FDA OVERVIEW: Protecting Consumers - Promoting Public Health

1. FDA OVERVIEW: Protecting Consumers - Promoting Public Health Frieda Houghton PhD Worldwide Regulatory Strategy Pfizer June 2012

2. FDA Mission • To promote and protect the public health by helping safe and effective products reach the market in a timely way, • To monitor products for continued safety after they are in use, • To advance public health by helping to speed innovations that make medicines more effective, safer and more affordable, • To help the public get the accurate science-based information to improve their health

3. FDA as US Government Agency • FDA operates within the US Department of Health and Human Services (HHS) - cabinet level department, reports to President • Fiscal Year 2008 budget - $US 707.7 billion (FY 2007: $US 698B) • HHS employees – 64, 750 (2007: 67,444) • FDA is part of the Public Health Service division of HHS • FDA: Regulates drugs, foods, cosmetics, biologics, medical devices (products = ~25% of US consumer spending) • Fiscal Year 2007 budget - $US 2.3 billion • FDA employees – ~10,070 (10,446 in 06) • ~1,000 “field” personnel (167 local offices) who inspect ~124,000 FDA-regulated firms; 17,000-22,000 inspections/year in recent years • Includes ~6,000 US pharmaceutical facilities • ~2000 scientists involved in review of new products and product analysis

4. What FDA Regulates • Biologics • Cosmetics • Drugs • Foods • Medical Devices • Radiation-Emitting Electronic Products • Veterinary Products

5. What FDA Does Not Regulate • General Advertising – Federal Trade Commission (FTC); *FDA regulates prescription drug and medical device advertising • Alcohol – Bureau of Alcohol, Tobacco and Firearms (Treasury Department) • Consumer Products – Consumer Product Safety Commission (CPSC) • Drugs of Abuse – Drug Enforcement Administration (DEA) • Health Insurance – Centers for Medicare and Medicaid • Meat and Poultry – Food Safety and Inspection Service (US Department of Agriculture); *FDA regulates game meats, such as venison, ostrich and snake • Pesticides – US Department of Agriculture; Environmental Protection Agency (EPA) • Restaurants and Grocery Stores – Local/county health departments • Water – Environmental Protection Agency (EPA); *FDA regulates labeling and safety of bottled water

6. FDA History • Pure Food and Drugs Act of 1906 (concentrated on food): • Agency was a “police force” with authority to seize adulterated or misbranded products shipped across state lines (“interstate commerce”). • Stimulus: Upton Sinclair’s The Jungle • Main Agency function: detect foods and drugs in violation; samples tested in field labs • Violators prosecuted; difficult: “false and fraudulent” - proof of intent to default consumers. Basis rested on product labeling. • Act less effective as preventative measure; other shortcomings • Few amendments did little to correct significant shortcomings

7. FDA History • Federal Food, Drug and Cosmetic Act of 1938: • Stimulus: Elixir of Sulfanilamide tragedy (diethylene glycol as a solvent) • Safety testing of drugs by manufacturer not required • Expanded police powers and powers to regulate drugs and the industry. • FDA power expanded to regulate devices and cosmetics • Factory inspections authorized • “New Drug” defined as one “not generally recognized as safe for its intended use” (“efficacy” added later) • Investigations in humans required to comply with Investigational New Drug provisions • New Drug Application (NDA) must be submitted to FDA; only safety assessment required initially (not efficacy) • Amended significantly over the years, often in response to medical tragedy, scandal/fraud • Basis of current US drug law

8. Drug Development and US Approval Process: Overview • To market a drug in the US, the law requires that the drug must be SAFE and EFFECTIVE (Benefits outweigh Risks) • The basic process: • The drug developer (firm, sponsor) must prove to the drug regulator (Food and Drug Administration - FDA) that the drug is safe and effective

9. Drug Development and US Approval Process: Overview • Sponsor activities: • Conduct laboratory, animal and human studies to demonstrate drug safety and efficacy • Develop testing, manufacturing and controls to assure that the drug meets all legal requirements and “has the identity and strength…quality and purity characteristics that it purports or is represented to possess” (GMPs) • Submit all the data and information in an appropriate format for FDA review (e.g., the IND, the NDA)

10. Drug Development and US Approval Process: Overview • FDA activities: • Decide what constitutes substantial evidence of safety and efficacy of the drug • Interpret Federal (US) Food and Drug Law • Write and enforce Federal Food and Drug Regulations • NB: Regulations have the force and effect of law!

11. Prescription Drug User Fee Act (PDUFA) • Passed in 1992 (reauthorized 1997, 2002, 2007) • Reauthorized until 2012 • Authorized FDA to collect fees from companies that manufacture certain products • Fee Rates for FY 2010 • Requiring clinical data: $1,405,500 • Not requiring clinical data: $702,750 • Supplements requiring clinical data: $702,750 • Establishments: $457,200 • Products: $77,720

12. The FDA Amendments Act (FDAAA) – Sept 27, 2007 • Reauthorized • Assessment of User Fees (PDUFA IV) • The Pediatric Research Equity Act (PREA) • The Best Pharmaceuticals for Children Act (BPCA) • Other major topics covered include • A new fee program for obtaining FDA advisory review of direct-to-consumer (DTC) television advertisements • New FDA authorities for requiring label changes and post-marketing studies, and for REMS (risk evaluation and mitigation strategies) • New/expanded requirements for registration of clinical trials and disclosure of results • Formation of the Reagan-Udall Institute in support of FDA's Critical Path initiative • New conflict of interest rules for FDA Advisory Committee members • New rules on citizen petitions

13. FDA Authority and Primary Sources of Information • Federal Food, Drug, and Cosmetic Act (1938) • Code of Federal Regulations, Title 21 (21 CFR) • IND : 21 CFR 312 • NDA: 21 CFR 314 • GMP: 21 CFR 210, 211 • GLP : 21 CFR 58 • GCP : • 21 CFR 50 - Protection of Human Subjects • 21 CFR 56 - Institutional Review Boards (IRBs) • 21 CFR 312 - IND regulations

14. FDA Authority and Primary Sources of Information • FDA Guidelines: No longer issued by FDA • FDA Guidances: Not legal requirements; however… • Compliance Policy Guides – Important for compliance related activities (e.g., inspections) • FDA written and voice communication to sponsor, “Advice” from Agency personnel, FDA presentations to industry/public NOTE: While the above are all subject to change, the processes in many ways are becoming more standardized.

15. FDA-Sponsor Interactions:Meetings - General • Meetings with FDA covered by “Guidance for Industry - Formal Meetings Between FDA and Sponsors or Applicants” • Final issued 5/09 • Specifies: • Types of meetings (including timing of FDA scheduling of meeting): • A - Immediately necessary for a stalled development program to proceed (30 days); e.g., dispute resolution, special protocol assessment • B - Pre-IND, EOP 1/EOP 2/Pre-Phase 3, Pre-NDA meetings (60 days) • C - Other (75 days) • Procedures for requesting a meeting • Contents and timing of submission of Information Package • Procedures for conduct of meeting • Documentation (e.g., minutes)

16. IND’s investigational new drug

17. IND - Investigational New Drug Application "Notice of Claimed Investigational Exemption for a New Drug" • Request to FDA by a sponsor to be allowed to study an investigational new drug (unapproved new drug) in humans • “Exemption” from provisions of FD&C Act that govern shipment of unapproved drugs via interstate commerce

18. IND Covers the Following for Use in Clinical Investigations: • New Drugs • New Antibiotic Drugs • New Biological Drug • New Biological Products used in vitro for diagnostic purposes • New indication, different dosage or different route of administration for an approved product

19. IND – Not Needed For: • Approved/marketed product using an approved dosage and for an approved indication • Studies not supporting “significant”changes in labeling or advertising • Studies not putting patients at increased risk • Certain bioavailability/bioequivalence studies (See 21 CFR 320.31 Bioavailability and Bioequivalence Requirements) • A drug solely intended for in vitro or animal testing • In vitro biological product for diagnostic procedure that confirms diagnosis made by another medically established diagnostic product or procedure

20. IND Types • Types of INDs: • IND submitted by commercial sponsor (by a pharmaceutical company) • Treatment IND/Treatment Use IND • Sponsor-Investigator IND • Emergency Use (“Compassionate Use”) IND • For a single patient only

21. IND: Content • Provides data and information regarding: • The drug product • Its composition • Active ingredient, its source, synthesis • Method of manufacture and controls • How it is intended to be used in patients • Results of preclinical studies that show it is “reasonably” safe to begin/continue testing in humans • Detailed outline of the planned human studies (protocols)

22. IND: FDA Focus • Primary focus of FDA: Safety and rights of human subjects • Assure that human subjects are not subjected to unreasonable risks • Assess the adequacy of the preclinical program to support the proposed studies • Verify approval of the studies by the Institutional Review Board (IRB) • Review the credentials and commitments of the clinical investigators • Assess the likelihood that the clinical plan will produce information useful to the ultimate approval of the product • Assess the adequacy of the proposed clinical protocol to produce clinically meaningful results • Assess the "fair balance" of the investigator's brochure (labeling) and its ability to inform the clinical investigators of background scientific data

23. FDA Review of the IND • FDA receipt - Initial administrative review for completeness • Technical reviews: • Medical Officer - Generally the team leader • Chemist - Quality of clinical supplies, GMPs • Pharmacologist/Toxicologist- Adequacy of preclinical program • Statistician - Adequacy of statistical plan, power, patient numbers, etc. for statistical significance/proof • Project Manager - Liaison between FDA and sponsor • 30-day “review clock” • No formal IND approval: “No news is good news” • Minor issues, usually limited to requests for clarification - Communicated by phone • Major issues/concerns - Generally written response required • Clinical Hold - Serious concerns!

24. IND maintenance • Protocol amendments • New protocol • Changes to existing protocol(s) • IND information amendments • IND safety reports • Serious and unexpected adverse experiences • Written report of adverse reactions both serious and unexpected. NMT 15 calendar days after initial receipt of information by sponsor • Telephone/fax for unexpected fatal or life-threatening reactions. NMT 7 working days after receipt of information • IND annual reports • focus for reporting status of the studies and should update the general investigational plan for the coming year

25. IND Amendments and Reporting:Annual Reports • Individual study information • Summary information for past year: • Most frequent and serious ADRs • Summary of safety reports • Subjects who died, plus cause of death • Drop-outs associated with ADRs • Information learned regarding drug actions • Preclinical studies completed or ongoing • Significant manufacturing or microbiological changes • General investigational plan for coming year • Revisions of investigator brochure, plus copy • Significant Phase 1 protocol revisions not previously reported • Significant foreign marketing developments (e.g., approvals, withdrawals) • Outstanding business (if desired)

26. NDA’s New drug applications

27. Overview of NDA Process • Sponsor believes IND studies (supported by nonclinical studies) demonstrate that drug is safe and effective • Sponsor believes that CMC (Chemistry, Manufacturing and Controls = Quality) data and information demonstrate that the finished product can be manufactured consistently to conform to appropriate controls and specifications

28. Seeking Approval: Regulatory Strategy • Depending on the drug, disease, business decision, a Sponsor may seek the following types of approval • Traditional • Accelerated Approval • Orphan Drug • Can also have accelerated approval of an orphan drug • Also must consider the filing/review type • Fast Track • Priority • Standard

29. Overview of NDA Process • Sponsor submits New Drug Application (NDA), which contains detailed information regarding (among other things): • Composition of drug • Method of manufacture and control • Intended use and conditions of use of the drug (labeling: package insert, labels, other written, printed or graphic material accompanying the product) • Preclinical studies • Clinical studies • Statistical analysis of data

30. Overview of NDA Process • New Drug: • One which is not recognized in the US as being safe and/or effective for its intended use • Drug not yet approved in the US, even if approved in other parts of the world • NDA is reviewed by FDA team consisting of medical officer (physician), pharmacologist, chemist, statistician and other personnel • Major NDAs and scientifically complex NDAs may be referred to an advisory committee • “Deficiencies” identified by FDA during the review are addressed by sponsor

31. NDA Screening/Filing • Timeframe for Reviewing Applications • 10-month standard and 6-month priority review • Within 6 or 10 months of receipt of NDA, FDA must review it and issue an "action letter" (statutory requirement; “never” met prior to PDUFA*) • Review clock may be extended: • By mutual agreement, or • As a result of a "major" amendment to the NDA *PDUFA = Prescription Drug User Fee Act (1992, 1997, 2002; 2007)

32. NDA Screening/Filing • Review for Filing of an Application • 60-day timeframe for initial screening (statutory requirement) • Usually 45-day meeting of FDA project team • Threshold determination that application is sufficiently complete to permit a substantive review • FDA "checklists" - administrative, technical disciplines • Filing of an Application • If acceptable, NDA is considered "filed" • Applicant is notified in writing • FDA may refuse to file (RTF) the application based on quality, administrative, scientific and/or technical deficiencies

33. Overview: FDA Review of the Application • FDA has 60 days to accept or refuse to file. • FDA assembles the Review Team. • Role of an Advisory Committee - To provide independent advice that will contribute to the quality of the agency's regulatory decision-making and lend credibility to the product review process. • Key Decision: Do the benefits outweigh the risks?

34. NDA Amendments (during review) • Amendment - Change in a pending (unapproved) application • Can be initiated by sponsor or FDA • "Major" Amendment - Significant new data • Constitutes agreement by applicant to extend the "review clock" • FDA decides the extension time - up to 180 days • FDA must notify the applicant of the extension

35. Communication with FDA During NDA Review • General: • May be telephone, letters, meetings, whichever is most appropriate • Must be documented by FDA, according to regulations and policy • Should be documented by applicant • Notification of Easily Correctable Deficiencies • Information Request (IR) Letter: • Sent during an NDA review; request for information or clarification needed to allow completion of the discipline review • Discipline Review (DR) Letter: • Sent at conclusion of discipline review; used to convey “early thoughts” on possible deficiencies • Not mandatory; not always issued • IRs or DRs do not stop the “review clock,” but sponsors usually respond quickly; FDA may specify a submission time to avoid delays in review

36. FDA Action Letters:“Approval” and “Complete Response” • "Approval" Letter • Drug is safe and effective as prescribed • Approval becomes effective on the date of the letter • Allows marketing to begin, subject to specified conditions • “Complete Response" Letter • Describes the information or materials required or the conditions to be met for approval • Within 10 days after the date of the letter, applicant must notify FDA with one (1) of the following: • Amend the application • Intent to amend the application • Withdraw the application, without prejudice to resubmitting (failure to respond = withdrawal) • Request a hearing • Request an extension of the review period

37. Back-ups

38. Drug Regulation: Key Terms • FDA - Food and Drug Administration • IND - Investigational New Drug Application • NDA - New Drug Application • GMP, CGMP, cGMP - Current Good Manufacturing Practices • GLP, CGLP, cGLP - Current Good Laboratory Practices • GCP, CGCP, cGCP - Current Good Clinical Practices See also CDER Acronym List: 12 pages! http://www.fda.gov/cder/handbook/acronym.htm

39. The Discovery, Development, & Approval Process

40. IND • Focus of initial IND submission: The general investigational plan and the protocols for specific studies • Subsequent amendments, new or revised protocols: Should build logically and scientifically on previous submissions and should be supported by additional information • Annual reports to the IND: • Should serve as the focus for reporting status of the studies and should update the general investigational plan for the coming year

41. FDA-Sponsor Interactions: IND • Pre-IND Meeting • FDA's introduction to the drug (and sponsor?) • Sponsor provides in pre-meeting submission: • Product rationale • Product formulation, manufacture and controls • Preclinical program • Proposed clinical program, protocol(s) • Additional information as needed • At meeting, FDA provides: • Comments/guidance regarding the above • Items necessary for IND to be acceptable

42. IND Amendments and Reporting • Protocol Amendments • New Protocol • Study can begin, provided: • New Protocol has been submitted to FDA for review • New protocol has been approval by IRB • Changes in Protocol • Phase 1 - Significantly affects safety • Phase 2 and 3 - Significantly affects safety, scope of investigation or scientific quality of the study: • increase in dosage or duration of exposure • significant increase in number of subjects • significant protocol design change, e.g., add or delete a control group • addition or deletion of procedure for monitoring safety • Revised protocol can be implemented, provided: • Revised protocol has been submitted to FDA for review • Revised protocol has been approved by IRB

43. IND Amendments and Reporting • Protocol Amendments (cont’d) • Protocol change to eliminate immediate hazard to subjects • Change protocol immediately • Notify FDA and IRB • New investigator • Notify FDA within 30 days of addition • Can begin shipping drug as soon as added

44. IND Amendments and Reporting • Information Amendments • New toxicology, chemistry or other technical information • Report of discontinuance of an investigation • “Other” • Submit amendments no more frequently than every 30 days (can combine Protocol and Information amendments in one submission)

45. IND Amendments and Reporting • IND Safety Reports • Serious and unexpected adverse experience associated with the use of the drug • Serious: Death, a life-threatening ADE, inpatient hospitalization or prolongation of existing hospitalization, a persistent of significant disability/incapacity, or a congenital anomaly/birth defect • Unexpected: Specificity or severity not consistent with the current investigator's brochure; ADE not previously observed • Associated: Reasonable possibility that the experience may have been caused by the drug

46. IND Amendments and Reporting • IND Safety Reports • Written Report • For adverse reactions both serious and unexpected • Any finding from tests in lab animals that suggests a significant risk in humans • NMT 15 calendar days after initial receipt of information by sponsor • Telephone and Facsimile Transmissions Report • For unexpected fatal or life-threatening reactions • NMT 7 working days after receipt of information • Life-threatening: Immediate risk of death from the ADE as it occurred • Disclaimer: Submission does not necessarily reflect a conclusion by the sponsor of admission of causal relationship

47. IND Types • Treatment IND (21 CFR 312.34 and 312.35) • For serious or immediately life-threatening disease • When alternate drug/therapy not satisfactory/available • Drug is already under investigation in a controlled trial, or all clinical trials have been completed, and • Sponsor is actively pursuing marketing approval • Drug may be allowed for use in patients not in the clinical trials • Drug may be allowed for use as early as during Phase 2 • “Treatment protocol” required • All other IND requirements apply

48. IND Types • Sponsor-Investigator IND* • All legal requirements for both a sponsor and an investigator regarding conduct of an IND apply to sponsor-investigator, including the regulations for: • 21 CFR 312 (INDs) • 21 CFR 50 (Protection of Human Subjects/Informed Consent) • 21 CFR 56 (Institutional Review Boards) • Not intended to replace traditional company-sponsored IND to initiate clinical trials or commercialize usage *Defined in 21 CFR 312.3(b)

49. IND Types • Emergency Use IND* (21 CFR 312.36)** • Emergency need arises that does not allow time to submit a formal IND • FDA may authorize shipment of drug for specified use in advance of a submitted IND • Initial contact usually initiated by telephone • One-time use (i.e., one patient) only • Sponsor required to submit IND ASAP following authorization to ship drug • Usually initiated by Sponsor-Investigator with “permission” from drug sponsor (drug company) *AKA ”Compassionate Use” **See also the following link: http://www.fda.gov/cder/cancer/SingleIND.htm

50. FDA-Sponsor Interactions: IND • End-of-Phase 1 Meeting • Usually reserved for "expedited" review procedures (e.g., Treatment IND) • Agree on design of Phase 2 studies • End-of-Phase 2 Meeting • Determine the safety of proceeding to Phase 3 • Evaluate the Phase 3 plan and protocols • Identify additional information needed to support the NDA • Pre-meeting submission: • Summaries of Phase 1 and 2 studies • Phase 3 protocols • Plans for additional nonclinical studies, if any • Tentative labeling, if available; confirm target indication