Transcript CLINICAL RESEARCH IN LSUHSC

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: Crosssectional 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
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Saves time in the long run
Focuses efforts
Minimizes mistakes
Promotes success
Research Ethics
Sentinel Events
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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 – 1979
Basic Principles
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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 IRB
2. Informed consent by subjects
3. Institutional assurances of compliance
Code of Federal Regulations
ICH 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