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Ethics in clinical research

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Ethics in clinical research

  1. 1. Ethics in Clinical research DR. L S DESHMUKH DM (Neonatology) deshmukhls@yahoo.com
  2. 2. Disclaimer • Contents are drawn from various sources. • I am not authority / Expert on the topic • No conflict of Interest • Constructive criticism is welcome
  3. 3. Outline of presentation • What is Ethics ? • Why ethics in clinical trials- historical perspective • principles of ethics • Case studies • Complexities of doing research in India • Challenges • The way forward
  4. 4. What is Ethics? • The word 'ethics' is derived from the Greek word, ethos, which means custom or character. • Ethics is the systematic study of values, so as to decide what is right and what is wrong.
  5. 5. Deontology/Kantian Ethics • Requires that we treat people as ends and never simply as means or as subjects, and never simply as objects. Text (Desjardins, 2006) Photo (Buller, 2004)
  6. 6. Ethics • Ethics is a subject that deals with values, principles, beliefs, and opinions • Not a natural science but a creation of the human mind, open to the influence of time, place, and situation • A framework to determine what is right and wrong regarding human action, character, and behavior • comes from within, unlike law which regulates the external behavior
  7. 7. The first step in the evolution of ethics is a sense of solidarity with other human beings. — Albert Sweiter
  8. 8. Research • Human subject research is a systematic investigation that can be either research or clinically oriented and involves the use of human subjects in any capacity.
  9. 9. Moral problem in clinical research • The goal of clinical research is generation of useful knowledge about human health and illness • Benefit to participants is not the purpose of research (although it does occur) • People are the means to developing useful knowledge; and are thus at risk of exploitation
  10. 10. Ethics of Clinical Research • Ethical requirements in clinical research : – minimize the possibility of exploitation; – ensure that the rights and welfare of subjects are respected
  11. 11. History “Those who do not learn from history are doomed to repeat it.” George Santayana
  12. 12. 1. The Nuremberg Code (1947) 2. The Declaration of Helsinki (1964) 3. U.S. Code of Federal Regulations (1974) 4. The National Research Act and The IRB System (1974) 5. The Belmont Report (1979) 6. ICMR Guidelines (2000,2006) History
  13. 13. Nuremberg code Nazi Experiments
  14. 14. 1945-1947- The Nuremberg Trial Children in concentration camps who had been used for medical experiments
  15. 15. Thalidomide - phocomelia
  16. 16. 1945-1947- The Nuremberg Trial Photograph of an injury caused by a phosporous experiment conducted at Ravensbruek in 1941
  17. 17. 1945-1947- The Nuremberg Trial A Romani (Gypsy) victim to make seawater potable. Dachau concentration camp, Germany, 1944
  18. 18. 1945-1947- The Nuremberg Trial Bodies and parts of bodies of people subjected to medical experiments
  19. 19. 1945-1947- The Nuremberg Trial High Altitude Experiments
  20. 20. 1945-1947- The Nuremberg Trial Female Jewish victim
  21. 21. 1945-1947- The Nuremberg Trial A victim immersed in icy water at the Dachau concentration camp. Germany, 1942
  22. 22. 1945-1947- The Nuremberg Trial Execution of Jews by Nazis
  23. 23. 1945-1947- The Nuremberg Trial Nazi Camp Bunks
  24. 24. 1945-1947- The Nuremberg Trial Nuremberg holocaust
  25. 25. 1945-1947- The Nuremberg Trial 23 Physicians in Dock During the Trial
  26. 26. 1945-1947- The Nuremberg Trial Court Room Scene-N-trial 1945
  27. 27. 1945-1947- The Nuremberg Trial Doctor Hoven testifying in his own defense during the N-Trial
  28. 28. 1945-1947- The Nuremberg Trial Nazi-era doctor Heinrich Gross, who was accused of killing children
  29. 29. 29 Nuremberg Trials • Nazi Experiments – experimental starvation - induced gangrene – low barometric pressure – induced hypothermia – induced burns and wounds
  30. 30. Nuremberg Trials • Characteristics – conducted without consent of participants – caused unnecessary pain, suffering and death – absence of benefits for the participants – lack of adequate scientific rationale
  31. 31. Nuremberg Code • The Nuremberg Code is a set of research ethics principles for human experimentation set as a result of the Subsequent Nuremberg Trials at the end of the Second World War. • The ten points of the Nuremberg Code • "the voluntary consent of the human subject is absolutely essential"
  32. 32. The Declaration of Helsinki • 1964 - Adopted by the 18th World Medical Assembly (latest version 2008) • A notable change from the Nuremberg Code was a relaxation of the conditions of consent • obtain consent 'if at all possible‘ • introduced the concept of oversight by an 'independent committee” Or ethics committees
  33. 33. The Declaration of Helsinki • "all protocols must be submitted to an ethics committee for review, which must be independent of the investigator, the sponsor or any other kind of undue influence".
  34. 34. Belmont Report
  35. 35. Tuskegee Syphilis Study • cited as "arguably the most infamous biomedical research study in U.S. history”
  36. 36. Tuskegee Syphilis Study • "399 black men thought to have syphilis were recruited and followed to determine the course of the disease (what would happen to them). • Penicillin was known to be an effective treatment for syphilis by about 1947. • The subjects were not informed of what was being studied or of the treatment alternatives available.
  37. 37. Belmont Report • National Research Act/Belmont Report 1979 • The report established three tenents of ethical research,  respect for persons,  beneficence and  justice
  38. 38.  India has strong Ethics guidelines for clinical research  Every clinical trial program should be reviewed by an ethics committee – Initial review of proposed research protocols – Regular monitoring of compliance to ethics guidelines – Can be constituted by the institute where research is done – Independent – multi-disciplinary – multi-sectorial Ethics Guidelines in India
  39. 39. National Guidelines for Accreditation, Supervision & regulation of ART Clinics in India, 2005 Draft ICMR DBT Guidelines for Stem Cell Research and Therapy, 2006
  40. 40. Good Clnical Practices (GCP) For Clinical Research In India • Developed by Central Drugs Standard Control Organisation (CDSCO) • Components : - Pre-requisites for the study - Responsibilities - Record Keeping and Data Handling - Quality Assurance - Statistics
  41. 41. Why Ethics in Clinical Research? • Clinical Trials are an experiment • With investigational products • On human beings as participants • With some additional complexities in Indian context
  42. 42. Three basic principles • Justice • Respect for Persons • Beneficence and non-malaficence - maximize benefits - minimize harms and wrongs - do no harm Core Principles of Clinical Trial Ethics
  43. 43. Principals of Ethical Research - Components
  44. 44. Essential Elements of Ethical Research Balance of Risks and Benefits • Minimize risks to subjects • Maximize benefits to individual subjects and to society • Benefits should be proportional to or outweigh risks. Non-maleficence and Beneficence
  45. 45.  Test on human beings only if absolutely essential  Does all current research certify that the drug is safe? Essentiality
  46. 46.  Provide remuneration to test subjects  Inform subjects about all potential side effects and risks  Ensure ample compensation for accidental injury Insurance, Rehabilitation, Life-long support Non-Exploitation
  47. 47.  Inform subjects about the extent to which personal info would be disclosed  Do not divulge identity and records of test subjects as far as possible  Do not Provide information which will allow identity to be guessed Privacy & Confidentiality
  48. 48.  Design the study such that risks to the subjects is minimized  Ensure there are no adverse side effects Precaution
  49. 49. Balancing principles • Balancing the need for a rigorous design with the obligation to maximize benefits and minimize harms – Equipoise – Randomization – Choice of control – Example: Randomized Controlled Trials
  50. 50. Choice of control • “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.” (Helsinki 2000)
  51. 51. Clinical Equipoise ? • “Genuine uncertainty within the scientific community...” about the comparative merits of intervention ‘A’ and ‘B’ (Freedman, 1987)
  52. 52.  Professional Competence  All personnel involved in trials should be trained and qualified  A strong sense of ethics essential for personnel Competence
  53. 53.  No aspect of the study should be hidden Except for privacy reasons  Prior disclosure of all conflicts of interest  Maintain permanent records of all research data and notes  Fix responsibility for the study and its outcomes  Burden of Proof is always with those who conduct the trial Transparency & Accountability
  54. 54.  Benefits of research should be equally distributed  Research on genetics should not lead to racial inequalities  Do not conduct research on economically weak sections to create advantage for those that are better off  Avoid implicit coercion  Do not enroll people at a disadvantage in the study - Prisoners / Students / Subordinates/Employees  Ensure complete freedom of choice when they are enrolled Distributive Justice
  55. 55. Distributive justice - the local study populations will not significantly benefit from the research if the new therapies will not be affordable to them, although they are taking a higher proportion of the risk.  Distributive justice is violated
  56. 56. Patient rights • Use in the country after approval - drug is marketed only in the affluent countries - insist on drug would be released in India also at a price that is reasonable
  57. 57. Patient rights Vulnerability of patients in a trial • money paid • health care to the family • free medicines at the hospital • Free diagnostic tests • counter to the cardinal principle of autonomy • not be compelled or unfairly enticed to participate • truly a free choice?
  58. 58. Patient rights Patients enrolled in clinical trials when trials are closed • numbers are completed because of recruitment of patients in other countries • important to ensure that all persons in the trial receive their drugs • should be a built-in safeguard when approving a clinical trial
  59. 59. Patient rights Access to drugs - Participants cannot afford the Drug • should be able to obtain at a reduced price or entirely free. Information • No information is ever provided about the outcome • Must be provided not only to the participants of the trials but also to the community.
  60. 60. Patient rights Use of the placebo • unethical to give a placebo to a group of patients when there is a drug available to cure • no role for a placebo in conditions for which there is already an effective drug • e.g. evaluation of new drugs for diabetes Chaudhury R R , ICMR
  61. 61. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand • The study was designed to test the superiority of nevirapine-nevirapine regimen over the placebo- placebo regimen • Critics: Use of placebo unethical • Supporters: Poor countries can anyway never afford the expensive AZT regimen and the shorter treatments were needed • argued for “local standard of care”, In this case it was “absence of care” New Engl Jr Med 2004; 351: 217-28.
  62. 62.  Pregnant/Nursing Women Only for research to better the health of pregnant/nursing women, foetus or infants Ensure that there is no risk to foetus or infant Special Groups
  63. 63.  Children  Only trials for drugs to improve child health  Only conduct trials on children after phase 3 clinical trials on adults Exception: drugs for diseases only affecting children  Consent from parents and/or legal guardians  Consent from child in the case of mature minors and adolescents Except where parents have given consent and there is no other medical alternative to the tested therapy Special Groups
  64. 64. Research Involving Children (1977); The Belmont Report (1979) Respect for Children Declaration of Helsinki (2000) • Obtain informed consent from parent • If child capable, obtain assent The National Commission (1977, 1979) • Parental Permission (but within limits) Protect child’s health and safety (i.e., beneficence) • Child Assent (not as a right, but a benefit) Nurture child’s moral growth and developing autonomy
  65. 65. Two Pillars of Ethics • Informed Consent Process • Institutional Ethics Committees
  66. 66. Informed consent
  67. 67.  Informed Consent  Subjects should consent to participate in the study  Subjects should be fully informed about the objectives of the study  Subjects have the right to withdraw at any point during study No refund of remuneration should be demanded on early withdrawal Informed consent
  68. 68. Informed consent- Indian situation • Getting informed consent difficult in developing countries • 30% each consented after full or partial disclosure • Significant gender difference with fewer females consenting to participate (P=0.043) • Understanding of consent poor B Gitanjali et al JPGM 2003; 49: 109-113.
  69. 69. ETHICS COMMITEE Independent review of clinical research ensures the public that investigator biases have not distorted the approach, that ethical requirements have been fulfilled, and that subjects will not be exploited. Minimize conflict of interest Public Accountability
  70. 70. Ethics committee members 1. Chair person, preferably from outside the institution 2. 1-2 basic medical scientists 3. 1-2 clinicians from various institutes 4. One legal expert or retired judge 5. One social scientist 6. One philosopher or ethicist 7. One lay person from community 8. Member secretary
  71. 71. Criteria for IEC Review • Risks … are minimized. • Risks are justified by anticipated benefits, • Subjects will be selected and treated fairly • Informed consent is adequate
  72. 72. Reporting ethical processes in Indian journals • Research articles of 2006 published in Indian Pediatr and Ind J Peds analyzed • N = 132, 98 studies prospective • 39 (29.53%) reported ethical approval • 46/98 (46.94%) mentioned informed consent from parents or guardians • 54/98 (55.1%) studies enrolled children, 8 (14.81%) mentioned assent • 4 (7.41%) studies reported ethics committee approval, Informed consent and assent Bavdekar SB & Gogtay NJ.
  73. 73. WHO-ICMR study on status of Ethics Committees in India • Many institutions do not have IECs • Many do not have written SOPs • Paucity of trained personnel to work for EC • Lack of training facilities for EC members • Variability in quality of ethical review • No regulation/ registration/ accreditation • Lack of time for monitoring
  74. 74. Medical research in India • unrelated to the country’s major health problems. • “little influence” on health care delivery. • scant regard for standard ethical guidelines • problem in defining local priorities
  75. 75. Clinical Trials Registry of India • launched in July 2007 • editors of 12 Indian biomedical journal • encourages the registration of all clinical trials • meant to bring transparency • publication of a trial only if it has been previously registered. • no legal requirement to register a trial
  76. 76. Clinical Trials • Phase I - Human Pharmacology • Phase II - Therapeutic exploratory trials • Phase III - Therapeutic confirmatory trials • Phase IV - Post Marketing Trials
  77. 77. Trials in India - Concerns • Lack of formal training in bioethics and research methodology • heavy burden of clinical duties • sub-optimal administrative support • a lack of regulation of private trials • Variation in requirements for informed consent • Lack of proper ethics review.
  78. 78. Trials in India - Concerns • quality of clinical research, • timelines for regulatory approval, • deficiencies in the functioning of the ethics committees • an unethical approach to the recruitment of trial subjects
  79. 79. Trials in India - Concerns Limited awareness amongst investigators -Do all studies require EC clearance? -What documents need to be submitted? -Can EC look at scientific aspects as well? -Requirements for Regulatory clearances
  80. 80. Gardasil Trial - India • HPV vaccine trial (AP & Gujrat ) 2010 • marketed in India by MSD Pharmaceuticals Pvt Ltd. • four deaths and complications among 120 girls • The vaccine has been approved for adult women aged 27, without any trials on them. • No Phase III trials in adults before use in children • scientific logic and ethical guidelines violated at each step
  81. 81. Trials in India - Concerns Unethical and dubious ? • trials to develop a contraceptive vaccine • cervical dysplasia (a pre-cancerous condition) untreated to study the progress of the disease • trials on quinacrine sterilisation • trial of ‘anti-cancer’ cure conducted in Calcutta in 2000.
  82. 82. Trials in India – Preferred Destination? • a technically competent workforce • patient availability, • low costs • a friendly drug-control system.
  83. 83. Trials in India- The benefits • participation by Indian researchers and clinicians • platform for carrying out clinical trials • creating expertise • increasing job opportunities • bringing resources into the country. ( ? 2.2 billion US dollars by 2015 )
  84. 84. Challenges - 1 • Research Ethics: A new specialty • Informed Consent: Several inherent difficulties -Illiteracy, too many languages, lack of time for health professionals to explain • Bioethics education: Not in the curriculum • Boom in clinical research has not been matched by regulatory reform and ethical practices
  85. 85. Challenges- 2 Group 1 No major feasibility issues. Singapore Capable of hosting Hong Kong GCP trials Group 2 Minor barriers that can be Taiwan easily overcome. Thailand Group 3 Significant feasibility China, Japan issues But solutions India, Malaysia can be found. Philippines Group 4 Major barriers. Very difficult Indonesia, to conduct studies in the Korea, Vietnam near term. Myanamar Proceedings of DIA International Symposium Taipei, Taiwan October 2-3, 1998
  86. 86. Challenges- 4 Ethics Committees • No funds allocated to EC • Space crunch: Documentation and archiving difficult • Infrequent Meetings • Limited resources for monitoring studies • Not all research studies undergo review
  87. 87. Complexities in Indian context • Developing country • Socio-economic considerations • Healthcare availability and access • Literacy and education status • Conflicts of interest • “Guinea pig” perception • Questions about clinical trials in India • Acceptability of Indian data • Issues of post trial access
  88. 88. Pluses • By 2010, it is estimated that a fifth of all global studies will be done in India Why? -Rx naïve patients -Highly skilled GCP trained investigators ? -Excellent technological infrastructure -Lower costs of drug development -Fast regulatory approvals ? The Lancet 2007; 369: 1233
  89. 89. Pharma: Assets (?ethics) • Pharmaceutical company assets may exceed many nations’ Gross Domestic Product – The current global drug market is $520 billion • Governments and officials kowtow to the power and money • “Democracy” transforms into Corporate Feudalism • Science turned into a marketing tool | www.plosmedicine.org June 2007 | Volume 4 | Issue 6 | e184
  90. 90. The way forward
  91. 91. Regulations • Ethical Guidelines into Law (like US) • Training in ethics at UG & OG level • Involvement of UG students in observational Research
  92. 92. Power of the People • Democracy only works with Civil Society’s full engagement • The hegemony of Greed must be stopped • Can NGOs/Civil Society conduct our own clinical studies? • Non-violence in the face of violence • Engage and involve stakeholders
  93. 93. Life has become complex RReellii ggiioonn MMoorraa lliittyy EEtthh iiccss LL aaww TTaabb ooooss TTrraaddii ttiioonnss CCuusstt oommss Ethics has always been in the gray zone – 256 shades of Gray
  94. 94. Resources • The Helsinki Declaration reflects international values. http://www.wma.net/e/ • The Nuremburg Code: http://www.nihtraining.com/ohsrsite/guidelines/nuremberg.html • Belmont Report: http://ohsr.od.nih.gov/guidelines/belmont.html • Council for International Organizations of Medical Sciences http://www.cioms.ch/ • Indian GCP for clinical trials http://cdsco.nic.in/html/GCP.htm • Indian biomedical research ethics guidelines available at: ICMR Ethical Guidelines for Biomedical Research