Ethics In Ct 2 Mar2011


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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

  1. 1. Ethical Issues in Clinical TrialsJacquie Mardell<br />© 2011 J. Mardell, All rights reserved<br />Ethics in Clinical Trials, San Diego<br />March 2, 2011<br />
  2. 2. Who Am I?<br />30 years clinical trials<br />15 years global<br />7 years emerging regions<br />UC Santa Cruz clinical trials certificate instructor<br />Clinical services, consulting, training business owner in India and US<br />
  3. 3. Topics<br />Context<br />Chernobyl, AIDS vert tx Africa, Trovan<br />Patient availability<br />Ethical Issues<br />Placebo <br />Clinical trials as treatment <br />and marketing<br />Opportunism of crisis<br />Consent and vulnerability<br />Application<br />India & China<br />
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  7. 7. Growth in Overseas Trials<br />Over 40% of US-regulated trials are off-shore<br />Central-Eastern Europe saw greatest growth<br />Projected to >65% by 2011<br />Source: Tufts Center for Drug Dev, 2008<br />
  8. 8. Driving Factors<br />Number of trials increasing<br />FDA demands increasingly large samples sizes <br />Intensified competition in some therapeutic areas<br />Hypertension, oncology, diabetes, HIV<br />Patent explosion  patent cliff<br />Western patient pools shrinking<br />Treatment saturation  drug-drug interactions<br />
  9. 9. Expansion in Patient Demand<br />Post WWII pharma boom in US, EU<br />Regulatory limitations on prisonor research<br />ICH globalizes drug development<br />CROs shift from preclinical work to monitoring and clinical data<br />Low-cost, rapid pt recruitment becomes primary business driver<br />
  10. 10. Status<br />“Rescue” countries evolve<br />2008: 80% of NDAs contained some foreign clinical data<br />Top 20 US pharma companies conduct one-third of their clinical research elsewhere<br />
  11. 11. Clinical Trials Registry Today<br />BRIC=13.5 %<br />61928<br />7765<br />2355<br />47623<br />8787<br />4391<br />1824<br />2650<br />2662<br />6046<br />3500<br />Source:, 26 Feb 2011<br />
  12. 12. What Relevance?<br />Results from developing countries may not be applicable to industrialized patients<br />Endemic diseases may skew results<br />Ethical variances may make data invalid<br />
  13. 13. Challenges in Ethics<br />Crisis opportunism<br />Placebo controls<br />Clinical trials as treatment<br />Or marketing<br />Vulnerability and consent<br />
  14. 14. Crisis Opportunism - Chernobyl<br />Slack state response <br /> ready-made experimental conditions<br />Experimental BMT on Zone workers<br />FIH testing of rhGM-CSF for leukemia<br />No clinical protocol<br />Limited ethical review<br />
  15. 15. Crisis Opportunism - Trovan<br />Bacterial meningitis, measles and cholera outbreak in Nigerian northern territories<br />12000-15000 deaths<br />Pfizer sought US approval <br />Kano Infectious Diseases hospital<br />MSF  effective low-cost antibiotic<br />
  16. 16. Trovan Irregularities<br />No US IRB approval<br />“Inadequate” host country ethics review<br />Backdated informed consent forms<br />Parents believed it was an ‘approved’ treatment<br />Low dose comparator <br />Untested formulation<br />
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  18. 18. Placebo – HIV Perinatal Transmission, Africa 1994 & Thailand 1997<br />“Protocol 076” (ACTG 076) 67.5% more effectivethan placeboin US<br />Maternal oral dosing 5x/day weeks 14-34<br />IV dosing during birth<br />Infant oral dosing q6h x 6 weeks<br />Cost ~$800 per mother/infant pair<br />Actual results: 7.6% (AZT group), 22.6% (PLA)<br />“Unfeasible” absent medical infrastructure and state financial commitment<br />Short oral course AZT vs placebo<br />
  19. 19. Sponsors’* Defense of Placebo<br />AZT not available in country<br />Placebo patients “not worse off”<br />Ethicality based on host country’s needs, not sponsor’s (ethical imperialism)<br />Active control makes findings less clear<br />Superiority against placebo in US not definitive re effectiveness in another setting<br />*NIH/CDC<br />
  20. 20. Ethical Imperialism or Relativism?<br />Tuskegee – we’ve seen this before<br />US critics should not dictate treatment standards over local authorities<br />Health crises grants legitimacy to certain kinds of experimentation<br />
  21. 21. Declaration of Helsinki<br />“The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention.” (emphasis added)<br />“…placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or… for compelling and scientifically sound methodological reasons.”<br />If taken literally, would bar all clinical trials<br />
  22. 22. Proponents of Placebo Control<br />Placebo controls are ethical as long as:<br />Patients are protected from increased risk, and<br />Patients are fully informed of any alternatives<br />Many ‘effective” medicines have never been fully characterized due to small response<br />Therefore require placebo control to demonstrate effectiveness<br />
  23. 23. The Debate Rages On<br />FDA approval requires either:<br />Superiority against placebo<br />Statistically superior – easier<br />Clinically superior – harder<br />Inferiority against an active comparator <br />Requires more patients  more time, cost to complete<br />
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  25. 25. Clinical Trial as Treatment<br />Patients don’t understand <br />Research<br />Purpose<br />Control groups<br />Randomization<br />Illiteracy amplifies these gaps<br />Absent, deteriorating or stressed health care modalities<br />
  26. 26. MD Anderson<br />
  27. 27. And yet…<br />A clinical trial may be safer than no treatment<br />Or even routine medical care<br />
  28. 28. Vulnerability and Consent<br />
  29. 29. Belmont Principles:Respect for Persons - Autonomy<br />Some non-Western cultures value the collective over individual autonomy<br />Vulnerable patients may be even more vulnerable<br />Children<br />Women<br />Use (and explanation of) contraception may not be acceptable<br />Lack of self-determination<br />Potential coercion due to lack of available medical care, poverty, illiteracy<br />
  30. 30. Conflict For Two Parties<br />For investigators: Individual treatment is secondary to the protocol<br />Physician’s primary interest is her patient<br />Researcher’s primary interest is studying disease and treatment<br />For patients: Primary concern is for own welfare and those close to them<br />All subjects can therefore be vulnerable<br />
  31. 31. Beneficence<br />Maximize benefits, minimize risk<br />Individual risk:benefit takes prominence over generalizable benefit to science and society<br />Implications for study design<br />Use alternate procedures that lower risk<br />Additional safeguards and precautions<br />Ability to react even more quickly if harm should occur<br />This may result in a different protocol than would be appropriate in the West<br />
  32. 32. Justice<br />Selection based on ability to bear the burdens<br />When many communities may benefit<br />Not just those easily available, easily discarded<br />Sponsor must determine what <br />Products<br />Services<br />Compensation<br />Should be available in conjunction or after<br />
  33. 33. Obtaining Informed Consent<br />Founded on principles of respect reflected in freedom of choice<br />Asymmetry in knowledge and authority<br />Sponsor/investigator must <br />Provide information<br />Assess comprehension<br />Assess voluntariness<br />Process may be continuous<br />
  34. 34. How Much is Understood?<br />In one survey in West Africa,<br />90% of participants did not understand withdrawal criteria, possibility of side effects<br />75% did not understand they were in a study (i.e., not receiving therapy)<br />In another study in Gambia<br />10% (of 189) parents of pediatric patients understood there was a placebo group<br />Different study, also Gambia<br />45% (of 800 mothers) did not know or remember the study purpose<br />
  35. 35. Not Limited to Developing World<br />Australian parents interviewed did not understand:<br />Randomization<br />Rationale for use of placebo<br />
  36. 36. Why is So Little Understood?<br />Too much information<br />20 page consents<br />Incomprehensible information<br />Compensation<br />Data protection<br />Explanations of how the therapy may work<br />
  37. 37. Cultural Considerations<br />Some non-Western cultures value the collective over individual autonomy<br />Subjects may have to get permission to participate from<br />Spouse, elders, community leaders<br />To ignore this fact could stir up conflict within the community<br />Physician as God<br />
  38. 38. Twin Tenets of Medical Ethics<br />Respect for persons<br />Patient should be informed of treatment options<br />Consent obtained without coercion<br />Beneficence<br />Physician should look after best interests of each patient<br />Adequacy of informed consent is a key factor in clinical trial ethics<br />
  39. 39. Reciprocity<br />If treatment is effective, will it be offered post-trial?<br />If so, to whom?<br />All study patients<br />Population at large?<br />Responsibility to build research capacity<br />Research advances healthcare development<br />Investigators gain experience with new therapies<br />This may mean including less experienced investigators and taking responsibility for training them<br />
  40. 40. Challenges in Application<br />Source: FierceBiotech, April 2010<br />
  41. 41. Outsourcing Lifecycle<br />
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  43. 43. Clinical Trial Environments:India and China<br />CTA processes in continual state of flux<br />GCP accepted and legislated<br />Ethical review process developing<br />
  44. 44. Practical Issues Overwhelm Ethics<br />Ethical issues become procedural questions<br />Informed consent<br />Clinical conduct<br />Ethical variability – <br />Guidelines recast to organize global trials<br />West and non-West<br />Imperialism vs relativism<br />Crisis conditions legitimate ethical variability<br />
  45. 45. China <br />Shanghai - Pharma employees give free samples of drugs on the streets<br />Traditional medicines<br />Non-standardized, virtually unregulated<br />
  46. 46. Conclusion<br />Clinical trial growth to emerging regions in search of patients<br />There are a number of wrong ways to get access to those patients<br />The right way can be a long, winding (for the sponsor), and expensive (again for the sponsor) road<br />
  47. 47. Contact Info – I’m all over the Web<br />LinkedIn –<br />Blog –<br />Twitter (yes Twitter) – @jacquiemardell<br />Google Voice: +1-774-ANHVITA (264-8482)<br />Email:<br />
  48. 48. Questions?<br /><br />
  49. 49. References<br />Simon, R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists? Ann Intern Med. 2000 Sep 19;133(6):474-5.<br />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<br />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<br />
  50. 50. References<br />Adriana Ptreyna, et. al. Global Pharmaceuticals: Ethics, Markets, Practices. Durham: Duke University Press, 2007<br />Adriana Ptreyna. When Experiments Travel: Clinical Trials and the Global Search for Subjects. Princeton: Princeton University Press, 2009<br /><br />Marcia Angell, The Truth About Drug Companies: How They Deceive Us and What to Do About It. New York: Random House, 2004<br />
  51. 51. Thank you!Leo Intelligence &Participants!<br /><br />
  52. 52. Backup slides<br />
  53. 53. Clinical Trials as Marketing<br />Under-regulated areas<br />Leveraging<br />Misrepresentation of data<br />Ghost writing<br />
  54. 54.
  55. 55. Are Placebo Controls Ethical?<br />With a highly and consistently effective standard treatment:<br />Design a therapeutic equivalence trial instead<br />With a modestly or inconsistently effective treatment, and new treatment is expected to be:<br />More effective – no placebo control<br />Equally effective at best – placebo control may be warranted<br />
  56. 56. Critics of Placebo Control<br />Any untreated or under-treated arm is unethical based on Helsinki<br />No patient should suffer unnecessary pain<br />Placebo controlled studies rarely show how effective a new treatment is, only that it is marginally better than no treatment<br />
  57. 57. Chernobyl<br />Shaky state response<br />BMTs on “Zone” workers<br />rhGM-CSF – human testing not approved by FDA<br />Humanitarian ethics legitimized transfer and use of unapproved drugs<br />
  58. 58. Consensus <br />Placebo controlled groups should not be included for life threatening conditions or for harmful non reversing conditions when an effective treatment exists<br />Placebo controlled trials may be used when there are no proven effective treatments in clinical trials for newly developed drugs<br />Placebo control group may be appropriate with add-on treatment in all groups<br />Insulin in diabetes; calcium+vitD in PMP osteoporosis<br />
  59. 59. Controversies<br />Methodological in nature<br />Deprive patients of the best available treatment<br />Best proven standard of treatment is to be defined in a international or local context.<br />
  60. 60. Advantages of Active Comparator (AC) Study<br /><ul><li>Scientific and clinical advantages
  61. 61. More clinically relevant than placebo-controlled trial
  62. 62. A placebo-controlled trial asks: “Is this treatment better than nothing?”
  63. 63. AC study asks: “Is this treatment as good as what we are using now?”</li></li></ul><li>Advantages of AC study: Scientific and Clinical, cont<br /><ul><li>Possibility of using multiple hypotheses
  64. 64. toxicity
  65. 65. a new treatment is of interest if it is roughly equally efficacious and has less side effects
  66. 66. negative symptoms
  67. 67. a new treatment is of interest if it is roughly equally efficacious and is better at treating negative symptoms</li></li></ul><li>Advantages of AC study: Regulatory<br />A new drug may be superior to placebo but substantially inferior to standard treatment<br />Cost to society:<br />“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)<br />
  68. 68. Advantages of AC study: Ethical & Legal<br />Patients are not knowingly given inferior treatment<br />Potential liability:<br />doctors owe a duty of care to their patients<br />an investigator’s chief concern ought to be the health and well being of his patient<br />providing a placebo may be negligent<br />
  69. 69. Disadvantages of AC <br />Cost and time of superiority trials<br />If active control is very effective, can be hard to show test drug is more effective<br />If active control is minimally effective AND test drug is effective<br />Need large sample size<br />Active control must be effective in current trial<br />Failure to add placebo in non-inferiority can lead to lack of internal validity<br />Delay new treatments for physicians and patients<br />
  70. 70. Failure of Active Controlled Studies<br />Incomplete, non-standard medical histories<br />Inconsistent diagnoses<br />Poor patient compliance<br />Proscribed concomitant meds<br />Spontaneous recovery<br />
  71. 71. Summary of arguments for and against placebo controlled trials<br />Ref: Hong Kong Med J , Vol 9 No3, June 2003<br />
  72. 72. Conclusion<br />Placebo-controlled trials: Are they ethical? Are they necessary?<br />Placebo controls may be acceptable in carefully defined circumstances (add-on treatment, treatment-resistant patients…)<br />AC study is to be preferred: scientific, clinical, regulatory, ethical and legal advantages.<br />