Course Objective

1. Development and Approval ofDrugs and DevicesEPI260 Lecture 1: OverviewApril 1, 2010Richard Chin, M.D.

2. Course Objective Provide a survey of drug and device development from late preclinical through Phase 3 clinical studies

3. Course Outline • Overview • Case Study: How to Assess an Early Stage Drug Candidate • What You Need to File an IND/IMPD • Phase I trials: Dosing and Designs • Early Phase Clinical Development-Phase II studies; Statistics • Late Phase Clinical Trials • Development of Vaccines and Cell/Gene-Based Therapies; Cell, Tissue, and Gene Therapies • Devices and Drug/Device Combinations • Case Study: Safety Issues, Adverse Event Reporting, Signal Detection • Case Study: Drug Development Lessons

4. Overview Outline • History, background, and ethics of drug development • Regulatory framework • Phases of drug development • Program design • Intellectual property and economics

5. Characteristics of Modern Drug Development • Modern drug development relies primarily on randomized clinical trials • Aggregate data • Controls • Parallel group • Other valid sources of knowledge: • Observational data • Non-assigned data • Non-aggregate data • Modern drug development, like RCT, is a relatively recent phenomenon

6. Characteristics of Modern Drug Development • Highly successful and productive • Many effective new drugs • Excellent return on investment • Heavily constrained by regulatory requirements • Expensive and long • Pre-industrialization stage

7. Key success facrtors in modern drug development • Protect patient safety and rights • Scientific parsimony • Economic parsimony • Speed

8. History • 1747 – James Lind’s comparative trial testing citrus fruit on scurvy • 1948 – Publication of “Streptomycin treatment of pulmonary tuberculosis” • 1962 – Kefauver-Harris Drug Amendments to FDA FD&C Act requiring demonstration of efficacy for new drugs • 1970s – NDA rewrite • 1990s – International Conference on Harmonisation • 1995 – Formation of EMEA (now EMA)

9. Ethics • Equipoise • Informed consent • IRB/EC • Declaration of Helsinki • Nuremberg Code • Safety monitoring • Publication of data

10. FDA and U.S. Regulations • FDA’s mission: • “Protect the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, food supply, cosmetics, and products that emit radiation” • FDA role in drug development: • Regulates most clinical research (IND) • Approves drugs (NDA/BLA) • Regulates marketing of drugs after approval

11. Current FDA Centers • CDER - Center for Drugs Evaluation and Research • Small molecules • Biologic drugs (antibodies, therapeutic proteins) • CBER – Center for Biologics Evaluation and Research • Blood products, gene therapy, vaccines, etc. • CDRH – Center for Devices and Radiological Health • CFSAN – Center for Food Safety and Applied Nutrition • CVM – Center for Veterinary Medicine • NCTR – National Center for Toxicological Research

12. Levels of Regulation • Laws • Public Health Services Act (Biologics) • Food, Drug and Cosmetic Act (Foods, Drugs, Medical Devices) • Regulations • Code of Federal Regulations (CFR) Title 21 – Food and Drug Administration Regulations • Guidance Documents • Represent FDA current thinking on a specific topic • “Do not confer any rights and do not bind the FDA or the public” – but de facto they do

13. Simple Picture Preclinical, CMC Clinical Studies NDA IND

14. Complex Picture Advisory Committee Meeting Clinical Hold Special Protocol Assessment Preclinical, CMC Clinical Studies NDA IND Pre- Phase II Meeting End of Phase II Meeting 120 day Safety Update Inspections Pre-IND Meeting

15. Investigational New Drug Application (IND) • Application to start clinical trials • Requires three main sections • Preclinical and toxicology information • CMC (manufacturing information) • Clinical protocol and investigator information • Animal data must show drug is likely to be reasonably tolerated in humans • IND is not required for studies conducted outside United States

16. New Drug Application (NDA) • Application for approval of a drug • BLA for biologics • Answers the following questions • Is the drug safe and effective? • Do the benefits outweigh the risks? • Is the drug’s proposed labeling appropriate? • Are the methods used in manufacturing the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?

17. Compliance • GXP: • Good Manufacturing Practice • Good Laboratory Practice • Good Clinical Practice • Harmonized by International Conference on Harmonization (ICH) • Purpose: • Protect patients rights and safety • Insure data and product integrity

18. Where to Find Regulatory Information • Federal Register • FDA website • Guidance documents • Advisory Committee transcripts and briefing material • Working group transcripts • Summary Basis of Approval • Freedom of Information requests • Internal procedures manuals (BIMO guidelines, Good Review Practice) • Drug Information Association conferences • Trade publications (BioCentury, etc.) • Consultants • EMEA website/material • Ask the FDA !

19. Formal Meetings • Type A, B, C meetings • Pre-IND Meeting • Usually to discuss toxicology plan rather than CMC • Pre-Phase II Meeting • To discuss Phase II design • End of Phase II Meeting • To discuss Phase III design, especially endpoint, size of safety database • Pre-NDA Meeting • To discuss results and format of submission • Additional dialog along the way

20. FDA Meeting How-To • Questions should be in yes/no format • Good: “Would the proposed Phase III endpoint be acceptable for submission in an NDA if the study were positive?” • Bad: “ What should the Phase III endpoint be?” • Bad: “Will the Agency approve the drug if it meets the proposed Phase III endpoint?” • Never ask a question you don’t want an answer to • Never ask a question you already have an answer to • Never ask a question that asks the FDA to speculate • FDA cannot answer questions not included in the briefing package • They must caucus internally first

21. Most Common Regulatory Mistakes • Don’t get advice from the FDA • Don’t listen to advice from the FDA • Think you’re smarter than the FDA • Think that matters • CMC issues • GCP issues • Inadequate monitoring • Inadequate oversight of CROs

22. Common Points of Disagreement with the FDA • Enough data • Safety database • Dose ranging data • Risk management • How many patients can you expose to the drug and when • Endpoints • Magnitude of difference in endpoint, dichotomous endpoint • Risk benefit • Which populations • How much safety monitoring • Statistical analysis • Which patients can you include and exclude • How to impute the data

23. Understanding the FDA: Context • Main job is to protect the American public • “What will I say if I need to explain this to Congress?” • Policies affected by history – not understandable without context • FIAU incident • CAST study • University of Pennsylvania incident • Tysabri withdrawal • TeGenero CD28 study • Bureaucracy - must follow laws and rules – check the boxes

24. Understanding the FDA: Culture • Not a monolithic organization • Different divisions with different standards – e.g., oncology, neurology • Dual nature • At high levels, policies are influenced by Congress • At lower levels, highly scientific and rigorous • Internal politics, just like other large organizations (CDER vs CBER)

25. Understanding the Reviewers • FDA is an M.D. driven organization • Individual reviewers have their own take on things • Reviewers are extremely overworked, under-resourced, incredibly conscientious, highly ethical, highly scientific • Many reviewers hold commissions in the U.S. Public Health Service Commissioned Corps • In general, they do a superb job under difficult circumstances

26. Remember • The FDA has access to information from other sponsors • If they are making demands that don’t seem reasonable, they probably have a good reason they can’t share with you • The FDA talks to other regulatory agencies • FDA will often impose less stringent requirement on smaller companies and academic investigators • Number of patients at risk very important • Sometimes there is no regulatory pathway to approval • Extreme unmet medical need lowers bar

27. Working with the FDA • Be honest • No hiding data in the appendix • They rely on sponsors a great deal, so they must be able to trust you • Talk with the FDA often and early • Listen to their advice – they can be subtle in their communications • Be scientifically rigorous (statistically) • Help them help you • Don’t box them in • Help them check off the necessary boxes • Help them minimize the number of patients put at risk • Provide publications and statistical help as needed • They will never ask you to do less than what you propose (for toxicology studies, clinical studies, etc.) • You never win a fight with the FDA

28. Influencing the FDA • The time to influence FDA decision is before their internal decision making meetings • Mid-cycle review on NDA • At the time of briefing package submission for IND • FDA is not influenced by pressure, except from Congress • FDA can be more lenient with sister agencies such as NIH, NCI • Personal connections can be very important in resolving issues • Can sometime get more information informally • Can increase level of trust • With rare exception, FDA will not lower their standards on statistics

29. Regulatory Strategy • Regulatory strategy • Understanding the regulatory rules and • Maximizing the speed, probability of success, and efficiency within the rules • Components • Which indication? • What type of manufacturing/formulation? • What kind of toxicology studies? • Which clinical study design (patients, endpoints)? • How to maximize exclusivity period

30. EMA Three approval pathways Centralised approval Decentralised approval Mutual recognition Centralised approval is preferred way Some European countries are outside the EU/EMEA

31. Centralised Process Approval Process Similar to U.S. in Many Ways IMPD is similar to IND MAA, like BLA/NDA is based on Common Technical Document Two rapporteurs assigned Rapporteurs make recommendation EMEA make final decision

32. Points of differences with FDA No true equivalent to Advisory Committee, although there can be a defense Less availability of documents such as briefing book, summary basis of approval, etc. Approval is based on superiority to standard of care Pricing is a factor in decision Sometimes a lower statistical bar Pricing negotiations follow approval

33. Drug Development Phases

34. Traditional Drug Development • Traditional steps • Discovery • Hit to Lead • Lead optimization • Preclinical/Biology • Toxicology • Phase 1 • Phase 2 • Phase 3 • Commercialization and Phase 4

35. Types of Therapies/Prophylactics • Small molecules • Biologics • Purified proteins/peptides • Recombinant proteins/peptides • Vaccines • Therapeutics • Prophylactic • Oligonucleotides • Devices • Other interventions • Surgery • Psychotherapy • etc.

36. Discovery: Find a Molecule • Old way: • Mass screening of natural products • Low throughput biological/whole animal assays • Black box MOA • New way: “Rational Drug Design” • Understand biology • Clone the target • High throughput assay • Assay is critical • Rational drug design has, in general, been a disappointment

37. Steps in Discovery • Hit • Lead optimization • Binding and potency • Solubility • Absorption • Basic metabolism • Elimination of toxicophores • Tractability of chemical synthesis

38. Preclinical Validation • Options • In vitro assays • Cell based assays • Animal models • Animal models range widely in design and predictability • An unvalidated animal model is usually NOT very helpful for predicting efficacy • Validation requires both positive and negative correlation with clinical outcome

39. Toxicology and IND Enabling Studies • Typically, at least two species (rodent and non-rodent) • Acute toxicity • Chronic toxicity • Reproductive toxicity • Mutagenesis studies • PK and exposure • Absorption, distribution, metabolism, and excretion (ADME) • Length and scope of toxicology work depends on intended clinical use, dose, and duration

40. CMC • Consistent, safe, controlled manufacturing of drug product is important and non-trivial • Analytic methods to determine the above and to determine stability are also important and non-trivial • For biologics, manufacturing and CMC can be more difficult

41. Clinical Phases • Phase I • Safety • Phase II • Safety • Dose selection • Initial efficacy (often surrogate endpoints) • Phase III • Confirmatory/efficacy • Phase IV • Safety • Effectiveness • Adaptive design/flexible design will obsolete this paradigm

42. Clinical Development – Key Success Criteria • Put patient safety first • Put compliance second • Kill drugs early and aggressively • Prespecify go/no-go criteria • Don’t kid yourself about the data • Don’t data mine a negative study • Work closely with regulatory agencies • Work with a good clinical trialist

43. Compliance and GCP • GCP is the process • Predefining how you will control and oversee the study • Following what you said you would do • Having the controls to detect and correct any deviations • GCP protects • Data integrity • Patient safety • Patient rights • GCP is the process, not the outcome

44. Competencies for Drug Development • Clinical/medical development • Clinical Operations • Statistics and programming • Data management • Regulatory • Drug supply/IVRS • Pharmacovigilance • Quality and Compliance • Medical writing • Project management • Program management • Vendor management • Partner management

45. Intellectual Property and Economics

46. Intellectual Property • Patents • Trademarks • Trade secrets • Market exclusivity • Priority review vouchers

47. Patent A right to exclude others from using your invention You may not be able to use your invention without obtaining a license from another holding a dominant patent Article I of the U.S. Constitution - “to promote the Progress of Science and useful Arts” Requirements Novel Non-obvious Useful

48. Types of Patents • Utility • Composition of mattewr • Method • Design • Plant

49. Logistics • Provisional vs. regular patent • Patent Cooperation Treaty vs. local filings • Geography of filings • Publication • First to file vs. first to invent • Enablement • Inventorship must be correct

50. Trends in biotech patents 1980 – Living organisms are patentable Broad patentability of biotech discoveries, but now being narrowed Written description: “The specification shall contain a written description of the invention, and of the manner and process of making it and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same”