clinical trial regulations

Clinical Trial Regulations

P.Olliaro

Nov04

Clinical Trials: a Phase of Product Development

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Toxicity20%

Efficacy40%

ADME33%

Toxicity34%

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ADME12%

Toxicity38%

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< discovery > <pre-clinical> < clinical >

R&D ATTRITION RATESR&D ATTRITION RATES

OVERVIEW OF THE R&D PROCESS

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DISCOVERY

PRE-DEVELOPMENT REGULATORYREVIEW

DEVELOPMENT

MARKETING

PRE-CLINICAL CLINICAL PHARMACEUTICAL

•Bulk active synthesis•Analytical development preformulation•Formulation development

•Pharmacology•PK & metabolism•Toxicology

•Clinical trial packaging•post-IND tox•Bioanalytical sample analysis

•Phase I•Phase II•Phase III

•Validation, QC analysis•Commercial packaging•Long-term stability

INDfiling

NDAfiling$ 4.9-5.3

million $ 9.9-26.6 million

$ 5.3-8.0 million

$ 76-115 million

$ 40-125 million

TOTAL Discovery + Development 115-240 million(including cost of failure)

Cost of TB New drug - Source: GATB webpage

NEED

OPPORTUNITY

NEW TOOL

DEPLOYMENTIMPLEMENTATION

INTELLIGENCE,SURVEILLANCE R&D

“OPERATIONALRESEARCH”

MONITORING& EVALUATION

Regulatory Clinical studies (Phase I, II, III)

First In Humans

Discovery& Pre-clinicalResearch

Registration

Post- registration studies to inform policy

Policy,Practice

Capacities & capabilitiesfor sustained, durable clinical research

in Developing Countries

GCP, GCLP requirements

The Critical Path of a Clinical Trial

*START *END

Data Data Statistical FinalEntry Clean-up Analysis ReportData Data Statistical FinalEntry Clean-up Analysis Report

Study Termination

Periodic Monitoring

Patient Recruitment

Site Assessments

Planning

Protocol • CRF

Regulatory andEthical Approval

Trial Documents • Materials

Select Investigators

Initial Visits

Special features

Mission: provide affordable, adapted public health priority products

Corollary: provide data in support of registration, policy & practice; availability of quality product

Context: developing country capacities & capabilities

GCPs (& GCLPs)ICH Guidelines

Good Clinical Practice

Guidelines established to ensure clinical research is consistently performed to high ethical and scientific standards

Primary considerations are to: protect the rights and safety of clinical subjects ensure quality and integrity of data

What is GCP ?Good Clinical Practice

A standard for the design, conduct, performance, monitoring,

auditing, recording, analyses, and reporting of clinical trials that

provides assurance that the data and reported results are credible and accurate, and that

the rights, integrity and confidentiality of trial subjects are protected.

Ref: ICH Harmonized Tripartite Guideline for Good Clinical Practice (1.24), 1997

Ref: www.ifpma.org

www.fda.gov

For what/whom? GCP Applies to All Research All sponsors: private, government,

university, industry All study designs: RCTs, double-blind,

open-label, comparator, etc All study phases: Phase I to IV All investigational products: new drugs,

new indications, biomedical device, new methodology, new surgical techniques, etc

Why GCPs? Historical eventsEvent Year Reaction

Publication of a book (“The Jungle” by Upton Sinclair) exposing the unsanitary conditions in Chicago slaughterhouses

1906 Pure Food and Drug Act: created the Food & Drug Administration Every product needed to be

accurately labeled Did not require testing for either

safety or efficacy More than 100 children die after taking Strep-Elixir (sulfanilamide and diethyleneglycol)

1938 Federal Food, Drug & Cosmetic Act required that drugs be tested for safety

Nazi Experiments conducted without consent of

participants caused unnecessary pain,

suffering and death absence of benefits for the

participants lack of adequate scientific

rationale

1948 Nuremberg Code – to prevent atrocities from happening again subject participation must be

voluntary physical or mental suffering or

damage is not acceptable subject has the right to withdraw

from the study at any time experiments must be supported

by strong science

Why GCPs? Historical eventsEvent Year Reaction

Children are born with phocomelia eventually linked to the

administration of Thalidomide to mothers for the treatment of morning sickness

Thalidomide had been tested in 300 individuals with no side effects

1962 Kefauver-Harris Amendment passed by the U.S. Congress experiments must be supported

by strong scientific material required evidence of efficacy

before approval evidence of safety before

testing in humans gave protection to humans in

research active review of test data before

approval 1964 Helsinki Declaration - Adopted by

the 18th World Medical Assembly (latest version 2000, Edinburgh, Scotland): Justice (Fair distribution of

burdens and benefits) Beneficence (Maximize benefit,

minimize harm) Non-maleficence (“Do no harm”) Respect (Autonomy, protect the

vulnerable)

Continuing Development ofGCP Guidelines USA( FDA GCP Regulations)

Protection of human subjects:Informed consent; Standards for IRB - 1981

Guidelines for monitoring of Clinical Investigations – 1988 EU: Good Clinical Practice for Trials on Medicinal

Products in the European Community - 1991 Japan: Good Clinical Practice, GCP Manual - 1991 WHO: Guidelines for GCP for trials on

Pharmaceutical Products - 1994

GCP is a process, not a book

Th

e st

and

ard

Investigator

Sponsor

ICH - International Conference on Harmonization

ICH Guidelines: 4 major categories Q: "Quality" Topics = chemical & pharmaceutical Quality

Assurance.E.g: Q1 Stability Testing, Q3 Impurity Testing

S: "Safety" Topics = in vitro & in vivo pre-clinical studies. E.g : S1 Carcinogenicity Testing, S2 Genotoxicity Testing

E: "Efficacy" Topics = clinical studies in human subject. E.g : E4 Dose Response Studies, E6 Good Clinical Practices. (NB: Clinical Safety Data Management is also classified as an "Efficacy" topic - E2)

M: "Multidisciplinary" Topics = cross-cutting M1: Medical Terminology (MedDRA) M2: Electronic Standards for Transmission of Regulatory

Information (ESTRI) M3: Timing of Pre-clinical Studies in Relation to Clinical

Trials M4: The Common Technical Document (CTD) M5: Data Elements and Standards for Drug Dictionaries

ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH-GCP) Joint initiative by regulators and industry from

three regions - US, EU & Japan. A framework for pharmaceutical companies

and investigators to conduct clinical trials According to similar rules and regulations Conforming to high ethical and scientific

standards.

ICH-GCP – Harmonized Tripartite Guidelines - Whom? Founder members:

European Union: EC + EFPIA (European Federation of Pharmaceutical Industries’ Associations)

Japan: Ministry of Health & Welfare + JPMA ( Japan Pharmaceutical Manufacturers Association)

USA: FDA + PhRMA (Pharmaceutical Research and Manufacturers of America)

ICH-GCP - When? Introduced in 1996

ICH 1November 1991

ICH 2October 1993

ICH 3November 1995

Development of tripartite GCP agreement

Update status of:• tripartite agreement• progress toward harmonization

Review of progress toward harmonization in areas of:• efficacy• safety• quality assurance

ICH 4July 1997

Review and update of the implementation and impact of the ICH GCP Guideline

* 1996

ICH-GCP – Why?

Rapid increase in laws, regulations and guidelines for testing safety, quality and efficacy of new products

Different technical requirements by regulatory agencies, although fundamental guiding principals same

Industry becoming global Duplication of time consuming & expensive

testing.

ICH-GCP - GoalsBenefits Reduce rising cost of health care Reduce escalating R&D costs Minimize delay in making new treatments available to

patientsGoals Decrease country-to-country differences in guidelines Decrease differences between regulatory authoritiesGoals are designed to: Streamline drug development and regulatory process Increase efficiency of clinical research and enforcement of GCP guidelines

GCPs: roles of sponsor, investigators, monitor

Sponsor

ICH sections E6 5.1-5.23 Definition: an individual, company, institution,

or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial

Medical expertise; Trial design; Allocation of duties and functions

Sponsor Responsibilities Monitoring: SOPs Trial Management, Data handling Record Keeping Investigator selection & support (adequacy of CI’s to comply with

GCPs) Provide insurance or indemnify CI; Trial subject compensation Financing Notification/Submission to Regulatory Authority Confirmation of Review by IRB/IEC Information on Investigational Product (IB) Manufacturing, Packaging, Labelling & Coding Supplying & Handling Record access QA and QC

Monitor

Audit/ Inspection

Archiving

Patient Follow-up

Annual/Safety Rep.

DocumentationDocumentation

Report SAEs

Ability to conduct

Pre-trial Data

Regulatory

Protocol

Informed Consent

Drug Control

CRF

GCP– role of Sponsor

SPONSOR

Monitor

Selected by sponsor Appropriately trained & familiar with GCPs,

regulations, product, protocol, SOPs Ensures that trial is conducted & documented

properly ‘Communication link’ between sponsor & CI On site monitoring visits pre-, during, post-trial Verify compliance to procedures

Notifications, applications, submission, reports are accurate, complete, timely/dated

Identifies & corrects problems. Communicates deviations to investigator

Investigator

ICH sections E6 4.1 - 4.13 A person responsible for the conduct of

the clinical trial at a trial site. If a trial is conducted by a team of individuals, the investigator is the responsible leader of the team and may be called the principal investigator” ICH Guideline for GCP 1.34

Investigator Qualifications

Appropriate education and training, with evidence there of (e.g. CV, certificate/diploma)

Experience and respect in therapeutic field of study

Publication recordReputation and IntegrityAdequacy and quality of staffAccess to and adequate number of patients for

the study

Investigator Responsibilities

(Contribute to) Understand & comply with protocol

Obtain ethical approval Obtain inform consent Ensure adequate medical care of trial subjects Accountability & storage of investigational

product Ensure adequate resources (NB: capacities in

DECs) Appropriate supervision &/or delegation

QUALITY CONTROL:

PERMIT MONITORING, AUDITING AND INSPECTIONS Sponsor: Section 5.1.1. ICH GCP

“The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data generated, documented, and reported in compliance with the protocol, GCP and the applicable regulatory requirements.”

Investigator: Section 4.1.4 ICH GCP “The investigator/institution should permit monitoring and

auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).”



Documentation “If it is not written, it did not happen” Document what happened and well as what did

NOT happenAssure direct access to records

Submit progress reports to IRB/ECPromptly report all SAEs to sponsor and

IRB/EC (if required)Report all Adverse Events and lab

abnormalities to sponsor

Failure to follow the protocol ,

70

Falsification, 67

Informed Consent Issues

, 55

Inadequate Records, 25

Qualifications of persons

performing physicals , 27

Failure to report adverse events

, 40

Failure to get IRB approval,

report changes , 20

Failure to follow FDA regulations

, 13

Misconduct at Investigational Sitesn = 118, SW Woollen, FDA’s OGCP, 2001

GCP – Role of Investigator

Monitor

Audit/ Inspection

Archiving

Patient Follow-up

Annual/Safety Rep.

DocumentationDocumentation

Report SAEs

Ability to conduct

Resources

Medical Care

Ethics Approval

Informed Consent

Drug Control

Protocol AdherenceINVESTIGATOR

Safety in clinical trials

Safety: definitions

Adverse Event (or Adverse Experience) = Any untoward medical occurrence in a patient or clinical investigation subject administered pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment

Adverse Drug Reaction (ADR) = All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reaction

Safety: definitions Unexpected Adverse Drug Reaction = An adverse

reaction, the nature or severity of which is not consistent with the applicable product information (e.g., IB for an unapproved investigational medicinal product)

Serious adverse event (experience) or reaction = any untoward medical occurrence that at any dose: results in death, is life-threatening (an event in which the patient was at risk

of death at the time of the event; not an event which hypothetically might have caused death if it were more severe)

requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Safety: definitions

Severe DIFFERENT from Serious Severe = Refers to the intensity (severity) of a

specific event (minor, moderate, severe) and can be of relatively minor medical significance (e.g. severe headache).

Serious = Refers to the previous definition. Based on patient/event outcome or action criteria usually

associated with events that pose a threat to a patient’s life or functioning.

Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

Safety Information and reporting : Sponsor’s obligations Responsible for the ongoing safety evaluation Promptly notify all concerned investigators &

regulatory authorities of findings that could affect adversely the subjects safety

Adverse drug reaction reporting Expedite the reporting to all investigators of all

adverse drug reactions that are both serious and unexpected + regulatory requirements

CI Monitor, Sponsor IRB/EC; Health/Regulatory authorities; DSMC

Alert form: 24h; SAE Report Form: 5 wd’s

IEC / IRB:Independent Ethics Committees/ Institutional Review Boards

IEC / IRB:Independent Ethics Committees/ Institutional Review Boards

Any board, committee, or other group formally designated by an institution to review, approve the initiation of, and conduct periodic review of,

biomedical research involving human subjects.

Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997

IEC / IRB Independent body (a review board or a committee, institutional,

regional, national or supranational)

Constituted of medical/scientific professionals and non-scientific professionals and non-scientific members,

Responsibility:

to protect the rights, safety and well-being of human subjects involved in a trial and

to provide public assurance of that protection by: Reviewing and approving/providing favorable opinion on, trial

protocol, suitability of the investigator(s), facilities,

And the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997

IEC / IRB The legal status, composition, function, operations, and

regulatory requirements pertaining to IEC’s may differ among countries, but should allow the IEC to act in agreement with GCP as described in the ICH-GCP guideline.

Other names of such include: independent review board, institutional review board, independent ethics committee, institutional ethics committee, committee for the protection of human subjects.

IEC/IRBComposition Heterogeneous: at least 5 members; ar least one member with

primary area of interest in a non-scientific area; at least one member independent of the trial site

Without conflicting interest Nonmembers (special expertise) may be invited ad hoc

Functions and Operations Meetings: frequency, scheduling, notification, quorum,

hierarchy, minutes Procedures: submission requirements, confidentiality, majority

vote, appeal, amendments Reports

Criteria for Approval Suitability of investigator

Qualifications Experience Time Supporting staff Available facilities

Suitability of protocol Scientific efficiency Justification of inconveniences and risks vs. Benefits

Equitable selection of subjects Time provision

Monitoring the data Confidentiality of subjects and data

Remember ! Inform subjects of any new relevant

information as it becomes available

Consent should be in writing

Language used: non-technical and understandable by the subject

Provide sponsor with access to patient’s medical records

Provide patient with a copy of the signed and dated consent form

Informed Consent in Clinical Trials

Informed Consent

E6 Guideline for Good Clinical Practice: Section 4.8.1 - 4.8.15

“A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.”

Informed Consent Process

Intended to: Give a subject all the information he or she

reasonably would want about a study Ensure that the subject understands this information Give the subject an opportunity to agree to

participate Permit the investigator and the subject to exchange

information freely and to ask questions Provide protection for “vulnerable subjects”

Informed Consent

Must comply with GCPs/Declaration of Helsinki

Must be approved by IRB/EC and sponsor prior to use (govt approvals may also be required)

Subject must be fully informed of all pertinent aspects of the trial

Should be revised for new information Subject must be informed of new information

Informed Consent

Must be understandable to the subject practical nontechnical in the subject’s language

May not cause subject to waive legal rights Must provide ample time to consider Investigator must answer questions

Informed Consent

Consent form must be signed and personally dated by the: subject (or subject’s legally acceptable

representative) person who conducted the informed consent

discussion Subject should receive a copy of the signed

informed consent form

Informed Consent

Subject’s legally acceptable representative can sign for subject if: subject not able to read subject not able to understand emergency situations

If subject or legal representative are unable to read, an impartial witness must be present and must sign and date the ICF

Elements of the Informed Consent Form (ICF) The trial involves research

The purpose of the trial and previous experience

Trial treatments and probability of random assignment to each

Trial procedures, including invasive procedures

Subject’s responsibilities

Elements of the Informed Consent Form (ICF) Experimental aspects of the trial

Reasonably foreseeable risks or inconveniences

Reasonably expected benefits, if any Alternative procedures or treatments Compensation/treatment if injured Anticipated payment and/or expenses

Elements of the Informed Consent Form (ICF) Participation is voluntary

Access to records will be granted Confidentiality of records Subject will be informed of new information Contact information

subject rights safety information general information about the study

Elements of the Informed Consent Form (ICF) Circumstances for discontinuation

Expected duration of trial Number of subjects in the trial (number of

sites) Copy of the Informed consent document to

the subject

Informed Consent Vulnerable Subjects

Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy, in case of refusal to participate.

- ICH-GCP 1.61

Informed Consent Vulnerable Subjects

Children Persons under discipline (soldiers, army, police) Laboratory assistants Medical students Ethnic minorities Persons in nursing homes Those mentally incapacitated (poor understanding) Persons with incurable diseases or in emergency situations Those economically disadvantaged (unemployed,

impoverished, homeless, nomads, refugees)