CLINICAL RESEARCH IN LSU HCSD

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CLINICAL RESEARCH IN LSU HCSD

• Frank A. Riddick Jr. MD
• Leonard J. Chabert Medical Center

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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.

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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.

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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

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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

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Institutional Review Board

• When in doubt consult LSUHSC-NO IRB
• http//www.lsuhsc.edu/no/administration/rs/irb

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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.

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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.

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Attributes of Clinical Research
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Objectives

• Identify key components of getting a study
  started
• Identify the importance of appropriate
  preparation for a study

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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

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Study Design Descriptive Studies

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

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Descriptive StudiesCase 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

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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

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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))

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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)

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Study Design-Analytic Studies

• Analytic Studies
• Observational Studies
• Case Control
• Cohort
• Interventional/Clinical Trials

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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

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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

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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

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Determining if Institutional Review Board (IRB)
approval is required
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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.g
  po.gov/nara/cfr/)
• Need HIPAA authorization or waiver

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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)

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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

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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

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Assessing the Impact of Health Insurance
Portability and Accountability Act(HIPAA) on
data collection
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HIPAA and PHI

• HIPAA Compliance Date April 14, 2003 for
  privacy ruleimpacts 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

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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

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Importance of Preparation

• Saves time in the long run
• Focuses efforts
• Minimizes mistakes
• Promotes success

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Research Ethics
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Sentinel Events

• Tuskegeee Study 1932-1960s
• Nazi MD Research 1940-1945
• Willowbrook Study 1963
• Thalidomide Tragedy 1960s

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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

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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

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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

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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

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Belmont Report 1979Basic Principles

• Protection of vulnerable populations
• Respect for persons
• Beneficence
• Justice

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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.

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Federal Regulations

• The Common Rule
• Review of research by IRB
• Informed consent by subjects
• Institutional assurances of compliance
• Code of Federal Regulations
• ICH Guidelines

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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

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Programs to Protect Human Participants in Research

• Multiple functional elements (in addition to IRB)
• Accreditation standards
• Education
• Quality improvement
• Monitoring and feedback

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MANAGING CONFLICTS OF INTEREST IN CLINICAL TRIALS
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The Environment

• 80 Thousand clinical trials in progress
• 20 million persons involved as research subjects

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The Environment

• Shift of clinical trials out of academic medical
  centers
• 40 academic medical centers
• 60 others
• CROs
• MD practices

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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

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The Environment

• Financial pressures on practicing MDs
• Shrinking reimbursements
• Managed care
• Participation in clinical trials advocated as
  revenue source and practice enhancer

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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

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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

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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

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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

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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

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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

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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

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Ethical Tensions for MD

• Informed consent - Is it informed when presented
  in therapeutic setting by long time trusted MD?
• Authorship attributed without meaningful
  involvement

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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

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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

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Recommendations

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

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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
  patients informed consent
• This individual should be insulated from
  pressures of financial incentives

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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

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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

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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

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Recommendations

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