1. Biomarkers and Subparts Rules and Exceptions James Witter MD, PhD Analgesic, Anti-inflammatory, and Ophthalmologic Drug Products HFD-550/ODEV/CDER/FDA

2. FDA and Medical Care The FDA approves drug and biologic therapeutics for interstate commerce The FDA does not regulate medical care Thus FDA-approved therapies may be used in ways that are deemed “standard- of-care” by any specific community “off label” use “off label” use

3. Drug Development & Regulations Pre-1938 FDA existed (established 1906) FDA existed (established 1906) Only responded to problems No requirement for testing or approval Public Health Disasters Public Health Disasters DNP for weight loss 1 % cataracts (women), deaths (1930’s) 1 % cataracts (women), deaths (1930’s) Elixir sulfanilamide for “all conditions in which the hemolytic streptococci appear” (1937) Killed 107 (many children) Killed 107 (many children) From diethylene glycol poisoning From diethylene glycol poisoning Food, Drug and Cosmetic Act (1938)

4. Food Drug & Cosmetic Act -1938- Established requirement for safe therapies Marketing required “NDA” but passive approval i.e. only if FDA did not object Application refused if: Investigations did not establish safety under proposed label Investigations did not establish safety under proposed label Tests show unsafe, or not safe Tests show unsafe, or not safe Insufficient information to establish safety Insufficient information to establish safety Label false or misleading Label false or misleading

5. 1962 Amendments to FD&C Requirement for efficacy Mechanism to conduct clinical studies Goal to predict safety and efficacy when the product is marketed Goal to predict safety and efficacy when the product is marketed Accomplished through carrying out adequate and well controlled trials Accomplished through carrying out adequate and well controlled trials

6. FD& C Act: Section 505 -2003- Requires substantial evidence of safety and efficacy as the basis of approval FDA must give positive approval Permits the FDA to grant exemptions from the FD&C Act to study new drug products IND for drugs and biologics IND for drugs and biologics

7. Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use (Form FDA 356H) Section 505 (b) (1): application has full reports of investigations to show whether drug is safe and effective and has details about components, composition, methods and controls

8. CFR Code of Federal Regulations Codification of rules published in Federal Register by Executive department of the Federal Government Divided into 50 titles Represent broad areas subject to Federal regulation Represent broad areas subject to Federal regulation Titles divided into chapters Often bears name of issuing agency Often bears name of issuing agency Chapters divided into parts and subparts

9. Title 21: Food and Drug Laws Composed of 9 volumes with parts Parts 1-1299 (first 8 volumes = Chapter 1) Comprises Food and Drug Administration Comprises Food and Drug Administration Part 1300-end (single volume) includes: Chapter 2 (Drug Enforcement Agency-Justice) Chapter 2 (Drug Enforcement Agency-Justice) Chapter 3 (Office of National Drug Policy) Chapter 3 (Office of National Drug Policy)

10. Application to Market New Drug Part 314 (Subparts) Application to Market New Drug A-General Provisions B-Applications C-Abbreviated Applications D-FDA action on B or C above E-Hearing Procedures F-Administrative Procedures for Antibiotics G-Miscellaneous H-Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses

11. 21 CFR-Subparts H and E Subpart H: 314.500 Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses 21 CFR 314: NDA regulations Subpart E: 312.80 Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses 21 CFR 312: IND regulations

12. CFR definitions Life-threatening: 314.81(a) (1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted: and (1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted: and (2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. (2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. Severely Debilitating: 314.81(b) Diseases or conditions that cause major irreversible morbidity Diseases or conditions that cause major irreversible morbidity

13. “Surrogate” Approval Subpart H 21 CFR 314.510 FDA may grant marketing approval for a new drug product on the basis of adequate and well- controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible mortality.

14. Subpart H Approval Caveats 314.510 Requirement that applicant study the drug further to verify and describe its clinical benefit where there is uncertainty of the surrogate to clinical benefit of the surrogate to clinical benefit of observed clinical benefit ultimate outcome of observed clinical benefit ultimate outcome Post-marketing studies usually underway must be adequate and well controlled must be adequate and well controlled must be carried out with due diligence must be carried out with due diligence

15. Subpart H Withdrawal Caveats 314.530 FDA may withdraw approval, following a hearing if: Postmarketing clinical study fails to verify clinical benefit Postmarketing clinical study fails to verify clinical benefit Applicant fails to perform the required postmarketing study with due diligence Applicant fails to perform the required postmarketing study with due diligence The promotional materials are false or misleading The promotional materials are false or misleading Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use

16. Subpart E Caveats 312.80 FDA can exercise flexibility in applying standards while preserving safety and effectiveness Procedures reflect recognition that physicians and patients are generally willing to accept greater risks of side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products to treat less serious illnesses

17. Subpart E Caveats 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life- threatening and severely-debilitating illnesses not approvable (drug) or deficiency (biologic) letter may be issued after review of data not approvable (drug) or deficiency (biologic) letter may be issued after review of data 312.85 Phase 4 studies FDA may seek agreement from the sponsor to conduct certain phase 4 studies to delineate additional information about the drug’s risks, benefits,and optimal use FDA may seek agreement from the sponsor to conduct certain phase 4 studies to delineate additional information about the drug’s risks, benefits,and optimal use

18. Biomarkers and Surrogate Endpoints NIH/FDA sponsored meeting April 15-16, 1999 definitions conceptual model possible relationships

19. Conceptual model Biomarker and Surrogate Endpoints - 1999 Biomarkers include the measurements considered directly related to clinical outcomes, but are not the outcomes themselves Biomarkers can evaluate the safety or efficacy (or both) of therapeutic intervention Some biomarkers may achieve the status of a surrogate endpoint in a clinical trial difficult due to disease complexity and single marker limitations difficult due to disease complexity and single marker limitations

20. Possible relationships B iomarker and Surrogate Endpoints - 1999 Biomarker of no value as surrogate endpoint intervention affects disease, not marker Biomarker measures unfavorable outcome intervention worsens clinical outcome intervention worsens clinical outcome Biomarker has partial value intervention’s positives and negatives not fully measured (most current surrogate endpoints) intervention’s positives and negatives not fully measured (most current surrogate endpoints) Biomarker is ideal surrogate endpoint full effect of intervention measured full effect of intervention measured

21. Biomarkers in SLE may: be useful in exploratory studies help identify or prioritize new therapies help assess safety help identify “at risk” or “resistant” patients help compare therapies help patients and doctors to select and monitor therapies help assess efficacy (? surrogate endpoint)

22. Surrogate Endpoint: Definition A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint Only valid if the effect on the surrogate leads to a clinical benefit

23. Surrogates vs. Biomarkers Surrogate endpoints are candidates for drug approval Biomarkers do not have the same regulatory implication Surrogates may be biomarkers, but not all biomarkers are surrogates.

24. Clinically Meaningful Outcome Biomarker Surrogate marker

25. Current State: Surrogates Blood pressure Lipid lowering agents Blood sugar/HBA1c Bone mineral density HIV load

26. Surrogates: Problems Do not always account for adverse effect which may cancel out part or all of the apparent treatment benefit: Cardiac Arrhythmia Suppression Trial (CAST) NEJM 324: 781-788 (1991) Anti-arrhythmics with worse survival Deaths and cardiac arrests Encainide/Flecainide: 63/755 (8.3%) Placebo: 26/743 (3.5%)

27. Subparts H and E Potential advantage accelerated approval accelerated approval Potential disadvantage accelerated withdrawal accelerated withdrawal

28. Uric acid: Biomarker or Surrogate Serum uric acid is a laboratory measure Elevated levels can correlate with gout attacks, tophaceous disease or renal disease in the right patient Does lowering in serum uric acid Decrease incidence of ESRD or stone formation? Decrease incidence of ESRD or stone formation? Decrease gouty arthritis or size of tophi? Decrease gouty arthritis or size of tophi? How much is enough? How much is enough? Lower uric acid to < 6.0 mg/dl or more than placebo? In all patients or only a proportion?

29. Surrogate Approval-Example? DS-DNA hypothetically proposed as surrogate for trial in SLE (renal disease?) Responder approach to analysis Endpoints in phase 2/3 trials to address short-term benefit renal renal ? quality of life outcome ? quality of life outcome Post-marketing commitment to verify long- term clinical benefit ? preservation of renal function ? preservation of renal function