Biomarkers and SubpartsBiomarkers and SubpartsRules and ExceptionsRules and Exceptions

James Witter MD, PhDJames Witter MD, PhDAnalgesic, Anti-inflammatory, and Analgesic, Anti-inflammatory, and

Ophthalmologic Drug ProductsOphthalmologic Drug Products

HFD-550/ODEV/CDER/FDAHFD-550/ODEV/CDER/FDA

FDA and Medical CareFDA and Medical Care

The FDA approves drug and biologic The FDA approves drug and biologic therapeutics for interstate commercetherapeutics for interstate commerce

The FDA does not regulate medical careThe FDA does not regulate medical care

Thus FDA-approved therapies may be Thus FDA-approved therapies may be used in ways that are deemed “standard-used in ways that are deemed “standard-of-care” by any specific communityof-care” by any specific community ““off label” useoff label” use

Drug Development & RegulationsDrug Development & Regulations

Pre-1938Pre-1938 FDA existed (established 1906) FDA existed (established 1906)

Only responded to problemsOnly responded to problemsNo requirement for testing or approvalNo requirement for testing or approval

Public Health DisastersPublic Health DisastersDNP for weight lossDNP for weight loss

1 % cataracts (women), deaths (1930’s)1 % cataracts (women), deaths (1930’s)

Elixir sulfanilamide for “all conditions in which the hemolytic Elixir sulfanilamide for “all conditions in which the hemolytic streptococci appear” (1937)streptococci appear” (1937)

Killed 107 (many children)Killed 107 (many children) From diethylene glycol poisoningFrom diethylene glycol poisoning

Food, Drug and Cosmetic Act (1938)Food, Drug and Cosmetic Act (1938)

Food Drug & Cosmetic Act Food Drug & Cosmetic Act -1938--1938-

Established Established requirement for safe therapiesrequirement for safe therapies

Marketing required “NDA” but passive approval Marketing required “NDA” but passive approval i.e. only if FDA did not objecti.e. only if FDA did not object

Application refused if:Application refused if: Investigations did not establish safety under proposed Investigations did not establish safety under proposed

labellabel Tests show unsafe, or not safeTests show unsafe, or not safe Insufficient information to establish safetyInsufficient information to establish safety Label false or misleadingLabel false or misleading

1962 Amendments to FD&C1962 Amendments to FD&C

Requirement for Requirement for efficacyefficacy

Mechanism to conduct clinical studiesMechanism to conduct clinical studies Goal to predict safety and efficacy when the Goal to predict safety and efficacy when the

product is marketedproduct is marketed Accomplished through carrying out Accomplished through carrying out adequate adequate

and well controlled trialsand well controlled trials

FD& C Act: Section 505FD& C Act: Section 505-2003--2003-

Requires substantial evidence of safety Requires substantial evidence of safety and efficacy as the basis of approvaland efficacy as the basis of approval

FDA must give positive approvalFDA must give positive approval

Permits the FDA to grant exemptions from Permits the FDA to grant exemptions from the FD&C Act to study new drug productsthe FD&C Act to study new drug products IND for drugs and biologicsIND for drugs and biologics

Application to Market a New Drug, Application to Market a New Drug, Biologic, or an Antibiotic Drug for Biologic, or an Antibiotic Drug for

Human Use (Form FDA 356H)Human Use (Form FDA 356H)

Section 505 (b) (1): application has Section 505 (b) (1): application has full full reportsreports of investigations to show whether of investigations to show whether drug is safe and effective and has details drug is safe and effective and has details about components, composition, methods about components, composition, methods and controls and controls

CFRCFRCode of Federal RegulationsCode of Federal Regulations

Codification of rules published in Federal Codification of rules published in Federal Register by Executive department of the Register by Executive department of the Federal GovernmentFederal GovernmentDivided into 50 titlesDivided into 50 titles Represent broad areas subject to Federal Represent broad areas subject to Federal

regulationregulation

Titles divided into chaptersTitles divided into chapters Often bears name of issuing agencyOften bears name of issuing agency

Chapters divided into parts and Chapters divided into parts and subpartssubparts

Title 21:Title 21:Food and Drug LawsFood and Drug Laws

Composed of 9 volumes with parts Composed of 9 volumes with parts

Parts 1-1299 (first 8 volumes = Chapter 1)Parts 1-1299 (first 8 volumes = Chapter 1) Comprises Food and Drug AdministrationComprises Food and Drug Administration

Part 1300-end (single volume) includes: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)

Part 314 (Subparts)Application to Market New DrugApplication to Market New Drug

A-General ProvisionsA-General ProvisionsB-ApplicationsB-ApplicationsC-Abbreviated ApplicationsC-Abbreviated ApplicationsD-FDA action on B or C aboveD-FDA action on B or C aboveE-Hearing ProceduresE-Hearing ProceduresF-Administrative Procedures for AntibioticsF-Administrative Procedures for AntibioticsG-MiscellaneousG-MiscellaneousH-Accelerated Approval of New Drugs for H-Accelerated Approval of New Drugs for Serious or Life-Threatening IllnessesSerious or Life-Threatening Illnesses

21 CFR-Subparts H and E21 CFR-Subparts H and E

Subpart H: Subpart H: 314.500314.500 Accelerated Approval of New Drugs for Accelerated Approval of New Drugs for

Serious or Life-Threatening IllnessesSerious or Life-Threatening Illnesses21 CFR 314: NDA regulations21 CFR 314: NDA regulations

Subpart E:Subpart E: 312.80312.80 Drugs Intended to Treat Life-threatening Drugs Intended to Treat Life-threatening

and Severely-debilitating Illnessesand Severely-debilitating Illnesses21 CFR 312: IND regulations21 CFR 312: IND regulations

CFR definitionsCFR definitions

Life-threateningLife-threatening: 314.81(a) : 314.81(a) (1) (1) Diseases or conditions where the Diseases or conditions where the

likelihood of death is high unless the course of likelihood of death is high unless the course of the disease is interrupted: andthe disease is interrupted: and

(2) (2) Diseases or conditions with potentially Diseases or conditions with potentially fatal outcomes, where the end point of clinical fatal outcomes, where the end point of clinical trial analysis is survival. trial analysis is survival.

Severely Debilitating: Severely Debilitating: 314.81(b)314.81(b) Diseases or conditions that cause major Diseases or conditions that cause major

irreversible morbidityirreversible morbidity

““Surrogate” ApprovalSurrogate” ApprovalSubpart HSubpart H

21 CFR 314.51021 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 HSubpart HApproval Caveats 314.510Approval Caveats 314.510

Requirement that applicant study the drug Requirement that applicant study the drug further to verify and describe its clinical further to verify and describe its clinical benefit where there is uncertainty benefit where there is uncertainty of the surrogate to clinical benefitof the surrogate to clinical benefit of observed clinical benefit ultimate outcomeof observed clinical benefit ultimate outcome

Post-marketing studies usually underwayPost-marketing studies usually underway must be adequate and well controlledmust be adequate and well controlled must be carried out with due diligencemust be carried out with due diligence

Subpart HSubpart HWithdrawal Caveats 314.530Withdrawal Caveats 314.530

FDA may withdraw approval, following a hearing FDA may withdraw approval, following a hearing if:if: Postmarketing clinical study fails to verify clinical Postmarketing clinical study fails to verify clinical

benefitbenefit Applicant fails to perform the required postmarketing Applicant fails to perform the required postmarketing

study with due diligencestudy with due diligence The promotional materials are false or misleadingThe promotional materials are false or misleading Other evidence demonstrates that the drug product is Other evidence demonstrates that the drug product is

not shown to be safe or effective under its conditions not shown to be safe or effective under its conditions of useof use

Subpart ESubpart ECaveats 312.80Caveats 312.80

FDA can exercise flexibility in applying FDA can exercise flexibility in applying standards while preserving safety and standards while preserving safety and effectivenesseffectiveness

Procedures reflect recognition that physicians Procedures reflect recognition that physicians and patients are generally willing to accept and patients are generally willing to accept greater risks of side effects from products that greater risks of side effects from products that treat life-threatening and severely-debilitating treat life-threatening and severely-debilitating illnesses, than they would accept from products illnesses, than they would accept from products to treat less serious illnessesto treat less serious illnesses

Subpart ESubpart ECaveatsCaveats

312.84312.84 Risk-benefit analysis in review of Risk-benefit analysis in review of marketing applications for drugs to treat life-marketing applications for drugs to treat life-threatening and severely-debilitating illnessesthreatening and severely-debilitating illnesses not approvable (drug) or deficiency (biologic) not approvable (drug) or deficiency (biologic)

letter may be issued after review of dataletter may be issued after review of data

312.85312.85 PhasePhase 4 studies 4 studies FDA may seek agreement from the sponsor to FDA may seek agreement from the sponsor to

conduct certain phase 4 studies to delineate conduct certain phase 4 studies to delineate additional information about the drug’s risks, additional information about the drug’s risks, benefits,and optimal usebenefits,and optimal use

Biomarkers and Surrogate EndpointsBiomarkers and Surrogate Endpoints

NIH/FDA sponsored meetingNIH/FDA sponsored meetingApril 15-16, 1999April 15-16, 1999

definitionsdefinitions

conceptual modelconceptual model

possible relationshipspossible relationships

Conceptual modelConceptual model Biomarker and Surrogate Endpoints - 1999Biomarker and Surrogate Endpoints - 1999

Biomarkers include the measurements considered Biomarkers include the measurements considered directly related to clinical outcomes, but are not the directly related to clinical outcomes, but are not the outcomes themselvesoutcomes themselves

Biomarkers can evaluate the safety or efficacy (or both) Biomarkers can evaluate the safety or efficacy (or both) of therapeutic interventionof therapeutic intervention

Some biomarkers may achieve the status of a surrogate Some biomarkers may achieve the status of a surrogate endpoint in a clinical trialendpoint in a clinical trial difficult due to disease complexity and single marker difficult due to disease complexity and single marker

limitations limitations

Possible relationshipsPossible relationshipsBBiomarker and Surrogate Endpoints - 1999iomarker and Surrogate Endpoints - 1999

Biomarker of no value as surrogate endpointBiomarker of no value as surrogate endpoint intervention affects disease, not marker

Biomarker measures unfavorable outcomeBiomarker measures unfavorable outcome intervention worsens clinical outcomeintervention worsens clinical outcome

Biomarker has partial valueBiomarker has partial value intervention’s positives and negatives not fully intervention’s positives and negatives not fully

measured (most current surrogate endpoints)measured (most current surrogate endpoints)

Biomarker is ideal surrogate endpointBiomarker is ideal surrogate endpoint full effect of intervention measuredfull effect of intervention measured

Biomarkers in SLE may:Biomarkers in SLE may:

be useful in exploratory studiesbe useful in exploratory studies

help identify or prioritize new therapies help identify or prioritize new therapies

help assess safety help assess safety

help identify “at risk” or “resistant” patientshelp identify “at risk” or “resistant” patients

help compare therapieshelp compare therapies

help patients and doctors to select and help patients and doctors to select and monitor therapiesmonitor therapies

help assess efficacy (? surrogate endpoint)help assess efficacy (? surrogate endpoint)

Surrogate Endpoint: DefinitionSurrogate Endpoint: Definition

A surrogate endpoint of a clinical trial is a A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used laboratory measurement or a physical sign used as a substitute for a as a substitute for a clinically meaningful clinically meaningful endpoint that measures directly how a endpoint that measures directly how a patient feels, functions, or survivespatient feels, functions, or survives

Changes induced by a therapy on a surrogate Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a endpoint are expected to reflect changes in a clinically meaningful endpointclinically meaningful endpoint

Only valid if the effect on the surrogate leads to Only valid if the effect on the surrogate leads to a clinical benefita clinical benefit

Surrogates vs. BiomarkersSurrogates vs. Biomarkers

Surrogate endpoints are candidates for drug Surrogate endpoints are candidates for drug approvalapproval

Biomarkers do not have the same regulatory Biomarkers do not have the same regulatory implicationimplication

Surrogates may be biomarkers, but not all Surrogates may be biomarkers, but not all biomarkers are surrogates. biomarkers are surrogates.

Clinically Meaningful Outcome

Biomarker

Surrogate marker

Current State: SurrogatesCurrent State: Surrogates

Blood pressureBlood pressure

Lipid lowering agentsLipid lowering agents

Blood sugar/HBA1cBlood sugar/HBA1c

Bone mineral densityBone mineral density

HIV loadHIV load

Surrogates: ProblemsSurrogates: 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 survivalDeaths and cardiac arrests

Encainide/Flecainide: 63/755 (8.3%) Placebo: 26/743 (3.5%)

Subparts H and ESubparts H and E

Potential advantagePotential advantage accelerated approvalaccelerated approval

Potential disadvantagePotential disadvantage accelerated withdrawalaccelerated withdrawal

Uric acid: Biomarker or SurrogateUric acid: Biomarker or Surrogate

Serum uric acid is a laboratory measureSerum uric acid is a laboratory measure

Elevated levels can correlate with gout attacks, Elevated levels can correlate with gout attacks, tophaceous disease or renal disease in the right patient tophaceous disease or renal disease in the right patient

Does lowering in serum uric acidDoes 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?Lower uric acid to < 6.0 mg/dl or more than placebo?

In all patients or only a proportion?In all patients or only a proportion?

Surrogate Approval-Example?Surrogate Approval-Example?DS-DNA DS-DNA hypothetically hypothetically proposed as surrogate for proposed as surrogate for trial in SLE (renal disease?)trial in SLE (renal disease?)

Responder approach to analysisResponder approach to analysis

Endpoints in phase 2/3 trials to address short-Endpoints in phase 2/3 trials to address short-term benefitterm benefit renalrenal ? quality of life outcome ? quality of life outcome

Post-marketing commitment to verify long-term Post-marketing commitment to verify long-term clinical benefit clinical benefit ? preservation of renal function? preservation of renal function