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Janet Woodcock, MD Director, Center for Drug Evaluation and Research Food and Drug Administration Todays Biomedical Innovation: Lost in Translation? QB3.

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Presentation on theme: "Janet Woodcock, MD Director, Center for Drug Evaluation and Research Food and Drug Administration Todays Biomedical Innovation: Lost in Translation? QB3."— Presentation transcript:

1 Janet Woodcock, MD Director, Center for Drug Evaluation and Research Food and Drug Administration Todays Biomedical Innovation: Lost in Translation? QB3 Entrepreneurs Discussion University of California, San Francisco Thursday, April 26, 2012

2 Will New Scientific Discoveries Revolutionize Treatment of Disease (Soon)? Advances in both science and technology are providing unprecedented opportunities for new approaches to disease prevention, diagnosis and treatment However, in some senses, the barriers to successful development have never been higher New paradigms for evaluation of diagnostic and therapeutic interventions must be developed –Faster –More efficient –But equally or more informative 2

3 3 Drug Development Currently takes more than 10 years and requires an investment of over $1B to bring a single innovative drug to market Clinical investigation, premarket application, and postmarket stages are heavily regulated in most developed countries Ongoing concern about ability of the drug development enterprise to translate innovative science and bring needed therapies to market Ongoing concern about the ability, and willingness, of societies to pay for novel therapies

4 4 Research and Development Process 3-6 YEARS6-7 YEARS YEARS PRE-DISCOVERY DRUG DISCOVERY PRE CLINICAL CLINICAL TRIALS FDA REVIEW LARGE SCALE MFG IND SUBMITTED TO FDA NDA SUBMITTED TO FDA PHASE 1 PHASE 2 PHASE 3 Number of Volunteers PHASE 4: POST MARKETING SURVEILLANCE 5,000-10,000 COMPOUNDS ONE FDA- APPROVED DRUG SOURCE: PhRMA 2008, Stages of Drug Development Process and attrition rate of compounds as they travel through the drug development process over time.

5 5 For 12 PhRMA companies Research Spending vs New Drugs Approved during the Period

6 6 Private & Public Research and Development Spending Source: Burrill & Company, PhRMA, NIH Office of Budget

7 FDA NME Approvals Basically stable output over long term (vs increased investment in basic research and R&D) Decline from late 1990s reflects primarily decrease in submission of me-too drugs: now difficult to get on formulary FDA seeing increased novelty in applications over recent 5 year period; more game-changing therapies Possibly reflects adjustment of industry strategies PDUFA program (currently up for re-authorization) ensures that review times are relatively predicatable 7

8 8 In 2011, CDER approved 30 NMEs, the highest total of NMEs approved in seven years *The final number of NME Applications filed in 2011 is projected, pending final validation of the data and dependent outcome of 12 applications submitted in late 2011.

9 9 CDER met review goal dates for 97% of the new molecular entities approved in 2011 Met PDUFA Target Dates 1. Adcetris 2. Benlysta 3. Caprelsa 4. Dificid 5. Edarbi 6. Edurant 7. Erwinaze 8. Eylea 9. Gadavist 10. Incivek 11. Jakafi 12. Onfi 13. Tradjenta 14. Victrelis 15. Viibryd 16. Xalkori 17. Yervoy 18. Zelboraf 19. Zytiga 1. Adcetris 2. Arcapta 3. Benlysta 4. Brilinta 5. Caprelsa 6. Darilesp 7. Datscan 8. Dificid 9. Edarbi 10. Edurant 11. Eylea 12. Ferriprox 13. Firazyr 14. Gadavist 15. Horizant 16. Incivek 17. Jakafi 18. Natroba 19. Nulojix 20. Onfi 21. Potiga 22. Tradjenta 23. Victrelis 24. Viibryd 25. Xalkori 26. Xarelto 27. Yervoy 28. Zelboraf 29. Zytiga First Cycle Approval

10 10 Innovation in drug approvals for Adcetris 2. Benlysta 3. Darilesp 4. Firazyr 5. Jakafi 6. Nulojix 7. Potiga 8. Victrelis 9. Xalkori 10. Yervoy 11. Zelboraf 12. Zytiga First in-Class Drugs Approved First in the U.S. 1. Adcetris 2. Benlysta 3. Caprelsa 4. Dificid 5. Edarbi 6. Edurant 7. Eylea 8. Incivek 9. Horizant 10. Jakafi 11. Natroba 12. Nulojix 13. Tradjenta 14. Victrelis 15. Viibryd 16. Xalkori 17. Yervoy 18. Zelboraf 19. Zytiga Orphan Drug Approvals 1. Adcetris 2. Caprelsa 3. Erwinaze 4. Ferriprox 5. Firazyr 6. Jakafi 7. Nulojix 8. Onfi 9. Xalkori 10. Yervoy 11. Zelboraf

11 Role of Regulatory Standards Certainly some of the costs are driven by increased expectationsover the last several decades--about evaluating the performance of the drug (both for safety and efficacy) before it goes on the market Even after an expenditure of $1B per successful drug, multiple important clinical questions remain unanswered (e.g. dose and regimen, use with other therapies, optimal duration of therapy, consequences of long-term use) Academic clinical community constantly clamors for more data to be generated premarket and postmarket Payer community has rising expectationse.g., Europe 11

12 Key Issues How to balance information needs of prescribers, patients and payers against desire for speedy access to better therapies (more effective, less toxic etc.) on the part of prescribers and patients? How to keep the biomedical innovation sector alive with a viable business model, but also keep new innovations affordable for society? How to translate the vast amount of new knowledge about human health and disease efficiently, rather than using the time-consuming, costly and inefficient methods currently in place? Is there a more prominent role for the academic biomedical sector? 12

13 Can the Academic Biomedical Sector Become a more Integral Part of the Drug Development Ecosystem?

14 14 Background: A Very Long Time Ago Professors were engaged in drug discovery (and experimented upon themselves and their grad students) Industry commercialized discoveries Industry largely unregulated

15 15 Background: s Growth of mainstream (and other) pharmaceutical houses 1000s of unstudied, possibly ineffective drugs on the market Start of a long period of seminal drug discoveries: cardiovascular disease; infectious disease; cancer; psychiatric disorders Beginning of the requirement to show drug efficacy (1962)

16 16 Modern Era Huge pharmaceutical companies: massive fully integrated drug discovery and development enterprises Academic focus on molecular biology of health and disease: basic biomedical science Outpouring of novel therapies and also xs in a class (e.g., 17 NSAIDS) Society increasingly less impressed with novelty –Decreased tolerance of uncertainty –Regulators respond with more testing requirements –Cost effectiveness questions arise

17 17 Now Pharmaceutical industry: progressively greater investment and diminished return Biotech: success, but can society afford the products? Venture capital: fleeing medical products sector Academia: 30 year investment in biomedical research sectorwill funding keep rising? What is the academic role in translational research? Regulators blamed for: –Current problems in drug development –Excess conservatism –Excess enthusiasm

18 18 Current Government and Industry Roles in Pharmaceutical Research & Development

19 19 Future: Opportunities for New Roles and Relationships to Improve Process Pharmaceutical Sector Competencies –Rigor –Medicinal chemistry –High throughput screening –Lead optimization –Manufacturing and scale up –Late phase development –Marketing and distribution

20 20 Future: Potential Shift in Roles? Academic Strengths –Molecular biology of target; pathways; pathogenesis –Animals and in vitro models and testing scenarios; in depth disease understanding –Relationships with relevant patients –Proximity of patients and laboratory

21 21 Future Role of Academia in Drug Discovery and Development Partnering with industry in discovery and translation of specific products or therapeutic areas Research leading to new evaluative tools for predicting, understanding and assessing the effects of medical products in the relevant species (people) Hubs for clinical trial networks that incorporate community practitioners and also have the capacity for integration of sophisticated bench science

22 22 Role of Academia: Urgent Need for New Evaluative Tools Drug manufacturing and scale up –Multiple academic consortia working on this; poorly funded Safety evaluation: little changed in decades –Traditional empirical evaluation in animals –Human safety evaluation a side effect of efficacy evaluation Efficacy evaluation: Predicting and confirming efficacy still a huge challenge; generally still empirical –Affects academic efforts as well as industrial –Many late failures due to efficacy problems

23 23 Discovery and Translation of Specific Innovations Academic based drug development Thousands of less common disorders that are not subject to industrial development Specific pathways or mechanisms that have been the subject of extensive research in a particular laboratory Early bench to bedside translation –Proof of concept studies –Pharmacodynamic evaluations

24 24 Streamlining the Bench to Bedside Transition Exploratory IND guidance –Tailor required toxicology studies to proposed investigations –Can be significantly reduced for single dose or microdose trials, or brief administration Phase 1 trial cGMPs –Remove phase 1 clinical trial material from extensive cGMP requirements in regulations –These were written for commercial products –Companion guidance: ability to use laboratory produced material with specific safeguards

25 25 Development of Evaluative Tools: A Tremendously Neglected Area Better science is needed to both predict and assess safety and efficacy of investigational products Now: Build an airplane and then see if it can fly Major causes of failure in Phase 3 clinical development –Lack of effectiveness against placebo or active –Unexpected drug toxicity –Commercial non-viability (not better than existing therapy)

26 Evaluative Tools Current drug development might be viewed as what physics would be without engineering Large amount of biochemical knowledge but few ways to assess state of whole organism and impact of interventions at the organism level Most assessment tools are not standardized so limited ability to compare one experiment to another Little insight into sources of variability of treatment response, even current therapies As a result, most clinical development programs are brute force empirical efforts: extremely costly and time-consuming 26

27 27 Safety Evaluation: Opportunities Routine rat or dog studies good for predicting safe first-in-human dose but not for understanding less common toxicities Structure Activity Relationships –FDA has collaborated to make some screening programs available that correlate computer readable structural motifs with known animal or clinical adverse outcomes from FDA databases –Opportunities to link structure with other assays that are becoming available and also do more extensive link to clinical data

28 28 Safety Evaluation: Opportunities Systems biology approach to drug toxicity Screens for off-target receptor binding Gene expression in response to drug exposure: safety pharmacogenomics Cellular systems for assessing drug responses broadly Human pharmacogenomics: not just drug metabolism –Allelic variability in drug target –Uncommon alleles increasing risk of major drug toxicity

29 29 Development of Biomarkers for Prediction of Safety or Efficacy Many potential biomarkers discovered in academic laboratories but never understood sufficiently for: –Use in drug development –Regulatory decision making FDA attempting to introduce more rigorous process as part ofCritical Path Initiative FDA Guidance on Drug Development Tools qualification process: US and EU will work with groups on qualifying new tools for use in drug development A central role for academic scientists

30 30 Predicting, Measuring, and Improving Efficacy New endpoints New trial designs Use of biomarkers to subset disease ( prognostic or response predictors) –Jupitor trial (C-reactive protein; rosuvastatin) –Screening tumors for activating pathways –Known as enrichment, CDER guidance Use of patient-reported outcomes Conducting natural history studies to understand disease courseparticularly in rare diseases

31 31 New Endpoints Foundation for the National Institutes of Health (FNIH) Scientific work on endpoints and clinical trial designs –FNIH and the Biomarkers Consortium are developing endpoints for clinical trials in skin infections and community acquired pneumonia –Helps reduce uncertainty around using a new endpoint or trial design –Includes academia, industry, IDSA, NIH, and FDA

32 32 New Endpoints in Pain Trials Why ACTION? Clinical studies, particularly efficacy trials, notoriously flawed for analgesic drug development Frequent failed studies with drugs known to be effective Extremely small treatment effects even when successful Multiple causes, e.g.: Large placebo effect Missing data Study design flaws Study analysis flaws Investigator quality Frequent use of foreign sites

33 33 New Endpoints Innovative clinical trial design to facilitate schizophrenia drug development… FDA and National Institute of Mental Health (NIMH) MATRICS clinical trial guidelines designed to facilitate novel compound development to treat cognitive impairment from schizophrenia (MATRICS) clinical trial guidelines for cognitive- enhancing drugs in schizophrenia

34 34 Developing New Biomarkers and Patient Reported Outcomes Measures (PROs) C-Path Institute (nonprofit): submitted new biomarkers for drug induced kidney injury (data produced by a consortium); FDA and EMA accepted; undergoing clinical evaluation PROMIS (NIH PRO effort) C-Path Institute: PROs for specific diseases for qualification

35 35 Quantitative Disease-Drug-Trial Models Disease Model Drug Model Trial Model Biology Natural Progression Placebo Biomarker-Outcome Pharmacology Effectiveness Safety Early-Late Preclinical-Healthy-Patient Patient Population Drop-out Compliance FDA Data Diverse Expertise Physiology Disease-drug-trial models are mathematical representations of the time course of biomarker-clinical outcomes, placebo effects, drugs pharmacologic effects and trial execution characteristics for both the desired and undesired responses, and across experiments.

36 36 Quantitative Disease-Trial Models: Alzheimer Disease Disease Model Trial Model Natural Progression Placebo Response Patient Population Drop-out FDA Data Diverse Expertise Physiology

37 37 Adaptive Design with Biomarkers I-Spy 2: screening trial for investigational breast cancer drugs Biomarker Consortium--- public/private partnership: FDA / NIH / PhRMA companies Attempts to identify biomarker-defined response subgroups Adaptive design against standard-of-care Ability to screen multiple investigational agents in one trial Selected compounds could have rapid route to accelerated approval based on larger trial in responsive subgroup

38 Re-engineering the Clinical Research Enterprise Currently, clinical research is: –Extremely expensive –Unpleasant for most participants –Inefficient –Not totally reliable –Unavailable for the vast majority of patients (e.g., cancer patients) 38

39 Clinical Research in Drug Development Unique clinical trial at multiple stages of development New investigators, support personnel, unique CRFs Long lead time to set up Frequently slow recruitment, many sites fail to recruit adequately Lack of involvement of community practitioners, so that available universe of patient limited, often sites are competing for patients for several protocols Rapid movement of clinical trials in drug development overseas 39

40 How to Address Problem? Consider clinical trial networks with the capacity to perform multiple trials Include community practitioners with appropriate logistical support Academic medical centers as hubs Standardized CRF templates for much of data collection Ultimately improve quality of data, involve community in clinical research 40

41 41 The Clinical Trials Transformation Initiative (CTTI) Formed in 2008 FDA and Duke University - founding members of a public-private partnership Members include stakeholders from government, industry, academia, patient and consumer representatives, clinical investigators, professional societies, and clinical research organizations

42 42 CTTI Current Projects Improving the public interface for use of aggregate data in clinicaltrials.Gov Site metrics for study start up Building quality in Use of central IRB for multicenter clinical trials Investigator SponsorPatient IND Safety Reporting

43 43 Summary There are major problems with current drug development paradigms New scientific knowledge provides huge opportunity for improvement The biomedical research community should have a greater role in many aspects of drug discovery and development Future drug development must include many innovative partnerships The clinical research enterprise in the US must be transformed

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