sets as early as
possible
– Better drugg safetyy modelingg and simulation capabilities
p
“Integration of Pre-clinical, Clinical and Post-marketing Safety Data”, Philip MacLaughlin;
NEmerging
E Safety
O Science,
S Silver Spring, MD April 23-24, 2007
New Er a of Safet y
34/22
Conclusion
T il d AApproaches
Tailored
h
• Stronger interface between disease
biologists, early development
colleagues
g
and drug
g safety
y
• Early and effective epidemiological
analyses which promote greater
understanding
d
t di of
f di
disease and
d it
its
treatment.
• Earlyy risk detection based on a
holistic approach will integrate
non-SAE data and information to
predict serious events
• Safety expertise for disease
understanding in biomarkers and
personalized healthcare,
medicine
N translational
E O S
New Er a of Safet y
Stratification and
Personalized
H lth
Healthcare
• Integrated
g
safety
y management
g
throughout product lifecycle in
a “high value partnership”
with internal and external
stakeholders
• Different expertise and skills
d d for safety in early
l
sets needed
and late development phases,
which will increase skill set
and educational costs
35/22
When the wind of change blows
Some build walls, others build windmills
N E O S
New Er a of Safet y
36/22
Wee Innovate
ovate Healthcare
ea t ca e
N E O S
New Er a of Safet y
37/22