History & Overview of the Drug Development Process & Timeline

Brown Bag lunch series (1/6)

JoAnn PfeifferNovember 17, 2010

Goal

Through training on the conduct of human subject research the Velos staff will acquire a better understanding and knowledge of the steps and requirements in the day-to-day operations of a clinical trial. Through a better understanding of clinical trial operations the Velos staff will be able to respond more effectively to client requests and requirements.

Session One

AgendaHistoryDrug Development ProcessKey players- roles and

responsibilities

Session One

Objectives At the end of session the participant

will be able to : Describe the drug development process &

timeline Identify the key players involved in

research Describe the roles & responsibilities of

the key players

Historical Events

Pre 1906: all drugs could be bought or sold like any other consumer good

Pure Food & Drugs Act (1906) Upton Sinclair: “The Jungle” Prohibits interstate commerce of

misbranded or adulterated foods, drinks, and drugs

Regulated product labeling Did not address drug safety or efficacy

Historical Events

The Federal Food, Drug and Cosmetics Act—1938

Sulfanilamide: treat streptococcal infections

Massengill Co: introduced a liquid form (1937)

107 people died that year Contained diethylene glycol First time FDA required that drugs must

be safe before being introduced to the market.

Tuskegee Syphilis trial (1932 - 1972) Sponsored by PHS Study the effects of untreated syphilis in

black men Exposed by media in 1972 Ramifications into late 1990’s

▪ $9M, free medical treatment to survivors & descendants

▪ Presidential apology in 1997

History Drug Development Process

Study Design Roles/ responsibilities

Tuskegee

U.S. Code of Federal Regulations (CFR)

Nuremburg Code (1947-1948) Nuremburg war crimes trials: Nazi experimentation Ten points for legitimate medical research Voluntary consent; fruitful results; based on animal

experimentation; free of unnecessary physical or mental suffering; end result cannot be death or disability; risk/benefit; conducted by scientifically qualified persons; subject at liberty to withdraw; terminate if cause to believe harm; adequate facilities

Declaration of Helsinki (1964) World Medical Association Set of ethical principles for the medical community

regarding human experimentation

History Drug Development Process

Study Design Roles/ responsibilities

Thalidomide

Thalidomide (1950’s & 60’s) Approved as sedative in Europe and

Japan Mfg. sent “samples” to US physicians Patients not informed that the drug was

investigational in US Used for morning sickness > 10,000 children in 46 countries were

born with deformities in late 1950’s and early 1960’s

History Drug Development Process

Study Design Roles/ responsibilities

Milgram Study

The Milgram Study (1961 – 1962)67.5% administered the max shock

(450 V) Teacher – Learner Teacher ask multiple choice questions Administer a shock if answer incorrect Start at 45 volt, could go up to 450 volt

shock▪ All paused to question experiment▪ None refused prior to 300 volt shock▪ Female subjects –same results, higher stress

Kefauver-Harris Amendment

Kefauver-Harris Amendment – 1962 Subjects informed of experimental

nature Informed consent must be obtained Safety and efficacy must be proven

prior to approval to marketBelmont Report – 1978 Respect Beneficence Justice

History Drug Development Process

Study Design Roles/ responsibilities

Phase I

Primary Objective:

First in human Safety and tolerability 20 – 80 healthy volunteers Single dose or repeated doses Low dosage, escalate to higher doses Determine maximum tolerated dose

History Drug Development Process

Study Design Roles/ responsibilities

Phase II

Primary Objectives

Determine optimal dose and regimen Safety & efficacy Patients with disease Up to 200 subjects Multi-center Adverse events

History Drug Development Process

Study Design Roles/ responsibilities

Phase III

Primary Objectives

Gather additional information to evaluate the overall benefit-risk relationship

Large: up to thousands Multi-center : representative of patient pop Most expensive, time consuming

History Drug Development Process

Study Design Roles/ responsibilities

Key Players

FDASponsorPrinciple Investigator (PI) Institutional Review Board (IRB)Study Coordinator Data ManagerStudy Monitor

History Drug Development Process

Study Design Roles/ responsibilities

FDA

Protect safety of the consumerCode of Federal Regulations IND and NDA (drugs) IDE and PMA or 510k (device)Post-approval

Inspections Recalls Fines

History Drug Development Process

Study Design Roles/ responsibilities

Study Sponsor

Academic institutionPharmaceutical company

Device/ biologic/ drug Investigator initiatedGovernment

NCI/ NIH/ CDC/ NSF, etc

History Drug Development Process

Study Design Roles/ responsibilities

Sponsor roles

Develop Investigator Brochure (IB), protocol, informed consent

IND submission to FDA (30 days) IRB approvalSite evaluations/ selectionMonitor the study sites (compliance)NDA submissionPost-market evaluation

History Drug Development Process

Study Design Roles/ responsibilities

IRB roles

Institutional or central IRBEnsure safety of the study subjects

Review/ approve protocols Review/ approve consents Review/ approve any marketing

materials Review/ approve any amendments Review AE & SAE reports Review periodic reports from each sites

History Drug Development Process

Study Design Roles/ responsibilities

IRB Operation ProcedureA Proposed Research

Protocol

IRB receives a proposed research protocol with informed consent

General board reviews, discusses and votes

Requires modification

IRB disapprove the protocol

IRB notifies investigator of

protocol approval

ResearchIRB conducts

ongoing review

Change protocol?

YesHistory Drug Development

ProcessStudy Design Roles/

responsibilities

Investigator role

Understand the IB and protocolConduct study in compliance with

protocolResponsible for the safety of study

subjectsDelegate work to qualified staff Informed consent processReport any SAE/ AEMaintain accurate records for

inspectionEnsure protocols, consents,

amendments have been approved by IRB

History Drug Development Process

Study Design Roles/ responsibilities

Study Coordinator Role

Conduct study from screening to close-out Informed consent process Screening process to determine

eligibility Schedule/ conduct patient visits Responsible

▪ Study documents (drug logs, AE logs, conmeds, medical history, patient procedures/visits, etc)

▪ CRF or eCRFReport AE/ SAE

History Drug Development Process

Study Design Roles/ responsibilities

Data Manager role

Oversight data collection Review accuracy and completeness Create queries Oversight for biostatisticians: analyze &

report on data Data lock

History Drug Development Process

Study Design Roles/ responsibilities

Paper CRF or Electronic data

Data Management

Clinical Database

Data queryAutomatic or manually

CRCPI Approves

Database revisedResolve all the queries

Database lock

Data Analysis (Statistical analysis)

Data Flow

Study Monitor role

Study Monitor represents the sponsor All study documents complete &

submitted Review all study related documents for

accuracy and completeness Generate queries based on review Drug Accountability logs Conduct trainings Ensure site compliance Study site close-out

History Drug Development Process

Study Design Roles/ responsibilities

Participant Knowledge Assessment

List 2 – 3 roles/responsibilities of each of the following:

1. FDA2. Sponsor3. IRB4. Investigator5. Coordinator6. Monitor