Good Clinical Practice

A Review for OCRA US RAC Study GroupSeptember 2005

Ginger Clasby, MSPromedica Internationalgclasby@promedica-intl.com714-799-1617 x 25

GCPWhat It Is

• An international ethical & scientific quality standard for designing, conducting, recording & reporting human clinical studies

– EU

– Japan

– US

• Applies to registration studies that may have an impact on safety & welfare of human subjects

GCPParticipating Parties

• IRB/Ethics Committee

• Investigators

• Sponsor

• Regulatory Authorities

GCPKey Documents

• Investigator Brochure

• Study Protocol

• Informed Consent Document

GCPPrinciples

1. Studies in accordance with Declaration of Helsinki; consistent with GCP & applicable regulatory requirements

2. Studies initiated & continued only if anticipated benefits outweigh risks

3. Rights, safety & welfare of human subjects take priority over interests of science & society

4. Available non-clinical & clinical info on product adequate to support study

GCPPrinciples

5. Studies scientifically sound; described in clear, detailed protocol

6. Study in compliance with IRB/EC approved protocol

7. Medical care given to subjects is the responsibility of qualified medical professional(s)

8. Individuals conducting studies qualified by education, training & experience

9. Freely given informed consent obtained from every subject prior to study participation

GCPPrinciples

10. Study information recorded, handled & stored to allow accurate reporting, interpretation & verification

11. Confidentiality of subject records protected in accordance with applicable regulatory requirements

12. Investigational products manufactured, handled & stored in accordance with GCP & used in accordance with approved protocol

13. Systems/procedures implemented to assure quality of study

IRB/ECRoles & Responsibilities

To safeguard study subjects’ rights & welfare by:

• Evaluation/disposition of study proposal

• Evaluation of proposed subject consent materials

• Evaluation of emergency use consent methodology

• Evaluation of investigator qualifications

• Ongoing review of study progress (at least yearly)

• Evaluation of proposed subject compensation plans

IRB/ECComposition & Operations

• Membership has qualifications & experience to evaluate science, medical aspects & ethics of proposed study

– ≥ 5 members

– ≥ 1 member whose primary interest in nonscientific

– ≥ 1 member independent of institution or study site

• Written SOPs & records

• Decisions rendered at announced meetings with quorum in attendance

IRB/ECComposition & Operations

• Only members participating in review should vote

• Investigator may provide info on study, but should not be involved in review or vote

• Nonmembers with expertise in special areas may be invited to assist with review (but cannot vote)

IRB/ECProcedures

• Document group membership & qualifications

• Schedule meetings & notify members

• Conduct initial & ongoing review of studies

• Determine ongoing review frequency

• Provide expedited review of minor study changes, in accordance with regulatory requirements

• Specify that no subject should be enrolled in study prior to IRB/EC approval

IRB/ECProcedures

• Specify that no deviations from protocol should be initiated without prior IRB/EC approval

– Emergency situations require immediate notification of IRB/EC after the fact

• Specify that Investigator should promptly report:

– Protocol deviations

– Changes increasing subject risk or study procedures

– Serious and unexpected adverse events

IRB/ECProcedures

• Notify Investigator promptly of:

– Study-related decisions

– Reason for decisions

– Procedures for appeal of decisions

IRB/ECRequired Records

• Relevant records maintained ≥ 3 yr after study completion

• Records available for review by regulatory authorities

IRB/ECWhat is Reviewed

• Investigator Brochure or Report of Prior Investigations

• Study protocol & amendments

• Investigator qualifications

• Informed consent documents, including subject recruiting tools

• Other written information provided to subjects

• Subject compensation plans

• Adverse events

• Protocol deviations

IRB/ECWhen Reviews Occur

• Prior to study initiation at site

• At least yearly during study

• During study, as necessitated by:

– Changes in protocol, consent documents, etc.

– Changes in study investigator

– Reports of serious or unanticipated device-related adverse events

• At study completion or termination

InvestigatorRoles & Responsibilities

• Qualified to conduct study

• Have adequate resources to conduct study

• Provide medical care to study subjects

• Regular communication with IRB/EC reviewing study

• Compliance with study protocol

• Maintenance of investigational product accountability

• Compliance with study randomization & unmasking procedures

• Provide informed consent to study subjects

Investigator ResponsibilitiesAppropriate Qualifications

• Training & experience demonstrated via:

– Medical license

– CV

– Specialized study training

– GCP training

• If study responsibilities delegated, need a list of qualified persons to whom responsibilities are delegated

Investigator ResponsibilitiesAdequate Resources

• Suitable staff & good methods for keeping them apprised

• Suitable facilities

• Appropriate patient population

– Access to disease or condition

– Volume of patients with disease or condition

Investigator ResponsibilitiesMedical Care

• Make medical decisions regarding patient treatment

• Adequate care for study-related adverse events

• Diligence in ascertaining reason(s) for subject withdrawals from study

Investigator ResponsibilitiesIRB/EC Communications

• IRB/EC approval prior to study initiation

• IRB/EC kept apprised of events & progress during study

Investigator ResponsibilitiesProtocol Compliance

• Conduct study in accordance with protocol

• May not deviate from protocol without Sponsor/IRB approval

• Document deviations from protocol

Investigator ResponsibilitiesInvestigational Product Accountability

• Maintain accountability at study site

• Document product receipt & disposition

• Maintain product in a secure area

• Use product only in accordance with protocol

• Disallow use of product by anyone not registered with study

Investigator ResponsibilitiesRandomization Procedures & Unmasking

• Follow study randomization procedures

• Unmask only in accordance with protocol

• Document noncompliance or premature unmasking

Investigator ResponsibilitiesSubject Informed Consent

• Comply with regulatory requirements

• Update consent documents as necessary

• Inform subject that study involves “investigational” product

• May not coerce subject to participate

• May not waive subject’s legal rights

• Keep subject informed of new information regarding study

Investigator ResponsibilitiesSubject Informed Consent

• Provide informed consent in understandable language

• Give subject the chance to ask questions

• If subject can’t read, need impartial witness

• If subject is “disadvantaged”, need legally authorized witness

• Get subject consent in writing prior to initiation of study procedures

• Give subject a copy of signed consent document

Investigator ResponsibilitiesRequired Records & Reports

• Essential regulatory document file(s)– Protocol & amendments

– Approved informed consent documents

– Product accountability documentation

– Investigator qualifications & agreements

– IRB correspondence

– Study delegation list

– Subject screening/enrollment logs

– Study monitoring reports

– Calibration/maintenance logs

– Memos to file

Investigator ResponsibilitiesRequired Records & Reports

• Source documentation

• Data capture forms (study-specific)

• Data clarification forms

• Fully executed informed consent documents

Investigator ResponsibilitiesRequired Records & Reports

• Written periodic status reports to IRB/EC

• Written reports of protocol deviations to Sponsor & IRB/EC

• Serious or unanticipated product-related adverse events to Sponsor & IRB/EC

• Notification of study suspension or termination to IRB/EC

• Final study report to IRB/EC

• Retain ≥ 2 yr

SponsorRoles & Responsibilities

• Study quality assurance

• Appropriately qualified medical personnel to advise on study

• Utilization of qualified personnel in study design & operations

• Study management, data handling & record keeping

• Investigator selection & training

• Definition/allocation of study responsibilities

SponsorRoles & Responsibilities

• Facilitation of communications between Investigators

• Study compensation (investigators and/or subjects) & financing

• Regulatory authority notification/submission

• Confirmation of IRB/EC review/approval

• Investigational product information

• Investigational product manufacturing, packaging, labeling & coding

• Investigational product supply & handling

SponsorRoles & Responsibilities

• Record access

• Ongoing safety evaluation & reporting

• Serious/unanticipated adverse event reporting

• Study monitoring

• Study noncompliance procedures

• Study termination or suspension notification

• Study reports

SponsorRoles & Responsibilities

• Sponsor may transfer responsibilities to CRO

– Transfer must be documented in writing

– Sponsor still has ultimate responsibility for study quality and data integrity

Study ProtocolComponents

• General administrative info

• Background

• Study purpose & objectives

• Study design

• Subject eligibility requirements

• How subjects will be treated

• How safety & efficacy will be assessed

• Sample size justification & statistical analysis methods

Study ProtocolComponents

• How data will be captured & maintained

• Monitoring procedures

• Proposed informed consent document

Informed Consent DocumentComponents

• Statement that study involves “research” & product “experimental” (if applicable)

• Study purpose

• Number of expected study subjects to be enrolled

• Study treatment(s) & probability for random assignment

• Study exams & procedures for duration of trial

• Subject’s responsibilities

• Foreseeable risks to subject (embryo, fetus, nursing infant)

Informed Consent DocumentComponents

• Expected benefits

• Alternatives procedures or therapies & associated risk/benefit

• Compensation available in event of study-related injury or sickness

• Anticipated payments to subject for study participation

• Anticipated expenses to subject for study participation

• Statement that participation is voluntary

Informed Consent DocumentComponents

• Description of extent to which confidentiality can be assured

• Commitment to keep subject apprised on new information that may affect subject’s willingness to participate in study

• Contact info for questions re: subject rights; trial-related adverse events

• Circumstances under which subject’s participation may be terminated

Investigator BrochureWhat It Is

A compilation of clinical & non-clinical data on the product that is relevant to the product’s study in humans

Necessary for Investigator & IRB/EC review to assess the risks/benefits associated with study

Investigator BrochureComponents

Product formulation summary

Introduction/background info regarding product & investigational plan

• Investigational product physical, chemical & pharmaceutical properties & formulation

• Non-clinical studies

• Human clinical studies

• Summary of data & guidance for Investigator

Good Clinical PracticeReference Documents & Links

• ICH - E6: Guideline for Good Clinical Practice

• 21 CFR 50 - Informed Consent

• 21 CFR 56 - Institutional Review Board

• http://www.ich.org/cache/compo/276-254-1.html

• http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm