this work was made possible by a grant from the state attorney general consumer & prescriber...

This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®.

U.S. Food and Drug Administration

Practices, People, Politics and Prescriptions


Mission

http://www.fda.gov/opacom/morechoices/mission.html



Overview

• Development & Evolution of the FDA

• Limitations of the FDA Regulatory System

• Contemporary Challenges Facing the FDA


Development & Evolution Cycle• Crisis – Public health

disaster

• Legislation – Congressional response

• Adaptation – Steps FDA took to implement the new law


Early Medicines

• Buyer beware

• Boastful and extravagant claims

• Alcohol as the main ingredient

• Addictive and dangerous ingredients


Significant Milestones in Drug Law

• Biologic Control Act 1902

• Pure Food and Drugs Act of 1906

• Federal Food, Drug and Cosmetic Act of 1938

• Durham-Humphrey Amendment of 1951

• Kefauver-Harris Drug Amendments of 1962

http://www.fda.gov/opacom/backgrounders/miles.html



A Public Outcry for a New Law• Upton Sinclair’s book, The Jungle,

drew attention to adulterated meat (Meat sales dropped by 1/3)

• Roosevelt was persuaded to sign Pure Food and Drugs Act on June 30, 1906 along with the Meat Inspection Act

• 1906 Act transformed a scientific bureau into a regulatory agency that would become FDA


1906 Pure Food and Drugs Act

• “Adulteration” and “Misbranding

• Prohibited interstate transport of unlawful products

• New labels• Sanctioned drug

standards


Limitations of the 1906 ActCrazy Crystals Radio/Print Advertising…


A Turning Point

• Elixir Sulfanilamide

– First wonder drug– Used untested “solvent” DEG– Proved deadly– Legal Implication…


Federal Food, Drug, and Cosmetic Act 1938

• Pre-market safety approval of all new drugs• Prohibited false therapeutic claims for drugs• Drugs labeled with adequate directions for safe

use• Food standards “in the interests of consumers”• Cosmetics and medical devices under FDA’s

jurisdiction


A Disaster Averted Thalidomide

• Sedative sold over-the-counter in Europe – Treated morning sickness during

pregnancy– Produced birth defects in European

babies

• FDA received application for marketing in the US– Reviewer Frances Kelsey had concerns – Delay in approval prevented its being

sold in US


Amendments – 1960-80s

• Kefauver-Harris Amendments - the most significant changes in the Food, Drug and Cosmetic Act

– Pre-market efficacy and safety– Good manufacturing practices– Prescription drug advertising


Drug Regulation Changes

• New drug approvals based on safety AND efficacy

• Required GMPs and later GLPs

• New controls over Rx advertising

• New patient protection policies


Significant Milestones in Drug Law• Tamper-Resistant Packaging Regulations of 1982

• Orphan Drug Act of 1983

• Drug Price Competition & Patent Term Restoration Act of 1984

• Prescription Drug Marketing Act of 1987

• Medicare Prescription Drug Improvement & Modernization Act of 1997

• Prescription Drug User Fee Act (PDUFA) of 1992, 1997, 2002, 2007




Critical Thinking QuestionsGiven the history of the U.S. Food and Drug Administration (FDA) as a regulatory agency constantly reacting to a series of “crisis---legislative---adaptation cycles:

1. What do you think the U.S. medication system would be like if these regulations were not in place?

2. Do you think the U.S. is on the verge of another “crisis”--legislative—adaptation cycle?


Overview





Mission

• http://www.fda.gov/opacom/morechoices/mission.html




Modern FDAModern FDA

20

(Borchers AT, et al. The history and contemporary challenges of the US Food and Drug Administration. Clin Ther 2007;29:1-16)

NCTR CBERCDRH

CFSAN CVM

Food and Drug Administration

Center for Drug Evaluationand Research

CDER

ORA

http://www.gpoaccess.gov/cfr/index.html

IndustryGuidance

IndustryGuidance

http://www.gpoaccess.gov/cfr/index.html

PRE-CLINICALRESEARCH

FDA & INDUSTRY TIME

FDA TIME

INDUSTRY TIME

SPONSOR/FDA MEETINGS ENCOURAGED

DIS

CO

VE

RY/S

CR

EE

NIN

GSYNTHESISAND PURIFICATION

DIS

CO

VE

RY/S

CR

EE

NIN

GPRE-CLINICALRESEARCH

SYNTHESISAND PURIFICATION

ANIMALTESTING

SHORT-TERM

LONG-TERM

IND

CLINICAL STUDIES

NDAFDA & INDUSTRY TIME

INDUSTRY TIME


FDA TIME

DIS

CO

VE

RY/S

CR

EE

NIN



ANIMALTESTING

CLINICAL STUDIES

PHASE 3

PHASE 1

PHASE 2

FDA REVIEW

SHORT-TERM

LONG-TERM

IND NDA/ BLAFDA & INDUSTRY TIME

INDUSTRY TIME


FDA TIME FDA ACTION

26

PHASE 1 PHASE 2 PHASE 3

CLINICAL STUDIES

DIS

CO

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RY/S

CR

EE

NIN



ANIMALTESTING

PHASE 3

PHASE 1

PHASE 2

PHASE 4

CLINICAL STUDIES

ADVERSEREACTION

SURVEILLANCEPRODUCT DEFECT

REPORTING

POSTMARKETING

SURVEYS/SAMPLINGTESTING

POST APPROVALINSPECTIONS

SHORT-TERM

LONG-TERM

FDA REVIEW

PARALLEL TRACK

TREATMENT USE

ACCELERATED APPROVAL

ACCELERATED REVIEW: SUBPART E

ACCELERATED REVIEW

EEXPANDED ACCESS:

PARALLEL TRACKTREATMENT USE

IND NDA/BLA FDA ACTIONFDA & INDUSTRY TIME

INDUSTRY TIME


FDA TIME

New Drug Application (NDA) or Biologic License Application

(BLA) contains the following:

• Pre-clinical studies

• Human clinical studies

• Manufacturing details

• Labeling – Indication(s)

• Additional information

ODE I ODE II ODE III ODE IV ODE V

Neuro-pharmacological

Oncology

Cardio-Renal Metabolic andEndocrine

Pulmonary

Gastrointestinal and Coagulation

Anesthetic, Critical Care,

and Addiction

Medical Imaging and

Radiopharmaceuticals

Anti-Viral

Anti-Infective

Special Pathogen

and Immunologic

Anti-Inflammatory, Analgesic and Ophthalmologic

Dermatologic and Dental

Over-the-Counter

Reproductiveand Urologic

ODEVI

TherapeuticBiologicalOncology

TherapeuticBiological

InternalMedicine

ReviewManagement &

Policy

DRUG PRODUCT DIVISIONS

Review Team

Project ManagerMedical OfficerChemistMicrobiologistStatisticianPharmacologistEstablishment/Facility ReviewerSupport Personnel

• Panel of OUTSIDE experts• Provide advice and opinions to the FDA drug review team • FDA advisory committee

information, 1-800-741-8138 or 301-443-0572

ADVISORY COMMITTEE

http://www.fda.gov/oc/advisory/default

http://www.fda.gov/oc/advisory/default

Prescription DrugUser Fee Act (PDUFA)

http://www.fda.gov/oc/pdufa/default.htm

• Permits CDER/CBER to charge pharmaceutical manufacturers a fee to review drug applications

• These fees provide appropriate resources to accelerate the review of applications

• Not the only source of funds for CDER/CBER

• Funds go directly to CDER/CBER, not individuals

DIS

CO

VE

RY/S

CR

EE

NIN



ANIMALTESTING

PHASE 3

PHASE 1

PHASE 2

PHASE 4

CLINICAL STUDIES

ADVERSEREACTION

SURVEILLANCEPRODUCT

DEFECTREPORTING

POSTMARKETING

SURVEYS/SAMPLINGTESTING

POST APPROVAL

INSPECTIONS

SHORT-TERM

LONG-TERM

FDA REVIEW

IND NDABLA

ACTIONFDA & INDUSTRY TIME

INDUSTRY TIME


FDA TIME

PARALLEL TRACK

TREATMENT USE

ACCELERATED APPROVAL

Post-market Surveillance

Potential Regulatory Action for Postmarketing Safety Issues

• Labeling Change

• Scientific publication

• "Dear Doctor" letter (for specific warnings)

• Restricted use

• Restricted distribution

• Patient Medication guide

• Product withdrawal

36

Office of Drug Safety

• Division of Drug Risk Evaluation

• Division of Medication Errors and Technical Support,

• Division of Surveillance, Research, and Communication Support

37

MedWatch Website

• Safety Information Retrieval

• Adverse Event Reporting for Drugs,Devices, Biologics and Dietary Supplements

www.fda.gov/medwatch

http://www.fda.gov/medwatch

• Database

• Internationally compatible

Adverse Event Reporting System (AERS)

Office of Drug Safety (ODS) uses AERS to:

• triage

• review

• assess risk

39

DDMAC (Division of Drug Marketing Advertising and Communications)

• Promotional Materials Review

• Guidance and policy development

• Research

• Surveillance and enforcement

CDER’s Office of Compliance

• Sets labeling, manufacturing, and testing standards

• Monitors the quality of marketed drugs

• Evaluates, classifies, and recommends human drug recalls

Can We Improve the Current FDA System


Overview





Problems With the Current System?

1. Initial review for approval often fails to detect serious ADR’s

2. FDA’s surveillance system is plagued with underreporting

3. Threshold for action in response to ADR reports is subjective



4. Performance of post-marketing surveillance studies is out of FDA controls

5. FDA lacks direct legal authority to hold accountable drug companies that violate its recommendations

6. FDAs intrinsic structure is viewed as presenting a potential conflict of interest



7. FDA is highly dependent on user fees

8. Shortage of FDA expertise in drug safety and public health


Vision for the Next Century

• Critical Path Initiative

– Transform medical product development

– Keep pace with expected medical advances

http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html


Debate on Current FDA Issues• Independent Agency

– Transperent– Accountable

• Science-based– Enhanced Predictive Tools– Allow for Disagreement

• Increased Legal Authority– Enforcement/Oversight– Minimize Conflict of Interest

• Culture of Safety– Enhanced Communication


Perspective Practices, People and

Politics


Classroom Activities• Post-Marketing (Phase IV) studies


• Prescription Drug User Fees• Act (PDUFA) of 1992, 1997, 2002, 2007


Classroom Discussion• Post-Marketing (Phase IV) studies



Classroom Discussion• Prescription Drug User Fees

• Act (PDUFA) of 1992, 1997, 2002, 2007


Perspective Practices, People and

Politics• Protecting the Health of the Public

http://content.nejm.org/cgi/content/full/355/17/1753/DC1


Perspective

Put this information in the context of your:

• Group assigned medication exercise• Classroom learning• Direct-patient care activities next year• Professional practice

“Be a part of the DEBATE”

ChallengesAre We Headed for Another Public

Health Crisis?

this work was made possible by a grant from the state attorney general consumer & prescriber...

Documents

prescription drug neurontin

fda slide

drug law biologic control

drug administration

new law slide

cosmetic act

pure food

extravagant claims alcohol