1 Protection of Human Research Subjects: A Key Investigator Responsibility Charles H. Pierce, MD, PhD, CPI

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Protection of Human Research Subjects:

A Key Investigator Responsibility

Charles H. Pierce, MD, PhD, CPI

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What you can expect: Drug Development overview Protecting Human Subjects is the key

Why human Study Participants need protecting FDA form 1572 Protected Health Information

International Conference on Harmonization Investigator Responsibilities: everything including

• Adverse Events• Informed Consent Form and process• Source documents, • Safety reporting

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Phases of Clinical Drug Development

I IIa IIb III FDA IV

SubjectsHealthyNormals

First timein Patients

Patients Patients Patients

Number 20 - 100 25 - 75 50 - 200 >300 >1,000

Measures

Dosage,Kinetics,Safety,

Equivalence

Dose range,M O A

Efficacy,Safety

Efficacy,Safety

Efficacy,Safety

Efficacy,Safety,

New uses

Value Kinetics,Dynamics

Proof ofConcept

Confirmmechanism

of action

Confirmusefulness

ReviewApprove ordisapprove

Surveillance,extend patent

expand market

Cost(Millions)

$8 $12 $7 $43 ?Varies with

The drug andits use

Time(Years)

1 - 1.5 1 1 - 1.5 3 - 6 2 - 3 1 - 2

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Physician Investigators

Have a dual responsibility and a potential conflict of commitment, if not interest

• Goal of clinical care is to diagnose, treat, and cure disease or to reduce pain and suffering in individual patients - Patient care oriented.

• The goal of clinical research is to systematically collect information from groups of persons to produce generalizable findings to ….. . . . in a whole population - Drug effect oriented

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Achieving Ethical Clarity

To view clinical trials as therapeutic and as falling under the physician-patient relationship because some aspects of research are associated with care constitutes an ethical distortion that ought to be scrupulously resisted

Miller & Rosenstein, NEJM 2003; 348(14):1383-1386

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Patient Perceptions Whites Blacks

Believe they could be used as 52 80

“guinea pigs” for medical research

Do NOT trust doctor to fully 23 42

explain their participation on a study

Docs would enroll patients on a 20 37

research study that was harmful

Do not feel they can freely ask or 8 15

question their doctors

G. Corbie-Smith et al, Arch Int Med;162:2458,2002

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Guarantees to Protection Physicians and Nurses are an integral part of the

process of clinical research – built in privacy + HIPAA

Independent oversight committee (the IRB / IEC)

Informed Consent is a process not just a signature

Principles of GCP in research with human subjects

Conflict of Interest (CoI) guidelines

Data & Safety Monitoring Plans (DSMP) / Boards (DSMB)

Research Subject Advocacy (RSA) program

Physician Investigator certification (CPI, CI) is available

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The power of Law: the 1572Signing a 1572 is the PI’s commitment in writing that

she/he will be responsible for the study in question; totally responsible and for everything

This means she/he agrees to follow: 21 CFR 50 - Informed Consent process 21 CFR 56 - IRB does what it should 21 CFR 312

21 CFR 312.64 - AE reporting 21 CFR 312.62 - Record keeping 21 CFR 312.68 - Being audit ready

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The commitments of the 1572 Personally conduct or supervise the investigation

Ensure that all associates, colleagues, and employees assisting in the study conduct are informed of obligations

Conduct the study in accordance with the protocol

Comply with all requirements / obligations of the PI including preparation and maintenance of study records

Inform the SP of the investigational nature of the study

Ensure that the IC process is clear / valid and all IRB requirements are met

Accurately report all AE’s to the sponsor

Read and understand the Investigators Brochure (IB)

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PHI Protection Health Insurance Portability and Accountability

Act (Aug 96 - 14 Apr 2003)

Effects the collection, recording, transmission, and storage of patient health information

The effect is your ability to access and use this information for research

Protected Health Information (PHI)

Individual identifiable health information past, present, or future physical or mental health condition in any medium (oral, paper, or e)

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HIPAA means One obtains “permission” to use PHI

Authorization to use PHI for research Waiver to use the information for …. De-Identified data: the list is not short Prior agreement to use the data or limited use OK to use for SOC including payments

Subject has access to the records The right to inspect and copy Access may be suspended during trail conduct

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International Conference on Harmonization - ICH

The Efficacy topics concern the Clinical Investigator. They are: ICH -

E1 - Exposure of the agent to populations

E2 - Clinical Safety

E3 - Study Reports - structure and content

E4 - Dose Response Studies

E5 - Ethnic Factors in acceptance of data

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ICH E6 Topics

E6 - Good Clinical Practice

1. Glossary 2. Principles of ICH GCP 3. The IRB / IEC 4. The Investigator 5. The Sponsor 6. The Trial Protocol and Amendments 7. The Investigators Brochure 8. Essential Documents

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ICH E6 Topics

E7 - Special Populations e.g. Geriatrics

E8 - Clinical Trial Design general considerations

E9 - Statistical Principles of Clinical Trials

E10 - Choice of Control group in clinical trials

E11 - Pediatrics

E12 - Therapeutic categories• E12A is Clinical trials on antihypertensives

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GCP and the Investigator

E6 - Good Clinical Practice

1. Glossary 2. Principles of ICH GCP 3. The IRB / IEC 4. The Investigator 5. The Sponsor 6. The Trial Protocol and Amendments 7. The Investigators Brochure 8. Essential Documents

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Investigator Responsibilities ICH - E6

4.1 - Investigators Qualifications

4.2 - Adequacy of Resources

4.3 - Medical Care of Study Participants

4.4 - Communication with the IRB / IEC

4.5 - Compliance with the Protocol

4.6 - Investigational Product care

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4.7 - Randomization & unblinding proced.

4.8 - The Informed Consent

4.9 - Records and Reports

4.10 - Progress Reports

4.11 - Safety Reporting

4.12 - Stopping or suspending a study

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4.1 - Investigators Qualifications

– Properly qualified to assume the responsibilities for conduct of the study.

– Very familiar with the drug under investigation

– Will comply with Regulations and be prepared for audits and monitoring

– Has available detailed list of all to whom responsibility is delegated

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Investigator Responsibilities - E6

4.2 - Adequacy of Resources

– Can recruit SP in sufficient numbers & on time

– There is enough time to complete the study

– There are enough qualified staff and adequate facilities to complete the study

– The staff are well informed about the Test Agent and the Protocol

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4.3 - Medical Care of Study Participants

– All medical decisions are made by qualified physicians

– All medical acts are performed by qualified physicians

– The Investigator is responsible for care of SP when there are “Adverse Events”*

– The primary physician of the SP is notified regarding the participation of their patient on the (or a) study

– The Study Physician knows when and why a Study Participant leaves a study - accounting for all SP

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Adverse Events are: Signs which are asymptomatic findings as: changes

in BP, temperature, rashes, etc.

Symptoms represent a change in function such as unsteady gait, lightheadedness, nausea, HA

Lab result of concern i.e. well beyond the reference range for the protocol or judgment

Inter- current Illness occurring while on study even if (the usual case) unrelated to the test medication

Study conditions causing or contributing to an abnormality i.e. shivering, hematoma, fainting...

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4.4 - Communication with the IRB / IEC

– Written approval is obtained before the Study begins

– Informed Consent is in the language of the SP

– The IRB has a current Investigators Brochure

– The IRB has all documents when needed

– The IRB is immediately informed of SAE (deaths etc)

– Protocol amendments are submitted on time

– The IRB / IEC gets an annual report of each study

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4.5 - Compliance with the Protocol

– Has signed Protocol confirming agreement to comply with it to the letter

– Has not deviated from the Protocol without written agreement from the sponsor and the IRB / IEC

– Has documented each and every deviation (for subject safety reasons) from the protocol when it occurs

– Implements deviations to avoid risk but immediately submits amendments to IRB, Sponsor and the FDA

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4.6 - Investigational Product care

– Accepts responsibility for the product, its usage, and its storage according to the Protocol

– Only a Pharmacist involved under PI’s supervision

– Explains to SP, and uses test agent, properly only

– Detailed records of test agents use kept throughout the study

– Retained unused test agent and destroy only under the written instruction from the sponsor

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4.7 - Randomization and unblinding procedure

– The study randomization procedures (documented in the protocol) are followed exactly

– The randomization code is only broken in accordance with the protocol

– If the study was blinded, any unblinding was documented and sponsor notified in writing

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4.8 - The Informed Consent

– Insure that the declaration of Helsinki and the principles of GCP are adhered to

– Insure that there is no coercion, of subjects to be on, or stay on, a study at any time

– Insure SP understanding* of the information they are presented by you or your designees

– Insure that the Informed Consent is signed and dated by the SP or SP’s legal representative

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Informed Consent “Process” Assure the sponsor that the IRB is functioning in

compliance with 21 CFR 56

Seek consent only under circumstances that provide sufficient opportunity to consider whether or not to participate - 21 CFR 50.20

The process must minimize the possibility of coercion or undue influence

Provide the ICF in a language understandable to the subject – 6th grade reading level recommended

Insure that the ICF contains no exculpatory language

Confirm that the ICF contains all of the required elements – 21 CFR 50.25

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Essential Elements of an ICFCFR 50.25 - Essential elements of an “informed consent”

That the study is research

The risks and discomforts are described

The benefits for subject and others

Disclosure of alternative therapies or procedures

Statement regarding confidentiality of the records

Explanation of what will happen on the study

Who to contact for questions and their rights

That participation is completely voluntary

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Essential Elements of an ICFCFR 50.25 - Additional (read: also essential) elements of

an “informed consent” are statements which state:

Statement regarding risks to the SP, an embryo, or fetus;

The circumstances regarding termination of the subjects participation without their consent;

Any additional costs to the subject resulting from participation in the research study;

The consequences of withdrawal and tests that would need to be completed;

Statement regarding disclosure of new information as it becomes available;

The approximate number of subjects involved in the study

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4.9 - Records and Reports

– Data is ALCOA (accurate, legible, contemporaneous, original and attributable) and complete

– Data on the CRF’s is consistent with (exactly the same as) that of the source documents (raw data)

– All changes to a CRF are dated and signed such that the original data is not obscured

– Essential documents are retained at least 2 years after the last approval of the test agent for market

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It’s the Data, s….. How and where the data is recorded is the Key

Good, auditable data is “ALCOA”

Accurate Legible Contemporaneous Original Attributable

If it is not documented, it does not exist

Source Documents

Source documents are original documents and records for each study subject. Be clear - this is any and all original documents

Their purpose is to verify the existence of the subject and verify the integrity of collected data.

Source DocumentsExamples:

All Study related Medical Hx and Px forms Demography sheets Dosing documentation sheets Blood draw recording sheets Vital sign recording sheets Subject diaries Notes to file Laboratory records Phone records (even yellow sticky’s) Study related data even on scrap paper

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Source DocumentsOther Administrative points:

Never erase or overwrite – use single horizontal line to strike through unwanted words etc.

No blank spaces on any page

All loose pages are identified clearly

All entries are legible and self explanatory

Corrections are clearly and consistently made

Subject / patient identifiers are consistent

All loose pages are identified clearly

All entries are initialed and dated when done

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The Handling of data is Important

Corrections: documentation CPierce 25 Jun04

Clear documantation is …

Date Format goal is to be unambiguous:Day = 2 digits

Month = 3 letters

Year = 2 digits i.e. 25/Jun/04 or 25-Jun-04

08/Sep/03 or 08-Sep-03

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4.10 - Progress Reports

– A written report is submitted to the IRB /IEC at least annually is required but….

• Low Risk – yearly is OK• Moderate Risk – twice a year• High Risk – monthly to quarterly as needed

– A written report is submitted to the IRB / IEC if the PI notes any change that might significantly change the conduct of the trial

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4.11 - Safety Reporting

– All SAE’s are immediately reported to the sponsor and followed up by a written report forthwith

– Study Participants are not to be identified to anyone

– All AE’s critical to the safety evaluation are reported to the sponsor per protocol

– The sponsor and the IRB are given all details in the event of a death of a SP while on study

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Monitoring Data Safety Subject Safety under the microscope

Data & Safety Monitoring Plans (DMP, DSMP)

Data & Safety Monitoring Committee (DMC, DSMB)

- Separate and independent - No conflict of interest (scientific, financial, etc)

When to discontinue a study – one of the main functions of a DSMB is to establish “stopping rules”:

Clear evidence of harm or harmful AE’s No likelihood of demonstrating benefit Overwhelming evidence of benefit

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Aims of a DSMPTo ensure the safety of all participating

subjects to the greatest extent possible

On-going oversight and monitoring of the conduct of a study

To ensure the validity and integrity of the data

To periodically decide whether of not the study should continue or be stopped

To specify the responsibilities and charter of the DSMB if one is required

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Adverse Events (AE’s)AE’s are one of the key ways the Clinical Investigator

has of monitoring the safety of subjects or patients in her/his charge.

Determining the relationship between the study drug and an AE requires not only the physicians power of observation but great care.

The algorithm: 1 - Likely / almost certainly

2 - Probably

3 - Possibly

4 - Unlikely / remotely possible

5 - Unrelated

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4.12 - Premature stopping or suspending a study

– All SP are informed if a study is terminated or even suspended

– The institution, the sponsor, and the IRB are informed in writing if the PI terminates the study

– The institution and the IRB are informed in writing if the sponsor terminates the study

– The institution and the sponsor are informed in writing if the IRB terminates the study

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4.13 - Final Report(s) by Investigator– The Principal Investigator is expected to file a

written report at the conclusion of a study

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Final Report

Upon completion of the study, the investigator must notify the IRB and the sponsor.

The final report should contain the introduction, description of the methods, results, and discussion of the findings.

Of greatest importance to the Investigator is the section dealing with the effect of the test article on the Study Participants as reflected in the AE / test article relationship

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What the FDA is Finding Protocol is not followed - I/E criteria, tests & timing,

route of admin., timing of events

Informed Consent inadequacies - Timing, elements missing, risks listed, copies

Test article accountability problems - Dispensing, inventory & receipt records

Reporting deficiencies - AE’s, final reports, Yearly IRB reporting

IRB approvals missing - Timing, amendments, ICFs, Advertising

Records in disarray - Corrections, storage requirements, equipment maintenance

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An Answer Investigator Certification

AAPP - Certified Physician Investigator (CPI) ACRP - Certified Clin. Res. Investigator (CCRI) SoCRA - Certified Clin. Res. Professional (CCRP) DIA - Certified Clinical Investigator (CCI)

Study Personnel CertificationACRP - CCRA (’95), CCRC (’92)SoCRA - CCRP (’91)

IRB Certification

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Summary

The overall role of the clinical investigation team is to protect the rights and safety of volunteers and patients enrolled in studies.

Moreover, the clinical investigation team is charged with ensuring that the data obtained from trial subjects is accurate and valid.

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Clinical InvestigatorResponsibilities

In the end…

…a physician doing clinical research is still a physician with all that that entails. She/he

takes great care in all aspects of the care of those with whom she/he is responsible. This

care includes accurate record keeping, patient safety and clear documentation of

ones thought process

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Addendum

The Drug / Adverse Event

relationship algorithm

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AE / Study Drug Relationship Algorithm

1 - Likely / almost certainly

2 - Probably

3 - Possibly

4 - Unlikely / remotely possible

5 - Unrelated

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1 - Likely / almost certainly

a causal relationship exists when the event:

- is a well known effect of the drug (PDR, IB)

- follows a clear temporal sequence from the

drugs administration

- ceases with discontinuation of the test agent

(and reoccurs on restarting)

- is not related to study / environment

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2 - Probably

A causal relationship exists when the event:

- is a known or suspected effect of the drug

- follows a reasonable temporal sequence from

the test med’s administration

- ceases or diminishes with discontinuation of

the study medication

- cannot be readily explained by Study

participant or study factors

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3 - Possibly

A causal relationship exists when the event:

- is a known, or possible, effect of the drug

- follows a fair temporal sequence from the

drug’s administration; but

- could be explained by subject/patient or

study factors

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4 - Unlikely/remotely possible

That a causal relationship exists when the event:

- is not known, or suspected to be an effect of the test medication; or

- is a possible or known effect of the drug but does not follow a reasonable time

sequence from the drug’s administration

- can be readily explained by either Study Participant or study factors

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5 - Unrelated

as a causal relationship when the event:

- is not known to be an effect of the test agent; and

- does not follow a temporal sequence from the drug’s administration; and

- can be readily explained by study participant and / or study factors