Informed consent in Clinical Trials

A brief discussion on informed consent process and its implementation in clinical trial.

1. Informed Consent in Clinical Trials Dr. Kaushik Mukhopadhyay Assistant Professor, Department of Pharmacology ESI-PGIMSR, KOLKATA

2. Please Download the presentation first and open in MS PowerPoint or equivalent software for smooth animation effect Thank you 2

3. Why Informed consent ? Doctor Knows Better Every individual has the right to ‘Bodily integrity’ R ight to Bodily integrity 3 There is no Black and white border.. There is always grey zone

4. “ A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.” Informed Consent - definition International Conference on Harmonization E6 - Good Clinical Practice 4

5. Goal “ The goal of the informed consent process is to provide people with sufficient information so they can make informed choices about whether to begin or continue participation in clinical research.” 5

6. HISTORICAL BACKGROUND OF INFORMED CONSENT 1891 - Prussian Minister of Interior, tuberculin for the treatment of tuberculosis must not be used against a person’s will . 1898- Dr . Albert Neisser was fined by the Royal disciplinary court of Prussia for not seeking patient’s consent for his experimental studies of vaccination for Syphilis . 1907- Sir William Osler endorsed the necessity of informed consent in medical research. 6

7. Walter Reed & his ICF The informed consent contract for Antonio Benigno , dated 26th November, 1900 ( e xperiments on yellow fever in Cuba ) Walter Reed 7

8. Timeline Nazi human experimentation Nuremberg Code 1964 Declaration of Helsinki Tuskegee syphilis experiment 1945-46 1939-45 1932-72 Belmont Report 1979 National Research Act 1974 GCP Guidelines, ICH 1997 8

9. Informed consent gone wrong? recent incidents.. Jesse Gelsinger (gene transplant ) James Quinn (artificial heart ) Ellen Roche ( Johns Hopkins hexamethonium death) 9

10. Nuremberg Code (1947) The Nuremberg Code is a group of research ethics principles for human experimentation set as a result of the Nuremberg Trials at the end of the Second World War. Doctor’s Trial Nuremberg , Germany December 9, 1946 to August 20, 1947 10

11. Nuremberg Code…..Highlights The voluntary consent of the human subject is absolutely essential . Investigator’s responsibility to obtain consent. All unnecessary physical and mental suffering and injury has to be avoided. Subject should be at liberty to bring the experiment to an end Adequate facilities provided to protect the experimental subject against even remote possibilities of injury 11

12. Declaration of Helsinki, 1964 A set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association Originally adopted in June 1964 in Helsinki, Finland , Since it has undergone six revisions ( the most recent at the General Assembly in October 2008 ) 12

13. DoH …cont. The Declaration developed the ten principles first stated in the Nuremberg Code , and tied them to the Declaration of Geneva (1948), a statement of physician's ethical duties The Declaration more specifically addressed clinical research, reflecting changes from the term 'Human Experimentation ' used in the Nuremberg Code . R elaxation of the conditions of consent, now research was allowed without consent where a proxy consent , such as a legal guardian, was available. 13

14. Tuskegee Syphilis Study Tuskegee study of untreated syphilis in Negro male began in 1932 in Tuskegee, Alabama by PHS (Public Health Service) Study purpose – to observe progression of disease in black male (To compare result with OSLO study) In 1940s penicillin became a standard treatment for Syphilis Still Penicillin was withheld from the patients 14

15. Tuskegee Syphilis Study…THE END End of Experiment- 28 men died directly form syphilis 100 dead of related complications 40 wives infected 19 children - congenital syphilis On May 16, 1997, President Bill Clinton formally apologised. 15

16. National Research Act (1974) Congress mandated the establishment of Institutional Review B oards ( IRBs) to review all federally funded human research Created the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research . One of the Commission’s statements was “ The Belmont Report : Ethical Principles and Guidelines for the Protection of Human Subjects of Research ’’ 16

17. The Belmont Report Issued on 30 September, 1978 and published in the Federal Register on 18 April, 1979 Objective - “to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects .” The Belmont Report is presented in three discussion topics : Boundaries between practice and research, Basic ethical principles Applications 17

18. Boundaries Between Practice and Research Practice - interventions intended to solely improve the health condition of the patient. The goal of practice is to provide a diagnosis , preventive treatment , or therapy that will enhance the patient’s wellness. Research - activities designed to develop or contribute to the general body of knowledge which includes theories, principles, and relationships . Subjects must clearly know which study activities are standard practice and which are research . 18

19. Belmont Report : Basic Ethical Principles Respect for Persons: Two presumptions - Persons should be treated as autonomous individuals, capable of making their own decisions. Not every person is capable of self-determination e.g. persons who are immature or incapacitated Beneficence: Beneficence is the practice of doing good, making all efforts to improve an individual’s well being. Potential for risks must be justified by the greater good to the society - a primary responsibility of the IRB Justice : (benefits and burdens equally distributed) Justice requires that each person is treated fairly, equitably, and given what he or she is due . Justice is relevant to the selection of subjects at two levels: i ) Individual level ii ) Social level 19 Am I Doing JUSTICE ?

20. Application of Belmont Principles: Applications of these principles to conduct research requires careful consideration of Informed consent Risks benefit assessment Selection of subjects of research 20

21. Belmont Report : Informed Consent Research subjects are told every thing about the study, including risks . The information must be easy to understand . Research subjects who agree to participate must do so voluntarily , they must not be pressurized or swayed into it. 21

22. INFORMED CONSENT PROCESS INFORMATION COMPREHENSION VOLUNTARINESS 22

23. Conceptual framework – informed consent process 23

24. Difficulties With Informed Consent Problems Physicians may face Use of technical language Uncertainties intrinsic to all medical information Worried about harming or alarming the patient Hurried and pressed by multiple duties Problems Patients may face: Limited knowledge May be inattentive or distracted Overcome by fear and anxiety Selective hearing because of denial, fear, or preoccupation with illness 24

25. Informed Consent ….. Guidelines & Laws Guidelines Nuremberg Code DOH ICH , E-6 Section 4.8 (GCP) ICMR guidelines, 2006 Laws 45 CFR 46.116 Common Rule 21 CFR 50. 25 FDA Schedule Y (appendix V) 25

26. ICMR Guidelines Ethical guidelines for research involving humans “ Ethical Guidelines for Biomedical Research on Human Subjects ” Published by the Indian Council of Medical Research in 2000 Revised version - 2006 26

27. Required components of ICF (ICMR guideline, 2006) Nature and purpose of study stating it as research Duration of participation with number of participants Procedures to be followed Investigations , if any, to be performed Foreseeable risks and discomforts adequately described and whether project involves more than minimal risk 27

28. Components of ICF…..cont. Benefits to participant, community or medical profession as may be applicable Alternative treatments, if available Steps taken for ensuring confidentiality Policy on compensation Availability of medical treatment for such injuries or risk management 28 Compensations in trial related injury (a) Adverse effects of Investigational product(s) (b) Departure from approved protocol , scientific misconduct or negligence by the Investigator (c) Failure of an Investigational Product to provide attended therapeutic effect (d) Administration of placebo providing no therapeutic benefits. (e) Compensation for injury to a child in utero because of the participation of parent in Clinical Trial. Drugs and Cosmetics Rules (3 rd amendment), 2011

29. Components of ICF …..cont. No loss of benefits on withdrawal Benefit sharing in the event of commercialization Contact details of PI or local PI/Co-PI in multicentric studies for asking more information Contact details of Chairman of the IEC for appeal against violation of rights Voluntary participation 29

30. Components of ICF …..cont. If test for genetics and HIV is to be done, counselling for consent for testing must be given as per national guidelines Storage period of biological sample and related data with choice offered to participant regarding future use of sample , refusal for storage and receipt of its results 30

31. Obligations of investigators Communicate to prospective participants Exclude unjustified deception, undue influence and intimidation. Seek consent only after the prospective participant is adequately informed Obtain a signed form as an evidence of informed consent (written informed consent) preferably witnessed by a person not related to the trial. 31

32. Obligations of investigators Take surrogate consent from the authorized relative or legal custodian F resh informed consent of participant wherever applicable I f participant loses consciousness or competence to consent during the research period ( AD / Psychiatric conditions) surrogate consent may be taken from LAR Assurance for continuation of existing benefits even after withdrawal of consent 32

33. Fresh or Re-consent Availability of new information which would necessitate deviation of protocol. When a research participant regains consciousness from unconscious state When long term follow-up or study extension is planned later. When there is change in treatment modality , procedures, site visits . Before publication if there is possibility of disclosure of identity ( data, photograph etc.) 33

34. Waiver of consent When it is impractical to conduct research since confidentiality of personally identifiable information has to be maintained throughout research. e.g. study on disease burden of HIV/AIDS . Emergency situations, when surrogate consent unavailable Research on anonymised biological samples from deceased individuals, left over samples, cell lines etc. Research on publicly available information , documents, records, works, performances , reviews etc. 34

35. Informed consent - Schedule Y In all trials, a freely given, informed, written consent is required to be obtained from each study subject. The Subject’s consent must be obtained in writing using an ‘Informed Consent Form’. Both the PIS and the ICF should be approved by the ethics committee and furnished to the Licensing Authority. Where a subject is not able to give informed consent, it may be obtained from a legally acceptable representative . An impartial witness should be present if LAR is illiterate. A checklist of essential elements given in Appendix V 35

36. Format of informed consent form for Subjects participating in a clinical trial 36

37. Assent ‘ Assent’ means a child's affirmative agreement to participate in research . “All paediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand .” – Schedule Y 37

38. Community consent Community consent is generally obtained through a process of dialogue with the community leadership. Agreement from the community leadership is obtained prior to , but does not replace , the consent and/or assent of individual participants. 38

39. Victims of Drug Trials @ India 39

40. Drug Trials & India Recently, a PIL submitted to the SC suggested that big pharmaceuticals including GlaxoSmithKline and MSD – had tested two HPV vaccines ( gardasil and cervarix ) on almost 24,000 tribal girls in Andhra Pradesh and Gujarat without proper consent.   ‘Poor, sick, desperate. What more could Big Pharma ask in Indian drug trials?’ - Anjana Ahuja, 2006   40

41. NIH Informed Consent Authoring Tool Web-based application, Beta Version – Pilot phase 41

42. Summary Informed consent is a process, not just a signed document. Important landmarks –Nuremberg Code, DoH , Belmont report Three basic components – Information Comprehension Voluntariness ICMR Guidelines / Schedule Y recommendations 42

43. References GCP Guidelines 4.8, ICH Wikipedia ICMR Guidelines, 2006 Schedule Y (amended version) The Hindu 43

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