1. UCSF-CDDS 2007 Role of FDA in Guiding Drug Development Carl Peck Center for Drug Development Science UCSF, UC-Washington Center Washington DC Principles of Clinical Pharmacology NIH,April 26, 2007 NIH, April 26, 2007

2. UCSF-CDDS 2007 ? Why FDA ? When does FDA get involved ? How does FDA guide drug development? What comprises FDA guidance ? What’s new at FDA ? New !

3. UCSF-CDDS 2007 Guiding Drug Development Why FDA? FD&C Act: history and its supporters –resulted from public safety events or public health challenges ~ 1902/6, 1938, 1962, 1972, 1987, 1997, 2004 –a uniquely American phenomenon Evolution of Drug Regulation (R. Temple) SAFETY EFFECTIVENESS INDIVIDUALIZATION ….. PERSONALIZATION SAFETY

4. UCSF-CDDS 2007 When does FDA get involved ? Preclinical (voluntary) phase –animal testing –Pre-IND guidance: Subpart E, Fast Track, Orphan designations Clinical development phase –IND NDA review Marketing phase –ADR surveillance –new uses, product changes, withdrawals

5. UCSF-CDDS 2007 FDA Initiative: Innovation vs Stagnation - Challenge & Opportunity on the Critical Path to New Medical Products, March 2004

6. UCSF-CDDS 2007 How does FDA guide drug development? Written guidances –Regulations, guidelines (incl. ICH), guidances 1 –Regulatory letters –(Statute, Congressional Reports) Face-to-face meetings –Pre-IND, EOP2a, EOP2, as-needed FDA Advisory Committee meetings Podium presentations 1 Website - www.fda.gov

7. UCSF-CDDS 2007 What comprises FDA guidance ? Standards –chemistry and manufacturing controls (CMC) –preclinical animal toxicology requirements –ethics of human clinical trials –documentary requirements for INDs, & NDAs –Electronic records (21 CFR part 11) –Clinical trials safety effectiveness trial design

8. UCSF-CDDS 2007 How Many Guidances and are they Binding ? GUIDANCES ( http://www.fda.gov/cder/guidance.htm) –344 guidances –344 guidances (final/draft, FDA/ICH), 3/31/00 Guidance documents: –Cannot legally bind FDA or the public –Recognizes value of consistency & predictability –Because a company wants assurance –So staff will apply statute & regulations consistently

9. UCSF-CDDS 2007 Planned Guidances (as of 2000)

10. UCSF-CDDS 2007 EXAMPLE 1 Clinical/Pharmacological Guidances CDER Comprehensive List of Guidance Documents(April 2006; n ~ 500) CDER Comprehensive List of Guidance Documents (April 2006; n ~ 500) Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro (97); In Vivo (99) Pharmacokinetics in Patients with Impaired Renal Function (98) Population Pharmacokinetics ( 99)Population Pharmacokinetics ( 99) Exposure-Response (02)Exposure-Response (02) Exploratory IND Studies (April 2005)Exploratory IND Studies (April 2005)

11. UCSF-CDDS 2007 EXAMPLE 2 Clinical/Pharmacological Guidances General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products Pharmacokinetics in Patients With Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling

12. UCSF-CDDS 2007 EXAMPLE 3 Clinical/Medical Guidances Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (98)Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (98) Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (93) Study of Drugs... used in the Elderly (89) Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research

13. UCSF-CDDS 2007 EXAMPLE 4 Statutory Guidance: FDA Modernization Act of 1997 “FDAMA ” Sec. 111. Pediatric studies of drugs –PK bridging studies Sec. 115a. Clinical investigations –support of one adequate and well-controlled clinical investigation by “confirmatory evidence” comprising PK or PK/PD

14. UCSF-CDDS 2007 FDAMA, Sec. 111 Pediatric studies of drugs “(g) Definitions. - the term `pediatric studies' or `studies' means at least one clinical investigation (that.. may include pharmacokinetic studies) in pediatric age groups....”

15. UCSF-CDDS 2007 Pediatric Labeling Regulations (21 CFR 201.56) “FDA may approve a drug for pediatric use based on... studies in adults, with other information supporting pediatric use…. additional information supporting pediatric use must ordinarily include data on the pharmacokinetics of the drug in the pediatric population ….Other information, such as data on pharmacodynamic studies…..”

16. UCSF-CDDS 2007 FDAMA, Sec. 115a Clinical investigations based on relevant scienceone adequate and well-controlled clinical investigation confirmatory evidence “If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence …. are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence..”

17. UCSF-CDDS 2007 FDAMA, Sec. 115a Clinical investigations CONGRESSIONAL COMMITTEE REPORTS 1 “confirmatory evidence”“scientifically sound data from any investigation“confirmatory evidence” = “scientifically sound data from any investigation in the NDA that provides substantiation as to the safety and effectiveness of the new drug” pharmacokineticconfirmatory evidence = “consisting of earlier clinical trials, pharmacokinetic data, or other appropriate scientific studies” 1 House Commerce Committee, 10/7/97, and Committee of Conference on Disagreeing votes of the two Houses, 11/9/97

18. UCSF-CDDS 2007 New Formulations and Doses of Already Approved Drugs * Where blood levels... are not very different, it may be possible to conclude... is effective on the basis of pharmacokinetic data alone. Even if blood levels are quite different, if there is a well- understood relationship between blood concentration and response,..., it may be possible to conclude... is effective on the basis of pharmacokinetic data without an additional clinical efficacy trial. * Guidance for Industry “Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products”, May 1998

19. UCSF-CDDS 2007

20. FDA – what’s new? Leadership –Commissioner Eschenbach, (Henney), (McClellan) (Crawford) –Deputy Commissioner (Woodcock) Initiatives –Improving drug development FDA leadership to improve drug development (2003)FDA leadership to improve drug development (2003) Critical Path Initiative (2004)Critical Path Initiative (2004) –End-of-Phase 2a (EOP2a) meeting (04) –Model-based Drug Development (05) –Critical Path Opportunities List (06) –Safety Drug withdrawals (Vioxx et al) (04) –Safety Oversight Board (05) CBER CDER: protein therapeutics

21. UCSF-CDDS 2007 McClellan Initiative (2003): FDA leadership to improve drug development Aims to achieve predictable, 1-cycle NDA/BLA reviews –‘Root cause’ analysis –Intensified FDA-industry communications –Continuous marketing application project –Reviewers and Reviews Training Review standards Peer review ‘Quality Systems’ review improvements

22. UCSF-CDDS 2007 “Academics” Meeting April 5, 2003

23. UCSF-CDDS 2007 How can academics help? Investigate ‘root causes’ of inefficient drug development Share findings and innovative solutions with FDA –Causes and remedies for failed phase 3 trials –Rationale and examples to motivate abandonment of inefficient, costly, empirical traditional drug development, replacing with a quantitative, causal-model and simulation approach Advance methods for optimization of clinical drug testing –Learn-confirm approach –Integration of intensified early clinical pharmacology –Pharmacometrics - population PK/PD, modeling & simulation of clinical trials –Pharmacogenetic guided development –Effective use of biomarkers and Surrogate Endpoints

24. UCSF-CDDS 2007 ‘Academics to CDER’ History of academic sabbaticals –Ludden, Weintraub, Amidon, Derendort et al –Currently - Don Stanski, Bob Powell, Felix Frueh Woodcock’s ‘Academics to CDER’ courses –PK/PD (x2), pharmacogenomics, QT, safety, scientific basis of drug development

25. UCSF-CDDS 2007

26. US Pharmaceutical R&D Total NIH Budget 10 year Trend in Biomedical R&D Spending Adapted from J. Cossman: “The Critical Path Institute” 2007 & FDA Critical Path Initiative 2004

27. UCSF-CDDS 2007 New Drug Applications New Biological Applications 10 year Trend in New Applications to FDA Adapted from J. Cossman: “The Critical Path Institute” 2007 & FDA Critical Path Initiative 2004

28. UCSF-CDDS 2007 Prototype Design or Discovery Clinical Development Basic Research FDA Filing/ Approval & Launch Preclinical Development Market Application Approval CRITICAL PATH Adapted from S. Buckman: “Biomarkers 101”, RAPS, 2006

29. UCSF-CDDS 2007 Coordinate collaborative efforts among government, academia, industry & patient groups Encourage “toolkits” for better product development, safety, medical utility & manufacturing Build support for academic science bases in relevant disciplines Build opportunities to share existing knowledge & databases Develop enabling standards Guiding Principles of Critical Path Initiative Adapted from S. Murphy: “FDA Update on Critical Path Initiative”, RAPS 2006, & FDA Critical Path Initiative 2004

30. UCSF-CDDS 2007 Organization of Critical Path Initiative within FDA Commissioner’s Office: Office of Critical Path Programs –Critical Path Steering Committee CDER: Office of Translational Sciences –Clinical Pharmacology –Biostatistics –Critical Path Initiatives –Intramural Research

31. UCSF-CDDS 2007 http://www.fda.gov/oc/initiatives/criticalpath/

32. UCSF-CDDS 2007

33. Executive Summary Six Priority Public Health Challenges BiomarkerBiomarker development clinical trialsStreamlining clinical trials BioinformaticsBioinformatics manufacturingEfficient, quality manufacturing infectionsbioterrorism antibiotics and countermeasures to combat emerging infections and bioterrorism children and adolescentsDeveloping therapies for children and adolescents

34. UCSF-CDDS 2007

38. http://www.fda.gov/oc/initiatives/criticalpath/opportunities06.html

39. UCSF-CDDS 2007 Critical Path Collaborations with NIH Joint workshops with FDA –Genetic basis of Adverse Events –December 11&12, 2006 – Imaging in Alzheimer’s Disease Drug development education for NIH –NIAID –National Institute on Aging –Individual Scientist Assistance

40. UCSF-CDDS 2007 Public/Private Partnerships - I Predictive Safety Testing Consortium –CDER-OCP, CPath Institute, 15 pharma firms –Pre-clinical toxicogenomic biomarkers Nephrotoxic biomarkers expected early 07 Biomarker Consortium –NIH/ PhRMA/ FDA/CMS –regulatory pathway for biomarker validation FDG-PET in NHL Oncology Biomarker Qualification Initiative –FDA, NCI and CMS Microarray Quality Consortium Duke/FDA ECG Collaboration

41. “American Course on Drug Development and Regulatory Science” Website: http://acdrs.ucsf.edu Ellen G. Feigal, M.D. Course Director University of California, San Francisco Department of Biopharmaceutical Sciences/CDDS Public/Private Partnerships - II

42. “ACDRS” Vision and Mission Modernization of development and regulation of medical products via –Certified, comprehensive instruction –Integration of cutting-edge concepts – Best practices in medical product development and regulatory sciences

43. “ACDRS” Emphases Three Principles of Optimal Development –Learn-Confirm Approach –Regulatory Collaboration –Efficient Program Execution

44. “ACDRS” Faculty and Teaching Methods International faculty network from universities, companies, and regulatory authorities –Experts in regulatory sciences, medical product discovery and development, product evaluation and business practices Teaching methods –Lectures –Workshops –Panel discussions –Team-oriented case studies –Interactive learning –Accreditation and credit, and certifying examination

45. The Launch East and West coasts –Washington DC in September 2007 CDDS, FDA –San Francisco in September 2008 UCSF Mission Bay Campus

46. UCSF-CDDS 2007 Critical Path Initiative Projects that impact Exploratory Clinical Development - two examples Exploratory IND End-of-Phase 2a Meeting

47. UCSF-CDDS 2007

48. Goals of the Exploratory IND Reduce time & resources on drugs unlikely to succeed –Select most likely to succeed from group of candidate drugs –To learn PK, biodistribution, mechanism of action –Reduced preclinical requirements due to less risk

49. UCSF-CDDS 2007 Exploratory IND “Phase 0” studies – prior to traditional drug development Phase I trials Microdose, sub-pharmacologic or pharmacologic dose –Single dose or limited period of administration

50. UCSF-CDDS 2007 Types of Exploratory Studies Single Dose –PK, Imaging Multiple Dose –Pharmacological, Pharmacodynamic endpoints CMC –GLP (+/-) –Summary report

51. UCSF-CDDS 2007 Requirements CMC –GLP (+/-) –Incomplete impurity profile –Summary report Toxicology - depends upon goal –Single Dose - 1/100 est. pharmacological dose or < 100 ug Single species (rodent), 14 day observation –Multiple Dose (<1/50 NOAEL + max 1/4 of 2 wk NOAEL) Two species, 14 day repeat dose

52. UCSF-CDDS 2007

54. End of Phase 2a meeting Two Year’s Experience Reviewed at FDA Pharmaceutical Sciences Advisory Committee Meeting, November 14, 2005 http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_Slide-Index.htm

55. UCSF-CDDS 2007 End of Phase 2a Meetings PurposePurpose: ↓ Late phase clinical trial (2b, 3) unnecessary failure FormatFormat: non-binding scientific interchange. Marketing issues should be in the development plan, not at this meeting DeliverablesDeliverables: –Perform modeling (relevant phase 1/2a data) & simulation of next trial design employing Mechanistic or empirical drug-disease model Literature estimates for comparative drug effects if relevant Placebo effect (magnitude & time-course) Rates for dropout and compliance. (prior FDA experience) –Recommendation on sponsors trial design + alternative including patient selection, dosage regimen,… –Code from FDA work, Sponsor can extend work (EOP2, NDA) –Answers to other questions from the clinical and clinical pharmacology development plan Time-courseTime-course: ~ 6 weeks Key sponsor & FDA participantsKey sponsor & FDA participants: physician, biostatistician, clinical pharmacology (pharmacometrics), project management Adapted from R. Powell, FDA

56. UCSF-CDDS 2007 Completed 12-15 EOP2a meetings Mixed, mostly positive value Suspending EOP2a ‘experiment’ –Resource issue –Functional EOP2a meetings permitted as ‘Type C’ –Important to notify OCPB to ensure FDA clin pharm involvement End of Phase 2a Meetings current status* * Bob Powell, LBS Symposium December 5, 2006

57. UCSF-CDDS 2007 Of about a total of 244 NDAs, 42 included a pharmacometrics component…. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of 14 reviews that were pivotal to approval decisions, … 6 reduced the burden of conducting additional trials.

58. UCSF-CDDS 2007 PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs.

59. UCSF-CDDS 2007 Model Based Drug Development What is it? ModelModel : mathematical explanation of relationships thought to explain outcome over time period of interest Drug-Disease ModelDrug-Disease Model (empiric & mechanistic) Disease model: relationship of patient (e.g., gender, age, genotype), biomarker (e.g., biochemical, imaging) relationship to disease morbidity and mortality Drug-Disease model: addition of drug (dose, concentration, combination, placebo) and patient (e.g., size, age, adherence, dropout) effects and adverse effects to the disease model SimulationSimulation- Target Clinical trial design- optimal –New designs-enrichment, randomized withdraw, adaptive Dosage regimen(s) selection Go/No go- Sponsor &/or FDA Labeling- Sponsor &/or FDA R. Powell, FDA

60. UCSF-CDDS 2007 Model Based Drug Development : Drug, Efficacy (Potency) & Safety Information Late Discovery Pre-ClinicalPhase IPhase IIPhase III NDAIND a:Proof of Principleb:Dose Ranging DESIGN DECIDE SELECT EOP2 EOP2a Pre-IND Clinical Development Plan Recommendations Quantitate drug effect & disease progression (biomarker strategy) Define Proof of Concept criteria Phase I-IIa Study Plans Criteria for risk assessment Data submission format Provide comments on Phase IIb & III trial designs based on modeling & clinical trial simulation Estimate dose-response Propose bridging strategy for subpopulations Approve Phase III trial design or recommend alternative designs based on modeling including IIb trial results & trial simulation Support approval decision based on cross- trial efficacy & safety modeling analysis for: Drug approval Label dosage regimen & claims Phase IV commitments R. Powell, FDA

61. UCSF-CDDS 2007 Universities’ Responses to ‘Critical Path’ Initiative “JETS”“ACDRS”UCSF - “JETS”“ACDRS” “CPATh Institute”U Arizona - “CPATh Institute” “CE-PK/PD”SUNY Buffalo - “CE-PK/PD” “ICIS”U Indiana - “ICIS”

62. UCSF-CDDS 2007 SOME FINAL OBSERVATIONS FDA clinical guidances are increasingly based on principles of clinical pharmacology “guidance” versus “regulation” –value added versus barrier FDA guidance –national “treasure” versus “national nuisance” –a bargain ! Value of FDA guidance is related to the quality of sponsor data and preparation