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 reservedEthics in Clinical Trials, San DiegoMarch 2, 2011

2. Who Am I?30 years clinical trials15 years global7 years emerging regionsUC Santa Cruz clinical trials certificate instructorClinical services, consulting, training business owner in India and US

3. TopicsContextChernobyl, AIDS vert tx Africa, TrovanPatient availabilityEthical IssuesPlacebo Clinical trials as treatment and marketingOpportunism of crisisConsent and vulnerabilityApplicationIndia & China

7. Growth in Overseas TrialsOver 40% of US-regulated trials are off-shoreCentral-Eastern Europe saw greatest growthProjected to >65% by 2011Source: Tufts Center for Drug Dev, 2008

8. Driving FactorsNumber of trials increasingFDA demands increasingly large samples sizes Intensified competition in some therapeutic areasHypertension, oncology, diabetes, HIVPatent explosion  patent cliffWestern patient pools shrinkingTreatment saturation  drug-drug interactions

9. Expansion in Patient DemandPost WWII pharma boom in US, EURegulatory limitations on prisonor researchICH globalizes drug developmentCROs shift from preclinical work to monitoring and clinical dataLow-cost, rapid pt recruitment becomes primary business driver

10. Status“Rescue” countries evolve2008: 80% of NDAs contained some foreign clinical dataTop 20 US pharma companies conduct one-third of their clinical research elsewhere

11. Clinical Trials Registry TodayBRIC=13.5 %6192877652355476238787439118242650266260463500Source: clinicaltrials.gov, 26 Feb 2011

12. What Relevance?Results from developing countries may not be applicable to industrialized patientsEndemic diseases may skew resultsEthical variances may make data invalid

13. Challenges in EthicsCrisis opportunismPlacebo controlsClinical trials as treatmentOr marketingVulnerability and consent

14. Crisis Opportunism - ChernobylSlack state response  ready-made experimental conditionsExperimental BMT on Zone workersFIH testing of rhGM-CSF for leukemiaNo clinical protocolLimited ethical review

15. Crisis Opportunism - TrovanBacterial meningitis, measles and cholera outbreak in Nigerian northern territories12000-15000 deathsPfizer sought US approval Kano Infectious Diseases hospitalMSF  effective low-cost antibiotic

16. Trovan IrregularitiesNo US IRB approval“Inadequate” host country ethics reviewBackdated informed consent formsParents believed it was an ‘approved’ treatmentLow dose comparator Untested formulation

18. Placebo – HIV Perinatal Transmission, Africa 1994 & Thailand 1997“Protocol 076” (ACTG 076) 67.5% more effectivethan placeboin USMaternal oral dosing 5x/day weeks 14-34IV dosing during birthInfant oral dosing q6h x 6 weeksCost ~$800 per mother/infant pairActual results: 7.6% (AZT group), 22.6% (PLA)“Unfeasible” absent medical infrastructure and state financial commitmentShort oral course AZT vs placebo

19. Sponsors’* Defense of PlaceboAZT not available in countryPlacebo patients “not worse off”Ethicality based on host country’s needs, not sponsor’s (ethical imperialism)Active control makes findings less clearSuperiority against placebo in US not definitive re effectiveness in another setting*NIH/CDC

20. Ethical Imperialism or Relativism?Tuskegee – we’ve seen this beforeUS critics should not dictate treatment standards over local authoritiesHealth 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 ControlPlacebo controls are ethical as long as:Patients are protected from increased risk, andPatients are fully informed of any alternativesMany ‘effective” medicines have never been fully characterized due to small responseTherefore require placebo control to demonstrate effectiveness

23. The Debate Rages OnFDA approval requires either:Superiority against placeboStatistically superior – easierClinically superior – harderInferiority against an active comparator Requires more patients  more time, cost to complete

25. Clinical Trial as TreatmentPatients don’t understand ResearchPurposeControl groupsRandomizationIlliteracy amplifies these gapsAbsent, deteriorating or stressed health care modalities

26. MD Anderson

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

28. Vulnerability and Consent

29. Belmont Principles:Respect for Persons - AutonomySome non-Western cultures value the collective over individual autonomyVulnerable patients may be even more vulnerableChildrenWomenUse (and explanation of) contraception may not be acceptableLack of self-determinationPotential coercion due to lack of available medical care, poverty, illiteracy

30. Conflict For Two PartiesFor investigators: Individual treatment is secondary to the protocolPhysician’s primary interest is her patientResearcher’s primary interest is studying disease and treatmentFor patients: Primary concern is for own welfare and those close to themAll subjects can therefore be vulnerable

31. BeneficenceMaximize benefits, minimize riskIndividual risk:benefit takes prominence over generalizable benefit to science and societyImplications for study designUse alternate procedures that lower riskAdditional safeguards and precautionsAbility to react even more quickly if harm should occurThis may result in a different protocol than would be appropriate in the West

32. JusticeSelection based on ability to bear the burdensWhen many communities may benefitNot just those easily available, easily discardedSponsor must determine what ProductsServicesCompensationShould be available in conjunction or after

33. Obtaining Informed ConsentFounded on principles of respect reflected in freedom of choiceAsymmetry in knowledge and authoritySponsor/investigator must Provide informationAssess comprehensionAssess voluntarinessProcess 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 effects75% did not understand they were in a study (i.e., not receiving therapy)In another study in Gambia10% (of 189) parents of pediatric patients understood there was a placebo groupDifferent study, also Gambia45% (of 800 mothers) did not know or remember the study purpose

35. Not Limited to Developing WorldAustralian parents interviewed did not understand:RandomizationRationale for use of placebo

36. Why is So Little Understood?Too much information20 page consentsIncomprehensible informationCompensationData protectionExplanations of how the therapy may work

37. Cultural ConsiderationsSome non-Western cultures value the collective over individual autonomySubjects may have to get permission to participate fromSpouse, elders, community leadersTo ignore this fact could stir up conflict within the communityPhysician as God

38. Twin Tenets of Medical EthicsRespect for personsPatient should be informed of treatment optionsConsent obtained without coercionBeneficencePhysician should look after best interests of each patientAdequacy of informed consent is a key factor in clinical trial ethics

39. ReciprocityIf treatment is effective, will it be offered post-trial?If so, to whom?All study patientsPopulation at large?Responsibility to build research capacityResearch advances healthcare developmentInvestigators gain experience with new therapiesThis may mean including less experienced investigators and taking responsibility for training them

40. Challenges in ApplicationSource: FierceBiotech, April 2010

41. Outsourcing Lifecycle

43. Clinical Trial Environments:India and ChinaCTA processes in continual state of fluxGCP accepted and legislatedEthical review process developing

44. Practical Issues Overwhelm EthicsEthical issues become procedural questionsInformed consentClinical conductEthical variability – Guidelines recast to organize global trialsWest and non-WestImperialism vs relativismCrisis conditions legitimate ethical variability

45. China Shanghai - Pharma employees give free samples of drugs on the streetsTraditional medicinesNon-standardized, virtually unregulated

46. ConclusionClinical trial growth to emerging regions in search of patientsThere are a number of wrong ways to get access to those patientsThe 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 WebLinkedIn – www.linkedin.com/in/jacquiemardellBlog – www.2decades.blogspot.comTwitter (yes Twitter) – @jacquiemardellGoogle Voice: +1-774-ANHVITA (264-8482)Email: jacquie@anhvita.com

48. Questions?www.anhvita.com

49. ReferencesSimon, 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):455-63Ellenberg 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. ReferencesAdriana Ptreyna, et. al. Global Pharmaceuticals: Ethics, Markets, Practices. Durham: Duke University Press, 2007Adriana Ptreyna. When Experiments Travel: Clinical Trials and the Global Search for Subjects. Princeton: Princeton University Press, 2009http://www.slideshare.net/kclauson/superiority-equivalence-and-noninferiority-trial-designsMarcia 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 MarketingUnder-regulated areasLeveragingMisrepresentation of dataGhost writing

55. Are Placebo Controls Ethical?With a highly and consistently effective standard treatment:Design a therapeutic equivalence trial insteadWith a modestly or inconsistently effective treatment, and new treatment is expected to be:More effective – no placebo controlEqually effective at best – placebo control may be warranted

56. Critics of Placebo ControlAny untreated or under-treated arm is unethical based on HelsinkiNo patient should suffer unnecessary painPlacebo controlled studies rarely show how effective a new treatment is, only that it is marginally better than no treatment

57. ChernobylShaky state responseBMTs on “Zone” workersrhGM-CSF – human testing not approved by FDAHumanitarian 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 existsPlacebo controlled trials may be used when there are no proven effective treatments in clinical trials for newly developed drugsPlacebo control group may be appropriate with add-on treatment in all groupsInsulin in diabetes; calcium+vitD in PMP osteoporosis

59. ControversiesMethodological in natureDeprive patients of the best available treatmentBest proven standard of treatment is to be defined in a international or local context.

60. Advantages of Active Comparator (AC) StudyScientific and clinical advantages

61. More clinically relevant than placebo-controlled trial

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

63. AC study asks: “Is this treatment as good as what we are using now?”Advantages of AC study: Scientific and Clinical, contPossibility of using multiple hypotheses

64. toxicity

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

66. negative symptoms

67. a new treatment is of interest if it is roughly equally efficacious and is better at treating negative symptomsAdvantages of AC study: RegulatoryA new drug may be superior to placebo but substantially inferior to standard treatmentCost 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)