The document discusses ethical issues in clinical trials conducted in emerging regions. It summarizes that over 40% of US-regulated trials are now conducted overseas, driven by increasing trial numbers, large sample size demands, and availability of lower-cost patient recruitment abroad. However, ethical challenges arise from cultural differences, vulnerability of populations, and crisis opportunism in places with limited healthcare. Informed consent can be difficult given literacy and comprehension issues. Placebo controls remain controversial, though active controls are preferred from scientific, ethical and regulatory perspectives when proven treatments exist.

1. Ethical Issues in Clinical TrialsJacquie Mardell © 2011 J. Mardell, All rights reserved Ethics in Clinical Trials, San Diego March 2, 2011

2. 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

3. Topics Context Chernobyl, AIDS vert tx Africa, Trovan Patient availability Ethical Issues Placebo Clinical trials as treatment and marketing Opportunism of crisis Consent and vulnerability Application India & China

7. 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

8. 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

9. 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

10. 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

11. Clinical Trials Registry Today BRIC=13.5 % 61928 7765 2355 47623 8787 4391 1824 2650 2662 6046 3500 Source: clinicaltrials.gov, 26 Feb 2011

12. What Relevance? Results from developing countries may not be applicable to industrialized patients Endemic diseases may skew results Ethical variances may make data invalid

13. Challenges in Ethics Crisis opportunism Placebo controls Clinical trials as treatment Or marketing Vulnerability and consent

14. 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

15. 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

16. 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

18. 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

19. 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 *NIH/CDC

20. 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

21. 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

22. 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

23. 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

25. Clinical Trial as Treatment Patients don’t understand Research Purpose Control groups Randomization Illiteracy amplifies these gaps Absent, deteriorating or stressed health care modalities

26. MD Anderson

27. And yet… A clinical trial may be safer than no treatment Or even routine medical care

28. Vulnerability and Consent

29. Belmont Principles:Respect for Persons - Autonomy Some non-Western cultures value the collective over individual autonomy Vulnerable patients may be even more vulnerable Children Women Use (and explanation of) contraception may not be acceptable Lack of self-determination Potential coercion due to lack of available medical care, poverty, illiteracy

30. 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

31. 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

32. 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 Products Services Compensation Should be available in conjunction or after

33. 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

34. 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

35. Not Limited to Developing World Australian parents interviewed did not understand: Randomization Rationale for use of placebo

36. Why is So Little Understood? Too much information 20 page consents Incomprehensible information Compensation Data protection Explanations of how the therapy may work

37. 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

38. Twin Tenets of Medical Ethics Respect for persons Patient should be informed of treatment options Consent obtained without coercion Beneficence Physician should look after best interests of each patient Adequacy of informed consent is a key factor in clinical trial ethics

39. 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

40. Challenges in Application Source: FierceBiotech, April 2010

41. Outsourcing Lifecycle

43. Clinical Trial Environments:India and China CTA processes in continual state of flux GCP accepted and legislated Ethical review process developing

44. 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

45. China Shanghai - Pharma employees give free samples of drugs on the streets Traditional medicines Non-standardized, virtually unregulated

46. 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

47. 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

48. Questions? www.anhvita.com

49. 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

50. 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 http://www.slideshare.net/kclauson/superiority-equivalence-and-noninferiority-trial-designs Marcia Angell, The Truth About Drug Companies: How They Deceive Us and What to Do About It. New York: Random House, 2004

51. Thank you!Leo Intelligence &Participants! www.anhvita.com

52. Backup slides

53. Clinical Trials as Marketing Under-regulated areas Leveraging Misrepresentation of data Ghost writing

55. 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

56. 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

57. 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

58. 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

59. 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.

61. More clinically relevant than placebo-controlled trial

62. A placebo-controlled trial asks: “Is this treatment better than nothing?”

64. toxicity

65. a new treatment is of interest if it is roughly equally efficacious and has less side effects

66. negative symptoms

68. 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

69. 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

70. Failure of Active Controlled Studies Incomplete, non-standard medical histories Inconsistent diagnoses Poor patient compliance Proscribed concomitant meds Spontaneous recovery

71. Summary of arguments for and against placebo controlled trials Ref: Hong Kong Med J , Vol 9 No3, June 2003

72. 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.