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Ethics In Ct 2 Mar2011

Ethics In Ct 2 Mar2011



This slide set is for my talk at Ethics in Clinical Trials, San Diego, Mar 2 2011

This slide set is for my talk at Ethics in Clinical Trials, San Diego, Mar 2 2011



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    Ethics In Ct 2 Mar2011 Ethics In Ct 2 Mar2011 Presentation Transcript

    • Ethical Issues in Clinical TrialsJacquie Mardell
      © 2011 J. Mardell, All rights reserved
      Ethics in Clinical Trials, San Diego
      March 2, 2011
    • Who Am I?
      30 years clinical trials
      15 years global
      7 years emerging regions
      UC Santa Cruz clinical trials certificate instructor
      Clinical services, consulting, training business owner in India and US
    • Topics
      Chernobyl, AIDS vert tx Africa, Trovan
      Patient availability
      Ethical Issues
      Clinical trials as treatment
      and marketing
      Opportunism of crisis
      Consent and vulnerability
      India & China
    • Growth in Overseas Trials
      Over 40% of US-regulated trials are off-shore
      Central-Eastern Europe saw greatest growth
      Projected to >65% by 2011
      Source: Tufts Center for Drug Dev, 2008
    • Driving Factors
      Number of trials increasing
      FDA demands increasingly large samples sizes
      Intensified competition in some therapeutic areas
      Hypertension, oncology, diabetes, HIV
      Patent explosion  patent cliff
      Western patient pools shrinking
      Treatment saturation  drug-drug interactions
    • Expansion in Patient Demand
      Post WWII pharma boom in US, EU
      Regulatory limitations on prisonor research
      ICH globalizes drug development
      CROs shift from preclinical work to monitoring and clinical data
      Low-cost, rapid pt recruitment becomes primary business driver
    • Status
      “Rescue” countries evolve
      2008: 80% of NDAs contained some foreign clinical data
      Top 20 US pharma companies conduct one-third of their clinical research elsewhere
    • Clinical Trials Registry Today
      BRIC=13.5 %
      Source: clinicaltrials.gov, 26 Feb 2011
    • What Relevance?
      Results from developing countries may not be applicable to industrialized patients
      Endemic diseases may skew results
      Ethical variances may make data invalid
    • Challenges in Ethics
      Crisis opportunism
      Placebo controls
      Clinical trials as treatment
      Or marketing
      Vulnerability and consent
    • Crisis Opportunism - Chernobyl
      Slack state response
       ready-made experimental conditions
      Experimental BMT on Zone workers
      FIH testing of rhGM-CSF for leukemia
      No clinical protocol
      Limited ethical review
    • Crisis Opportunism - Trovan
      Bacterial meningitis, measles and cholera outbreak in Nigerian northern territories
      12000-15000 deaths
      Pfizer sought US approval
      Kano Infectious Diseases hospital
      MSF  effective low-cost antibiotic
    • Trovan Irregularities
      No US IRB approval
      “Inadequate” host country ethics review
      Backdated informed consent forms
      Parents believed it was an ‘approved’ treatment
      Low dose comparator
      Untested formulation
    • Placebo – HIV Perinatal Transmission, Africa 1994 & Thailand 1997
      “Protocol 076” (ACTG 076) 67.5% more effectivethan placeboin US
      Maternal oral dosing 5x/day weeks 14-34
      IV dosing during birth
      Infant oral dosing q6h x 6 weeks
      Cost ~$800 per mother/infant pair
      Actual results: 7.6% (AZT group), 22.6% (PLA)
      “Unfeasible” absent medical infrastructure and state financial commitment
      Short oral course AZT vs placebo
    • Sponsors’* Defense of Placebo
      AZT not available in country
      Placebo patients “not worse off”
      Ethicality based on host country’s needs, not sponsor’s (ethical imperialism)
      Active control makes findings less clear
      Superiority against placebo in US not definitive re effectiveness in another setting
    • Ethical Imperialism or Relativism?
      Tuskegee – we’ve seen this before
      US critics should not dictate treatment standards over local authorities
      Health crises grants legitimacy to certain kinds of experimentation
    • Declaration of Helsinki
      “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention.” (emphasis added)
      “…placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or… for compelling and scientifically sound methodological reasons.”
      If taken literally, would bar all clinical trials
    • Proponents of Placebo Control
      Placebo controls are ethical as long as:
      Patients are protected from increased risk, and
      Patients are fully informed of any alternatives
      Many ‘effective” medicines have never been fully characterized due to small response
      Therefore require placebo control to demonstrate effectiveness
    • The Debate Rages On
      FDA approval requires either:
      Superiority against placebo
      Statistically superior – easier
      Clinically superior – harder
      Inferiority against an active comparator
      Requires more patients  more time, cost to complete
    • Clinical Trial as Treatment
      Patients don’t understand
      Control groups
      Illiteracy amplifies these gaps
      Absent, deteriorating or stressed health care modalities
    • MD Anderson
    • And yet…
      A clinical trial may be safer than no treatment
      Or even routine medical care
    • Vulnerability and Consent
    • Belmont Principles:Respect for Persons - Autonomy
      Some non-Western cultures value the collective over individual autonomy
      Vulnerable patients may be even more vulnerable
      Use (and explanation of) contraception may not be acceptable
      Lack of self-determination
      Potential coercion due to lack of available medical care, poverty, illiteracy
    • Conflict For Two Parties
      For investigators: Individual treatment is secondary to the protocol
      Physician’s primary interest is her patient
      Researcher’s primary interest is studying disease and treatment
      For patients: Primary concern is for own welfare and those close to them
      All subjects can therefore be vulnerable
    • Beneficence
      Maximize benefits, minimize risk
      Individual risk:benefit takes prominence over generalizable benefit to science and society
      Implications for study design
      Use alternate procedures that lower risk
      Additional safeguards and precautions
      Ability to react even more quickly if harm should occur
      This may result in a different protocol than would be appropriate in the West
    • Justice
      Selection based on ability to bear the burdens
      When many communities may benefit
      Not just those easily available, easily discarded
      Sponsor must determine what
      Should be available in conjunction or after
    • Obtaining Informed Consent
      Founded on principles of respect reflected in freedom of choice
      Asymmetry in knowledge and authority
      Sponsor/investigator must
      Provide information
      Assess comprehension
      Assess voluntariness
      Process may be continuous
    • How Much is Understood?
      In one survey in West Africa,
      90% of participants did not understand withdrawal criteria, possibility of side effects
      75% did not understand they were in a study (i.e., not receiving therapy)
      In another study in Gambia
      10% (of 189) parents of pediatric patients understood there was a placebo group
      Different study, also Gambia
      45% (of 800 mothers) did not know or remember the study purpose
    • Not Limited to Developing World
      Australian parents interviewed did not understand:
      Rationale for use of placebo
    • Why is So Little Understood?
      Too much information
      20 page consents
      Incomprehensible information
      Data protection
      Explanations of how the therapy may work
    • Cultural Considerations
      Some non-Western cultures value the collective over individual autonomy
      Subjects may have to get permission to participate from
      Spouse, elders, community leaders
      To ignore this fact could stir up conflict within the community
      Physician as God
    • Twin Tenets of Medical Ethics
      Respect for persons
      Patient should be informed of treatment options
      Consent obtained without coercion
      Physician should look after best interests of each patient
      Adequacy of informed consent is a key factor in clinical trial ethics
    • Reciprocity
      If treatment is effective, will it be offered post-trial?
      If so, to whom?
      All study patients
      Population at large?
      Responsibility to build research capacity
      Research advances healthcare development
      Investigators gain experience with new therapies
      This may mean including less experienced investigators and taking responsibility for training them
    • Challenges in Application
      Source: FierceBiotech, April 2010
    • Outsourcing Lifecycle
    • Clinical Trial Environments:India and China
      CTA processes in continual state of flux
      GCP accepted and legislated
      Ethical review process developing
    • Practical Issues Overwhelm Ethics
      Ethical issues become procedural questions
      Informed consent
      Clinical conduct
      Ethical variability –
      Guidelines recast to organize global trials
      West and non-West
      Imperialism vs relativism
      Crisis conditions legitimate ethical variability
    • China
      Shanghai - Pharma employees give free samples of drugs on the streets
      Traditional medicines
      Non-standardized, virtually unregulated
    • Conclusion
      Clinical trial growth to emerging regions in search of patients
      There are a number of wrong ways to get access to those patients
      The right way can be a long, winding (for the sponsor), and expensive (again for the sponsor) road
    • Contact Info – I’m all over the Web
      LinkedIn – www.linkedin.com/in/jacquiemardell
      Blog – www.2decades.blogspot.com
      Twitter (yes Twitter) – @jacquiemardell
      Google Voice: +1-774-ANHVITA (264-8482)
      Email: jacquie@anhvita.com
    • Questions?
    • References
      Simon, R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists? Ann Intern Med. 2000 Sep 19;133(6):474-5.
      Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000 Sep 19;133(6):455-63
      Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and specific cases. Ann Intern Med. 2000 Sep 19;133(6):464-70
    • References
      Adriana Ptreyna, et. al. Global Pharmaceuticals: Ethics, Markets, Practices. Durham: Duke University Press, 2007
      Adriana Ptreyna. When Experiments Travel: Clinical Trials and the Global Search for Subjects. Princeton: Princeton University Press, 2009
      Marcia Angell, The Truth About Drug Companies: How They Deceive Us and What to Do About It. New York: Random House, 2004
    • Thank you!Leo Intelligence &Participants!
    • Backup slides
    • Clinical Trials as Marketing
      Under-regulated areas
      Misrepresentation of data
      Ghost writing
    • Are Placebo Controls Ethical?
      With a highly and consistently effective standard treatment:
      Design a therapeutic equivalence trial instead
      With a modestly or inconsistently effective treatment, and new treatment is expected to be:
      More effective – no placebo control
      Equally effective at best – placebo control may be warranted
    • Critics of Placebo Control
      Any untreated or under-treated arm is unethical based on Helsinki
      No patient should suffer unnecessary pain
      Placebo controlled studies rarely show how effective a new treatment is, only that it is marginally better than no treatment
    • Chernobyl
      Shaky state response
      BMTs on “Zone” workers
      rhGM-CSF – human testing not approved by FDA
      Humanitarian ethics legitimized transfer and use of unapproved drugs
    • Consensus
      Placebo controlled groups should not be included for life threatening conditions or for harmful non reversing conditions when an effective treatment exists
      Placebo controlled trials may be used when there are no proven effective treatments in clinical trials for newly developed drugs
      Placebo control group may be appropriate with add-on treatment in all groups
      Insulin in diabetes; calcium+vitD in PMP osteoporosis
    • Controversies
      Methodological in nature
      Deprive patients of the best available treatment
      Best proven standard of treatment is to be defined in a international or local context.
    • Advantages of Active Comparator (AC) Study
      • Scientific and clinical advantages
      • More clinically relevant than placebo-controlled trial
      • A placebo-controlled trial asks: “Is this treatment better than nothing?”
      • AC study asks: “Is this treatment as good as what we are using now?”
    • Advantages of AC study: Scientific and Clinical, cont
      • Possibility of using multiple hypotheses
      • toxicity
      • a new treatment is of interest if it is roughly equally efficacious and has less side effects
      • negative symptoms
      • a new treatment is of interest if it is roughly equally efficacious and is better at treating negative symptoms
    • Advantages of AC study: Regulatory
      A new drug may be superior to placebo but substantially inferior to standard treatment
      Cost to society:
      “Many new drugs are expensive, and in some countries drug budgets are growing faster than other health care sectors…The key questions are: how much better are the new drugs than the old ones, how much more does it cost to obtain the additional benefits, and does the extra cost represent value for the money. (Henry and Hill, BMJ, 1995)
    • Advantages of AC study: Ethical & Legal
      Patients are not knowingly given inferior treatment
      Potential liability:
      doctors owe a duty of care to their patients
      an investigator’s chief concern ought to be the health and well being of his patient
      providing a placebo may be negligent
    • Disadvantages of AC
      Cost and time of superiority trials
      If active control is very effective, can be hard to show test drug is more effective
      If active control is minimally effective AND test drug is effective
      Need large sample size
      Active control must be effective in current trial
      Failure to add placebo in non-inferiority can lead to lack of internal validity
      Delay new treatments for physicians and patients
    • Failure of Active Controlled Studies
      Incomplete, non-standard medical histories
      Inconsistent diagnoses
      Poor patient compliance
      Proscribed concomitant meds
      Spontaneous recovery
    • Summary of arguments for and against placebo controlled trials
      Ref: Hong Kong Med J , Vol 9 No3, June 2003
    • Conclusion
      Placebo-controlled trials: Are they ethical? Are they necessary?
      Placebo controls may be acceptable in carefully defined circumstances (add-on treatment, treatment-resistant patients…)
      AC study is to be preferred: scientific, clinical, regulatory, ethical and legal advantages.