Alex A. Adjei, MD, PhDResponsibilities of a Principal Investigator

Definition of Clinical Research

• Research: “class of activities designed to develop or contribute to generalizable knowledge”

vs• Practice: “interventions designed solely to enhance the well-being of an

individual patient or client”

Belmont Report, 1979.

Who Is a Principal Investigator (PI)*?

• “The” person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and is usually called the principal investigator.

• If a trial does not have a sponsor, the PI is the Sponsor-Investigator.

• Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decision (eg, associates, residents, fellows) are, under the regulations, considered sub-investigators, not PIs or Co-investigators.

*Source: FDA’s Official Guidance on Good Clinical Practice. Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf. Accessed March 04, 2015 . Please note that the respective guidance or provisions may vary for other countries or regions.

General Responsibilities of the PI

• An investigator is responsible for– Ensuring that an investigation is conducted according to ICH guidelines– Signed investigator statement (FDA 1572); study protocol, IRB requirements, all

applicable federal, state, and institutional regulations– Control of all drugs/agents/devices under investigation– Protecting the rights, safety, and welfare of subjects under the investigator’s care

Qualifications for PIs

• Qualified by education, training, and experience to assume proper conduct of the trial

• Aware of and comply with GCP• Familiar with the use of investigational product(s)• Interested in the scientific aspects of the trial

Qualifications for PIs (continued)

• Have adequate time to:– Discuss, read and approve protocol– Identify and recruit subjects– Properly assess and follow subjects

• Have adequate personnel and resources to conduct the trial

• Able to meet the recruitment targets• Conduct the trial in compliance with the protocol without deviation

Qualifications for PIs (continued)

• Maintain a list of research team members to whom trial-related duties have been delegated

• Keep research team members well informed about the trial at all times• Permit monitoring, auditing, and inspection by sponsors and regulatory

authorities

Consent of Subjects

• An investigator must obtain the informed consent of each human subject to whom the drug/agent/device is distributed.

– Note: “informed consent” is more than handing the subject a form. It is a process.

Investigational Agents

Control of Investigational Drug/Agent/Device

• An investigator shall distribute the drug/agent/device only to subjects under the investigator’s personal supervision or under the supervision of a sub-investigator responsible to the investigator.

• The investigator shall not supply the investigational drug/agent/device to any person not authorised by the investigator to receive it.

Investigator Recordkeeping and Record Retention

• Case Report Form (CRF): a printed or electronic document designed to record protocol-required information on each subject

• Source Document: may include hospital records, clinical/office charts, lab reports, subject diaries, etc.

• Investigator should ensure the accuracy, completeness, and timeliness of data in CRFs

• Data in the CRFs must be consistent with and verifiable with the source documents

• Correct data in the CRF by striking out and initialing– Do not use “white out”– Do not scribble out words

Investigator Recordkeeping and Record Retention (continued)

• Case Histories– Prepare and maintain adequate and accurate case histories that record all

observations and other data pertinent to the study on each individual distributed to or employed as a control on the protocol.

• CRF, supporting data, signed consent forms, medical records, progress notes, hospital charts, nurses notes

– Case histories should document that informed consent was obtained prior to the subject’s participation…this is in addition to the consent form.

Investigator Recordkeeping and Record Retention (continued)

• Disposition of drug/agent/device– Maintain adequate records of the disposition of all drugs/agents/devices– Dates, quantity, subject use, shipping, storage, return/destruction

• Record Retention– Retain records for a period of 2 years following the date a drug/agent/device is

approved for the indication in which it is being investigated or if no application is filed/approved, 2 years after the investigation is discontinued.

Maintenance of a Study Binder for Every Protocol

• List of all study personnel:– Their initials and signatures– Their qualifications and responsibilities– Dates of their participation

• Up-to-date, signed, and dated CVs for staff who:– Undertake consent and assessments of subjects– Make entries in case report forms (CRFs)

• Up-to-date licenses of laboratories providing test results and their normal ranges

Investigator Reports

• Progress Reports– Sending reports to the sponsor as required by the protocol.– Sponsor-investigators are required under 312.33 to submit annual reports to FDA

on the progress of the clinical investigation.

• Safety Reports– Promptly report to the sponsor any adverse effect that may reasonable be regarded

as caused by, or probably cause by, the drug/agent/device.– Sponsor-investigators are required to report adverse effects that are both serious

and unexpected and/or deaths directly to FDA in accordance with 312.32.

Investigator Reports (continued)

• Final Report– Provide the sponsor/FDA (for sponsor-investigators) with an adequate report shortly

after completion of the investigation.

• Financial Disclosure Reports– Provide sponsor with sufficient accurate and current financial information to allow

for accurate certification/disclosure as required under part 54.

Investigator Reports (continued)

• New Information– New information available during the course of the trial must be passed along to the

IRB– If the new information is relevant to the subject’s participation, consent form must

be updated and approved by the IRB– For subjects already on study, provide the new information at their next visit or

sooner if there is a risk to the patient or if consent is likely to be revoked– Current subjects should be “re-consented” with the new IRB-approved consent form– Delay accrual until IRB approval of new information

Investigator Reports (continued)

• Adverse Event/Safety Reporting– Adverse Event (AE): any untoward medical occurrence in a trial subject, which

does not necessarily have a causal relationship with the study treatment– Serious Adverse Event (SAE): any untoward medical occurrence that meets one or

more of the following:• Results in death• Is life-threatening• Requires inpatient hospitalisation or prolongation of an existing hospitalisation• Is a congenital anomaly or birth defect• Is a medically significant event, for any reason, these might include pregnancy, cancer,

overdose, etc.

Investigator Reports (continued)

• Adverse Event/Safety Reporting-Questions to Ask– Is the event “unexpected”?

• Reported in the Investigator’s Brochure• Known events that have become more frequent or severe

– Is the event treatment-related?• Reasonable causal relationship to be determined based upon prior experience with

treatment• If an association cannot be ruled out, then it should be considered to have a reasonable

relationship• Not-related, unlikely, possible, probable, definite

The Therapeutic Misconception

“the belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge….

It is not a misconception to believe that participants probably will receive good clinical care during research.

But it is a misconception to believe that the purpose of clinical trials is to administer treatment rather than to conduct research”

National Bioethics Advisory Commission. Ethical and Policy Issues in International Research. 2001.

The Clinician-Investigator

• The Clinician-investigator has a dual allegiance– to study/community– to patient/subject

• This creates a (legitimate) conflict of interest • Important to be aware of this tension

Miller et al. JAMA. 1998;280:1449.

Example of Conflict

• NSABP trials 1994– PI at St-Luc Hospital in Montreal falsified procedure dates and hormone-receptor

status so that breast cancer patients would appear to meet eligibility criteria for a clinical trial

PI Response

“My sole concern at all times was the health of my patients. I firmly believed that a patient who was able to enter into an NSABP trial received the best therapy and follow-up treatment.

For me, it was difficult to tell a woman with breast cancer that she was ineligible to receive the best available treatment because she did not meet 1 criteria out of 22…”

Case

• Patients with imatinib-refractory GIST • Offered participation in RCT of sunitinib vs placebo• Trial includes open-label access to drug at time of progression• Two medical centres…refused to join in

Mishra R. Placebos break taboo in cancer drug tests. Boston Globe. A1, July 4, 2004.

Case (continued)

“When patients have an advanced cancer and the cancer is growing, there isn’t any way the placebo can be helpful (to the patient). To argue that a placebo trial is in society’s interests has nothing to do with helping these patients.”

– Assoc. Director, U of Michigan Cancer Center (quoted in R. Mishra, Boston Globe, July 4, 2004)

Case: 1997

• HIV infected pregnant women enrolled for anti-retroviral therapy to prevent neonatal infection in Central Africa

• Randomised to AZT vs placebo• Even though an NIH-funded randomised, controlled trial demonstrated in

1994 that AZT (zidovudine) reduced transmission from mother-to-infant by approximately two-thirds

Mishra R. Placebos break taboo in cancer drug tests. Boston Globe. A1, July 4, 2004.

Criteria for Ethical Research

Emanuel et al. JAMA. 2000;283:2701.

Social Value

• Study must ask an important question– Valuable for improving health and/or for basic scientific knowledge– Research is unethical if question is trivial, has already been answered, etc

Scientific Validity

• Even if the question is important, the study is unethical if the methods are not likely to answer it

– Not feasible– Poor measures– Inadequate sample size– Poor statistical analysis– Biased reporting (or non-reporting)

Fair Subject Selection

• Historically, risky or non-beneficial research has disproportionately enrolled vulnerable populations

– Ethnic minorities– Low socio-economic status– Mentally incapacitated, institutionalised

• Conversely, beneficial research should not selectively enroll privileged subjects

You’re In Charge

• Running a clinical trial can be complex– You will need full support from your research team– You will need to be careful and stringent on every trial-related issue– You will need to protect the rights and integrity of your trial subjects

Alex.Adjei@RoswellPark.org