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