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Ethical Issues in Clinical trials.pptx012
- 1. Ethical Issues inClinical Trials
- 2. 1. What ismedical ethics? 2. Principles of ethics 3. Informed consent 4. Assessing risk and harm 5. Implications of justice and equality
- 3. Practice Vs Research Medical practice – best known methods / medicines should be used while treating. Research – Unproven and risky new interventions are used. Is this justifiable? By following certain guiding principles that can protect the participants
- 4. Medical Ethics The studyof a moral ideals, rules and codes of conduct that govern behavior of medical professionals. (Grenz & Smith, 2003) Is there any difference between ethics and morals? Ethics - Greek word; moral - Latin word for the same idea. Strictly, ‘ethics’ refers to a set of principles, whereas ‘morals’ refers to individual behavior and often has emotional component.
- 5. Principles of Ethics Autonomy Beneficence& Non-maleficence Justice & Equality
- 6. Buzz 1 (Realscenario) Few obstetricians conducted a clinical trial for Sun Pharmaceuticals in which letrozole was tested for induction of ovulation in 2003 in India. At this time, letrozole was approved only for breast cancer in postmenopausal women. As they encountered many women who are trying multiple times in vain to conceive, the obstetricians thought if this drug works it will benefit them. They administered letrozole to these patients and conducted the trial without the knowledge of the patients. Did the investigators violate any principle(s) of ethics?
- 7. Autonomy Ability of aperson to make his or her own decision How is this principle implemented? By obtaining full written informed consent
- 8. Components of InformedConsent Voluntary participation. Option to withdraw at any time. Right to services. Privacy and confidentiality. Explanation in lay terms in regional language
- 9. Privacy & Confidentiality Privacy Right of study participants to decide the extent to which there is access to their personal data. Confidentiality Preservation of the participants anonymity when handling data during research and publication.
- 10. Informed Consent Document(ICD) Has two parts. Part 1 – Participant information sheet. Part 2 – Signed document. Adequate time should be provided for the participants to read, think and decide, before signing the document.
- 11. Elements of ICD– Part 1 Nature & purpose of study. Complete procedure – Inc. & Exc. criteria, investigations, interventions, duration, follow up, etc. Foreseeable risks and benefits. Storage period of biological samples & data. Compensation Contact details of P.I. & Chairman of IEC
- 12. Elements of ICD– Part 2 Explains participation is voluntary. Can withdraw from study at any time without loss of routine patient care. Voluntarily agree to participate in the study after knowing the risks and benefits Signatures of participant & witness. (At least one should be a signature)
- 13. Re-consent When investigatordeviates from protocol. When a participant regains consciousness from unconscious state or becomes mentally competent.
- 14. Informed Consent inChildren Parent / legally accepted representative (LAR) should sign consent. Assent of child should also be obtained (mandatory for child > 7 years; advisable for all children). If child refuses to participate, the consent of parent/LAR becomes invalid.
- 15. Buzz 2 Atrial was conducted to evaluate the efficacy of an analgesic. The investigator approached the head of a remote village and explained all the details of the study. The head of the village instructed that one person from every house should participate in the study.(Everyone in this village obeys the chief in all matters) The investigator recruited these people and completed the study. The investigator’s friend feels that he was unethical. The investigator argues that he has explained all the details completely to the village head and hence was right. Did the investigator violate any principle(s) of ethics?
- 16. Vulnerable Population &Diminished Autonomy People who lack decision making capacity. Patients of questionable capacity. People having decision making capability but vulnerable because of culture, disease or inability to speak. They have a diminished autonomy. Justified only if the research is responsive to the health needs or priorities of this group and it cannot be carried out in a nonvulnerable group. (Declaration of Helsinki)
- 17. Vulnerable Population &Diminished Autonomy Orphans, prisoners. Mentally challenged. Tribals. Students. Pregnant women & children.
- 18. Can you thinkof a clinical trial in India which (unjustifiably) recruited vulnerable population? HPV Vaccine Trial Recruited 13791 girls aged 10 to 14 (mostly tribals) in Andhra Pradesh and 9637 in Gujarat. Conducted by Program for Appropriate Technology in Health (PATH), New Delhi. Funded by Bill and Melinda Gates Foundation; vaccine supplied by Merck & GSK. Trial suspended in March 2010.
- 19. Terms of referenceof enquiry committee Excerpts from Report of enquiry committee
- 21. Buzz 3 A clusterrandomized trial was undertaken to evaluate the quality of care in family welfare program. Investigators wanted to interview all healthcare workers in PHC. IEC recommended that all information that could lead to identification of specific PHC should be avoided. An investigator noticed a health worker is reusing disposable needles. Without mentioning the name, the investigator reported this to the supervisor. A week later he observed that the health worker is still reusing the needles and nothing has been done. He knows that confidentiality to the clinic and its workers was assured. Should the principle of confidentiality be strictly upheld in this case?
- 22. When can identitybe revealed? When there is a threat to a person’s life (e.g. infant fed with dirty water, child abuse, needle being reused). Risk to public health (e.g. diagnosis of contagious disease). In court of law when ordered by a judge.
- 23. Research Autonomy Beneficence & nonmaleficence Justice and equality Beneficence& nonmaleficence Autonomy Justice and equality Justice and equality Beneficence & nonmaleficence Autonomy Practice Teaching Hierarchy of Principles of Ethics
- 24. Beneficence To actin a way that benefits the patient. Nonmaleficence Obligation not to inflict harm intentionally. In medical practice, the most important tenet (primum non nocere) Difficult to comply by, as almost all interventions have some adverse effect. Hence need to weigh the risks and benefits.
- 25. Are research benefitsand harm fairly distributed? Research raises concern when the knowledge obtained does not serve participants best interest. When research coincides with participants interest they are usually unproblemistic. Research should be in line with national priorities and sensitive to social, cultural and economic context of the region.
- 26. How to maximizebenefits? 1. Good study design Improperly designed study cannot yield any benefit. Rather can harm the participants. Hence it is unethical to carry out a study with flaws in design.
- 27. How to maximizebenefits? Cont… Issues in study design Less sample size and hence results are invalid. Inappropriate selection criteria, incomplete blinding. Subclinical doses of the comparator drug. End points chosen to favour the test arm.
- 28. Is there aclinical trial in India which inflicted harm due to flawed design? Screening for Cervical cancer Three-cluster randomized controlled trial for a cheap screening method for introduction into public health program Three groups – visual inspection (control), pap smear (standard of care), HPV screening. Study compared cervical cancer death rate between groups. This funded trial conducted in Mumbai, Osmanabad & Dindigul. Among 2,24,929 women, 1,38,624 were not screened at all and 254 died.
- 30. Buzz 4 Adrug company wanted to test a new antiepileptic and contacted a neurologist. It was proposed to administer the new drug to one group of epilepsy patients and placebo to another group of epilepsy patients. The neurologist was hesitant to use placebo, but the company assured him that the primary aim of this study is to establish the safety of new drug and not evaluation of efficacy. Hence comparing with a placebo is more appropriate for such studies. The neurologist agreed to this and undertook the study. Are there any ethical issues involved in this study?
- 31. How to maximizebenefits? – cont… 2. Use of placebo Effectiveness of a new intervention must be tested against the best proven intervention. Where no proven intervention exists, the use of placebo or no intervention is acceptable. (Declaration of Helsinki) Placebo or no intervention is justifiable, if it does not lead to additional risk or irreversible harm. (Declaration of Helsinki)
- 32. Can you thinkof a clinical trial in India in which the use of placebo was unethical? Risperidone for Acute Mania Trials (2003) Acute mania patients were taken off their medication and subsequently started on risperidone or placebo Funded by Johnson & Johnson Company defended that placebo controlled trials expose less patients to a potentially ineffective treatment (But they could never explain why a proven existing treatment was discontinued)
- 33. Buzz 5 Adrug company from Europe conducted a clinical trial (with three years follow up) for a new antiretroviral drug in Africa. After two years, the interim analysis clearly showed that the new drug is very effective. The drug company stopped the trial, filed application for approval of the new drug in Europe. Later the drug was made available in Europe but not in Africa. Are there any ethical issues involved in this study?
- 34. Does this remindus a similar scenario in India? Imatinib and Novartis (2003 to 2006) After launch of imatinib in US & EU in 2001, 7500 patients received the drug during clinical trials for regulatory approval in various countries including India. Novartis had announced free supplies for people around the globe who could not afford. But in Hong Kong, it threatened to end free supplies to trial participants to pressurize govt. to subsidize the drug. In India it got market exclusivity in 2003 & patients could not afford. In 2006 market exclusivity was cancelled by govt.
- 35. How to maximizebenefits? – cont… 3. Benefits after trial (Post trial access) At the end of trial every participant should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. (Declaration of Helsinki) Rationale – The patient has voluntarily taken the risk and has aided in the development of this drug. Hence he should be supplied the drug free of cost. Moreover, harm might be inflicted if we withdraw the drug.
- 36. Buzz 6 Ayusoft,an Ayurveda company approached a famous cardiologist to conduct a trial for their new ayurvedic drug for angina. Approval was obtained from the Independent Ethics Committee and after this the cardiologist obtained full written informed consent from all the participants and completed the study successfully. Did the cardiologist violate any principle(s) of ethics?
- 37. Incompetency can leadto maleficence It would neither be ethical nor morally justifiable if an allopathic physician carries out clinical evaluation of a plant product without any concept or training in these systems of medicine (ICMR Guidelines 2006, p. 55). It is essential that such clinical trials be carried out only when a competent Ayurveda, Siddha or Unani physician is a coinvestigator (ICMR Guidelines 2006, p. 55).
- 38. Nonmaleficence 1. Professional Competency Investigator should be competent enough to do the various procedures involved in research. Should have good knowledge about research methodology.
- 39. Nonmaleficence – cont… 2.Compensation for participation Can be paid for the time spent, expenses incurred for participation in research. When a participant withdraws for any reason, he should be paid a proportionate amount. This compensation cannot be termed as benefit. The amount should be approved by the ethics committee.
- 40. Nonmaleficence – cont… 3.Compensation for injury Participants who suffer physical injury during research are entitled for financial and medical assistance. In a clinical trial conducted for regulatory approval, this is an obligation of the sponsor. An Arbitration Committee or Appellate Authority could be setup to decide the issue of compensation on a case by case basis. Participants should not be asked to waive their right to compensation.
- 41. Justice and Equality Treat people fairly. Fair sharing of burdens and benefits of research. An injustice occurs when: Benefits to which a person is entitled are denied without good reason. Burdens are imposed unduly.
- 42. Buzz 7 A drugcompany conducted a multinational, multicentric, clinical trial to evaluate the efficacy of a new drug for a metabolic disease. For the sites in USA & Europe, the new drug was compared with the drug that is already available in these countries. Placebo was used as a comparator for the sites in Africa. Some investigators in Africa objected to this. The drug company argued that there is no drug available for this disease in Africa and hence the use of placebo in these sites is justified. It also stated that if this trial is done in Africa, this new drug will be introduced and their patients will be benefitted Did the drug company violate any principle(s) of ethics?
- 43. Can you thinkof a clinical trial in India in which justice and equality was violated? Alosetron for Irritable Bowel Syndrome Trial (2000) In 2000, Glaxo withdrew alosetron from US market because of FDA safety concerns. But around 7500 trial participants in various countries continued to take this drug after it was withdrawn in US.
- 44. Not publishing resultsof trials is unethical Researchers have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. (Declaration of Helsinki, 2013).
- 45. Points & ‘Toonsto Ponder
- 46. What is thecommon thread that runs through all the real time clinical trial scenarios we discussed? Funding by pharmaceutical company Point to Ponder Is (company) funded research fraudulent research?
- 47. Give the newdrug to rich patients and placebo to the poor. No sense getting their hopes up. They wouldn’t be able to afford even if it works.
- 48. Our scientists sayit would be a public health hazard. But our market research shows it would sell like hot cakes. What do you think?
- 49. Earlier Are present dayregulations and standards of ethics, preventing clinical trials in India? Now No. of Clinical Trials (CT.gov)