finding the needle in the haystack just got easier.
Transcription
finding the needle in the haystack just got easier.
ADVERTISEMENT APRIL/MAY 2016 FINDING THE NEEDLE IN THE HAYSTACK JUST GOT EASIER. CALL TO LEARN MORE ABOUT OUR SIMPLIFIED PATIENT RECRUITMENT PROCESS. The Americas +1.888.COVANCE | Europe/Africa +00.800.2682.2682 Asia Pacific +800.6568.3000 | Or go to covance.com Covance Inc., headquartered in Princeton, NJ, USA, is the drug development business of Laboratory Corporation of America Holdings (LabCorp). COVANCE is a registered trademark and the marketing name for Covance Inc. and its subsidiaries around the world. © Copyright 2016. Covance Inc. N E SU ta IS a T e/D ion EX urc rat o g eS Inte Volume 25 Number 4/5 Volume 25 Number 4/5 April/May 2016 YOU R P EER -R E V IE W ED G U IDE TO G L OBA L C L INICA L T R I A L S M A NAGEM EN T appliedclinicaltrialsonline.com 1992–2015 th th 24 ce ACT Year of Ser v i Precision Medicine Precision Medicine A PPLIED C LINICAL T RIALS BIOSIMULATION BLUEPRINT: PEDIATRICS VALUE-BASED PLANNING, EXECUTION TARGETED DRUGS: EARLY-PHASE GUIDE TRIAL DESIGN CRO/SPONSOR MASTERING IMMUNOTHERAPY TRIALS ALSO IN THIS ISSUE: ■ Europe’s Data Disclosure Debate ■ Fixing Protocol-Amendment Burden ■ The Keys to Precision Medicine April/May 2016 An experienced team that listens? That would be unique. When you partner with Spectra Clinical Research, you get more than just a central laboratory with state-of-the-art facilities and the capacity to support thousands of tests daily. You get a dedicated team of project managers, research scientists and service specialists who are ready, willing and able to align with your processes and deadlines, so you get the personalized service—and reliable outcomes—your unique trial deserves. www.spectraclinicalresearch.com © 2016 Fresenius Medical Care Holdings, Inc. All rights reserved. Spectra Clinical Research is a division of Spectra Laboratories, Inc. APPLIED CLINICAL TRIALS Editorial Advisory Board Moe Alsumidaie Thought Leader and Expert in the Application of Business Analytics Towards Clinical Trials and Healthcare New York, NY Kiran Avancha, PhD, RPh Chief Operating Officer HonorHealth Research Institute Scottsdale, AZ Townsend N. Barnett, Jr. Vice President, Global Head of Pre-Clinical and Clinical QA UCB Pharma S.A. Chemin du Foriest, Belgium Maarten Beekman, MD Vice President, Medical & Regulatory Affairs AstraZeneca Zoetermeer, Netherlands Timothy Callahan, PhD Chief Scientific Officer Biomedical Systems Saint Louis, MO Anthony J. Costello Chief Executive Officer Mytrus, Inc. San Francisco, CA Domenico Criscuolo, MD, PhD, FFPM Chief Executive Officer Genovax Colleretto Giacosa, Italy Srini Dagalur, PhD Specialist Leader, Life Sciences Technology Strategy Deloitte Parsippany, NJ Edward Stewart Geary, MD Chief Medical Officer & Vice President Eisai Co., Ltd. Tokyo, Japan Ashok K. Ghone, PhD VP, Global Services MakroCare 1 Washington Park, Suite 1303 Newark, NJ 07102 Rahlyn Gossen Founder Rebar Interactive New Orleans, LA Uwe Gudat, MD Head of Safety, Biosimilars Merck Serono Geneva, Switzerland Editorial Offices Ira M. Katz Consultant Insigniam Narberth, PA Wayne Kubick Chief Technology Officer Health Level Seven International Chicago, IL Darshan Kulkarni, PharmD, Esq Principal Attorney The Kulkarni Law Firm Philadelphia, PA Michael R. Hamrell, PhD, RAC President MORIAH Consultants Huntington Beach, CA Erica J. Heath, CIP, MBA President Ethical and Independent Review Services, LLC San Anselmo, CA Patricia E. Koziol, PhD President PEK Associates, Inc. Holmdel, NJ Jeffrey S. Litwin, MD Chief Scientific and Strategic Consultant ERT Philadelphia, PA VIcky Parikh, MD, MPH Executive Director Mid-Atlantic Medical Research Centers Hollywood, MD Timothy Pratt, PhD, MBA Senior Principal Medical Research Manager NAMSA Minneapolis, MN Stephen Senn, PhD Head of Competence Center for Methodology and Statistics CRP-Sante Strassen, Luxembourg Johanna Schenk, MD, FFPM Managing Director and Chief Operating Officer PPH plus GmbH & Co. KG Frankfurt am Main, Germany Philippa Marshall, MB ChB, BSc, FFPM, FICR 1st Vice President, Global Therapeutic Head, General Medicine PPD Laren, The Netherlands Thomas Sudhop, MD Director and Professor Federal Institute for Drugs and Medical Devices Bonn, Germany The expertise of Editorial Advisory Board members is essential to the credibility and integrity of Applied Clinical Trials. These clinical trials experts share with the editors the wisdom gained through their experience in many areas of drug development. EAB members review manuscripts, suggest topics for coverage, and advise the editors on industry issues. All manuscripts must first be submitted to the Editor-in-Chief, Applied Clinical Trials, 485 Route 1 South, Building F, Second Floor, Iselin, NJ 08830 USA. April/May 2016 485 Route 1 South, Building F, Second Floor, Iselin, NJ 08830 USA +1 (732) 346-3080 fax: +1 (732) 647-1235, www.appliedclinicaltrialsonline.com EDITOR-IN-CHIEF Lisa Henderson, [email protected] MANAGING EDITOR Michael Christel, [email protected] ART DIRECTOR Dan Ward, [email protected] EUROPEAN EDITOR Philip Ward, [email protected] PO Box 114, Deeside CH5 3ZA, UK +44 1244 538 583 WASHINGTON EDITOR Jill Wechsler +1 (301) 656-4634 fax: +1 (301) 718-4377 Sales Offices VICE PRESIDENT OF SALES/GROUP PUBLISHER Michael Tessalone 485 Route 1 South, Building F, Second Floor, Iselin, NJ 08830 USA (732) 346-3016. fax: (732) 647-1235, [email protected] DIRECTOR OF ADVERTISING Wayne K. Blow UK: +44 1244 629 304 fax: +44 1925 732 798, [email protected] EAST COAST SALES MANAGER Laurie Marinone +1 (508) 808-4723 fax: +1 (508) 675-0964, [email protected] NATIONAL SALES MANAGER Bill Campbell +1 (847) 283-0129 fax: +1 (847) 282-1456, [email protected] ADVERTISING SALES COORDINATOR Joanne Capone +1 (732) 346-3031 fax: +1 (732) 596-0012, [email protected] ACT CHESTER UK OFFICE: +44 1244 393 100 Marketing Services CLASSIFIED DIRECTORY SALES & EMPLOYMENT OPPORTUNITIES ADVERTISING Tod McCloskey +1 (440) 891-2793, fax: +1 (440) 756-5271, [email protected] AUDIENCE DEVELOPMENT MANAGER Rochelle Ballou (218) 740-7005, [email protected] C.A.S.T. DATA AND LIST INFORMATION Ronda Hughes (218) 464-4430, [email protected] PERMISSIONS/INTERNATIONAL LICENSING Maureen Cannon +1 (440) 891-2742 fax: +1 (440) 891-2650, [email protected] REPRINTS 877-652-5295 ext. 121/ [email protected] Outside US, UK, direct dial: 281-419-5725. Ext. 121 SUBSCRIPTIONS +1 (888) 527-7008 (toll-free within USA) +1 (218) 740-6477 (outside USA), [email protected] BACK OR CURRENT ISSUES +1 (800) 598-6008, +1 (218) 740-6480 (outside USA) Production Offices PRODUCTION MANAGER Karen Lenzen Advanstar Communications, 131 W. 1st Street, Duluth, MN 55802 USA +1 (218) 740-6371 fax: +1 (408) 962-1125 ACT’s Clinical Project Managers Committee Kenny Blades, PhD Senior Project Director PRA Health Sciences Reading, UK María Proupín-Pérez, PhD, PMP Project Leader PPH plus GmbH & Co. KG Germany Yakov Datsenko, MD Senior Clinical Research Physician Boehringer Ingelheim Pharma GmbH & Co. KG Germany Denise Sackner Director Project Management Standards Group PPD Brooke Derby, MBA, MS Associate Director BioDevelopment Operational Excellence Global Project Manager UCB Biosciences Inc. Raleigh, NC APPLIED CLINICAL TRIALS (Print ISSN: 1064-8542, Digital ISSN: 2150-623X) is published 6 times a year as combined issues in Feb/March, Apr/May, Jun/July, Aug/Sept, Oct/Nov, Dec/Jan by UBM Life Sciences 131 West 1st Street, Duluth, MN 55802-2065. Subscription rates: $70 for 1 year (12 issues), $120 for 2 years (24 issues) in the United States and possessions; $90 for 1 year, $140 for 2 years in Canada and Mexico; all other countries $130 for 1 year, $235 for 2 years. Single copies (prepaid only): $9 in the United States and possessions; $11 in all other countries. Add $6.50 per order for shipping and handling. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to APPLIED CLINICAL TRIALS, P.O. Box 6115, Duluth, MN 55806-6115. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: IMEX Global Solutions, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian G.S.T. number: R-124213133RT001. Printed in the U.S.A. ©2016 UBM. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/ educational or personal use of specific clients is granted by UBM for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://www.copyright. com online. For uses beyond those listed above, please direct your written request to Permission Dept. fax 440-756-5255 or email: [email protected]. UBM Americas provides certain customer contact data (such as customers’ names, addresses, phone numbers, and e-mail addresses) to third parties who wish to promote relevant products, services, and other opportunities that may be of interest to you. If you do not want UBM Americas to make your contact information available to third parties for marketing purposes, simply call toll-free 866-529-2922 between the hours of 7:30 a.m. and 5 p.m. CST and a customer service representative will assist you in removing your name from UBM Americas’ lists. Outside the U.S., please phone 218-740-6477. Applied Clinical Trials does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take responsibility for any losses or other damages incurred by readers in reliance of such content. To subscribe, call toll-free 888-527-7008. Outside the U.S. call 218-740-6477. appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 3 CONTENTS APPLIED CLINICAL TRIALS VOLUME 25, N UMBER 4/5 COVER STORY How Biosimulation Can Predict Drug Success COMSTOCK/GETTY IMAGES 18 J.F. Marier, Trevor N. Johnson, Suzanne Minton Pediatric trials now feature increased modeling and analytics for safer drug dosing and response. COMMENTARY CLINICAL TRIALS COMMUNITY TRIAL DESIGN VIEW FROM BRUSSELS 6 APPLIED CLINICAL TRIALS ONLINE 10 New Policy Could Temper Europe’s Data-Disclosure Debate 8 NEWS 26 Value-Based Planning & Drug Development Productivity Peter O’Donnell 48 BUSINESS AND PEOPLE Frederic L. Sax, MD, Marla Curran, DrPH, Sarah Athey, Christoph Schnorr, MD, Martin Gouldstone CLINICAL TRIAL INSIGHTS MARKETPLACE 16 The Impact of Protocol Amendments On Cycle Time How to integrate evidence-based planning and real-world evidence to boost clinical trial productivity. 49 CLASSIFIED Kenneth A. Getz 42 Overcoming Early Phase Oncology Challenges A CLOSING THOUGHT 50 The Promise of Precision Medicine Steve Rosenberg CRO/SPONSOR Karen Ivester 36 Imagining the Impossible: Immunity to Cancer How to meet the rigorous safety and efficacy demands critical to evaluating newer targeted cancer therapies. Chris Smyth, PhD The smaller biopharmaceutical company perspective on mastering oncology immunotherapy clinical trials. OUR MISSION Applied Clinical Trials is the authoritative, peer-reviewed resource and thought leader for the global community that designs, initiates, manages, conducts, and monitors clinical trials. Industry professionals learn effective and efficient solutions to strategic and tactical challenges within the tightly regulated, highly competitive pharmaceutical environment. 4 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com April/May 2016 PROVING VALUE HAS NEVER BEEN SO VALUABLE. Expertise every step of the way. In today’s competitive market there is no margin for error. PAREXEL® Access provides deep expertise, along with real world clinical research, commercial strategies and product lifecycle management solutions. All to help prove maximum product value to your stakeholders. Take a deeper look at our integrated approach at proof.PAREXEL.com/access © 2015 PAREXEL International Corp. All rights reserved. WEB CONTENTS appliedclinicaltrialsonline.com NOTEWORTHY www.linkedin.com/groups/Applied-Clinical-Trials-2949042/about Go to: twitter.com/clin_trials appliedclinicaltrialsonline .com to read these exclusive stories and other featured content. 4 S ite Staff Ranking of Sponsor-Driven Training Platforms Average of preferred rankings 3.5 Social Media 3 2.5 Do you follow us on Twitter or have joined our LinkedIn group? Here’s our most popular content from both. 2 1.5 1 0.5 0 Face-to-face meetings Self-directed online education modules WebEx/teleconferences Paper materials (e.g., pamphlets, newsletters, and product Monographs) Training platforms Source: Site Staff Perspective Survey, Axon Clinical Services, bit.ly/1Rp7urW eLearning eBooks Our latest update on Risk-Based Monitoring in Clinical Trials is now available for free download. The fourth edition includes features on current trends, employee support, and more. Download a copy at http://bit. ly/1PDo2XA. If you are interested in trials in Asia-Pacific, then Applied Clinical Trials’ CTMS: What You Should Know F or several years, increasing numbers of life sciences organizations have implemented a clinical trial management system (CTMS) that can provide insights gleaned from the system’s data to gain early and increased visibility into problems, progress, and possibilities. Many organizations have a constant need to expand CTMS capabilities, integrate clinical operations data across multiple systems, and update clinical trial processes—all in order to adapt to changing regulatory requirements and clinical trial practices. This is the dilemma facing clinical operations executives when selecting a CTMS solution to manage clinical trials—go with an existing approach/ solution or explore alternative options. eBook, Planning Successful Clinical Trials in the APAC Region, is for you. Get your free download at http://bit.ly/1mAnHON Webcasts Bookmark http://bit.ly/1pI7tEL for our popular webcasts, upcoming as well as those available on-Demand. A CTMS can reassure clinical operations executives that “you know what you should know.” It transcends organizational boundaries, improves interoperability, and addresses evolving regulatory standards. Systems can maintain and manage clinical trial planning, preparation, performance, and reporting, with an emphasis on keeping up-to-date contact information for trial participants and tracking deadlines and milestones (e.g., for securing regulatory approval, distributing drug supplies, or issuing progress reports). Typically, a CTMS provides data to a business intelligence (BI) system, which acts as a digital dashboard for clinical trial managers. Twitter: 1. Study Coordinators Prefer Paper COA bit.ly/1ojF7jc 2. Time to Re-Think ECGs? bit.ly/1QKZjYG 3. Califf Seeks Trials That Inform Labels bit.ly/1XfGsn7 LinkedIn: 1. Good Risk Management Starts at the Site bit.ly/1PDoBRn 2. BioCelerate for Preclinical Collaboration bit.ly/1Wcw8fj 3. DCRI: Limited Use of Open Trial Data bit.ly/1UKmiUm eNewsletters ACT Direct delivers updated news every Tuesday, with special topic news rotating each week: Oncology, RBM, Mobile Health, and Regulatory. ACT [Social Media] Trends will continue to deliver every other week on Wednesdays. Subscribe at bit.ly/NBvcNx to receive directly to your inbox. Visit bit.ly/1ZIBXTP for the full version of this article 6 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com April/May 2016 You are the person Who contacted the expert Who sourced the drug That was transported direct Running a clinical trial requires close collaboration between many different people. But however complex the process, we never lose sight of our objective – to help you bring lifesaving medicines to market. Make the connection with Clinigen CTS: Email: [email protected] Web: www.clinigengroup.com/clinical-trial-services Trust our chain reaction To the breakthrough trial That saved the life of my child. NEWS VIEW FROM WASHINGTON Califf: More Informative Clinical Research Key to Drug Development mong the multiple items on the “todo” list of new FDA Commissioner Robert Califf is to make clinical research more efficient and reliable to accelerate the development of safe and effective treatments for patients. Califf has long advocated for a “learning healthcare system” that taps electronic health records to facilitate clinical trial design and enrollment, and to provide ongoing information on the effects and side effects of therapies in real-world use. Now Califf has a ready platform to promote such strategies to further precision medicine and expedited approval of innovative medical products. In a March appearance before a Senate Appropriations subcommittee to discuss FDA’s requested budget for fiscal year 2017, Califf noted the agency’s success in approving more innovative drugs for market, many facilitated by expedited review programs and patient engagement in product development. His testimony cited efforts to refine clinical trial design and statistical methods of analysis, and to utilize advances in genomics and information technology to gain “more rapid, less expensive and more reliable answers about medical products” (see http://1.usa.gov/1pj7Kys). Most of the hearing, though, focused on the many other FDA activities important to the legislators, from effective monitoring of the nation’s food supply to halting the lethal abuse of opioids (see page 13). Other top priorities for FDA involve tobacco regulation, combating antibiotic resistance, reducing highrisk drug compounding, and developing medical countermeasures to Ebola and Zika. Califf promised to soon issue guidances and regulations to further biosimilar development and to better manage FDA’s IT infrastructure. He also will have to seek Congressional backing for multi- A 8 APPLIED CLINICAL TRIALS ple new user fee proposals now being finalized by FDA and industry task forces. During his confirmation process, Califf pledged that he would not lower FDA’s standards in evaluating the safety and efficacy of drugs and medical devices in response to challenges from legislators who feared that his ties to pharma would bias him towards industry. And while he avoids discussing drug prices, he recognizes that FDA can promote drug access by bringing more generic drugs to market, and that good information about medical product risks and benefits can support those who make coverage decisions. Califf’s expertise in biomedical research should help him tackle these and other difficult regulatory and policy issues, as seen in his activity as FDA deputy commissioner for the past year. At a December 2015 FDA workshop on enhancing the collection and assessment of clinical data on diverse patient subgroups, he described the challenges in managing trials to generate such data. He recently opened a meeting of FDA’s Science Board that was called to advise the agency on the development and regulation of medical treatments for pain, where new product research is important for lowering opioid abuse. A blog posted on FDA’s website in February cites progress in clarifying terms and definitions related to the development of biomarkers and other tools needed to advance biomedical research and inform clinical trials. And last October, the commissioner endorsed an FDA report on coordinating the review of combination products, a hot topic in the biomedical research community. Cancer advocates have been pressing for a new entity to coordinate the development and oversight of cancer therapies and diagnostics, and Califf has said he will appliedclinicaltrialsonline.com establish such a center under the White House Cancer Moonshot initiative. At a March Institute of Medicine (IOM) workshop on “Neuroscience Trials of the Future,” Califf described some of the difficulties and opportunities facing FDA and sponsors in achieving more effective clinical studies on treatments for nervous system disorders. In the “ideal world” of a learning healthcare system, Califf commented, sponsors and investigators would conduct concept studies that lead to informed clinical trials, and those results then would be used to write practice guidelines and to guide more “real-world” studies that, in turn, would provide more evidence and refine practice. Complexity and costs Unfortunately, Califf sees the research community opting for larger, more complex clinical trials, with the result that costs are “going off the scale.” Investigators enroll fewer patients per site because “we’re making things more and more complex,” something that he hopes FDA can address. He suggested that trials stop running multiple blood tests and collecting rare, non-serious adverse events from all patients, which “costs a ton of money.” It’s not necessarily FDA that seeks more data from larger studies, Califf observed, but sponsors that shy away from simplified studies—often to avoid greater uncertainty. The challenge for FDA, he said, is to develop study models that all parties “feel good about.” FDA can’t promise it will approve a new product if the researchers do things in a certain way, as there are “always surprises with medical products,” he commented. But the agency can assure, Califf said, that it won’t come back later and say it didn’t like that approach. — Jill Wechsler April/May 2016 Capsules DBcaps® capsules Sized to fit more clinical trials. S DBcaps® capsules are available in both gelatin and our new HPMC manufactured without gelling systems for true ionic and pH independence. The smaller size and unique tamperevident design improves patient compliance and minimizes bias. M Maintain DBcaps capsules in our compact and resealable CapsuleCaddyTM Containers with smaller capsule quantities perfect for clinical batches, R&D projects, or small manufacturing runs. Readily available for fast delivery to meet urgent timelines. Capsugel’s all-in-one approach to clinical materials manufacturing. L To ramp up production, the DB Filling System® enables rapid overencapsulation of comparator drugs in minutes with a customized drug loading ring and a vibrating table top assembly. Hand-held manual filling machines also available. Innovative Design Helps Improve Patient Compliance As the leading national supplier of over-encapsulation capsules, Capsugel offers comprehensive solutions for clinical trial professionals, Actual Sizes including a complete line of DBcaps capsules, multiple filling systems, DBcaps Size C capsule and full technical support. Call or visit us online to request a sample case of DBcaps capsules. (888) 783-6361 © 2016 Capsugel Belgium NV All rights reserved. Standard Size 0 capsule DBcaps.com NEWS To see more View From Brussels articles, visit appliedclinicaltrialsonline.com VIEW FROM BRUSSELS Will EMA Rules Take Heat Out of Transparency Debate? New policy hopes to calm the fervor around clinical trial data disclosure and confidentiality issues t’s a long-running battle, and the fat lady still hasn’t sung, so it ain’t over yet. But Europe moved one step closer in March to quenching the conflagration over transparency and clinical trial data. A weighty document running to nearly a hundred pages appeared from the European Medicines Agency (EMA), aiming to squeeze much of the oxygen out of the debate that has been raging for years about how much information companies should disclose about their products and their trials of them. (view the report at http://bit.ly/1RsfIeS). The guidance for the publication of clinical data explains to everyone who wants to know just how the agency is going to operate its new system of mandatory publication of data, and just what requirements are to be imposed on industry on submission of clinical data for publication. The new policy entered has been in force since Jan. 1, 2015, in that it covers the clinical reports contained in all marketing-authorization applications submitted from then onwards, but the first actual reports to appear are— because of the time-lag in processing applications—currently likely to appear only from this coming September. One of the hot spots in the document is the guidance on how to anonymize clinical reports for publication, so as to prevent any re-identification of trial I 10 APPLIED CLINICAL TRIALS participants. Bowing to the inevitable, given the wide range of methods available, EMA recognizes that no one method can be imposed, and permits some freedom of approach. But it gives recommendations to companies on how to best balance data utility for researchers with a minimal risk of reidentification, and companies will need to provide a report explaining their approach. That report will in turn be reviewed and published by EMA. But the real heat will be emitted by the document’s approach to commercially confidential information (CCI). Fierce arguments over the very concept of CCI have put drug companies (and regulators) at odds with healthcare campaigners in Europe, many of whom flatly refuse to recognize the merits of any methodology for identification and redaction of what companies perceive as sensitive material. In a scorched earth approach, the most vocal campaigners reject any such rights, and argue that the only ownership of such data lies with the trial participants whose involvement has generated the data. EMA has trodden a middle path of reason on the issue. It knows how inflammable this discussion is, and how determined industry critics are to pursue the fullest access to information. So its guidance makes clear that we are now appliedclinicaltrialsonline.com Peter O’Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. very much into open season for data hunters. “The vast majority of the information contained in clinical reports is not considered CCI,” it says. But “the vast majority” is not the totality, and EMA goes on to spell out its exceptions. It defines CCI as “any information contained in the clinical reports submitted to EMA by the applicant which is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant.” There are, it says, “limited circumstances in which clinical reports might contain CCI,” and the data classified as CCI may indeed be redacted (or, to put it plainly, lest this column should be accused of unjustified redaction, simply blacked out). With masterful understatement, the guidance document remarks: “It is anticipated that the preparation and publication of the documents will raise some practical questions, such as on how to apply the aforementioned redaction principles, and on the presentation and justification of the proposed redactions.” Where redaction takes place, companies will need to provide justification to EMA. The guidance clarifies which type of data EMA would typically refuse as being CCI and how the redaction of such data will be handled. Its broad framework starts from the principle that it will not accept redaction of any information in the public domain or that has no innovative features. It will also frown upon attempts to redact quality, non-clinical and clinical data which it believes to be necessary for the understanding of the rest of the clinical report, thus making its disclosure a matter of public interest. And the agency helpfully supplies some real-life examples of attempts that have already been rejected to justify redaction of material in reports. So don’t waste any time with the following arguments: “Unpublished data—These study results have not been published in any peered-reviewed [sic] April/May 2016 NEWS publication.” “Company confidential information—Disclosure of these elements will harm [the company]’s commercial interests because it may enable third-party access to businesscritical information.” “This information can be interpreted out of context. Such interpretation could lead to a misleading image of the safety profile of the product.” Clinical reports will be published at the conclusion of regulatory decisionmaking in the centralized marketing authorization procedures—irrespective of whether the decision on a marketing authorization application is positive or not. The reports—with anonymization and agreed redaction—will be published by EMA on its corporate website, within 60 days of the final decision for marketing authorization applications, line extension applications, and extension of indication applications. Where an application is withdrawn, the publication of the redacted/anonymized clinical reports will take place within 150 days after the receipt of the withdrawal letter. The hope within EMA is that its approach will damp down the debate and allow attention to return to the content of reports, rather than the processes for April/May 2016 accessing the data they contain. The agency has been engaged in extensive consultation with all parties concerned throughout 2015, and is cautiously optimistic that its patient negotiation has permitted a well-balanced set of requirements to emerge that can satisfy all sides. Now that D-Day is approaching for publishing the first reports under this new dispensation, the agency is planning to hold talks with the companies at the front of the firing line—those for which reports is only the first phase of the agency’s CT transparency bid. While this first phase deals only with publication of clinical reports, a second phase will deal with the still-more sensitive issue of publishing individual patient data. But this is still on the back burner; the agency says that although it is committed to moving in that direction, no dates have been set, and it “will be implemented at a later stage.” Ultimately, the success—or failure—of this attempt to calm spirits on access to trial data may depend more on emotion Ultimately, the success—or failure—of this attempt to calm spirits on access to trial data may depend more on emotion than on logic. the decision-making process has been finalized since the policy entered into force, and whose reports will constitute the first wave of publication. It is also planning a webinar in the late spring for companies to raise outstanding practical questions. Further down the track, still more fiery exchanges can still be expected, because the scheme now starting to deliver real than on logic. There are implacable views among the most earnest advocates of access to data, who recognize no claims for exemption and who, in the style of Wikileaks, demand full release of everything all the time. A lengthy and carefully-reasoned list of guidelines on the right and wrong way of doing things may not prove a sufficient response to that type of argument. appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 11 NEWS GLOBAL REPORT EMA Releases New Advice on Human Trials for Cancer Drugs he European Medicines Agency (EMA) has published draft guidance on the evaluation of anti-cancer medicines in humans. The 39-page document, which was issued on March 15 and is open for feedback until September 15, covers all stages of clinical development and addresses the development of treatments for malignancies, including drug resistance modifiers or normal tissue protective compounds. The agency is concerned that although many anti-cancer compounds are being developed, companies have only obtained a marketing authorization for a relatively small percentage of them due to poor activity or evidence of a detrimental safety profile. Until non-clinical models with good predictive properties have been defined, this situation is unlikely to change, and the absence of such models represents the greatest hurdle for efficient drug development in the near future, EMA noted. A central aim of the document is to promote the development of moleculespecific preclinical models to assess and predict anticipated activity as well as safety, which tends to be a standard approach used by developers of targeted molecules. The validation and predictive reliability of these models is a complex, time-consuming, and specialist process that requires tumor immunologists. EMA has sought to classify compounds according to reasonable designs of exploratory studies. This applies to cytotoxic compounds where the toxicity and overall response rate (ORR) are thought to be suitable markers of activity in dose-finding studies, compared with non-cytotoxic compounds where ORR and/or toxicity may not serve this purpose. Importantly, intra-patient dose escalation in Phase 1 can allow more effective drug levels to be reached, provided T 12 APPLIED CLINICAL TRIALS no toxicity is seen in two dosing cycles, state the authors of the document. This might help smaller biotech companies, for example. “The requirements of the characterization of the safety profile have changed with the emergence of molecularly targeted agents, immunomodulating drugs, and other non-cytotoxic agents. These types of agents may have other types of toxicity and are often dosed differently to conventional chemotherapy,” they wrote. “The dose-finding process and concepts such as dose-limiting toxicity may, therefore, need to be addressed differently than for standard cytotoxic agents.” Moreover, cumulative incidences by toxicity grade are not sufficient to characterize the toxicity profile. The impact of an adverse drug reaction on the benefit-risk balance may, for instance, differ importantly depending on how the incidence, prevalence, and severity change with time on treatment, and on the possibility to alleviate the reaction by dose reduction. Survival clues EMA is urging companies to submit overall survival data compatible with a trend towards favorable outcome to capture potential negative effects on the activity of next-line therapies and treatmentrelated deaths. This approach is likely to have consequences on interim analyses, other than for futility, and cross-over, which should be undertaken only when available survival data provide the information needed for a proper evaluation of benefits and risks, explained the authors. As well as defining the appropriate doses and schedules of a cancer drug, the EMA emphasize’s the importance of identifying a target population with optimized benefits and risks in the section about exploratory studies. Advice is also supplied about studies for combinations of drugs with minimal activity, as well as appliedclinicaltrialsonline.com combinations of conventional cytotoxics. No precise definition is given for either “trend towards favorable effects on survival” or “reasonably excluding negative effects on overall survival,” but the authors explain that if a major increase in toxicity is foreseeable, it is recommended that confirmatory studies are undertaken with the aim of showing overall survival benefit. They acknowledge that improved safety without loss in efficacy may constitute tangible aims and the design of non-inferiority efficacy studies. The safety focus of the document has added relevance in the light of the recent events of Zydelig, the PI3K inhibitor made by Gilead Sciences. The drug is being investigated by EMA after reports of serious side effects—including multiple deaths—among patients in several studies testing Zydelig in newly diagnosed leukemia and lymphoma. Gilead halted those trials in March. Earlier in March, EMA published long-awaited guidance on how to comply with its policy on publication of clinical data. The agency is moving toward the operational implementation of its proactive publication policy, which has launched a new era of transparency, said Noël Wathion, the agency’s deputy executive director. The guidance will ensure that companies are aware of what is expected of them and are ready for the publication of these critical data, he added. EMA wants to work with companies that are concerned by the first wave of publication (i.e., those for which the decision-making process has been finalized since the policy entered into force). EMA is organizing a webinar in the second quarter of 2016 to allow companies to ask any outstanding practical questions. This webinar will be a live broadcast and will be available for future reference on the EMA website. — Philip Ward April/May 2016 NEWS R EG U L ATO RY R E F O R M FDA to Address Opioid Trial Challenges DA is under tremendous pressure from Congress, state officials, and the public health community to do more to address the national epidemic of opioid abuse that is causing thousands of deaths and medical emergencies. But while patients and providers demand effective treatments for chronic and acute pain, the public wants safeguards to prevent overdosing and misuse of these products. Drug labels, boxed warnings, prescriber education, and postapproval monitoring have not deterred abusers. Now FDA leaders are implementing a new Action Plan to address the problem more forcefully, and hopefully to quell critics on Capitol Hill and in the medical community. One important element of the plan is to encourage development of new, more F effective pain medications with abuse deterrent (AD) properties, an issue addressed at a March meeting of the FDA Science Board. FDA is reassessing how it weighs risks and benefits in approving opioid drugs and expanded use of its advisory committees is part of this process. A main FDA strategy in recent years has been to encourage development of abuse-deterrent formulations (ADFs) of opioids. Five products with AD claims in labeling have been approved by the agency, supported by guidance finalized in 2015 on what studies and data is needed to support AD product development and approval. The Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER) is evaluating some 30 active investigational new drugs (INDs) for these products and other new technologies. Despite these efforts, many development programs for new pain medicines fail, said Sharon Hertz, director of the Division of Anesthesia, Analgesia and Addiction Products in OND. There are many sources of variability in clinical analgesic trials, which makes it very difficult to measure treatment effect, Hertz explained. FDA seeks to address such R&D issues through collaboration with academics, health professionals, advocacy groups, and industry. The aim is to gain consensus on standards for measuring pain intensity and on different outcomes in clinical studies and to optimize clinical trial methods to increase study efficiency. — Jill Wechsler Another European Approach to Early Drug Access ising concerns among Europe’s healthcare payers about the additional costs of innovative medicines are doing nothing to stem the tide of initiatives to speed new products to the market. The latest new scheme is the European Medicines Agency’s “PRIME” (short for “PRIority Medicines”), launched in March “to strengthen support to accelerate medicines that target an unmet medical need.” It will offer early advice to medicine developers so that they have the best chance of producing robust data on benefits and risks, and allow more rapid assessment. Improved clinical trial designs should ease data generation and the evaluation of applications for marketing authorization, and early dialogue will also serve to boost patient participation in trials and make best use of limited resources, said the European Medicines Agency (EMA) in its announcement. The scheme focuses on medicines that R April/May 2016 may offer a major therapeutic advantage over existing treatments, or benefit patients with no treatment options—drugs formally considered priority medicines within the European Union (EU). It builds on existing EU regulatory tools, and will take advantage of the shorter timeframe envisioned for decisions on drugs for unmet needs that have been evaluated under an accelerated assessment procedure. To qualify for the scheme, potential must be demonstrated by early clinical data, and once selected, a medicine will receive attention from an expert appointed by the EMA who will help build knowledge ahead of a marketing authorization application, organize meetings with relevant EMA committees and working parties, as well as with health technology assessment bodies, and will mentor throughout the development process. This arrangement is made in agreement with the European Commission, which is legally responsible for marketing authorization decisions in Europe’s tangled drug control system. Vytenis Andriukaitis, EU Commissioner for Health, gave his blessing to PRIME as “a major step forward for patients and their families that have long been hoping for earlier access to safe treatments for their unmet medical needs.” In fact, Andriukaitis is viewing it as something of a panacea for many current ills. He is looking forward to the enhanced scientific support of PRIME to help “accelerate the development and authorization of new classes of antibiotics or their alternatives in an era of increasing antimicrobial resistance.” He also sees it as “a potential godsend for those suffering from diseases for which there are currently no treatment options”—and particularly rare cancers, Alzheimer’s disease, and other dementias. — Peter O’Donnell appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 13 NEWS CLINICAL TRIAL TECHNOLOGY Sentinel Initiative Expands to Support Clinical Research fter eight years in development, FDA’s Sentinel system is poised to play a more visible role in assessing medical product efficacy, as well as safety. There are plans to expand it to gather information on the performance of medical products in real-world settings, which may assist researchers and clinicians in answering broader questions about treatment use. Sentinel has been a big investment for FDA, commented Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), at the recent 8th Annual Sentinel Initiative Public Workshop. A future pay-off, she noted, will enable other groups to utilize the system to “assess product performance beyond safety.” FDA intends to expand the use of A Sentinel by leveraging its data for additional research, public health, and quality improvement activities. The Sentinel program was launched in 2008 to expand FDA’s capacity to actively identify and assess postmarket risks for medical products. It now has become an “integral part of routine safety surveillance” for drugs, biologics, and other medical products, Woodcock noted. This has involved establishing an infrastructure and governance policies that are transparent and respect patient privacy. Health plans and providers participating in the Sentinel network now provide access to patient electronic health records and claims data on some 193 million individuals. An important recent addition is the Hospital Corp. of America, which can provide patient records from 168 hospitals and 113 surgery centers across the US. Data from the Medicare Virtual Research Center, moreover, will significantly increase information related to older patients. In addition to building Sentinel use by CDER, the system is expanding surveillance and analysis of vaccines and blood products by the Center for Biologics Evaluation and Research (CBER). A Sentinel “Tree Scan” project involves assessing vaccine safety and outcomes in pregnancy. Another CBER project will tap added hospital data to evaluate if there is a relationship between blood transfusion and lung injury and death. — Jill Wechsler D ATA A N A LY S I S Number of Countries in Phase III Studies Remains Steady re pharmaceutical company Phase III clinical trials becoming more complex? The most broadly based database available, ClinicalTrials.gov, does not support the assertion that clinical trials have become more complex in study/protocol design or execution. Illustrative is the number of countries used in pharmaceutical company sponsored Phase III clinical studies. The number of countries used in commercially sponsored Phase III trials has not changed in recent years. It is essential to stratify the results or otherwise the data appear to show that the number of countries per study has actually declined. The chart at right stratifies the studies by planned study duration: less than one year, 1 to 2 years and 3 or more years. This is important because the longer the planned study, the more likely the study may be open- A 14 APPLIED CLINICAL TRIALS ing sites in additional countries. When stratified this way, the data show practi- cally no change over the years covered. — Harold E. Glass, PhD Phase III Clinical Trials: Number of Countries and Duration 14 12 10 8 6 4 2 0 2008 2009 2010 <1yr 2011 1-3yrs 2012 2013 3+yrs Source: Department of Health Policy and Public Policy, University of the Sciences, Philadelphia, PA, using ClinicalTrials.gov data The average number of countries per study by designed study duration by year. appliedclinicaltrialsonline.com April/May 2016 TECHNOLOGY IS ONLY AS SMART AS THE THINKING BEHIND IT. An innovative approach. One that infuses clinical research expertise from across our organization into the designs of our Informatics solutions. And an eClinical platform, Perceptive MyTrials,® that brings them together in powerful new ways. So you can do more with your data—at every step. Find out why all top 15 biopharmaceutical companies use our solutions. Watch our video at proof.PAREXEL.com/informatics © 2015 PAREXEL International Corp. All rights reserved. CLINICAL TRIAL INSIGHTS To see more Clinical Trial Insights articles, visit appliedclinicaltrialsonline.com Acknowledging Cycle Time Impact from Protocol Amendments linical trials with at least one substantial protocol amendment require several hundred thousand dollars in unplanned direct costs to implement. But perhaps the most expensive impact is the unplanned incremental cycle time tacked on to the study. A new analysis by the Tufts Center for the Study of Drug Development (Tufts CSDD), in collaboration with more than a dozen sponsors and contract research organizations (CROs), indicates that protocols with at least one substantial amendment take an average of three unplanned months more to complete than do those without an amendment. These findings shed new light on the importance of adopting new strategies to reduce select amendments. C Collecting amendment data Between March and July 2015, Tufts CSDD and 15 pharmaceutical companies and CROs collected data from 836 Phase I – IIIb/IV protocols approved between 2010 and 2013. Protocols approved within the more recent 12-month period were excluded from the study, as these had the potential to continue accumulating amendments following the conclusion of clinical trial data collection. From the protocols reviewed, Tufts CSDD analyzed data from 984 amendments. Seven of the 15 participating companies also gathered direct cost data from 52 protocols for which substantial amendments had been identified during the January and May 2015 timeframe. This study was supported in part by an unrestricted grant from Medidata Solutions. Only substantial protocol amendments were evaluated in this study to ensure a more consistent assessment of prevalence and impact. Substantial amendments 16 APPLIED CLINICAL TRIALS were defined as any change to a protocol on a global level requiring internal approval followed by approval from the institutional or ethical review board or regulatory authority. Country-specific amendments that affected protocol designs for clinical trials within a given region alone were excluded. High prevalence... and avoidability The majority of protocols (57%) had at least one substantial amendment. On average, across all phases, the typical protocol had 2.1 substantial amendments. Phase II and III studies had the highest prevalence at 77% and 66% of the total, respectively. The average number of substantial amendments per Phase II protocol was 2.2; Phase III studies—typically the longest duration and the costliest to conduct—had the highest mean number (2.3) of substantial amendments. Sponsors report that the vast majority of changes made to an approved protocol originate internally. Only one-in-six (16%) stems from a regulatory agency request. The most common changes addressed by a substantial amendment are associated with modifications and revisions to study volunteer demographics and eligibility criteria (53%). Four-out-of-10 (38%) changes are related to modifications to safety assessment activity; 35% are appliedclinicaltrialsonline.com Kenneth A. Getz MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: [email protected] related to typographical errors; 27% are associated with endpoint modifications. In the Tufts CSDD study, sponsors and CROs reviewed their respective amendments and indicated the degree to which they could have been avoided. Oneout-of-four substantial (23%) amendments were considered “completely avoidable” and 22% were considered “somewhat avoidable.” Avoidable amendments included protocol design flaws, errors and inconsistencies in the protocol narrative, and infeasible execution instructions and eligibility criteria. Approximately one-third (30%) of substantial amendments were deemed “somewhat unavoidable” and 25% were classified as “completely unavoidable.” The causes of unavoidable amendments included manufacturing changes, the availability of new safety data, changes in standard of care, and regulatory agency requests to change the protocol design. The total median direct cost to implement a substantial protocol amendment for Phase II and III protocols was $141,000 and $535,000, respectively. The magnitude of impact No surprise — substantial protocol amendments significantly impact some study scope elements and the entire study conduct cycle. But the new Tufts CSDD study puts some real metrics on the table: Studies that had at least one substantial amendment saw a significantly higher reduction in the actual number of patients screened and enrolled relative to the original plan. This may have been due to sample size re-estimations and concrete steps taken to reduce patient screening and enrollment burden. In contrast, protocols that had no substantial amendments saw only a modest reduction in the actual number of patients screened relative to plan; and a modest increase in the actual number of patients enrolled relative to the original plan. Substantial amendments significantly increased cycle times at individual time points and throughout the study duration, suggesting that the delays associated April/May 2016 CLINICAL TRIAL INSIGHTS with amendment implementation are not recovered or reversed later in the study. Study initiation durations (i.e., protocol approved to first patient screened) were, on average, 18% longer for protocols with at least one substantial amendment compared to those without an amendment. This difference was not statistically significant, as expected, since the majority of substantial amendments are implemented once the study is underway. For those protocols with at least one substantial amendment, the time points from protocol approval to last patient last visit (LPLV) and from first patient first visit (FPFV) to LPLV were significantly longer— at 90 days and 85 days, respectively— compared with those protocols without an amendment. A whopping 5.5-month increase in time was observed in the “first patient participation cycle” (i.e., from first FPFV to first patient last visit [FPLV]), suggesting that the implementation of substantial amendments impacts study volunteers differently depending on when they are randomized and enrolled in the clinical trial. Eyes on the prize A large and growing number of sponsors and CROs recognize the incredible unplanned and unbudgeted toll that protocol amendments take on study budgets and timelines, and the major opportunity to improve clinical trial efficiency and performance. Companies are routinely gathering metrics to monitor their protocol amendment experience. A number of sponsors and CROs are leveraging new technologies and implementing new mechanisms, functions, and processes to optimize protocol design. Amgen, for example, has implemented a new Development Design Center to assist clinical teams in designing better studies before going to the protocolauthoring stage. The Center taps experts and data to facilitate decision-making and promote a deeper understanding of design-related trade-off decisions and their impact on executional feasibility. Pfizer and GlaxoSmithKline have implemented extensive internal review processes to improve protocol quality and reduce amendments. GSK implemented a new governance mechanism several years ago. Pfizer recently revised its standard operating procedures (SOPs) to require that all protocols go through a detailed protocol and amendment review prior to implementation. The first step in this process calls for a review by a senior- Impact of Implementing an Amendment on Study Cycle Times Protocols without a Substantial Amendment Protocols with at least one Substantial Amendment Days 700 580 600 490 500 437 403 352 400 238 300 200 100 0 First Patient First Visit (FPFV) to First Patient Last Visit (FPLV) FPFV to Last Patient Last Visit (LPLV) Source: Tufts CSDD, 2016; <csdd.tufts.edu> April/May 2016 Protocol Approved to LPLV level governance committee to achieve consensus on the design elements of the study, to ensure that the protocol is consistent with the overall development plan, and to challenge the executional feasibility of the protocol. Eli Lilly has implemented three core initiatives throughout the organization to simplify and focus protocol design; to incorporate patient-centered approaches; and to streamline the drug development process. One approach to support these initiatives is to solicit input—before protocol approval—from patients and investigative site staff during a simulation of study execution and the participation experience. Lilly’s study teams observe these simulations to identify and address feasibility issues that could potentially trigger the need to amend the protocol. EMD Serono routinely conducts patient advisory boards to solicit patient feedback on protocol design and the feasibility of the schedule of assessments. These boards are conducted globally, each among six to 10 patients in collaboration with patient advocacy groups. Lastly, TransCelerate BioPharma has made protocol feasibility one of its top areas of focus in 2016. TransCelerate recently released a Common Protocol Template, offering a common structure and language to drive protocol design quality and identify areas of misalignment between protocol endpoints and their respective procedures. TranCelerate’s initiative is among several other common authoring templates now available, including one developed by a community of global medical writers—the SPIRIT initiative—and launched a number of years ago. Sponsors and CROs are rallying to reduce the number of avoidable amendments and ultimately improve protocol quality, executional feasibility, and efficiency. The anticipated improvements in study performance and cost could not come at a better time, given rapid growth in the scientific and executional complexity of protocol designs and growing interest in patient-centric drug development. appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 17 TRIAL DESIGN How Biosimulation Can Predict Drug Success J.F. Marier, Trevor N. Johnson, Suzanne Minton Pediatric trials now feature increased modeling and analytics for safer drug dosing and response. PEER REVIEW 18 istorically, most medications given to children had not been evaluated in pediatric clinical trials due to logistical and ethical challenges. Indeed, while children represent about 40% of the world’s population, only 10% of the drugs on the market have been approved for pediatrics. 1 Without a proper and approved clinical process, physicians are left with potentially unsafe dosing and therapeutic approaches for children. The result is a continuation of the offlabel prescribing. To address this urgent medical need, both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) now require pediatric trial plans—the Pediatric Study Plan (PSP) and the Pediatric Investigation Plan (PIP), respectively—as part of the approval process for new drugs. The combination of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) and these new regulatory requirements are starting to move the pendulum towards safer, more effective medicines for children. During the five-year period between 2007 and 2013, 469 pediatric studies were completed under BPCA and PREA; by August 2014, 526 labeling changes were made.2 Similarly, in the European Union, around 300 products have had label changes approved for safety, efficacy, or dosing for pediatrics since 2007.2 While these requirements have spurred growth in pediatric clinical research, there are H APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com still major barriers to successful pediatric drug development. Almost half of the trials conducted in recent years have failed to demonstrate either safety or efficacy. A total of 44 products had failed pediatric drug development trials submitted to the FDA between 2007 and 2014. 3 An analysis by Gilbert J. Burckart, PharmD, and his FDA colleagues revealed several common factors that contributed to the widespread failures: suboptimal dosing, differences between adult and pediatric disease processes, and problematic study designs. In the cases where suboptimal dosing contributed to the failure to show efficacy, there were two frequent issues: not testing a range of doses, and limiting pediatric drug exposure to that which was shown to be efficacious in adults. Testing a range of doses is critical to understanding dose-response relationships for a drug. Also, if the disease process differs between children and adults, then matching the drug exposure to that observed in adults may not be effective, and ultimately result in clinical trial failure. An understanding of pediatric disease—its natural progression—is crucial for selecting outcomes for clinical studies, including the primary efficacy endpoint, safety, and biomarkers. Finally, problematic study designs are a significant contributing factor in clinical trial failures. Some of these issues included lack of a control group, stratification, and inadequate assay sensitivity. April/May 2016 ©2016 Chiltern International Ltd. All rights reserved. Chiltern is an Equal Opportunity Employer. Your clinical research program is different – because it’s yours. To make the most of it, you need a CRO who brings more to the table than a predetermined process. You need a partner who starts by understanding your situation and learning about your exact specifications – experienced professionals who customize engagements so the services you get are perfectly matched to your vision and goals. That’s our approach. Let’s talk about yours. US: +1 910 338 4760 UK: +44 0 1753 512 000 www.Chiltern.com TRIAL DESIGN A biosimulation framework to support strategic decision-making First, it’s important to clarify some definitions regarding pediatric age groupings. According to the FDA guidance, neonates are from birth to one month, infants are from one month to less than two years of age, children are from two to 11 years old, and adolescents are from 12 to 18 years old. As pharmacokinetics (PK) and pharmacodynamics (PD) may change between each age range, drug developers may need to develop dosing regimens specific to each subgroup.5 The very nature of human growth and maturation makes the prediction of pharmacokinetics in children especially challenging. Drug disposition in children differs from that of adults in numerous ways. For example, the kinetics of drug absorption may be different in children versus adults due to changes in the expression of intestinal drug transporters and drug metabolizing enzymes during development.4 Likewise, drug distribution changes with age as neonates (birth up to one month) have much higher total body water compared to adults. Finally, organ maturation has a significant effect on drug metabolism and excretion. Children have relatively larger livers, lower glomerular filtration rates, and less renal tubular absorption and excretion compared to adults. 6 This distinct physiology means that traditional approaches such as allometry risk greatly over or under predicting drug clearance in pediatric patients, especially those that are less than one year old.7 Because of the special needs of children as well as ethical concerns, there are significant differences in clinical trial protocols for children versus adults. The FDA guidance document discusses these issues at length. 5 Some of the major issues in pediatric clinical trials include the following: t The type of PK study that is possible is often different in adults and children. While rich sampling is often conducted in adults, a sparse sampling procedure is generally preferred for young children to minimize the number and volume of blood draws. t When studying neonates, sponsors may need to consider gestational as well as postnatal age when determining covariates for a population PK study. t The formulation of a drug may change between age groups. Young children generally cannot swallow pills and may require liquid formulations. How can pediatric drug developers satisfy regulatory requirements and maximize drug safety and effectiveness while minimizing children’s exposure to experimental medications? Biosimulation—also known as model-based drug development—includes both empirical “top down” PK/PD modeling and simulation as well as “bottom up” physiologically-based pharmacokinetic (PBPK) models. It leverages prior information from preclinical studies, 20 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com adult trials, peer-reviewed literature, and pediatric studies of related indications or drug actions. The integration of patient physiology, drug actions, and trial characteristics in models enables sponsors to optimize dosing and trial design. Indeed, in a study of 11 well characterized drugs, PBPK models of virtual subjects (birth to 18 years of age) showed greater accuracy in predicting drug clearance than simple allometry, especially in children less than two years of age.8 The increased certainty in biosimulated outcomes can help sponsors to ensure informative pediatric trials are performed and will gain approvals based on a smaller number of pediatric patients.9 An understanding of pediatric disease— its natural progression—is crucial for selecting outcomes for clinical studies, including the primary efficacy endpoint, safety, and biomarkers. Opportunities during drug development for applying modeling and simulation techniques As the benefits of biosimulation become increasingly clear, regulatory agencies are also advocating its use to improve the success rate of pediatric trials from current levels.10 Indeed, a 2014 draft guidance from the FDA states that “modeling and simulation using all of the information available should, therefore, be an integral part of all pediatric development programs.”5 At each stage of clinical development, there are specific trigger points and opportunities to apply modeling and simulation techniques to increase the likelihood of success. Submission of the PIP is required by the EMA by the end of Phase I clinical studies. Biosimulation methods should be used to support the dosing rationale stated in the PIP. Population PK and PBPK models based on Phase I data from adults are frequently used to develop a drug model that aids with pediatric dose selection. Population PK or PBPK models can predict drug exposure across a wide range of ages and weights as well as maturation and organ function. The predicted drug exposure in pediatric patients can then be compared against observed values in adult subjects in Phase I to confirm the models and optimize the safety of treatments. This approach can also be used to develop a sparse sampling strategy that optimizes the assessment of PK parameters while minimizing the number of blood draws and other invasive procedures. Pediatric PBPK and population PK models can be used synergistically during drug development. The former have recently been used to aid in the determination of optimal dose and sampling times for population PK.11 Conversely, April/May 2016 With LabConnect… the world revolves around you. With LabConnect, it’s so much more than central lab services. Complicated kits? We custom design, build and distribute site- and visit-specific collection kits with pre-labeled tubes to minimize errors. Losing track of your samples? Let our SampleGISTICS™ staff track your specimens in real time from collection through logistics to receipt at any lab or storage location worldwide. Looking for the perfect employee? LabConnect’s SciOps division provides dedicated contract scientific professionals based on the specific functional expertise you need. LabConnect’s combination of cutting-edge technology, world-class laboratories and specialized testing expertise means you can rely on a single provider for all of your central laboratory service needs. Central lab services that revolve around you. Join us for our May 26 webinar on “BioVisualization: The effective mining and interpretation of laboratory results data.” Visit www.appliedclinicaltrialsonline.com/act/biovisualization to register. TRIAL DESIGN the results from population PK models can be used to further optimize pediatric PBPK models. Another important use for PBPK models in pediatric drug development is evaluating the risk of drug-drug interactions (DDIs). DDIs are a primary threat to the safety and efficacy of clinical practice. Clinically-relevant drug interactions are primarily due to drug-induced alterations in the activity and quantity of metabolic enzymes and transporters. Indeed, DDIs that cause unmanageable, severe adverse effects have led to restrictions in clinical use, and even drug withdrawals from the market. The magnitude of any DDI depends on the fractional importance of the inhibited metabolic pathway. The pattern of CYP metabolic enzymes that contribute to the elimination of a drug may not necessarily be the same in children compared to adults. Thus, it is difficult to use information about DDIs in adults to inform the likelihood of pediatric DDIs. And, again, there are practical and ethical problems with evaluating DDIs in pediatric clinical studies. A 2012 guidance from the EMA states that PBPK simulations may be used to predict the effects of drug interactions in multiple special populations, including young pediatric patients.12 Use of the Simcyp Pediatric Simulator to simulate DDIs revealed that in certain scenarios, neonates could be more sensitive to a DDI than adults while the opposite might be true in other scenarios involving different CYP enzymes.13 Pediatric PBPK models may help provide information about the risk and magnitude of potential DDIs where there are no existing clinical data. Pharmacometrics tools are also invaluable in supporting pediatric study plans. The PSP should be submitted to the FDA at the end of the Phase II meeting, following the availability of exposure-response data in adults. To provide guidance on the conduct of pediatric trials, the FDA has articulated a pediatric study decision tree.14 The degree of similarity of disease progression and drug response between adults and children determines which of three major pediatric studies should be undertaken: PK only, PK/PD, PK, or efficacy. Safety studies are required in all of these scenarios. The regulatory path taken determines the strategy for optimizing dosing. In the case that PK studies alone are used, the sponsor should build a population PK model customized for size and maturation and perform dose simulations that will result in drug concentrations within the range of those observed in adults. Using the PK/PD approach means creating a population PK/PD model that is customized for size and maturation and performing dose simulations that will achieve a target concentration based on the PK/PD relationship. Finally, utilizing a PK and efficacy approach involves building a population PK model and an exposure-response model, and performing simula- 22 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com tions to find a dose that will produce a drug concentration that results in an adequate response. Phase III studies in adults are performed to determine whether there is statistically-significant evidence of clinical efficacy and safety for an investigational drug. At this point, the PIP and PSP should be updated to reflect any new insights. This is also the time to develop final pediatric protocols. Clinical trial simulations using Phase II results can be useful for evaluating probability of success in Phase III. The increased certainty in biosimulated outcomes can help sponsors ensure that informative pediatric trials are performed and will gain approvals based on a smaller number of pediatric patients. Two case studies showing successful use of biosimulation for pediatric drug development Learning from one indication to the next: Eculizumab for atypical hemolytic uremic syndrome In some cases, information gained developing a drug for one indication can be leveraged to inform its approval for a different indication. PNH (paroxysmal nocturnal hemoglobinuria) is a rare, progressive, and life-threatening disease. It is characterized by rampant destruction of red blood cells (hemolysis) and excessive blood clotting. 15 Likewise, aHUS (atypical hemolytic uremic syndrome) is an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body. The sequelae of aHUS include kidney failure, damage to other organs, and premature death. There were no FDAapproved treatments for this rare disease. Both aHUS and PNH are caused by chronic, uncontrolled activation of the complement system. During activation of the complement system, the terminal protein C5 is cleaved to C5a and C5b. C5a and C5b have been implicated in causing the terminal complement-mediated events that are characteristic of both aHUS and PNH. Eculizumab is a humanized monoclonal antibody (mAb) that binds C5, thereby inhibiting its cleavage. In 2007, this mAb received approval for treatment of PNH based on evidence of effectiveness from clinical studies.16 To help the sponsor obtain accelerated approval of eculizumab for the treatment of aHUS in both adults and pediatric patients, Certara scientists leveraged previous knowledge gained during its development for PNH. Their starting point was a population PK model that had been previously constructed in adult patients with PNH. 17 This model was customized and used to develop optimal dosing strategies for adult and pediatric aHUS patients. April/May 2016 TRIAL DESIGN Getty Images/ Phil Boorman Almost half of pediatric clinical trials conducted in recent years have failed to demonstrate either safety or efficacy. Comparing the case of adults with PNH to pediatric aHUS, it became apparent that children have a different response to intervention and that a different endpoint should be used. The PK/PD relationship in PNH was leveraged to measure the drug’s exposure and inform pediatric dosing for aHUS. Knowledge about eculizumab’s mechanism of action for PNH also suggested that optimal binding to the pharmacological target (C5) should translate into a clinical benefit. Identification of the therapeutic dosing window for a mAb in pediatric patients with a rare disease involved several steps. First, to ensure patient safety, the upper exposure limit needed to be determined. As a safeguard against toxicity, the upper exposure limit was capped at what had been previously observed in adults. To ensure efficacy, the minimum drug exposure also had to be determined. Using the predicted concentration of the soluble target and the binding characteristics of the mAb to its target, a minimum concentration threshold was set to obtain close to full inhibition of the target. Then, trial simulations using a population PK model were performed to determine which doses would optimize the probability of obtaining the mAb within the window of target engagement. This enabled the dosing recommendations to be determined for pediatric patients of varying weights.17 The clinical program for aHUS involved two Phase II studies and a retrospective observational study. A total of 57 patients with aHUS participated in these studies (35 adult, 22 pediatric patients). Two different biomarkers were used to assess the efficacy of treatment. The proximal biomarker, free C5, showed complete suppression upon treatment with the mAb. Likewise, the mAb caused April/May 2016 The high rate of trial failures, increasing regulatory demands, and ethical imperatives all require a reexamination of the current approach to pediatric drug development. full inhibition of hemolytic activity (the distal biomarker).17 The primary endpoint indicated that the response to the intervention exceeded 95%. Patients treated with the mAb experienced several benefits including higher improvement in platelet counts and other blood parameters and better kidney function, even eliminating the requirement for dialysis in some patients. Soliris® (eculizumab) received FDA approval to treat aHUS patients in 2011.18 Using PBPK modeling to assess differing drug formulations for pediatric patients Quetiapine is an atypical antipsychotic drug for the treatment of schizophrenia, bipolar disorder, major depressive disorder, and generalized anxiety disorder. An immediate release (IR) formulation of quetiapine was first approved by the FDA in 1997 and has been extensively studied in adults, children, and adolescents. Regulatory approval for the extended release (XR) formulation was granted for use in adults, with the requirement that pediatric studies must be carried out for children over the age of 12. Various factors influence the bioavailability of different formulations including the release of the active ingredient, its dissolution and permeability across the GI tract, as appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 23 TRIAL DESIGN well as intestinal metabolism. Furthermore, alterations in PK in children can be due to differences in absorption and transit rate, organ size, blood flow, tissue composition, and metabolic capacity at various developmental stages. The challenge was to integrate the available in vitro ADME, physiochemical, and clinical data into PBPK models to predict the effects of age and formulation on the PK of quetiapine in young subjects. Scientists at Certara and AstraZeneca developed PBPK models that predicted, with reasonable accuracy, the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in both children and adults, and the PK profile of quetiapine XR in adults. These validated models were then used to simulate relative exposure following XR formulation in adolescents (age 13-17) and children (age 10-12). In both groups, the predicted exposure to quetiapine XR followed a similar pattern to the IR formulation, with 300mg XR once-daily being comparable with 150mg IR twice-a-day.19 Conclusion The high rate of trial failures, increasing regulatory demands, and ethical imperatives all require a reexamination of the current approach to pediatric drug development. Biosimulation is a proven approach that will help optimize trial design and inform the drug label. This approach can support global regulatory strategies that increase the likelihood of success for pediatric drug development programs. References 1. Milne CP and Bruss JB. The economics of pediatric formulation development for off-patent drugs. Clinical Therapeutics. 2008; 30(11):2133-45. 2. Ito, S. Children: Are we doing enough? Clinical Pharmacology and Therapeutics. 2015. doi: 10.1002/cpt.167. [E-pub ahead of print] 3. Momper JD, Mulugeta Y, Burckart GJ. Failed pediatric drug development trials. Clinical Pharmacology and Therapeutics. 2015. doi: 10.1002/cpt.142. [Epub ahead of print] 4. Yaffe SJ and Aranda JV. (2010). Neonatal and pediatric pharmacology: Therapeutic Principles in Practice, 4th edition. Philadelphia, PA: Lippincott Williams & Wilkins. 5. U.S. Food and Drug Administration, “Guidance for Industry: General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products,” December 2014, http://www. fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm425885.pdf 6. Barrett JS, Della Casa Alberighi O, Läer S, Meibohm B. Physiologically-based pharmacokinetic (PBPK) modeling in children. Clinical Pharmacology and Therapeutics. 2012; 92(1):40-9. 7. Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clinical Pharmacokinetics. 2006; 45(7):683-704. 8. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of 11 drugs and associated variability in neonates, 24 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com infants and children. Clinical Pharmacokinetics. 2006; 45(9):931-56. 9. Maharaj AR and Edginton AN. Physiologically based pharmacokinetic modeling and simulation in pediatric drug development. CPT: Pharmacometrics and System Pharmacology. 2014. DOI: 10.1038/ psp.2014.45. 10.Gobburu, J. (2010, March). How to Double Success Rate of Pediatric Trials? Presented at the meeting of the American Society of Clinical Pharmacology and Therapeutics , Atlanta, GA. 11. Thai HT, Mazuir F, Cartot-Cotton S, Veyrat-Follet C. Optimizing pharmacokinetic bridging studies in paediatric oncology using physiologically-based pharmacokinetic modelling: application to docetaxel. British Journal of Clinical Pharmacology. 2015. Accepted manuscript DOI 10.1111/bcp.12702. 12. European Medicines Agency, “Guidelines on the Investigation of Drug Interactions,” June 2012, http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2012/07/ WC500129606.pdf 13. Salem F, Johnson TN, Barter ZE, Leeder JS, Rostami-Hodjegan, A. Age-related Changes in Fractional Elimination Pathways for Drugs: Assessing the Impact of Variable Ontogeny on Metabolic Drug–Drug Interactions. Journal of Clinical Pharmacology. 2013. 14. U.S. Food and Drug Administration, “Guidance for Industry: Exposure-response Relationships – Study Design, Data Analysis, and Regulatory Applications,” April 2003, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072109.pdf 15. Lathia C, Kassir N, Mouksassi MS, Jayaraman B, Marier JF, Bedrosian CL. Modeling and Simulations of Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH) and Atypical Hemolytic Uremic Syndrome (aHUS) Patients: Learning From One Indication to the Next. Clinical Pharmacology and Therapeutics. 2014, PII-107; 93(1): S97. 16.U.S. Food and Drug Administration. (2007) FDA Approves Firstof-its-Kind Drug to Treat Rare Blood Disorder [Press release]. Retrieved from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108869.htm 17. Lathia C, Kassir N, Mouksassi MS, Jayaraman B, Marier JF, Bedrosian CL. Population PK/PD Modeling of Eculizumab and Free Complement Component Protein C5 in Pediatric and Adult Patients with Atypical Hemolytic Uremic Syndrome (aHUS). Clinical Pharmacology and Therapeutics. 2014, PII-108; 93(1): S97. 18.U.S. Food and Drug Administration. (2011) FDA approves Soliris for rare pediatric blood disorder [Press release]. Retrieved from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm272990.htm 19. Johnson TN, Zhou D, Bui KH. Development of physiologicallybased pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents. Biopharmaceutics and Drug Disposition. 2014; 35(6):341-52. J.F. Marier, PhD, FCP, is a Vice President and Lead Scientist; Trevor N. Johnson, PhD, is a Principal Scientist; Suzanne Minton, PhD, is the Manager of Scientific Communications; all with Certara April/May 2016 J U N E 2 6 – 3 0 | P H I L A D E L P H I A , PA DIA 2016 is packed with 175+ educational offerings over 22 tracks on today’s hottest topics. It is our largest interdisciplinary event, bringing together a global network of 7,000+ life sciences professionals from industry, academia, regulatory and government agencies, and patient and philanthropic organizations from around the globe, to foster innovation in the discovery, development, and life cycle management of health care products. Keynote Speaker: Larry Brilliant, MD, MPH +* 5Čƫ 1*!ƫĂĈƫħƫĂčăĀĢąčĀĀ ..5ƫ.%((%*0ƫ%/ƫ0$!ƫ0%*#ƫ đƫ 2*%*#ƫ0$!ƫ,,.+,.%0!ƫ/!ƫ+"ƫ+%(!ƫ(%*%(ƫ $%.)*ƫ+"ƫ0$!ƫ+. ƫ+"ƫ0$!ƫ ƫƫƫ.%(/čƫ$!ƫ(%*%(ƫ.%(/ƫ.*/"+.)0%+*ƫ*%0%0%2! '+((ƫ(+(ƫ$.!0/ƫ1* Čƫ3$+/!ƫ)%//%+*ƫ%/ƫ0+ƫ +*".+*0ƫ#(+(ƫ0$.!0/ƫ/1$ƫ/ƫ* !)%/Čƫ(%)0!ƫ đƫ!#1(0+.5ƫ$((!*#!/ƫ%*ƫ0$!ƫ!2!(+,)!*0ƫ+"ƫ $*#!Čƫ0!.Čƫ1(!.ƫ.+(%"!.0%+*Čƫ* ƫ0$!ƫ% (!ƫ ƫƫƫ+)%*0%+*ƫ.+ 10/ƫ*2+(2%*#ƫ%#%0(ƫ /0ƫ+*ý%0ċƫ Technology đƫ)!.#!*0ƫ01 5ƫ!/%#*/ƫ* ƫ*(5/%/ƫ!0$+ /ƫ Preconference Tutorials | Sunday, June 26 ƫƫƫ .!//%*#ƫ//1!/ƫ//+%0! ƫ3%0$ƫ! %0.%ƫ Take advantage of additional educational and ƫƫƫ(%*%(ƫ01 %!/ *!03+.'%*#ƫ+,,+.01*%0%!/ƫ!"+.!ƫƫĂĀāćƫ+þ%((5ƫ đƫ.*/!(!.0!Ě/ƫ%/'ġ/! ƫ+*%0+.%*#čƫ$.%*#ƫ '%'/ƫ+ûċƫ$ƫ.!+*"!.!*!ƫ10+.%(ƫ%/ƫ !/%#*! ƫ ƫƫƫ$0ƫ!ƫ.!ƫ!.*%*# to increase your knowledge while allowing for đƫ.%*#%*#ƫ0$!ƫ.%(ƫ0+ƫ0$!ƫ0%!*0čƫ'%*#ƫ0$!ƫ small group interaction. ƫƫƫ0%!*0ƫ+%!ƫ!*0.(ƫ".+)ƫ.%(ƫ!/%#*ƫ*3. Featured Sessions: A G AT H E R I N G O F G L O B A L P R O P O R T I O N S %/%0ƫDIAglobal.org/DIA2016 for more information and to register. Observational Studies Benefit-Risk Social Media Strategies Mobile/Wearables Technology Pricing, Reimbursement & Access Big Risk-Based Personalized Medicine Data Monitoring Patient Registries Current Issues in Policy and Law Regulatory Harmonization Design Thinking Disruptive Technologies Biologics/Biosimilars IDMP Cloud Computing Clinical Trial Transparency Value-Based Evidence Patient Engagement 21st Century Cures Approval Pathways TRIAL DESIGN Value-Based Planning & Drug Development Productivity Frederic L. Sax, MD, Marla Curran, DrPH, Sarah Athey, Christoph Schnorr, MD, Martin Gouldstone How to integrate evidence-based planning and realworld evidence to boost clinical trial productivity. PEER REVIEW 26 ntil relatively recently, the number often quoted as the cost of bringing a new drug to market was $1 billion. 1,2 In November 2014, the Tufts Center for the Study of Drug Development reported that developing a new prescription medicine that gains marketing approval, a process often lasting longer than a decade, is estimated to cost $2.558 billion. 3 Recent analysis shows that not only have costs risen, but there is high variability among companies in their “costs-per-successfulproduct” reaching the market.4 Improvements in product selection, product development, and investment decision-making would all improve the likelihood of a product’s successful market entry. The key issue facing the industry can be described as development productivity. On a portfolio level, this can be defined as a ratio of the current projects in the pipeline (work in progress or WIP), the probability of technical success (p(ts)), and the value of the pipeline (V) divided by the cycle time (CT) and the cost to deliver the pipeline (C)5 P = WIP * p(ts) * V CT * C This equation conveys the balance of risk, time, and cost (with a factor included for numbers of compounds in a portfolio, though the equation is equally relevant for a single compound [i.e., WIP=1]), weighted against the probability of its technical success and its potential future value; each compound has its own set of dynamics related to the size of the popula- U APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com tion, market share/competitive landscape, unmet need, differentiation, and market access/pricing considerations. Biopharmaceutical companies have attempted to address the productivity issue by increasing the number of compounds entering a portfolio (“shots on goal”) and doing whatever they can do to decrease costs and cycle time. However, the productivity equation is dominated by the very low industry-wide “probability of success,” which, in the most recent data, is still only about 15% of new medical products entering human trials.6 Companies have tried to change these odds by targeting patient populations who are most likely to respond to therapy (e.g., through use of biomarkers); the goal is to try to increase the likelihood of positive efficacy results and corresponding positive pricing and reimbursement decisions. Even if a compound meets the regulatory standards that allow for its successful registration, there is no guarantee that the product will be accepted by boards/formularies responsible for pricing and reimbursement, making successful commercialization and patient access challenging. “Effectiveness” has essentially been added as the fourth hurdle to safety, efficacy, and manufacturing quality. Market access strategies continue to be shaped by influential stakeholders. There are a number of recent examples that speak to this point: England’s National Institute for Health and Care Excellence (NICE) did not April/May 2016 TRIAL DESIGN for decades. In Germany, the law governing pharmaceuticals (AMNOG) was amended in 2011, introducing a formal Health Technology Assessment (HTA). Following this change, Boehringer Ingelheim decided not to launch the new oral anti-diabetic compound linagliptin (Trajenta®). Under the new law, the comparator was not the agreed comparator and the submission was assessed as not adequately justified.8 9 Value Impact: Real-World Evidence Development Clinical development* $100-200m Launch In-market Initial pricing & market access* $100m Safety & value demonstration $200-600m Launch planning & tracking $150m Commercial spend effectiveness $200-300m Productivity and cost savings $100m *Selected operational opportunities only; excludes increased R&D pipeline throughput and better pricing The goal is to try to increase the likelihood of positive efficacy results and corresponding positive pricing and reimbursement decisions. 1 Hughes B, Kessler M. RWE market impact on medicines: A lens for pharma. IMS Health Access Point 2013; 3(6): 12-17 Source: Sax et al. Figure 1. Value capture from real-world evidence across the product life cycle for a top 10 biopharmaceutical company. These examples illustrate that only focusing on development costs and cycle times is not sufficient and needs to be balanced continuously with the potential for a product’s reimbursement and commercial viability to ensure an adequate return on investment for new therapies. This requires forward-looking (and likely, disruptive) thinking at the earliest stages of development. Bringing unmet medi- recommend GlaxoSmithKline’s belimumab for the treatment of active lupus erythematosus. 7 NICE concluded that there was insufficient evidence of improved efficacy versus standard of care and did not recommend use, even though it was the first new approved drug in this indication Introducing A Faster, Easier, and More Effective Approach to Risk-Based Monitoring ON-DEMAND WEBCAST Originally aired March 15, 2016 Register free at www.appliedclinicaltrialsonline.com/act/fastermonitoring EVENT OVERVIEW: Key Learning Objectives: During this webcast we will highlight how Oracle Health Sciences’ holistic, advanced risk-based monitoring cloud solution enables life sciences companies to automate their risk-based monitoring strategies, optimizing actionable results from the comprehensive analysis of clinical and operational data. We will demonstrate how this new and comprehensive approach aligns with regulatory guidelines and seamlessly incorporates TransCelerate tools and best practices, including the Risk Presenter: Assessment Categorization Tool (RACT) Jennifer Bush and TransCelerate Key Risk Indicators. Director of Product Strategy Oracle Health Sciences Who Should Attend: Moderator: 0 Provide insight as to how sponsors are using risk-based monitoring technology as part of their new and improved approach to monitoring 0 Demonstrate the ease with which sponsors and CROs can adopt a comprehensive central monitoring platform to enhance patient safety and trial quality. 0 Show how cloud solutions incorporating TransCelerate tools and practices deliver significant efficiency benefits while reducing the cost and manual effort of conducting RBM 0 Discover how to make critical decisions throughout the course of a trial through actionable insights, execute risk based monitoring strategies and increasing resource productivity with the ability to get access to information anywhere, anytime from any device Clinical operations, clinical data management, risk management, data quality, clinical research associates Sponsored by Lisa Henderson Editorial Director Applied Clinical Trials Presented by For questions contact Daniel Graves at [email protected] TRIAL DESIGN Net Present Value Time points: CDN: candidate selection; POC: proof of concept; DFL: development for launch; NDA/BLA: new drug or biologics approval Source: Sax et al. Figure 2. The relationship between development risk, cost, cycle time, and net present value. Net present value (green) is highly dependent on development risk (blue), development costs (red), and development cycle time. cal need, differentiation, and value-based thinking into the product development cycle in a way that is easily manifest and transparently addressable for both product development teams and decision-making stakeholders is essential in this approach. Integrating evidence-based planning and real-world evidence (RWE) has the potential to reap even bigger rewards for development productivity, as shown in Figure 1 (see page 27).10 To achieve this, we propose the Three-Pillar approach outlined in this paper. Enhance probability of technical success If biopharmaceutical companies are to realize the next level of transformation and achieve greater development productivity, they need to address the development cycle itself by integrating health outcomes, and using better, evidence-based decision-making approaches. As shown in Figure 2, the net present value of a product is highly dependent on development risk, costs, and cycle time. Not surprisingly, including commercial viability and market access in the value equation when addressing development risk and cost early provides a far more complete picture for sound development decision-making. To achieve the desired outcome of better development productivity and commercial success, we propose a Three-Pillar approach based on identification of evidence needed for successful market entry and selection of the right plan to generate this evidence. These three pillars are illustrated in Figure 3 on facing page. 28 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com In Pillar 1, a question-based process identifies what success looks like for the patient, physician, provider, payer, and regulators. A robust target product profile (TPP) is built from the answers to these questions; this will guide creation of an integrated evidence plan that incorporates the clinical and value evidence requirements to support the TPP. Refinement of product needs continues throughout the product life-cycle, including the design of late-stage development and post-marketing programs. This will result in intermittent, but iterative reassessments of the TPP and, correspondingly, the required evidence generation that such a reassessment will necessitate. Second, an integrated evidence plan (IEP) is designed. The goal is to create a direct line of sight from the TPP to the development strategy and straight through to the trials/studies in the program. The IEP divides required information into two categories: (i) data already available, and (ii) evidence that needs to be generated to advance stakeholder decision-making. The IEP then defines how the evidence will be generated within each clinical trial and real-world observational study, and how this will be leveraged to satisfy patient, physician, provider, payer, and regulatory requirements as defined by the TPP. When value-proving outcomes are investigated early in development, they validate the benefit statements and secure a positive recommendation from HTA and regulatory authorities. The IEP also allows a team to set futility criteria, so that if value evidence is not realized in a timely manner, informed and effective decisions to terminate the program can be made. In Pillar 3, scenario development and trade-off analysis are used to challenge assumptions both scientifically and operationally and create an evidence-based “level playing field.” This can be done most effectively through facilitated workshops where collective expertise (subject matter experts) and various options for generating needed evidence are reviewed, modified, and critically evaluated. Advanced analytics optimizes the evaluation of complex time/cost/ risk/value scenarios in a transparent way to drive the decision-making process for key stakeholders. Productivity will benefit most when the approach to the pillars is taken in the context of an integrated partnership of the key stakeholders, with early modeling, visualization, and agreement on the “end game.” True end-to-end integration leverages business processes aligned with the three pillars and also leverages good information technology. Using innovative design approaches, timely access to real-world data (RWD) and patient insights can further drive positive results. This is especially true if the entire endeavor is focused on increasing access to more affordable innovative medical solutions that are not only commercially viable, but also deliver better health outcomes for patients. April/May 2016 TRIAL DESIGN Identify evidence needs Rethinking the development model within today’s healthcare model requires companies to successfully apply the principle of “designing with the end in mind.” This means the starting point and the first pillar in our approach is a robust TPP, based on value to the patient, physician, and provider while meeting payers’ and regulators’ expectations (Pillar 1). Examples of key issues that might be addressed on a question-driven basis during this phase might include: defining the unmet medical need, key points of competitive considerations (versus the existing or emerging standard of care), key scientific claims required for registration, and early market access issues. These can be further refined to include the benefit of the treatment to the patient, how this benefit might be assessed, how the medicine will be differentiated in the market, what will drive physicians to prescribe the therapy, what would a payer require to increase or decrease access, and any likely evolution of regulatory requirements during the time-course of development. This forward-looking thinking is essential, since given the usual time-course of product development, it can be nearly a decade from the time of original decisions until a product reaches the market. ‘Three Pillar’ Value Approach Pillar 1 Pillar 2 Use a question-based approach to identify value to the patient, physician, payer, and regulator Create line of sight from target product profile through to the studies with an integrated evidence plan Pillar 3 Challenge assumptions using advanced decision analytics Source: Sax et al. Figure 3. The Three-Pillar approach linking clinical science and clinical operations underpinned by access to data, information, and knowledge. Advancing Drug Development with Digital Health Sponsored by 4 Key Ways to Integrate Patient-Generated Data into Trials ON-DEMAND WEBCAST Originally aired March 16, 2016 Register for free at www.appliedclinicaltrialsonline.com/act/digitalhealth EVENT OVERVIEW: Digital health is not only changing the way patient data is collected in healthcare, but it is also disrupting the way the pharmaceutical industry gathers data from clinical trial participants. By arming participants with wearable and FDA Class II medical devices, sensors and applications, pharmaceutical companies and CROs can remotely collect activity data along with key biometrics. This stands to significantly restructure the drug development process, allowing companies to bring a drug to market more efficiently and cost-effectively while also improving the clinical trial participants’ experience. Pharmaceutical companies looking to implement a digital health strategy should register for this webinar to: PRESENTERS DREW SCHILLER Chief Technology Officer and Co-Founder Validic JOE DUSTIN Principal, Mobile Health Medidata MODERATOR ■ Learn four key ways pharma and CROs can leverage participant data from digital health devices. ■ Hear real examples of how digital health data is being utilized by pharma. LISA HENDERSON Editorial Director Applied Clincial Trials ■ Discover the benefits, for both pharma and trial participants, of integrating digital health data into drug development. Presented by For questions, contact Daniel Graves at [email protected] TRIAL DESIGN Planning and design Scientific design Health outcomes and value Operational design Operational design Clinical operations Clinical science / commercial viabiltiy Clinical Synergy: Science & Operations Execution Source: Sax et al. Figure 4. The critical interplay of clinical science and clinical operations in driving successful drug development outcomes. Focusing on these issues upfront is essential to success of the Three-Pillar approach; the issues defined in the TPP will determine what evidence is required to support the program and ultimately, what results in terms of cost, time, risk, and value of the product. This closely knit interplay is shown in Figure 4. Furthermore, a value-based TPP defines the threshold that must be achieved for the product to be commercially viable. This then can be used to structure more formal “go/no-go” decisions that can help frame decision-making strategy and help to control biases that tend to favor continuing product development even in the face of low probabilities of success both scientifically and commercially. Create an integrated evidence plan Once key product attributes are defined, the next step (Pillar 2) is to identify key scientific and operational requirements (“specs”) in light of the evidentiary needs for the program. The process of defining requirements segments information into two groups: (i) data/information readily accessible, for example, real-world data, research, literature, and subject matter experts, and (ii) evidence that needs to be generated. The interplay between the data needs for the TPP and evidence needs incorporated into the IEP is shown in Figure 5 (see page 32). Once all the available information and evidence needs have been explored, the next step in the pillar is to use this information to create a line of sight from the TPP 30 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com through to potential studies (the fundamental unit of evidence-generation within a program) by developing an IEP. The development team will look at the evidence needs and begin to link them to study design options that can be used to generate this evidence. Generation of study options encourages teams to explore new and innovative approaches that can later be challenged and evaluated (Pillar 3). Use of unbiased historical data is critical to trial design because it informs the decision criteria for success, failure, and areas of uncertainty. Critical to this evaluation is transparency of data and information. Use of unbiased historical data is critical to trial design because it informs the decision criteria for success, failure, and areas of uncertainty. This has led to increased industry and regulatory efforts—such as the creation of TransCelerate BioPharma11 and the European Medicines Agency (EMA) policy on access to clinical trial data12—to open up “pre-competitive” data for appropriate and approved research. Biopharmaceutical companies have also taken independent steps to provide external researchers with the ability to request access to anonymized patient level data. This facilitates further independent research to improve scientific knowledge and patient care, which, in turn, can contribute to the information generation process during product development. Challenge assumptions Creating a level playing field with a focus on all relevant data, information, and collective expertise is an effective way to evaluate development options (right information/ people/time/decisions). In this third pillar, the team builds and evaluates scenarios based on integrated data, analytics, and subject matter expert knowledge. The trade-offs among options can then be transparently considered, to select the clinical program that optimally addresses the needs defined in the TPP and balances those requirements against cost/time/risk and value considerations. To accomplish this goal, internal siloed subject matter expertise is no longer sufficient—a truly beneficial outcome of Pillar 3 hinges on the ability of the team to model potential scientific, operational, and business outcomes simultaneously, and to identify the decision elements most likely to drive value. This makes integrated evidence planning an increasingly cross-functional responsibility that will benefit from an integrated decision-making framework, based on visualization of information and modeling of April/May 2016 TRIAL DESIGN options. Such a decision framework also provides the opportunity to identify clear futility criteria at the study level, and define program “go/no go” criteria. Maximum productivity and value benefits in the development cycle will occur when clinical development and health outcomes groups function interdependently while leveraging outside sources of expertise and data access. These outside sources can be used to refine the IEP and modify options during Pillar 3, further enhancing the precision of the decision-making process. Benefits of the Three-Pillar approach As of 2014, GSK had adopted facilitated workshops similar to the one described here and requires integrated evidence plans for all assets in development. GSK has also mandated study-level facilitated clinical reviews for all protocols in the design phase at the company. More specifically, an objective facilitator, external to the team, leads a full-team discussion regarding core components of protocol quality (i.e., alignment with product strategy, clarity of objectives/endpoints, appropriate entry criteria, and intent behind the assessment schedule); and offers study design alternatives. Since introducing these work- shops at the study level in 2010, GSK has demonstrated that studies that completed the review have experienced measurable benefits, such as fewer amendments and fewer non-recruiting sites, with a higher likelihood of recruiting to plan. Facilitated workshops have also been conducted at the above study, full program level, enabling development teams to identify and prioritize the critical questions, evaluate the evidence needs at each stage of development, and at times use more advanced decision analytics such as Decision Lens™ or D-Sight™, to identify the right plan and evaluate benefit-risk. For instance, a development team can be asked to identify development Plan A based on traditional study designs to generate required evidence and answer the critical questions, then consider options based on variations: Plan B (adaptive designs), Plan C (seamless designs), Plan D (observational studies and pragmatic trials included), etc. The team then considers the key factors that differentiate one plan from the next. These can be operational factors, such as the ability to recruit or availability of drug supply; or scientific, such as the ability to identify responders, select dose, or collect key endpoints. Once the BEST PRACTICES IN Acquiring, Tracking and Maintaining Biological Study Samples Across Global Trials ON-DEMAND WEBCAST | Originally aired March 17, 2016 Register for free at www.appliedclinicaltrialsonline.com/act/labconnect Increasingly complex biomarker and other specialized testing requirements present a significant challenge to sample testing, logistics and storage. Drug development for early stage and adaptive protocol designs requires a comprehensive, real-time grasp of exactly what samples you have, where they are, and how they are collected, shipped, processed and stored especially from the moment of collection. ■ Increasing blood collection volumes, unique specimen types and specialized collection materials have created new challenges for sites and sponsors for their early phase studies. Presenter: ■ Decisions regarding patient care/ Stephanie Weber safety and treatment are based Director, on real-time data from samples Early Development Services collected during the course of the LabConnect study. Moderator: ■ Protocols are amended quickly Lisa Henderson, needing flexible resources to Editorial Director, ACT implement changes quickly. Sponsored by Presented by Key Learning Objectives: ■ Learn how study complexity poses challenges in sample logistics and management in today’s early stage and adaptive protocol designs. ■ Learn about different methods that can be used to manage samples in these complex studies so you can obtain cleaner results and data real-time, allowing for faster decision making in protocol amendments and study direction. ■ Understand the benefits of a comprehensive sample tracking and management plan that forecasts and determines when, where and how samples will be collected, shipped and stored before the trial begins. Who Should Attend ■ Pharmaceutical and biotech companies. Anyone whose job responsibility is global clinical trial sample management. For questions, contact Daniel Graves at [email protected] TRIAL DESIGN Data-Driven Evidence Data Available Evidence to be Generated Scientific Scientific Burden of illness Natural history of disease Event rates (previous trials) Safety profile (pre-clinical, other therapies) Regulatory requirements Formulary requirements Patent life Potential risks biases Correct formulation Dosing regimen Responder population Efficacy endpoints Safety signals Risk-Benefit proposition TPP IEP Market opportunity Competitive landscape Points of unmet need/differentiation Estimated time to launch Likely market access/pricing/penetration ROI/NPV Pricing benchmarks Portfolio “fit” Commercial Site feasibility Patient eligibility Enrollment projections Operational risk assessments Drug supply/availability Trial costs Operational Early “value” data Key differentiation data Final Value Dossier Market access evidence Payer response to value proposition Pricing sensitivity analyses Feasibility assessment Patient availability Enrollment actual for reforecasting Frequency of risk triggers Ability to achieve milestones Commercial Operational Source: Sax et al. Figure 5. The interplay between the data driving the target product profile and the evidence required from the integrated evidence plan. team has decision drivers and plan options, prioritization can be conducted through advanced analytics, and selections made. Transparency, of development challenges and stakeholder opinions, is created when the session is conducted in this way. When making decisions under uncertainty, it is very helpful to have a framework that comprises the various quantitative pieces of available and important data, coupled with the more subjective, intuitive, and qualitative factors, with a clear understanding of how much weight or importance the various criteria have.13 Often, within companies, there is a challenge around the early assignment of senior expert resources to do such evaluations (i.e., costs will be incurred before the benefits are fully understood). However, better use of technologies that can be used to evaluate scenarios helps to identify the quick wins early on and can minimize the drain on senior expert time and facilitate decision-making. Early use of a computer-assisted design tool as the data-integration platform for facilitated workshops has also led to substantial reductions in early protocol amendments for Eli Lilly14 teams, as well as reductions in design cycle times. 32 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com Focused engagement by knowledgeable drug developers can lead to “quick wins” in decision-making that feed into early development planning. Focused engagement by knowledgeable drug developers can lead to “quick wins” in decision-making that feed into early development planning. The evidence requirements that result then naturally lead to a decision matrix (i.e., early “no-go” decisions based on informed futility criteria can be made with the confidence that a potential target has not been “killed” too early). Implications for drug development The critical success factors that will influence the probability of success are: (i) creating a focus on evidence generation to level the playing field across all players involved in development strategy planning and execution; (ii) making sure the right expertise is involved in the decision-making process; (iii) using all relevant data and advanced analytics to inform decisions and aligning this information with the TPP; April/May 2016 TRIAL DESIGN Productivity Measures Productivity = p (ts)* V] / C] Increase of value Decrease in cycle time Reduction of cost Target product profile drives integrated evidence plan ++ +++ ++ ++ IEP options consider internal and external data (both positive and negative) ++ +++ +++ +++ Stringent management of portfolio Strict limitations of collection of data point to objective(s) of trial Trial Execution [CT* Increase of probability of technical success Effect Planning & Design [WIP* ++ + ++ + Data-driven clinical trial execution ++ +++ ++ +++ Lean, but compliant closure of exit trials ++ Source: Sax et al. Positive effect: + Low ++ Medium +++ High Table 1. The level of impact on productivity in the planning and design and trial execution functions. and (iv) delivering excellence in planning and execution to reduce cycle time and decrease operational costs. The relative impact of these is shown in Table 1. One of the greatest challenges is establishing ownership of strategic decisionmaking and engaging all of the relevant experts. Including the right experts in a knowledge-sharing session (Pillar 1) at the start of the planning process, with access to all relevant data and information (Pillar 2), will enable creation of an initial set of risk-based scenarios for evaluation (Pillar 3). With data and evidence requirements in hand, the primary objective of the scenario-generation/trade-off analysis step is to evaluate plans based on cost, time, and risk to optimize value or probability of success. There should be a clear justification for each piece of evidence to be collected with a clear line-of-sight to the requirements for the trial, derived from the TPP. Time spent generating and testing options will ultimately lead to reduced protocol amendments, greater ability to predict enrollment, less redundant data collection, and fewer issues in data quality. This also allows a more accurate forecast of a trial’s budget, which can be mapped to actual costs in execution. The baseline assumptions also provide an objective basis for monitoring trial progress and outcomes, keeping subsequent decision-making evidence-based, and minimizing potential bias. Encouragingly, the industry recognizes that decisionmaking requires a business model that is expert-led, but data/evidence-driven. However, implementation of such a model requires an understanding of and sharing of risk by all key stakeholders. The healthcare environment is comApril/May 2016 Maximum productivity and value benefits in the development cycle will occur when clinical development and health outcomes groups function interdependently while leveraging outside sources of expertise and data access. plex and there is an urgent need to simplify and have efficient, directed development plan execution. This can only be done with early design and planning linked to evidence requirements based on value generation. Ultimately, bringing science, operations, and commercial understanding together to design a medicine’s development program can result in earlier and more successful product launches with value to the patient at the core. Success requires truly integrated end-to-end partnerships that go beyond current organizational paradigms, to bring evidence and execution together and into alignment. Joining efforts in this way will increase the probability of success and, therefore, patient access to more affordable, innovative, and commercially viable medical solutions. References 1. $1bn cost to bring a new medicine to the market. The Times, Nov 5 2005. http://www.thetimes.co.uk/tto/news/world/article1981765. ece appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 33 TRIAL DESIGN Getty Images/ Jupiterimages 2. Scannell JW, Blanckley A, Boldon H and Warrington B, Diagnosing the Decline in Pharmaceutical R&D Efficiency, Nature Reviews Drug Discovery, Volume 11, March 2012, 191 – 200 3. Tufts Center for the Study of Drug Development press release: Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion, November 18, 2014. http://csdd.tufts.edu/news/ complete_story/pr_tufts_csdd_2014_cost_study 4. Sources: InnoThink Center For Research In Biomedical Innovation; Thomson Reuters Fundamentals via FactSet Research Systems 5. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR et al, How to improve R&D productivity: the pharmaceutical industry’s grand challenge, Nature Reviews Drug Discovery, Volume 9 , 2010 , 203-214. 6. Hay M, Thomas DW, Craighead JL, Economides C and Rosenthal J, Clinical development success rates for investigational drugs, Nature Biotechnology, Volume 1, 2014, 40-51 7. NICE says no to belimumab for lupus. Arthritis Research UK, April 27 2012. Available at: http://www.arthritisresearchuk.org/news/general-news/2012/april/nice-says-no-to-belimumab-for-lupus.aspx 8. Trajenta will not be launched in Germany following AMNOG decision. Pharma Relations, May 2014. Available at: http:// www.pharma-relations.de/news/trajenta-r-steht-patienten-indeutschland-vorerst-nicht-zur-verfuegung 9. HTA in Germany: IQWiG assessment of Linagliptin (Trajenta) and Abirateron (Zytiga). European Confederation of Pharmaceutical Entrepreneurs. January 2 2012. Available at: http://www. eucope.org/en/2012/01/02/hta-in-germany-iqwig-assessmentof-linagliptin-trajenta-and-abirateron-zytiga 34 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com 10. Hughes B, Kessler, RWE market impact on medicines: A lens for pharma, IMS Health Access Point, Volume 3(6), 2013, 12-17 11. Mansell, P, TransCelerate’s Comparator Network now active, Pharma Times, August 17 2013. Available at: http://www.pharmatimes.com/Article/13-08-07/TransCelerate_s_Comparator_Network_now_active.aspx?rl=1&rlurl=/13-11-12/TransCelerate_ unveils_second-year_initiatives.aspx#ixzz2sGtSIOng 12. Publication and access to clinical-trial data EMA/240810/2013, Draft consultation paper, European Medicines Agency, June 2013. Available at: http://www.ema.europa.eu/ema/index. jsp?curl=pages/includes/document/document_detail.jsp?webC ontentId=WC500144730&mid=WC0b01ac058009a3dc 13. A new paradigm for decision-making in the pharma, biotech and life-sciences industries, report by Decision Lens, 2011. Available at: http://www.decisionlens.com/docs/WP_Decision_Making_in_Pharma_Biotech_LifeSciences_2.pdf 14. Sax R and Ramsey J, Using Computer-Assisted Design to Improve the Outcomes of Clinical Trials: A One-Year Follow-Up, Meeting presentation at Disruptive Innovations, Boston, Sept. 20, 2013 Frederic L. Sax, MD, is Global Head, Center for Integrated Drug Development, Quintiles, email: [email protected]; Marla Curran, DrPH, is Real World Evidence Director, Value Evidence and Outcomes US, RD Projects, Clinical Platforms & Sciences, GlaxoSmithKline, email: [email protected]; Sarah Athey is Director, Consulting Europe, Quintiles, email: [email protected]; Christoph Schnorr, MD, is Vice President, Drug Development, Consulting Europe, email: [email protected]; Martin Gouldstone is Director – Lifesciences Advisory, BDO LLP, email: [email protected] April/May 2016 Learn more about Mitigating risk using Risk-based Monitoring On-demand webinar: Originally aired March 22, 2016 View now for free! www.appliedclinicaltrialsonline.com/ act/mitigatingrisk Risk-based Monitoring (RBM) is quickly becoming the standard model for clinical development trial execution. Quintiles, as the RBM market leader, is delivering benefits from their RBM approach to improve data and study quality, enable faster, more informed decisions, and enhance patient safety while mitigating risk. Register for this webinar to understand how to: Presenters: Dr. Jonas Renstroem Associate Director, Strategic Solutions, Quintiles Edward Tumaian Senior Director, Global Project Leadership, Quintiles Moderator: Lisa Henderson Editorial Director, Applied Clinical Trials @ !:.(01>.)*39.+>549*39.&18&+*9>&3)6:&1.9>.88:*8 @ #*99-*7.,-97.802&3&,*2*39897&9*,>.3+472*)'>8.9* feasibility and extensive industry data. @ valuate scientific and operational risks using Key Risk Indicators (KRIs) and data checks. @ Mitigate risk while utilizing a risk-based monitoring (RBM) approach @ Understand key steps in developing an optimized RBM data management plan Presented by: Sponsored by: Quintiles: +1 973 850 7571 Toll free: +1 866 267 4479 www.quintiles.com/services/riskbased-monitoring [email protected] For technical questions about this webinar, please contact Daniel Graves at [email protected] Copyright © 2016 Quintiles @ Build a Risk Assessment Mitigation Plan for your RBM studies CRO/SPONSOR Imagining the Impossible: Immunity to Cancer Chris Smyth, PhD The smaller biopharmaceutical perspective on mastering oncology immunotherapy clinical trials. PEER REVIEW uring the past few years, several novel cancer treatments have emerged that are designed to leverage a patient’s own immune system to disrupt, halt, or reverse cancers. This category, known as immunotherapy or immunooncology, features mechanisms of action as varied as the candidates themselves. Early data with this class of drugs, particularly with checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab, as well as “personalized” immunotherapies such as chimeric antigen receptor T cells (CAR-T) and dendritic cell vaccines, has been so compelling that standards of care in a range of tumors are rapidly shifting, and drug developers are clamoring for ways to leverage these technologies. In light of such innovative treatments, many traditional clinical trial parameters common to chemotherapy or even the more recent targeted antibodies or kinase inhibitors must be revisited for their application to examine the safety and effectiveness of immunotherapies. This challenge, and others presented by immunotherapy trials, require expertise and experience to master, and can be especially challenging within biopharmaceutical companies with smaller staff. This article explores five challenges smaller biopharmaceutical companies should prepare for when embarking on immunotherapy studies. proaches, along with vaccines and non-specific immunotherapies, that pharmaceutical and biotech companies are pursuing to thwart cancer’s hallmark ability to evade the immune system. Targeted mAbs for cancer by themselves are not new—the first FDA approval being rituximab for the treatment of lymphoma, followed closely by trastuzumab for breast cancer nearly 20 years ago. What has emerged recently, however, is an ability to leverage mAbs to reengage the immune system to identify and attack one’s own cancer cells. This category, generally characterized as checkpoint inhibitors, has garnered much interest because such products are designed to, in combination with traditional agents or other immunotherapies, prompt immune attacks that target only cancer cells and spare healthy tissues. They can help the immune system act as it was designed to do, with quite durable effects that can last years. Immunotherapies, particularly more recent immuno-oncology products, are not yet as common as first-line therapies, but pharmaceutical and biotech companies are aggressively pursuing such indications as they examine candidates in a variety of combinations and against various tumor types. The estimated cancer immunotherapy market value, totalling about $41 billion in 2014, is almost half of the overall oncology drug market.1 Three approaches dominate Vaccines Monoclonal antibodies Immunotherapy cancer vaccines are designed to fight, not prevent, existing cancer. Together with preventive cancer vaccines, such as Gardasil and D Monoclonal antibodies (mAbs) are one of the three most significant immunotherapy ap- 36 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com April/May 2016 CRO/SPONSOR Cancer Fighters Source: Smyth Figure 1. These are the three main targets biopharmaceutical companies are focusing on in the immuno-oncology therapy space. Cervarix, which are designed to thwart human papilloma virus infections that can lead to cervical cancer, cancer vaccines sales comprised a market valued at about $4.0 billion in 2014, with modest growth rates anticipated to reach about $4.3 billion in 2019.2,3 One tally estimates more than 280 candidates in cancer vaccine pipelines globally.4 However, to date, the only immunotherapy cancer vaccine approved by the U.S. Food and Drug Administration (FDA) is Provenge (sipuleucel-T), made by Dendreon Corporation, now Valeant Pharmaceuticals. The vaccine was cleared for marketing in April 2010. A second vaccine was cleared in October 2015—Amgen’s T-VEC (talimogene laherparepvec)—which is a dual-acting cancer vaccine/viral therapy for melanoma patients.5 Non-specific immunotherapies Non-specific immunotherapies target cancer cells indirectly by prompting immune system attacks. Among this group of treatments are laboratory-made cytokines, interleukins, interferons, and GM-CSF, as well as mAbs designed to alter the function of T-cell checkpoints.6 PD-1/PD-L1. Cancer cells are adept at manipulating and controlling T cells to ignore tumor cells. Recent drugs are designed to target a T-cell checkpoint protein’s function to help counter that control. Such drugs interfere with either the programmed death 1 (PD-1) receptor or its binding protein, PD-L1. PD-1, when activated by PD-L1, puts the brakes on T cells, which while useful for regulating autoimmunity, also allows cancer to proliferate. Cancer cells can express PD-L1, thus permitting them undue influence over T cells. Such cancers are often aggressive and, in the past, patients had a poor prognosis. April/May 2016 Checkpoint inhibitors are helping to change this prognosis via two different mechanisms of action. They can protect PD-1 from cancer cell manipulation or they can bind up the cancer cells’ PD-L1 to limit its interaction with T cells. The mAb pembrolizumab was, in September 2014, the first PD1-blocking drug to receive FDA approval, with the second, Opdivo (nivolumab), made by Bristol-Myers Squibb, receiving approval in December 2014, both indicated for certain melanomas. In March 2015, the FDA expanded Opdivo’s indication to certain lung cancers, and in July it was approved in Europe for non-small cell lung cancer. Morningstar projects these two drugs will be worth $33 billion by 2022 because both are being tested for other cancer types.7 Small and mid-sized biopharmaceutical companies play significant, pioneering roles in innovating and adapting existing drug designs to create new immunotherapies. CAR immunotherapy uses a patient’s own T cells to fight cancer. Through genetic engineering, the T cells are modified and induced in the laboratory to produce CARs corresponding to an antigen of a patient’s specific cancer cells, such as the CD19 protein on the surface of cancerous B cells. After billions of copies are made and reintroduced to the patient, the T cells recognize the cancer cells bearing the antigen and induce a lethal immune response. Oncologists have hailed CARs as very promising for both solid tumor and hematologic malignancies; in fact, CARs eventually may “become a standard therapy for some B-cell malignancies.”8 BiTE antibodies are two separate laboratory-made antibodies that are bound together. One antibody binds to a patient’s T cells, while the other links to certain markers largely expressed on the cancer cell, such as CD19. When bridged together, the T cells can launch attacks that induce cancer cell death. Amgen’s investigational BiTE antibody blinatumomab received FDA breakthrough therapy designation in July 2014 and was approved in December 2014 for a specific type of acute lymphoblastic leukemia. The company also announced an agreement in January 2015 with The University of Texas MD Anderson Cancer Center to explore the use of BiTE technology for myelodysplastic syndrome (MDS).9 Special challenges for smaller biotechs pursuing immunotherapy clinical programs Small and mid-sized biopharmaceutical companies play significant, pioneering roles in innovating and adapting existing drug designs to create new immunotherapies. Because such sponsors typically have limited staff, they often require appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 37 CRO/SPONSOR outsourcing support to plan, launch, and manage clinical investigations. When seeking support, sponsors should assess their CROs and vendors for expertise and experience specific to immuno-oncology, because these types of trials, more than traditional chemotherapy studies, bring with them several obstacles, such as those characterized by the Society for Immunotherapy of Cancer (SITC).10 Obtaining protocol approvals Smaller-sized sponsors may find themselves for the first time negotiating the trial protocol, conduct, and endpoints, as well as the regulatory pathway, either alone or with a larger partner. A CRO can provide experience-based counsel and tactical support to write or review a trial protocol that ensures successful recruitment and data collection, as well as the required evaluations. Because immunotherapy endpoints are not traditional, and oncology practitioners are still gaining experience with this class of drugs, a well-written protocol can guide the investigators and trial staff as they adapt to this new class of treatments. The protocol design is particularly important because of the emerging popularity of testing combinations of drugs within the same protocol. As part of protocol drafting, or even a near-final review before finalization, sponsors should understand the “sticking points” in the regulatory processes as well as the institutional review boards and independent ethics committees (IRB/IEC) processes, enabling sponsors to address them proactively in their trial design and submission material. As with oncology practitioners, while site-level regulatory bodies have reviewed and approved immunotherapies, many IRB/ IECs may be unfamiliar with immunotherapy clinical trial designs, methods of action, evaluations, or side-effect profiles. Country-level approval processes for sponsors of international trials must address the varying requirements regarding the production and use of biologics by different national or regional regulatory bodies. For example, good manufacturing practice (GMP) regulations are required for trials in the European Union, but FDA recognizes that commercial production and warehousing, which are subject to GMP regulations, may not be appropriate for the manufacture of Phase I investigational drugs. Therefore, the FDA requests sponsors submit product chemistry, manufacturing, and control information as part of an investigational new drug application (IND) for a determination of sufficient safety. Enrolling and retaining the right patients Another challenge for sponsors is identifying, recruiting, and retaining specific patient populations as defined by their immune status and genetic makeup of their cancers, both of which are entwined with the development of enrollment and endpoint criteria and may require companion diagnostic tests. Addressing this challenge involves many evolving strategies, including the use of biomarkers and ge- 38 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com netic sequencing data. Smaller companies may need assistance from a CRO’s scientific and data team to plan robustly for how they and trial sites might address such issues for the duration of a trial. Immunotherapy clinical trials require larger scale product production but with the same purity and specificity as preclinical studies. The International Cancer Genome Consortium (ICGC), coordinated by the Ontario Institute for Cancer Research in Toronto, Canada, publishes information to help guide treatment development and patient selection. The ICGC aims to catalogue every genetic mutation in 50 different cancer types by analyzing a minimum of 500 individual samples of each type. ICGC participants hail from Australia, Canada, France, India, China, Japan, Singapore, the U.K., and the U.S. Another resource is a SITC catalogue of “references and online resources relevant to the discovery, evaluation, and clinical application of immune biomarkers” so that they might be applied to the “development, clinical evaluation and monitoring of cancer immunotherapies.”11 Moreover, the Cancer Immunotherapy Trials Network (CITN) is addressing diagnostics and bioinformatics as part of its mission to make immunotherapies broadly available to patients with cancer. CITN, funded by the National Cancer Institute (NCI) and Fred Hutchinson, designs and conducts early phase trials to provide “high-quality immunogenicity and biomarker data that elucidate mechanisms of response or failure and thereby facilitate the design of subsequent trials ... [and uses] only GMP agents with validated reproducible and reliable manufacturing at scale by a company, the NExT (NCI Experimental Therapeutics) program, the former RAID (Rapid Access to Interventional Development) program, or an equivalent experienced organization.”12 CITN member sites include NCI and 29 academic medical centers, and works in collaboration with foundation and industry partners. Planning for logistics, product production, and assessment Preclinical immunotherapies can be made in the laboratory on a small scale. In contrast, immunotherapy clinical trials require larger scale product production but with the same purity and specificity. Unlike small molecules, however, targeted vaccines are not typically made in homogenous batches. Rather, they require harvesting immune cells and tumor samples from individual patients and different trial sites at different times, transport of these samples to qualified facilities for manipulation and proliferation, and then shipping back to the investigator for patient infusions. April/May 2016 CRO/SPONSOR Response Criteria Adjusted Source: Smyth Figure 2. Measuring patient response is a known challenge for immunotherapies, a reality that has prompted the revision of clinical trial designs. Temperature control, customs clearance facilitation and regulation compliance are just part of what sponsors need to consider and require for their secure chains of custody during immunotherapy trials. Sponsors may need counsel on manufacturing sources for their candidate immunotherapies if they do not own facilities or have access to one via a large pharmaceutical partner. A CRO can advise sponsors on the availability and capability of academic or contract-based manufacturing facilities that can reliably provide the quality and quantity of product needed to support the trial’s sites. CROs also can advise on a trial’s assessments, such as the best methods and facility for centralization of immunological monitoring or how to use training and protocols to reduce data variability if different laboratories must be used to accommodate trial sites. Dosing and measuring response Determining the ideal dosing protocol for the best patient response can be novel territory for immunotherapy developers. Large pharma companies can obtain experience through multiple advisors, trials, and resources that permit revisiting the drawing board to make such determinations. In contrast, smaller sponsors usually have the budget for one trial. Early phase trials in oncology traditionally aim to establish the maximum tolerated dose (MTD) for later phase trials. The challenge for sponsors here is that immunotherapies can exhibit therapeutic responses at dose levels below where toxicity is seen, and thus one may not necessarily want to identify the highest possible dose that a patient can tolerate. In addition, immunotherapies are now typically being investigated as part of a combination treatment with other marketed or investigational agents. Even if the safety profile of each agent as a monotherapy is well characterized, the effects in combination are unknown and can be substantially different than anticipated. SITC noted that such combinations are problematic for using classical April/May 2016 methods to determine MTD and recommended that an optimal biologically active dose (BAD) might best consider both a toxicity grade and an immune response score.14 Measuring patient response is a known challenge for immunotherapies that has prompted the revision of clinical trial designs. No “universal” criteria to measure immunotherapy response have been adopted for research or clinical care, and the FDA still holds survival as a gold standard for cancer treatment. That said, both pembrolizumab and nivolumab were initially approved based on small, singlearm trials that utilized surrogate endpoints such as overall response rate and duration of response. Looking back, traditional chemotherapy patient response assessment drove the development of Response Evaluation Criteria in Solid Tumors (RECIST) and modified World Health Organization (WHO) criteria, which rely on a reduction in tumor burden. RECIST uses straightforward, one-dimensional measures, such as the sum of the longest diameter of the tumors.13 Immunotherapies are not well served by these criteria, in that patients’ responses may not immediately result in tumor burden reduction. Rather, they may experience pseudo disease progression before regression or stabilization. For example, an immune response such as T-cell infiltration can increase a lesion size that without a biopsy may appear as tumor cell proliferation. Of note, as part of the ipilimumab Phase II melanoma clinical trial program, investigators proposed four immunerelated response criteria (irRC), noting all were associated with favorable survival: “(a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions.”14 irRC, which quantifies response in two dimensions and then calculates their products and their sums, helps reinforce that disease progression is not equivalent to drug failure, and that longer times, even months, may be needed for therapeutic effect and evaluation. To address limitations of RECIST and irRC, new criteria, irRECIST, were introduced in 2014.15 Created as an adaptation of irRC, irRECIST is designed “to allow for treatment evaluations and assessments that better meets both investigators’ and patients’ needs and with that better reflects sponsors’ demands for more reliable and reproducible study data analyses.” irRECIST also contains guidance for ambiguous cases. Like RECIST, irRECIST is unidimensional and enables high reproducibility of results, and its design produces results that highly correlate to irRC. However, the clinical relevance of irRECIST needs confirmation. The authors intended that irRECIST would reduce ambiguity in assessments and promote harmonization between trial sites and central or independent data reviewers, so that all would use the same criteria specifically designed for immunotherapies. appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 39 CRO/SPONSOR Many immunotherapy clinical trials continue to use objective response and progression-free survival as endpoints, but overall survival is still strongly suggested. 3. Immunotherapy sponsors and investigators must be adept at recognizing, characterizing, and monitoring both immune-related adverse events and emergent resistance. 4. 5. 6. Reactions — adverse and otherwise Immunotherapy sponsors and investigators must be adept at recognizing, characterizing and monitoring both immunerelated adverse events (irAEs) and emergent resistance. Sponsors will readily anticipate known irAEs such as flu-like symptoms of chills, fatigue, fever, back pain, nausea, joint ache, and headaches. However, serious adverse reactions (SAEs) are possible in immunotherapy trials that for the unaware can have dire consequences. For example, SAEs among patients receiving sipuleucel-T included acute infusion reactions. One health concern with ipilimumab is its ability to enable damaging autoimmune responses, which can be fatal. Consequently, the FDA required a risk evaluation and mitigation strategy (REMS) and a patient medication guide as part of the ipilimumab approval. Cancer immunotherapies, because of their significant patient-specificities and durable responses even after treatment ends, have the potential to enable a patient’s immune response to recognize and adapt as a cancer mutates. To date, they have been quite successful for small populations of patients, while demonstrating the possibility to define optimal use for a majority of patients with cancer. Future studies will help define the optimal use of immunotherapies in different tumor types as single agents or as part of combination therapies with other immunotherapies or cancer drugs. If proven, first-line, earlier stage immunotherapy treatment may improve the efficacy and longevity of patient responses. Robust clinical trials that address the challenges of assessing the efficacy and safety of immunotherapies in the most appropriate patients will yield the data to build this new treatment paradigm. References 1. Kelly Scientific Publications, “Global & USA Cancer Immunotherapy Market Analysis to 2020.” April 2015. http://www.lifescienceindustryresearch.com/global-usa-cancer-immunotherapy-marketanalysis-to-2020.html 2. BCC Research, “Cancer Vaccines: Technologies and Global Mar- 40 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com kets.” January 2015. Report Code: PHM173A. http://www.bccresearch.com/market-research/pharmaceuticals/cancer-vaccinestechnologies-global-markets-report-phm173a.html. BCC Press Release, “Global Cancer Vaccine Market to Reach $4.3 Billion in 2019.” Dec. 19, 2014. Research and Markets, “Cancer Targeted Therapy Market & Clinical Insight 2015.” April 9, 2015. Press Release. http://globenewswire.com/news-release/2015/04/09/722930/0/en/Global-CancerTargeted-Therapy-Market-Clinical-Insight-2015.html. FDA, “FDA Approves First-of-its-Kind Product for the Treatment of Melanoma.” Oct. 27, 2015. Press Release. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm. American Cancer Society, “Non-specific cancer immunotherapies and adjuvants.” Sept. 5, 2014. http://www.cancer.org/treatment/ treatmentsandsideeffects/treatmenttypes/immunotherapy/cancer-immunotherapy-nonspecific-immunotherapies 7. Staton, T. “The PD-1 wave? Report says it’s a $33B tsunami, with BMS surfing for first place.” FiercePharmaMarketing. March 4, 2015. http://www.fiercepharmamarketing.com/story/pd-1-wavereport-says-its-33b-tsunami-bms-surfing-first-place/2015-03-04 8. NCI, “CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers.” October 16, 2014. http://www.cancer.gov/ cancertopics/treatment/research/car-t-cells 9. MD Anderson, “MD Anderson and Amgen announce agreement to develop BiTE® therapies for myelodysplastic syndrome.” Press Release January 12, 2015. http://www.mdanderson.org/newsroom/ news-releases/2015/md-anderson-amgen-agree-to-develop-bitetherapies-for-myelodysplastic-syndrome.html 10.Fox, B.A., et al. “Defining the critical hurdles in cancer immunotherapy.” Journal of Translational Medicine. 2011, 9:214. http://www. translational-medicine.com/content/9/1/214 (Dec. 14, 2011) 11. Bedognetti, D., et al. “SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery.” Journal of Translational Medicine 2011, 9:155. http://www.translational-medicine. com/content/9/1/155 (Sept. 19, 2011) 12. Cancer Immunotherapy Trials Network. 2015 http://citninfo.org/ index.html 13. Park, J.O., et al., “Measuring Response in Solid Tumors: Comparison of RECIST and WHO Response Criteria,” Jpn. J. Clin. Oncol. (2003) 33 (10): 533-537.http://jjco.oxfordjournals.org/content/33/10/533.full 14. Wolchok JD, Hoos A, O’Day S, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009, 15:7412-20 15. Bohnsack, O., Hoos, A., Ludajic, K., “Adaptation of the immune related response criteria: irRECIST,” Poster 1070P, ESMO 2014, Sept. 14, 2014. Annals of Oncology. 2014, 25 (suppl_4): iv361-iv372. 10.1093/annonc/mdu342. http://oncologypro.esmo.org/MeetingResources/ESMO-2014/Immunotherapy-of-Cancer/Adaptationof-the-immune-related-response-criteria-irRECIST. Chris Smyth, PhD, is Managing Director, Novella Clinical April/May 2016 Learn more about Immuno-Oncology Insights: Top 5 Challenges in Today’s Immuno-Oncology Trials Live webinar: Thursday, April 7, 2016 11 am – 12 pm EDT Register now for free! www.appliedclinicaltrialsonline.com /act/trials Presenters: Eric Groves, MD, PhD Vice President, Advisory Services, Quintiles Matthew Bentley, PhD Clinical Project Manager, Oncology, Quintiles Immunotherapy is one of the most promising avenues of research in the battle against cancer. As initial checkpoint inhibitors come to market, the immuno-oncology development landscape is exploding. Now, the pressure is on to apply insights from existing studies to ensure future trials are quick and efficient, yield high-quality data, and assure patient safety. In this webinar, we’ll share lessons learned for your immuno-oncology program through examining the challenges that come with the new complexities of immuno-oncology studies: A Rapidly changing SOC Kathleen Gray, PhD Scientific Advisor, Q2 Solutions A Highly complex early phase studies Moderator: A New safety signals and combination therapies Lisa Henderson Editorial Director, Applied Clinical Trials A Specialized laboratory criteria A Faster than expected enrollment By attending this webinar you will: A Understand the impact of new therapies and care standards on trial planning and design. A Identify new demands of laboratories for expedited TAT and fail-proof sample tracking. Sponsored by: Quintiles: +1 973 850 7571 Toll free: +1 866 267 4479 www.quintiles.com/oncology [email protected] For technical questions about this webinar, please contact Daniel Graves at [email protected] Copyright © 2016 Quintiles Presented by: A Learn about the new operational challenges of immuno-oncology studies and critical success factors TRIAL DESIGN Overcoming Early Phase Oncology Challenges Karen Ivester How to meet the rigorous safety and efficacy demands critical to evaluating newer targeted cancer therapies. PEER REVIEW eveloping novel, safer treatments that may be curative for many individuals living with cancer depends not only on continued use of existing products but on the clinical and regulatory success of the newest treatments—including promising developments focused on targeted/immunotherapy combinations and immune checkpoint blockade therapies which are demonstrating that immunity is the key to long-term responses. Rigorous evaluations in clinical trials to assess efficacy and safety in patients are critical to the development of these highly sensitive targeted/immunotherapy combinations. New molecular entity (NME) selection, protocol development, patient population, and principal investigator (PI) and site selection are key areas in which to focus to establish a foundation for the successful execution of an early phase oncology trial. drugs were approved under the FDA accelerated approval program, which allows early approval of a drug for serious or life-threatening illnesses that offer benefit over current treatment. Once accelerated approval is granted, these drugs must undergo additional testing. These recent approvals in oncology were based on a “surrogate endpoint” (e.g., a laboratory measure) or other clinical measure considered to predict the clinical benefit of a drug.1 Given the cost of drug development (which now exceeds $2.5 billion2), the selection of those molecules that have the highest potential for success is crucial. There is more at stake than the financial cost—we must consider the patient population, the PIs and the sites. They are all finite and the demands placed upon them are seriously impacting the future of clinical trials—especially early phase clinical trials. New molecular entity selection Protocol development and optimization of design D A substantial number of NMEs move through Phase I into Phase II; however, progression from Phase I through approval each year is very low. In 2014, approximately 64% of drugs moved from Phase I to Phase II and 10.4% moved from Phase I through approval. From 2005 through 2013, FDA’s Center for Drug Evaluation and Research (CDER) has averaged approximately 25 novel new drug approvals per year. These include drugs for all diseases and all indications. In 2014, 41 novel new drugs were approved—six in total for oncology. These 42 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com Nearly 60% of protocols are amended during the trial, according to the Tufts Center for the Study of Drug Development.2 In order to reduce or avoid costly protocol amendments, oncology sponsors must view early phase protocol development holistically and assist our sponsors in optimizing their protocol development. Important questions to consider include: t Has the early work been done (toxicology, animal studies, targeted starting dose established, appropriate formulation and manufacApril/May 2016 TRIAL DESIGN turing stability and scalability evaluated)? Performing a gap analysis can assist the client in identifying potential issues early on; therefore, an early evaluation by regulatory can be of added value. t Has the sponsor identified biomarkers for the mechanism of action (MOA)? Has the patient population been selected based on these biomarkers and the MOA? Are assays validated? t What is the turnaround time for any procedures or assessments and how will this impact patient enrollment? We must keep in mind these patients have been diagnosed or their disease has progressed and may also be aggressive. Asking them to wait four to six weeks may not be acceptable for them or for their treating surgical or medical oncologist. t Are all of the protocol-defined procedures and assessments appropriate for collecting data that will support a new drug application or investigational medicinal product dossier? t Is all of the information critical in a Phase I or Phase IIa (proof of concept, efficacy, or mechanism of action study) where the intent is to inform early go/no-go decisions? If it isn’t critical to inform the decision (e.g., not a critical variable) and not critical for safety, then there is a need to provide a rationale for collecting the variable, entering it into the data collection system and monitoring it. Significant costs lie in the collection of unnecessary information in early phase clinical research and this is an area where protocol and electronic case report forms (eCRFs) can be optimized and improved considerably. As sponsors, researchers, and contract research organizations (CROs) gain expertise in early phase research, this will greatly improve and reduce sponsor and CRO costs as well as reduce site burden in data collection. First-in-man studies for many candidate chemotherapies are constructed to identify the maximum tolerated dose and dosing schedule. Yet, technologies have yielded investigational agents that are designed to act with greater precision to inhibit cancer cell growth or promote cancer cell death. For sponsors of these newer targeted molecular agents, trial protocols may require an optimal biological dose endpoint rather than a more traditional maximum tolerated dose (MTD) endpoint. Consequently, the protocol will need to clearly define how to determine the recommended Phase II dose, and describe new assays or procedures to measure biologic endpoints, as well as to capture traditional patient safety assessments. The investigational brochure (IB) contains the information that will assist and guide the regulatory and safety advisory committees in assessing the risk/benefit of the NME. Early compound knowledge can also assist in the April/May 2016 most critical variables to collect regarding safety, thereby reducing the collection of unnecessary data. Thoughtful design of an early stage trial protocol can help characterize biomarkers that will facilitate appropriate patient enrollment in follow-on advanced trials. Re- For sponsors of newer targeted molecular agents, trial protocols may require an optimal biological dose endpoint rather than a more traditional maximum-tolerated dose endpoint. member that most of the oncology drugs approved in 2014 were approved based on a surrogate endpoint or a predictor of clinical benefit. Importance of adaptive design in early phase clinical trials Utilizing pharmacokinetic/pharmacodynamic (PK/PD) to guide dose escalation decisions and adaptive designs that enable adjustments to the study design and/or specific patient population as the trial progresses may increase the speed of the dose escalation and reduce patient exposure to doses that are not effective, as traditional designs often start with a dose well below animal toxicity. This lowest dose has no effect and the traditional method doesn’t allow reaching higher doses quickly. Interest in adaptive design study methods arises from the belief that these methods hold promise for improving drug development compared to conventional study design methods (such as 3 + 3 designs). Adaptive design approaches may lead to a study that provides the same information, but more efficiently, increases the likelihood of success, or provides more information regarding the drug’s effect, which may also lead to more efficient followon studies. The more progressive adaptive design algorithms permit a change in dose level after each patient is treated based on the accumulated responses of previously enrolled subjects. These algorithms lead to more dose-level changes, both increases and decreases of the dose, as the algorithm selects an exposure for each subject to the dose that will contribute the greatest amount of information towards the ultimate conclusion. By permitting escalation after each individual subject if that subject did not have a doselimiting toxicity (DLT), it is possible to reach the middle or higher end of the dose-response curve with fewer subjects at each of the prior levels. Adaptive designs allow for completing the study more rapidly than the traditional sequential fixed-size cohort appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 43 TRIAL DESIGN design. CROs can assist sponsors in exploring the features of different study designs with regard to the balance of efficiency (study size) and subject safety. Study simulations with multiple combinations of escalation criteria, dosestep size, and hypothetical assumptions around relationships of exposure to severity and frequency of adverse events (AEs) may be useful in evaluating different designs. These simulations can assist in assessing the risks and selecting a design that offers improved efficiency without increasing risk excessively.4 Adaptively designed studies that enroll patients who are most likely to benefit could finish faster and consume fewer resources, which could yield economies in time to development, as well as cost and reduced burden on PIs and sites. Finally, in assessing the protocol development, is the imaging, procedures, and assessments in line with the standard of care (SOC) for the patient population, the disease indication, and the country/site in which the clinical trial is being conducted? This can vary significantly and, prior to site selection, feasibility, and the use of prescribing data can help determine the most appropriate country/site mix. Keeping imaging and disease assessments SOC will decrease costs and minimize regulatory delays from radiation committees at both the country and site levels. Patient selection in early phase clinical trials Novel approaches to patient/subject selection can be used to ensure we are selecting the patients most likely to benefit from the NME. “Genotyping” tumors from patients is paving the way for targeted therapies for people living with cancer. The translational research and the technical capacity to screen large numbers of tumors have taken years and significant collaboration between oncologists and pathologists. Molecular profiles and tumor typing has identified the genetic abnormalities that activate and drive tumor growth. Understanding cancer development at the molecular genetic level, identifying mutations, and creating NMEs that target them are significantly improving outcomes for patients with lymphoma, breast, brain, GI, and lung cancers, as well as other indications. The process of extracting and purifying DNA and genotyping it using sophisticated software and assays can screen for hundreds of mutations that have been identified and linked with tumor growth.5 The identification of genetic mutations in tumors has been critical in the development of multiple treatments in oncology and now serves as the basis for personalized, targeted therapies as we have seen in adaptive clinical trials such as the I-SPY 2 TRIAL. This clinical trial was designed to treat patients with breast cancer, and the patients are assigned to treatment options (of which there 44 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com are many in a single trial) based on the molecular characteristics (or biomarker signatures) of their disease. 6 The genotype and mutations within specific tumors and indications are driving the patient population for targeted therapies. These innovative, genomically targeted therapies often provide good initial responses. For example, drugs that target a specific BRAF gene mutation in melanoma can shrink the tumors in about half of the patients. This approach has resulted in frequent, short-lived responses for multiple targeted therapies. Resistance develops when tumors have multiple genomic defects that drive the disease. After the targeted therapy knocks out one driver, another driver can take over and activate tumor growth again. To combat resistance and relapse, cancer immunotherapy has found a role in combination with genomically targeted therapies. This immune checkpoint blockade therapy has resulted in an approach that treats the immune system which is capable of recognizing distinctive features of cancer cells and launching T-cells that target and shut down tumor-specific antigens at the peptide level. The first immune checkpoint blockade, ipilimumab (Yervoy®), has been approved for melanoma. A second immune checkpoint inhibitor showed that pembrolizumab (Keytruda®) is also effective in the treatment of melanoma, and the drug was approved in 2014. Collaboration between researchers who focus on targeted therapies and researchers who focus on immune checkpoint therapies will likely result in the development of targeted/immunotherapy combinations which will have “curative potential.” 7 Patient selection, down to the genetic mutation level, is impacting early phase clinical trials in ways not previously anticipated. The institutions that have the capability to utilize genotyping, in mass, will be at an advantage to quickly identify patients with tumors that match the novel therapies in these clinical trials. As adaptive designs expand and we learn more about specific therapies and combination therapies for multiple indications, there will be more I-SPY 2-type clinical trials in which patients have their tumor genotyped initially and are then given combination(s) of treatment developed specifically for their disease. Currently, this means sites will need to identify patients for clinical trials that have these specific mutations. In reality, this translates to a lower enrollment rate in some instances, especially if there are rare or multiple genetic mutations in the targeted tumor types or indications. It becomes very important to research and learn more about the occurrence of each of the genetic mutations in various oncology indications in order to plan for the number of sites required to enroll the study. Working with feasibility teams to research the indicaApril/May 2016 TRIAL DESIGN tion, frequency of mutation, and specific line of therapy for each therapy or combination therapy will be critical to the success of early phase oncology clinical trials as the targets become more specialized. While challenging, the potential for effective, long-lasting treatment outcomes in multiple indications is a reality. Site selection and management With the NME identified, a well-designed protocol in place, and the patient population selected, attention turns to the selection and activation of appropriate clinical sites. Historical site data, specifically site enrollment patterns with similar oncology indications, are critical to choosing experienced and qualified sites. Knowledge of a site helps determine which facilities have reliable PIs and clinical research staff that both understand and can “bring to life” the complexities of Phase I clinical trial protocols, including: t Patient cohort management t Recruitment of niche patients, often with specific genetic mutations/alterations t Management of DLTs and participation in dose-escalation decisions t Collecting, processing, and analysis of PK/PD samples t Extensive biological specimens are collected, genotyped, and analyzed t Commitment to timely data entry and query resolution Site efficiencies can also be created when a sponsor or contracted CRO is familiar with each site’s institutional contracting procedures, scientific and ethics review board practices, and document requirements. Detailed knowledge of local trial site compliance with federal, local, and its own institutional regulations to protect and care for human subjects is critical. Finally, the use of document exchange por tals can accelerate overall clinical trial timelines and increase efficiencies without sacrificing quality or endangering regulatory compliance. are withdrawing from clinical research and development altogether. The number of clinical trial investigators has fallen significantly since 2008 and there is a high turnover rate among those filing 1572s. Patient selection, down to the genetic mutation level, is impacting early phase clinical trials in ways not previously anticipated. Thirty-five percent of investigators in the U.S. are not returning to conduct another clinical trial since initially submitting a 1572 in 2006. The numbers of investigators not returning to conduct clinical studies are even higher in other countries, as reflected below: t Canada: 55% t South America: 53% t Asia Pacific: 53% t Africa: 47% The reasons given are system and organization, time involvement, resources, lack of clinical or scientific ratio- When you’re passionate about what you do, it doesn’t feel like work. Principal investigator burden and impact on clinical trials While the number of NMEs and clinical trials are increasing, the number of PIs are declining and many April/May 2016 At WCG, we’re more than an IRB; we’re a clinical services organization. We’re passionate about protecting others, and committed to optimizing the performance of clinical trials. Join the team. Join the revolution. www.wcgclinical.com/careers. appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 45 TRIAL DESIGN nale for the research, lack of interest in the research topic, complexity of trials, excessive trial costs not covered by the sponsor, and disruption to clinical practice. Some of these barriers, such as ethics submissions, are essential; however, many of the system, organization, and other obstacles are under the direct control of the sponsor company and the contract research organization (CRO) partner.3 The most burdensome tasks identified by PIs and sites were: t Completing contractual and regulatory documents t Getting paid for clinical trial work on time t Recruiting patients t Budgeting clinical trials t Completing feasibility surveys t Reporting serious adverse events (SAEs) t Taking GCP training t Completing site information forms t Working with ethics committees t Interacting with remote and on-site monitors t Retaining patients t Tracking clinical trial supplies This leads to a lower proportion of experienced sites and a high turnover rates among new PIs. The resulting impact for sponsors is higher operational costs, including substantially higher site start-up costs in areas of site selection, qualification, and training. What can sponsors and CROs do to assist PIs and sites? It is important to: t Guarantee site payments within 30 days t Streamline start-up activities (GCP training, contracting, essential document collection) t Utilize innovations such as TransCelerate BioPharma Inc. t Standardize CDAs and CTA clauses t Share contractual preferences If we are to reverse the trends of declining early phase physicians and sites and reduce turnover, sponsors and their CRO partners must be willing and able to change their processes and to decrease the burden for clinical trial investigators and sites. By assisting sponsors in becoming selective regarding their NMEs, thoughtful about protocol designs and their selection of the right target patient population, we can significantly impact the exciting landscape of early phase clinical research. We have a lot of work to do in identifying the ideal sites and PIs and, when we find them, we must seek to understand their needs, minimize their burdens, and let them know we value them so they continue to engage in the collaborations that will result in bringing cancer treatments to people living with the disease. Sponsors, CROs, sites, PIs, and, most importantly, patients will benefit. 46 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com Getty Images/ SCIEPRO This is an exciting time in early phase oncology—novel, targeted/immunotherapy treatments are being identified that target significant mutations and engage the immune response using multiple formulations and delivery systems. Oncology drugs and medical device, diagnostics, radiation, proton therapy, and nanotechnology are fusing to have a significant impact on cancer treatment that will continue to fuel innovation. Within the next decade or two, many cancers could become a fully treatable illness for many individuals. We may even find, in many indications, cancer is curable as we focus and extend our collaborations and share knowledge as we move forward. References 1. CDER’s Novel New Drugs 2014 Summary, January 2015. 2. Source: Tufts Center for the Study of Drug Development 3. E. Cascade, M. Nixon, and C. Sears, “Sustaining the Investigator Pool: Understanding Operational Burden and Implementing Valuable Supportive Solutions,” Applied Clinical Trials (Nov. 3, 2014). 4. Adaptive Design Clinical Trials for Drugs and Biologics, Draft Guidance, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), February 2010. 5. L. Ellisen, K. Flaherty, and A. Shaw, “Tumor Genotyping Brings Personalized, Targeted Therapies to Patients, “Advances at the Mass General Cancer Center, Summer 2010 6. Sponsor: QuantumLeap Healthcare Collaborative, Clinical Trials.gov 7. P. Sharma and J Allison, “Review highlights potential of cancer immunotherapy plus targeted therapy, “MD Anderson News Release (April 9, 2015). Karen Ivester, RN, MA, is Vice President, Clinical Operations, Ivester Research April/May 2016 Learn more about Overcoming regulatory and statistical hurdles of biosimilars drug development Designing smarter trials Live webinar: Wednesday, April 6, 2016 11 am – 12 pm EDT Register now for free! www.appliedclinicaltrialsonline.com/ act/biosimilars Presenters: Kamali Chance, MPH, PhD, RAC Vice President, Head, Global Biosimilars Regulatory Strategy Biosimilars Center of Excellence at Quintiles Russell Reeve Sr. Strategic Biostatics Director, Center for Statistics in Drug Development, Innovation at Quintiles Moderator: Lisa Henderson Editorial Director, Applied Clinical Trials Bonus content Attend to recieve a free executive summary of this webinar. The success of biologics for many debilitating medical conditions such rheumatoid arthritis, cancers, etc. and their spiraling costs timed with patent expiries have led biopharmaceutical companies to develop biosimilar products. Biosimilars have the potential to increase access and provide lower cost options for treatment of many medical conditions. Before you consider putting your biosimilar drug through development, you need to be informed of the regulatory pathways and complexities that will be involved—as well as steps you should take to address these regulatory considerations for making important decisions about your biosimilar products. Join Quintiles biosimilar experts Kamali Chance, MPH, PhD, RAC, and Russell Reeve, PhD, as they address the following: @ $.+ '9+391/,,&.'9.'55+38942+*/)/3+8)42/3- off-patent and how are biosimilars capitalizing from these patent expirations? @ &.>'7+(/48/2/1'78/25479'3994(/45.'72' @ &.4'7+842+4,9.+945)425+9/9478/39./885')+ Presented by: @ &.'9'7+9.+*/,,+7+39)42543+3984,(/48/2/1'797/'18 @ 4<2/-.9>4:7*+)/8/43894*'>',,+)99.+,:9:7+4,>4:7 biosimilar trials and marketing success? Sponsored by: For technical questions please contact Daniel Graves at [email protected] Toll free: +1 866 267 4479 Direct: +1 973 850 7571 Web: www.quintiles.com Email: [email protected] COMMUNITY Business and People Update People tAdvanced Clinical B DMJOJDBM EFWFMPQNFOU PSHBOJ[BUJPO IBT QSPNPUFE Julie Ross UP 1SFTJEFOU tExco InTouch IBT DSFBUFE B OFX QPTJUJPO GPS JUT 7BMVFE 1BSUOFS /FUXPSL XIJDI JT OPX IFBEFE CZ Martin Cook 7JDF 1SFTJEFOU GPS 4USBUFHJD 1BSUOFSTIJQT tINC Research IBTBQQPJOUFE Judit h Ng- Cashin .% BT $IJFG 4DJFOUJGJD 0GGJDFS %S /H$BTIJO XJMM CF SFTQPO TJCMF GPS TDJFOUJGJD NFEJDBM BOE FUIJDBM HPWFSOBODF NBU UFST JODMVEJOH DPMMBCPSBUJPO XJUI LFZ NFEJDBM BOE TDJFO UJGJDTUBLFIPMEFST tCTI Clinical Trial and Consulting Services IBT OBNFE UIF GPMMPXJOH OFX IJSFT Felicia Cochran 1I% KPJOT BT "TTPDJBUF %JSFDUPS 3FHVMB UPSZ BOE 4DJFOUJGJD "GGBJST Yolanda Hill BT 1BUJFOU 3F DSVJUFS Beverly Martinez 1I% BT 4FOJPS .BOBHFS )FBMUI 0VUDPNFT 3FTFBSDI Jayne MinhamBT"TTJTUBOU%JSFDUPS $MJOJDBM5SJBMTScott Strassels 1IBSN% 1I% BT "TTJTUBOU %JSFDUPS )FBMUI 0VUDPNFT 3FTFBSDI BOE Renee Sylvester KPJOT BT 3FHVMBUPSZ 4QF DJBMJTU* 5IF DPNQBOZ IBT BMTP QSPNPUFE Colleen Colson UP "TTPDJBUF %JSFDUPS (MPCBM 2VBMJUZ "TTVSBODF BOE Matt Hodskins UP "TTPDJBUF %JSFD UPS 1SPKFDU BOE 1SPQPTBM .BOBHFNFOU tGreenphire B QSPWJEFS PG HMPCBM DMJOJDBM QBZNFOU TPMV UJPOT IBT BQQPJOUFE Wayne Baker BT $IJFG $PNNFSDJBM 0GGJDFS 48 APPLIED CLINICAL TRIALS Julie Ross Martin Cook tEmmes Corporation B $30 BOOPVODFE UIBU Paul VanVeldhuisen 1I% IBT CFFO QSPNPUFE UP UIF OFXMZ DSF BUFE QPTJUJPO PG $IJFG 0QFS BUJOH 0GGJDFS 7BO7FMEIVJTFO TUBSUFE BU &NNFT BT B TUBU JTUJDJBOBOEFQJEFNJPMPHJTU tCrown Bioscience B HMPCBM ESVH EJTDPWFSZ BOE EFWFMPQ NFOU TFSWJDFT DPNQBOZ IBT BQQPJOUFE Eric Murphy 1I% BT HMPCBM TDJFOUJGJD EJSFDUPS GPS USBOTMBUJPOBM PODPMPHZ 3FDFOUMZ .VSQIZ EFTJHOFE BOE JNQMFNFOUFE B TDSFFO JOH PQFSBUJPO GPS B CJPUFDI OPMPHZ DPNQBOZ GPDVTFE PO SFHFOFSBUJWFNFEJDJOF Company News tW o r l d w i d e C l i n i c a l Tr i als PQFOFE B OFX PGGJDF BU 8BUFSGSPOU )PVTF PO UIF #FFTUPO #VTJOFTT 1BSL JO /PUUJOHIBN &OHMBOE IPVT JOH FNQMPZF F T 5IF DPNQBOZ IBT BQQSPYJNBUFMZ FNQMPZFFTJOMPDBUJPOT BSPVOE UIF XPSME JODMVEJOH UIF6,64BOE8FTUFSOBOE &BTUFSO&VSPQF tWIRB-Copernicus Group BO OPVODFE UIF QVCMJDBUJPO PG i*ODPSQPSBUJOH FUIJDBM QSJO appliedclinicaltrialsonline.com Colleen Colson DJQMFT JOUP DMJOJDBM SFTFBSDI QSPUPDPMT B UPPM GPS QSPUPDPM XSJUFST BOE FUIJDT DPNNJU UFFTw JO UIF Journal of Medical Ethics 5IF QBQFS EFTDSJCFT &TTFOUJBM &MFNFOUT UIBU TIPVME CF DPOTJEFSFE GPS JO DMVTJPO JO B EFEJDBUFE FUIJDT TFDUJPO JO B DMJOJDBM SFTFBSDI QSPUPDPM XIJDI JODMVEFE JO QVUGSPNUXPPGJUTFYFDVUJWFT Recognition tQuintiles IBT CFFO OBNFE U P F o r t u n e N B H B [ J O F T i8PSMET .PTU "ENJSFE $PN QBOJFTw MJTU GPS UIF TFDPOE ZFBS JO B SPX GPS UIJT EJTUJODUJPO 2VJOUJMFT JT SBOLFE GJSTU PWFSBMM JO FortuneT i)FBMUIDBSF 1IBSNBDZ BOE 0UIFS 4FSWJDFT JOEVTUSZw DBUFHPSZ VQ GSPN UIF /P TQPUJO tPPD BOOPVODFE UIBU 5raining NBHB[JOF IBT OBNFE UIF DPNQBOZ GPS UIF GJGUI DPO TFDVUJWF ZFBS UP JUT 5PQ MJTU PG CVTJOFTTFT UIBU FYDFM JO FNQMPZFF MFBSOJOH BOE EF WFMPQNFOU*OBEEJUJPO11%T USBJOJOH QSPHSBN GPS DMJOJDBM SFTFBSDI BTTPDJBUFT $3"T SFDFJWFE BO 0VUTUBOEJOH 5SBJOJOH*OJUJBUJWF"XBSE Matt Hodskins tClincierge XBT OBNFE B XJOOFS PG UIF Clinical Informatics News #FTU 1SBD UJDFT BXBSE 5IF DPNQBOZ SFDFJWFE UIF BXBSE JO UIF DBUFHPSZ PG i4UVEZ 4UBSUVQ BOE%FTJHOwJOSFDPHOJUJPOPG JUT FGGPSUT SFMBUFE UP QBUJFOU SFDSVJUNFOU TVQQPSU BOE SFUFOUJPO GPS B SBSF EJTFBTF DMJOJDBM USJBM *O UIBU TUVEZ $MJODJFSHFT BDUJWJUJFT MFE UP B QBUJFOU ESPQPVU SBUF PG MFTTUIBOPWFSNPOUIT DPNQBSFE UP BO JOEVTUSZ BW FSBHF PG BDSPTT BMM DMJOJ DBMUSJBMT tPAREXEL IBT CFFO OBNFE UP UIF 'MFY+PCT 5PQ $PNQBOJFT UP 8BUDI GPS 5F M F D P N NV U J O H + P C T J O GPS UIF UIJSE DPOTFDV UJWFZFBS5IFMJTUSFDPHOJ[FT DPNQBOJFT XJUI B UFMFDPN NVUJOHGSJFOEMZ DPNQPOFOU UP TPNF PG UIFJS KPCT TVDI BT UIF BCJMJUZ UP UFMFDPN NVUF FOUJSFMZ PS QBS U PG UIF UJNF 1"3&9&- PGGFST BQQSPYJNBUFMZ PG JUT HMPCBM FNQMPZFFT GMFYJCMF XPSL PQUJPOT JODMVEJOH UFMF DPNNVUJOH GMFYJCMF TDIFE VMFT BOE IPNFCBTFE FN QMPZNFOU April/May 2016 Go to: marketplace.findpharma.com Products & Services SHOWCASE EQUIPMENT RENTAL Content Licensing for Every Marketing Strategy Marketing solutions fit for: t Outdoor t Direct Mail t Print Advertising t Tradeshow/POP Displays t Social Media t Radio & Television Logo Licensing | Reprints | Eprints | Plaques WOODLEY Search Leverage branded content from Applied Clinical Trials to create a more powerful and sophisticated statement about your product, service, or company in your next marketing campaign. Contact Wright’s Media to find out more about how we can customize your acknowledgements and recognitions to enhance your marketing strategies. For more information, call Wright’s Media at 877.652.5295 or visit our website at www.wrightsmedia.com FAST ACTION with the DYNAMICS of Get Marketplace Advertising! Contact Wayne K Blow Sales Director Applied Clinical Trials & Pharmaceutical Executive rXCMPX!BEWBOTUBSDPN Search for the company name you see in each of the ads in this section for FREE INFORMATION! April/May 2016 appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 49 A CLOSING THOUGHT To see more A Closing Thought articles, visit appliedclinicaltrialsonline.com The Promise of Precision Medicine ur health is a reflection of who we are and how we live. In an information age that allows freedom of choice and ubiquity of options, the rise of personalized care is inevitable. The promise of precision medicine not only offers a newfound science to treat life-threatening illnesses, but also realizes an ideal medical care approach, treating each person as a valued individual via pinpointed diagnostic assessments and optimized therapeutic interventions. O The marker of success for precision medicine is that the term simply vanishes, and its principles become fundamental to modern medicine. Steve Rosenberg Senior Vice President and General Manager, Oracle Health Sciences Technology continues to shape the way people live, with on-demand access to immense information and multichannel communication. The scientific boom of gene sequencing is amplified by our abilit y to correlate genot y pe with phenotype and behavior, enabling rapid advances in disease diagnosis and treatment. A single, human, whole genome sequence often can generate 500 megabytes of raw data. It’s easy to see how this can quickly turn into petabytes of data with even a relatively small cohort of patients. Even then, more data will be added to the mix, as pathogenomics, proteomics, and metabolomics evolve. Researchers require high-performance tools to manage increasingly large, complex data sets to extract scientific intelligence from raw data. The White House Precision Medicine Initiative’s Cancer MoonShot program migrates from the realm of fantasy, to distinct possibility, and perhaps, to reality through a merger of information technology and genetic science. To improve the lives of people with cancer and other life-threatening diseases, a set of key technology elements will be necessary to ensure success: t Collaboration between researchers and clinicians, aggregating data at the patient level in support of disease-oriented research cohorts. 50 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com t A high-performance, technology infrastructure to enable rapid, accurate analysis of large volumes of data. t Structured data models to ensure consistency and reproducibility in results. . t Scalability to ensure that knowledge generated through research can be applied broadly across the clinical setting, while longitudinally, clinical data continues to feed the research environment. Ultimately, cancer therapy is only the beginning of the coming wave of the kinds of scientific advancements linked to genomics and accelerated by informatics. Every aspect of the human care spectrum offers areas of potential advancement, from birth and hereditar y disorders, through wellness and pre-sickness, all the way to disease management. Today, only about 38% of consumers have heard of precision medicine, have only shallow knowledge about it and do not associate it with genetic medicine.* In the end, the marker of success for precision medicine is that the term simply vanishes, and its principles become fundamental to modern medicine. *PMC Survey: U.S. Public Opinion About Personalized Medicine, 2014 http://www.personalizedmedicinecoalition.org/ Userfiles/PMC-Corporate/file/us_public_opinion_personalized_medicine.slides.pdf April/May 2016 There are heroes among us. Pharma Heroes is a movement designed to shine a light on the heroes who walk among us. It’s time to celebrate the heroic and largely unrecognized daily acts that move our industry forward. We need your help! Join the movement by recognizing a Pharma Hero you know: www.PharmaHeroes.com ©2016 Express Scripts Holding Company. All Rights Reserved. Discover the POWER OF X ® Medpace is a physician led, global CRO that possesses the expertise, site relationships and technology to execute even the most complex studies. For over 20 years it’s been a powerful combination that helps deliver the results our clients demand. Experts, Experience, and Execution. A powerful combination that delivers the results you demand. Physician Driven. Site Approved. VISIT MEDPACE AT THESE UPCOMING INDUSTRY CONFERENCES4 World Orphan Drug Conference – Washington DC, 4/20 - Booth #34 4 OCT – East Coast – King of Prussia, 5/25 - Booth #4 4 ASCO – Chicago, 6/3 – Booth #17091 medpace.com 4 American Society of Microbiology – Boston, 6/16 - Booth #954 4 DIA – Philadelphia, 6/26 – Booth #1911 North America Latin America Europe Asia Pacific Middle East Africa