# Presentation: 840186

## Biomarkers and SubpartsRules and Exceptions

- James Witter MD, PhD
*Analgesic, Anti-inflammatory, and Ophthalmologic Drug Products*
*HFD-550/ODEV/CDER/FDA*

## 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

## Drug Development & Regulations

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

## 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
- Tests show unsafe, or not safe
- Insufficient information to establish safety
- Label false or misleading

## 1962 Amendments to FD&C

- Requirement for _***efficacy***_
- Mechanism to conduct clinical studies
- Goal to predict safety and efficacy when the product is marketed
- Accomplished through carrying out _***adequate and well controlled trials***_

## 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

## 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

## 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
- Titles divided into chapters
- Often bears name of issuing agency
- Chapters divided into parts and _***subparts***_

## 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
- Part 1300-end (single volume) includes:
- Chapter 2 (Drug Enforcement Agency-Justice)
- Chapter 3 (Office of National Drug Policy)

## 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*

## 21 CFR-Subparts H and E

- Subpart H: 314.500
***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***
**21 CFR 312: IND regulations**

## 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*
- (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*

## “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***.

## 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 observed clinical benefit ultimate outcome*
- Post-marketing studies usually underway
*must be adequate and well controlled*
*must be carried out with due diligence*

## Subpart HWithdrawal Caveats 314.530

- FDA may withdraw approval, following a hearing if:
- Postmarketing clinical study fails to verify clinical benefit
- Applicant fails to perform the required postmarketing study with due diligence
- 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

## 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*

## 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
**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*

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

## 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

## Possible relationshipsBiomarker and Surrogate Endpoints - 1999

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

## 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)

## 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

## 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.

## Clinically Meaningful Outcome

- Biomarker

- Surrogate marker

## Current State: Surrogates

- Blood pressure
- Lipid lowering agents
- Blood sugar/HBA1c
- Bone mineral density
- HIV load

## 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%)

## Subparts H and E

- Potential advantage
- accelerated approval
- Potential disadvantage
- accelerated withdrawal

## 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 gouty arthritis or size of tophi?
- How much is enough?
- Lower uric acid  to < 6.0 mg/dl  or more than placebo?
- In all patients or only a proportion?

## 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
- ? quality of life outcome
- Post-marketing commitment to verify long-term clinical benefit
- ? preservation of renal function

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