Clinical Research and Regulations

Marilyn Marshall QAO Office of the Vice President of Research

International Conference on Harmonization

E6: Good Clinical Practice: Consolidated Guideline

FDA’s Role in Clinical Research

• A new drug cannot be marketed in the United States until there is “substantial evidence” as to its safety and effectiveness

FDA’s Role in Clinical Research

• Regulation 21 CFR 314.126:

“substantial evidence” is collected in “adequate and well-controlled trials”

Characteristics of Adequate and Well-controlled Clinical Trials

• Protocol contains a clear statement of objects of the study

• Study design permits a valid comparison with a control to provide a quantitative assessment of the drug effect

• Methods of assessment of subjects’ responses [efficacy and safety] are well-defined and reliable

Characteristics of Adequate and Well- controlled Clinical Trials

• Study report provides sufficient details of study design, conduct and analysis

• Patients were assigned to treatment and control groups in a way that minimizes bias [e.g., randomization]

• Adequate measures were used to minimize bias of subjects, observers, and data analysts [e.g., blinding]

FDA’s Role in Clinical Research

Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is “substantial evidence” to support the claims of effectiveness for new drugs and antibiotics.

21 CFR 314.126

FDA’s Role in Clinical Research

The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences such as …

• Spontaneous change in the course of the disease

• Placebo effect

• Biased observation

21 CRF 314.126

Phases of Clinical Research:

• Phase 0: Exploratory

• Phase I: Pharmacokinetics and safety in humans

• Phase II: Dose finding and efficacy

• Phase III: Pivotal studies

• Phase IV: Post approval commitments

21 CFR Part 11 (overview)Electronic Records, Electronic

Signatures

21 CFR Part 11

March of 2003 the FDA withdrew the Guidance document on Part 11. However, this does not mean that we you should ignore the regulation.

21 CFR Part 11 (cont.)

Part 11 applies to Any Records that you choose to created, modified, maintained, archived, retrieved or transmitted in electronic form.

21 CRF Part 11 Key Requirements

Validation Audit Trails Security Record retention and protection

Electronic Systems Requirements

• 21CFR Part 11– Security– Data Integrity– Data Access– User Authentication– Audit Trail

• HIPPA– Security– Data Integrity– Data Access– User Authentication – Audit Control– Transmission

(Encryption)

21 CFR 50. 20 (overview)General Requirements for Informed

Consent

– …no investigator may involve a human being as a subject in research…unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.

– The information…shall be in a language understandable to the subject or the representative.

21 CFR 50. 20 (cont.)General Requirements for Informed

Consent– No informed consent,… may include any

exculpatory language… which the subject or the representative is to waive or appear to waive any of the subject’s legal rights,

– or release or appear to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

21 CFR 56.109 (overview) IRB Review of Research

An IRB shall:– review and have the authority to approve,

require modifications in…or disapprove all research activities covered by these regulations…notify investigators and the institution in writing of its decision to approve or disapprove…

– require that information given to the subjects as part of the informed consent is in accordance with §50.25.

– conduct continuing review of research…

21 CFR 312.56 (overview)Review of Ongoing Investigations

The sponsor shall monitor the progress of all ongoing investigations being conducted under its IND. A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA-1572), …shall either secure compliance, or discontinue shipments of the investigational new drug…and shall notify the FDA.

21 CFR 312.60 (overview)General Responsibilities of

Investigators

An investigator is responsible for:– ensuring that investigation is conducted

according to the signed investigator statement…

– protecting the rights, safety, and welfare of the subjects…

– Obtain the informed consent of each human subject…

– control of drugs under investigation

ICH 5.1 (overview)

ICH 5.1 Quality Assurance and Quality Control– 5.1.1 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 are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

Investigator-Initiated Clinical Research

• Form 1571

• Sponsor is the individual investigator and therefore assumes all responsibilities of both Sponsor an Investigator

Sponsor-Investigator

Obligations

SI is obligated to monitor the clinical study

• SI is responsible to IRB

• SI is required to keep accurate and complete records of study

Purpose of Clinical Study Monitoring

• Protect the interests of subjects involved in the clinical research

• Protect the interests of the sponsor or academic institution

• Adhere to federal and international requirements

Role of the Monitor

1.Verify subjects have been properly consented prior to any study related procedure

2. Verify eligible subjects are entered in the study and no eligible subjects excluded

3. Verify protocol is being followed as written

Role of the Monitor

4. Verify that adverse events are being recorded and reported to Sponsor in timely manner

5. Verify that violations and deviations are recorded and deviations are pre-approved where possible

6. Verify that the data are accurately and consistently recorder in CRF’s

Role of the Monitor

7. Verify that CRF data are supported by source documents

8. Verify that Principle Investigator is actively overseeing the conduct of the clinical study

9. Verify that all IRB approvals are in place before changes are implemented

Role of the Monitor

10.Verify that Regulatory binder is being maintained

11. Verify that drug study medication is returned as required and accounted for

12. Verify that only authorized study personnel are involved in conduct of study

Role of the Monitor

14. Verify that study is being conducted honestly and with no fraud

15. Ensure data will withstand FDA and other regulatory scrutiny for completeness and accuracy

Terms

Case Report Form [CRF]

A printed, optical or electronic document designed to record all protocol-required information to be reported to the sponsor on each trial subject

Terms

Adverse Event [AE]

Any untoward medical occurrence in a patient or clinical investigational subject administered an investigational drug and which does not necessarily have a causal relationship with the treatment/usage.

Adverse Event [AE]

• Any unfavorable and unintended sign, including an abnormal laboratory findings

• Symptom or disease temporally associated with the use of an investigational drug

Describing an Adverse Event

• Adverse events should be described in terms of a change in the status of a subject’s health, NOT in the action taken or outcome

Serious Adverse Event (SAE)

• Event that results in any one of the following…

• Death

• Life threatening

• Inpatient hospitalization

• Persistent/significant disability/incapacity

• Leads to any congenital anomaly/birth defect

Adverse Event Reporting

Investigators must report

• All AEs [routine and serious] in the CRF

• SAEs to both the sponsor and IRB immediately

• 7-calendar day notification if SAE is death or life threatening…followed by a 15 day written report.

Source Documents:

• Original documents, data, and records [e.g., hospital records, clinical and office charts, laboratory notes, memo’s, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated machines….]

Tools to Perform Audits

Logs and Checklists

Informed Consent Log

HSC: Principal Investigator:

Title of Protocol No.:

Reviewer

Date

Subject ID Consent Form

Version Date

IRB Approva

l Date

Date Subject Signed

Surgery Date

Date PI Signed

HIPAA Subject Signed

Comments

Tools to Perform Audits

Log for Informed Consent Verification

Informed Consent Log

HSC: Principal Investigator:

Title of Protocol No.:

Reviewer

Date

Subject ID Consent Form

Version Date

IRB Approva

l Date

Date Subject Signed

Surgery Date

Date PI Signed

HIPAA Subject Signed

Comments

y100 10.25.02 11.19.02 7.16.03 7.01.03 7.16.03 7.16.03

y101 10.25.02 11.19.02 7.23.03 7.22.03 7.23.03 7.23.03

y102 10.25.02 11.19.02 7.23.03 6.27.03 7.23.03 7.23.03

y103 10.25.02 11.19.02 7.14.03 7.15.03 7.14.03 7.14.03

y104 10.25.02 11.19.02 6.03.03 6.03.03 6.04.03 6.03.03

Materials and Equipment: HSPP Location

Project Approval Form Packet as approved by the IRB:

IRB Approval LetterDate of approval________ Informed consent as approved by the IRBApproval dates checklistsHIPAA Authorization Form as approved by the IRBApproval dates _____________Amendment ChecklistsSite Authorization FormProtocol Revision ChecklistsBrochure Revision ChecklistsPeriodic Review FormAdverse Events documentationCopy of Verification Of Training Forms and log in checklist dates of all VOTF changes

Investigators’ Location

Investigator’s File for clinical study and Patient Binders

Review Study SOPs/Protocol

Review Patient Informed consent/HIPPA and report on ConsentLog Form Review Inclusion/Exclusion Signature pages and report on Patient I/E FormReview Case Review Forms for protocol complianceReview payments to patients per protocol/approved by IRB

Review training records of personnel Review Regulatory Documents Review Drug or Device Accountability and HandingOther terms and conditions of IRB approval

Site Regulatory Binder

Section 1: Protocols and AmendmentsSection 2: FDA Form 1572Section 3: IRB Information and ApprovalsSection 4: Informed Consent & HIPAASection 5: Personnel CV’s & LicensureSection 6: Investigator BrochureSection 7: SAEs and IND Safety ReportsSection 8: Patient Screening & Enrollement

Site Regulatory Binder

Section 9: Drug AccountabilitySection 10: Laboratory InformationSection 11: Pharmacy InformationSection 12: Monitoring InformationSection 13: Site Signature Log Section 14: Case Report FormsSection 15: CorrespondenceSection 16: Other

Summary of GCP Requirements

Written Procedures SOPs, Protocol

Oversight IRB, Regulatory Agencies, Sponsor

Informed Consent Form (ICF) Subjects/ Patients

Summary of GCP Requirements (cont.)

Qualification/ Training - Investigator, Nurses, Monitors, CRO, Lab,

Auditors, etc

Documentation- Source, CRF, ICF, IDB,

Summary of GCP Requirements (cont.)

Sponsor responsible for implementing and maintaining quality systems

Must be covered by written SOPs Must assure adherence to the

protocol/SOPs/GCP/regulations Audit itself must be separate from routine

monitoring and QC functions Must report any sites that are prematurely

terminated from the study (ICH 5.21, CFR 312.56)

Summary of GCP Requirements (cont.)

Auditors must be:

– Independent of clinical trial/data collection– Qualified by training and experience– Qualifications must be documented

FDA Findings

Violations related to informed consent (21 CFR 50.25, 21 CFR 50.20, 21 CFR 312.60)

You failed to obtain proper informed consent in that the following essential elements of informed consent were not included in the consent form that was provided to the healthy volunteers.

The consent form failed to disclose that the inhalation of XX was an experimental use of the drug.

FDA Findings

Failure to inform the IRB of changes to the protocol [21 CFR 312.66].

You failed to inform and obtain approval from [X] Institutional Review Board [X] for the changes in the protocols;…

FDA Findings

Failure to conduct and investigation in accordance with the investigational plan 21 CFR Part 812.110(b)).

You failed to enroll subjects according to the inclusion/exclusion criteria.

You also failed to perform all required tests at study visits. Your records contained instances where study procedures, including laboratory testing, were either not performed or were not consistently followed at scheduled examinations.

FDA Findings

Your firm failed to ship investigational new drugs only to investigators participating in the investigation. [21 CFR 312.53(b)]

In May 2001, your firm shipped the wrong investigational vaccine to a clinical investigator who was not conducting a study for that test article. While the vial labels identified the test article that was shipped, it was not the test article that was intended for use with the type of cancer in the investigator’s protocol.

Fenster Warning LetterPublic Health Service Food and Drug Administration 9200 Corporate BoulevardRockville, Maryland 2085

 March 21, 2006 WARNING LETTERVIA FEDERAL EXPRESSPaul Fenster, M.D.Associate Professor of MedicineUniversity of Arizona1501 North Campbell Ave.P.O. Box 245037Tucson, AZ 85724-5037

Dear Dr. Fenster:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at your clinical site from October 3, 2005, through November 22, 2005, by an investigator from the FDA Los Angeles District Office. The purpose of this inspection was to determine whether activities and procedures related to your participation in the clinical study for the [redacted] , that ultimately resulted in approval under PMA [redacted] complied with applicable federal regulations. The [redacted] is a device as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h). This letter also requests prompt corrective action to address the violations cited and discusses your written responses to the noted violations.

FDA Findings

Failure to ensure that the investigation is conducted in accordance with the signed agreement with sponsor, the investigational plan, applicable FDA Regulations for protecting rights, safety and welfare of subjects under the investigator’s care and for control of devices under investigation, and any conditions of approval imposed by the FDA or IRB. [21 CFR812.100 and 21 CRF 812.114(b).

In addition, you failed to supervise device use. An investigator shall permit an investigational device to be sued only with subjects under the investigator’s supervision. [21CRF 812.110©].

Inspection Classifications

NAI-No Action indicated. Minor or no objectionable practices

VAI-Voluntary Action Indicated. Some objectionable conditions, but not serious enough for FDA to take action

OAI-Official Action Indicated. FDA further action recommended.

Fraud in Clinical Studies

Check for non-existent subjects and altered or fabricated data, personnel is as stated in the protocol

If fraud is confirmed, FDA must be notified