CLINICAL RESEARCH IN LSU HCSD

Frank A. Riddick Jr. MD

Leonard J. Chabert Medical Center

Institutional Review Board (IRB)

What is an IRB?

Broadly constituted body entrusted with evaluation of ethical and scientific integrity of proposed investigation involving human subjects and approving conduct of specific investigations within the institution.

Institutional Review Board (IRB)

What studies require IRB approval?

Any study involving human subjects – including those involving review of clinical information about individual patients or interpretation and collection of imaging, laboratory or anatomic pathology data on individual patients.

Institutional Review Board – (IRB)

Which IRB must approve proposed studies?

IRB of record is that of the employer of principal investigator (PI)

Approval of LSU HSC IRB NO required if studies carried out in LSU HCSD centers.

If PI is from institution with own IRB (Tulane or Ochsner) approval by that IRB must be reviewed and approved by LSU HSC IRB NO before studies undertaken in LSU HCSD center

Institutional Review Board (IRB)

Which IRB must approve proposed studies?

Protocols approved by outside IRBs (multicenter studies or clinical trials with commercial IRB approval) still require review and approval by IRB LSUHSC NO.

Protocols approved by IRB LSUHSC NO should be reviewed and approved by individual hospital medical staff executive committee before undertaken in that hospital

Institutional Review Board

When in doubt consult LSUHSC-NO IRB

http://www.lsuhsc.edu/no/administration/rs/irb

Research Grants

• Cover costs of conducting study: supplies, laboratory studies, personnel, participant payments (if any), etc.

• May cover: equipment, salary of investigator, statistical consultation.

• Carry contribution to institutional overhead of 12 – 40%.

Use of Unexpended Grant Funds

Unexpended grant funds

1. Belong to the institution.

2. Use restricted to research related activities e.g. professional travel to present research results, equipment.

3. Disbursement usually controlled by PI.

4. Control of funds revert to institution if PI leaves.

Attributes of Clinical Research

Objectives

• Identify key components of getting a study started

• Identify the importance of appropriate preparation for a study

Key Components of Getting a Study Started

• Identifying the study question• Specifying the study goals• Choosing the appropriate study design to

answer the question• Consult with a biostatistician/epidemiologist• Determining if IRB approval is required• Assessing the impact of HIPPA regulations

on data collection

Study Design – Descriptive Studies

• Descriptive Studies– Case Reports– Case Series– Cross-sectional Survey– Correlational Studies

Descriptive Studies:Case Report/Case Series

• Describe the experience of a unique patient or series of patients with a

• diagnosis

• Often useful in recognition of new diseases and generation of new questions concerning possible risk factors

Descriptive Studies: Case Report/Case Series

• Strengths– May lead to new hypothesis re risk factors– Hypothesis likely relevant to clinical practice

• Weaknesses– Not used to test for valid statistical

associations– Reflect experience of small number of

patients– Lack appropriate comparison group

Descriptive Studies: Cross-sectional Surveys

• AKA “prevalence surveys”

• Assess both disease and exposure status at the same time

• More popular recently with development and validation of a number of survey tools ( SF36, satisfaction surveys, disease-specific surveys (KCCQ))

Descriptive Studies-Correlational Studies

• Employ measures that represent characteristics of entire populations to describe a given disease in relation to some variable of interest (I.e. medication use, age, healthcare utilization)

• Uses correlation coefficient: measures extent to which there is a linear relationship between the exposure and the disease

• Range : –1 to +1 (+1 = perfect correlation; -1 = inverse correlation)

Study Design-Analytic Studies

• Analytic Studies– Observational Studies

• Case Control• Cohort

– Interventional/Clinical Trials

Analytic Studies-Case Control

• Subjects chosen based on whether they do (cases) or do not (controls) have the disease

• Cases and controls are then compared as to whether they have the exposure or characteristic of interest

• Differences in the prevalence of the exposure can then be tested

• Odds Ratio the appropriate statistical measure

Analytic Studies-Cohort Studies

• Follow-up studies-subjects defined based on presence or absence of exposure to a suspected risk factor

• Subjects must be FREE from disease at the outset of the study

• Retrospective (e.g.chart review) vs prospective. Example – Framingham Heart Study

• Relative risk can be calculated

Analytic Studies-Clinical Trials

• Experimental or intervention studies

• Subjects randomly enrolled into groups based on exposure to certain treatment

• If done correctly, there is high assurance of the validity of the results

• Usually therapeutic or preventive

Determining if Institutional Review Board (IRB) approval is required

To be or not to be…..the IRB

• If study is truly QA, then– No need for IRB approval– Records exempt from discovery in litigation– No need for HIPAA authorization or waiver of

authorization

• If QA is Research, – then all the requirements of the Common

Rule of the Federal Regulations apply (http://www.access.gpo.gov/nara/cfr/)

– Need HIPAA authorization or waiver

Definition of Research

• “A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge”

(As defined by the Common Rule and HIPAA)

Belmont Report: Research vs Practice

• Research– “an activity designed to test a hypothesis,

permit conclusions to be drawn, and thereby develop or contribute to generalizable knowledge”

• Practice– “interventions that are designed solely to

enhance well-being of an individual patient or client and that have reasonable expectation of success”

Issues in the Debate: QA vs Research

• QA efforts may lead to generalizable knowledge

• Individuals responsible for QA/QI activities want to publish their results

• One case study is not considered research; however, at what number in a case series does this become research?

• Some studies/projects may be in-between• CQI activities offer new challenges in the

distinction

Assessing the Impact of Health Insurance Portability

and Accountability Act(HIPAA) on data collection

HIPAA and PHI

• HIPAA Compliance Date: April 14, 2003 for privacy rule—impacts research studies

• PHI: Protected Health Information:– Identifying information of a patient (name, SSN,

contact information, email etc)– Survival status– Health status: past , present, future– Information may be on paper, electronic format, or

verbal

HIPAA: issues for research

• Determine if HIPAA authorization is required for your study/project

• Realize that there are 5 exceptions of the HIPAA authorization requirement:– HIPAA waiver– PHI access preparatory to research– Research on PHI of decedents– Limited data sets with data use agreement– Completely de-identifying the data based

on strict HIPAA definitions

Importance of Preparation

• Saves time in the long run

• Focuses efforts

• Minimizes mistakes

• Promotes success

Research Ethics

Sentinel Events

• Tuskegeee Study 1932-1960’s

• Nazi MD Research 1940-1945

• Willowbrook Study 1963

• Thalidomide Tragedy 1960’s

What Makes Clinical Research Ethical?

• Informed consent• Value (improved health, advance of

medical knowledge)• Scientific validity• Fairness in subject selection• Favorable risk-benefit ratio• Independent review• Respect for enrolled subjects

Rules of Research

Main sources of guidance for the ethical conduct of research

*Nuremburg Code*Belmont Report*Declaration of Helsinki*Code of Federal Regulations*ICH Guidelines

Nuremberg Code - 1949

• Informed consent, obtained without coercion

• Human experiments should be based on prior animal experiments

• Only qualified scientists to conduct research

• No expectation of death or disabling injury

National Research Act – 1974

• Regulations for protection of human subjects

• Requirements for informed consent

• Requirements for review of research from Institutional Review Boards

• Creation of National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Belmont Report – 1979Basic Principles

• Protection of vulnerable populations

• Respect for persons

• Beneficence

• Justice

Declaration of Helsinki - 2000

The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.

Federal Regulations

The “Common Rule”

1. Review of research by IRB2. Informed consent by subjects3. Institutional assurances of compliance

Code of Federal RegulationsICH Guidelines

Process of Informed Consent

Information: Exchange of information between the subject and investigator before, during, and even after the study

Comprehension: Investigator is responsible for ensuring that the subject comprehends the information

Voluntariness: Decision to participate is free of coercion and undue influence

Programs to Protect Human Participants in Research

• Multiple functional elements (in addition to IRB)

• Accreditation standards

• Education

• Quality improvement

• Monitoring and feedback

MANAGING CONFLICTS OF INTEREST IN CLINICAL

TRIALS

The Environment

• 80 Thousand clinical trials in progress

• 20 million persons involved as research subjects

The Environment

• Shift of clinical trials out of academic medical centers– 40% academic medical centers– 60% others

• CROs• MD practices

The Environment

• Well publicized problems– Death of research subjects– Irregularities in performance & documentation

• Overloaded IRBs– More studies to review– Expectation for monitoring and followup

• Pressure on pharmaceutical and device manufacturers to achieve approval

The Environment

• Financial pressures on practicing MDs– Shrinking reimbursements– Managed care– Participation in clinical trials advocated as

revenue source and practice enhancer

Areas of Concern

• Obligation to protect study participants

• Monitoring of studies

• Research expertise of MDs involved in clinical trials

• Postmarketing trials- ? Driven by Sales Division

• Independent IRBs - ? Hired guns

Areas of Concern

• Confusion of patient over role of MD• Financial conflicts of interest for MD

– Bonuses for quotas– Finders’ fees– Excessive payments vs usual clinical fees– Equity interest/stock options– Patents/royalties– Advisory board/speakers bureau

appointments

Areas of Concern

• Financial conflicts of interest for CROs, SMOs– Paid by sponsors dependent on positive trial

outcomes– Viability may be pitted vs research integrity

and safety of research subjects

Ethical Tensions for MD

• AMA Principles of Medical Ethics– “VIII A physician shall, while caring for a

patient, regard responsibility to the patient as paramount.”

– The greater the potential reward, the greater the potential conflict of interest

Ethical Tensions for MD

• AMA Principles of Medical Ethics– “V A physician shall continue to study, apply,

and advance scientific knowledge, maintain a commitment to medical education, make relevant information available to patients, colleagues, and the public…”

Ethical Tensions for MD

• Conflicting roles – Physicians as Investigators– Researcher generates scientific knowledge,

with potential for future therapeutic benefits– Practitioner is focused on present health and

welfare of patients

Ethical Tensions for MD

• When research offers medical benefit and is integrated into the course of clinical care, subjects may mispercieve the nature of the research project

Ethical Tensions for MD

• Informed consent - Is it informed when presented in therapeutic setting by long time trusted MD?

• Authorship attributed without meaningful involvement

Ethical Tensions for MD

• Financial conflicts – minimizing their influence– Disclosure may be a safeguard. Conflicts,

when identified, may be avoided or mitigated– Institutional monitoring of research trials

• Compliance programs• IRB follow-up and review• Prohibition of some level and forms of reward

Recommendations

• Requirement for MD participation in clinical trial– Must relate to scope of practice and expertise– Adequate training in conduct of research– Assure that protocols are scientifically sound– Must be familiar with ethics of research– IRB has reviewed protocol

Recommendations

• Requirement for MD participation in clinical trial– No undue risks to research subjects– Research conforms to government regulations

Recommendations

• When a current patient is eligible for clinical trial, process of informed consent should differentiate between roles of MD as clinician and investigator– Someone other than treating MD should get

patient’s informed consent– This individual should be insulated from

pressures of financial incentives

Recommendations

• Financial compensation from trial sponsors must– Be commensurate with efforts of MD

performing research– Be at fair market value– Not vary by volume of subjects enrolled– Meet other existing legal requirements– Not be solely for referral of patients to study

Recommendations

• MD should ensure that– Protocols have provisions for funding

subjects’ medical care required from complications

– Disclosure to participants list any uncertainties on funding for treatment of complications

– Such disclosure is included in written informed consent

Recommendations

• Nature and source of funding and financial incentives to investigators must be disclosed to a potential participant as part of informed consent process

• MD should not bill a 3rd party payor when sponsor has funded additional expenses related to conduct of the trial

Recommendations

• MD should ensure that presentation or publication of results will not be unduly delayed or otherwise obstructed by the sponsor of research