1. Ethical issues in Research

2. F RAMEWORK History Human Rights & health Ethics in medical practice & research Declaration of Helsinki, 2008 Rights and Responsibilities of Researcher Rights and Responsibilities of Institutions Institutional Ethics Committee (IEC) Relationship among researchers Selection of research participants Informed Consent Rights of participants Ethical issues in various research setting Epidemiological studies Drug trials Vaccine trial Research involving medical device/ diagnostic devices Herbal extracts/ Unani/Siddha Tissue/Organ Transplants Issue related to reporting/ publishing Rights & responsibility of funders/ sponsors

3. I NTRODUCTION Ethics is study of morality – careful & systematic reflection on & analysis of moral decisions & behavior, whether past, present or future. Medical ethics To recognize difficult situations & to deal with them rational & principled manner. to safe guard humanity

4. H ISTORY 1947 - Nuremberg Code 1947 - World Medical Association established 1948 -Universal Declaration of Human Rights (General Assembly UN) 1954 –Principles for Research and Experimentation (WMA) 1966 -International Covenant on Civil and Political Rights 1964 - Declaration of Helsinki ( 1975, 1983, 1989, 1996, 2000, 2008) 1980 - Policy Statement on Ethical Considerations involved in Research on Human Subjects ( ICMR) 1982 - International Guidelines for Biomedical Research involving Human Subjects (WHO & CIOMS ) 1991 - International Guidelines for Ethical Review in Epidemiological studies (CIOMS) 1993 - International Ethical Guidelines for Biomedical Research Involving Human Subjects ( revised 2002) (CIOMS) 2000 - 'Ethical guidelines for Biomedical Research on Human Subjects (ICMR) 2003 - The International Declaration on Human Gene Data (UNESCO) 2005 -Universal Declaration on Bioethics and Human Rights (UNESCO) In 2006, ICMR published “Ethical guidelines for biomedical research on human participants”

5. Human Rights & Health

6. E THICS IN MEDICAL PRACTICE & RESEARCH Basic principles Non-maleficence Beneficence Autonomy Justice Declaration of Geneva - “The health of my patient will be my first consideration” International Code of Medical Ethics - “A physician shall act in the patient's best interest when providing medical care.”

7. D ECLARATION OF H ELSINKI, 2008 3)6 ) …duty to safe guard participants….well being of research subject….. 7)21)…..primary purpose…improve present knowledge…..outweighs risk 10) …consider.. National & international norms……. 14) ….Protocol…..ethical issues….. 16) …by scientifically trained & qualified…………… 17)…..vulnerable & disadvantages…………fulfill their health needs….. 19)…..trials must registered…..public database…………… 22) …..participation …..voluntary…….. 25)…..human material & data……consent for collection, analysis, storage, reuse …if not possible…..from research ethics committee…. 28 ) ….incompetent research subject…….consent from legal authority…. 30 )…Authors, publishers & publisher……results available publicly…… 31) …….medical practice & research ….combined…if justified. 32) …new intervention..against best current proven intervention …except in ….no treatment…..or compelling & sound methodological reason..not subjected to any risk……… 33) …if beneficial….then post intervention access………….

8. R IGHTS AND R ESPONSIBILITIES OF R ESEARCHERS Qualification and competent Research should improve of knowledge on the subject No secret research – bring to public domain Should follow ethical guidelines honesty and transparency Respect, Protection & Promotion of rights of participants Unethical study, then can quit Right to publication Peer review

9. R IGHTS AND R ESPONSIBILITIES OF I NSTITUTIONS Respect autonomy of researchers Support ethical guidelines Should have Institutional Ethical committee Observance of ethical guidelines for research

10. I NSTITUTIONAL E THICS C OMMITTEE (IEC) Functions To resolve ethical dilemmas To safeguard dignity, rights, safety & well being of actual & potential participants Taking care of principle of ethics To support the researcher in ethical issues To examine compliance with all regulatory requirements, applicable guidelines and laws Ethical clearance irrespective of funding agency

11. C OMPOSITION OF IEC 7-9 members 1. Chairperson 2. 1-2 basic medical scientists. 3. 1-2 clinicians from various Institutes 4. One legal expert or retired judge 5. One social scientist / representative of NGO 6. One philosopher / ethicist / theologian 7. One lay person from the community 8. Member-Secretary Subject expert/ Independent consultants Duration of Membership – 2-3 years

12. A PPLICATION P ROCEDURES & D OCUMENTS Prescribed application form Name of applicant with designation Name of Institute/ Hospital / Field area where research will be conducted. Approval of HOD/ Institution Protocol of proposed research Ethical issues in study & plans to address these issues. Proposal should be submitted with all relevant enclosures like proformas, case report forms, questionnaires, follow - up cards, etc. Informed consent process, including patient information sheet and informed consent form in local language(s). For any drug / device trial, all relevant pre-clinical animal data and clinical trial data from other centres within country / countries, if available. Curriculum vitae of all the investigators with relevant publications in last five years. Any regulatory clearances required. Source of funding and financial requirements for the project. Other financial issues including those related to insurance An agreement to report only Serious Adverse Events (SAE) to IEC. Statement of conflicts of interest, if any. Agreement to comply with the relevant national and applicable international guidelines. A statement describing any compensation for study participation (including expenses and

13. R EVIEW PROCEDURES : Proposals sent to members at least 2 wks in advance Meetings on scheduled intervals Minimum 5 member for decision Decision by meeting not by circulation Researchers will be invited to offer clarifications if need Minute & notification by member secretary Communicating decision Record keeping & Archiving Updating IEC members

14. S ELECTION OF AS RESEARCH PARTICIPANTS be completely voluntary should give informed written consent no inducement but compensation( risk benefits, out of pocket expenses) No unjustifiable assurance Anonymity & confidentiality Selection of special groups as research participants Pregnant or nursing women Children - after phase III Vulnerable groups

15. R IGHTS OF PARTICIPANTS I NFORMED C ONSENT 1. Patient information sheet---Nature and purpose of study 2. Duration of participation with number of participants 3. Procedures to be followed 4. Investigations, if any 5. Foreseeable risks and discomforts 6. Benefits to participant/ community /medical profession 7. Policy on compensation 8. Medical treatment for injuries or risk 9. Alternative treatments if available 10. Steps taken for confidentiality 11. No loss of benefits on withdrawal 12. Benefit sharing in event of commercialization 13. Contact details of PI or local PI/Co-PI in Multicentric 14. Contact details of Chairman of IEC for appeal against violation of rights 15. Voluntary participation 16. If test for genetics & HIV, counseling for consent for testing must be given as per national guidelines 17. Storage period of biological sample and related data 18. Copy to participant

16. Written consent not possible? Third person, audio-visual but needs approval of IEC Age?

17. Fresh or re-consent Deviation of protocol Regains consciousness from unconscious Change in treatment modality, procedures, site, visits Before publication Waiver of consent Not more than minimal risk Do not come into contact When it is necessitated in emergency situations Research on anonymised biological samples from deceased individuals

18. O BLIGATIONS OF INVESTIGATORS REGARDING INFORMED CONSENT : Compensation for participation Free ancillary care or appropriate referrals

19. R ELATIONSHIP AMONG RESEARCHERS Principal researchers are responsible Ethical conduct but juniors, assistants, students & trainees have an equally responsibility Training to junior, assistants No discrimination Researchers should not mislead or force other researchers Co-operative, responsive, honest and respectful about the interest, opinion/view, capability and work of other researchers

20. Epidemiological studies Drug trials Vaccine trial Herbal extracts/ Unani/ Siddha Medical device/diagnostic devices Tissue/organ transplants Ethical issues in various research setting

21. E THICAL ISSUES IN EPIDEMIOLOGICAL STUDIES Consent from community &Community participation Inducements are not permissible All risks involved – explained to individual & community Maintaining confidentiality Minimize harm, maximum benefit for individuals and communities taking part in study Committees -- epidemiologists, clinicians, statisticians, social scientists, philosophers, legal experts and representatives from community/ voluntary groups Should not raise false hopes.

22. E THICAL PRINCIPLES FOR DRUG TRIAL Drugs Controller General of India (DCGI), ( Drugs and Cosmetics Act, 1940) Approval of IEC All guiding principles -irrespective of place of discovery of drug Risk-benefit should be favorable. It should registered as per International standard RCT Should be carried out in equipped center, m/m ASE Preferably clinical pharmacologist involved. Use of a placebo in drug trials/ sham surgery i. self limited disease; ii. where no proven prophylactic, diagnostic or therapeutic method exists

23. D RUG TRIAL ……. Post trial benefit Criteria of termination Breaking of code Partner notification -HIV/ AIDS related trial New drug (India)- Phase I to IV New drug (outside India)- Phase I data required

24. D RUG TRIAL …………. Phase I Change in protocol -approval of IEC must Started from lowest dose Sub-populations Duration between 2 trials in same volunteer - 3 mths Compensation is given by the sponsors or insurance Phase II The dose used is lesser than the highest dose used in phase I Phase III Drug in Indian patients Open non-comparative trials are unethical. Phase IV doesn’t require approval from DCGI

25. Multicentric Trials Acceptance of the protocol Approval IECs Meetings at initial & intermediary stages – Central monitoring committee Training – uniformity procedures, data entry in the case record forms, ethics & GCP Trial involving contraceptive Information about alternatives available Implant- proper follow & removal Failure of contraceptives Monitoring and reporting adverse reactions or events unexpected AE/ADR & all SAE (Indian Good Clinical Practice(GCP) Guidelines) Investigator to sponsers -24 hrs Investigator to EC - < 7 days Death information to Ec – 24 hrs Sponsor to Licensing Authority &Investigator(s) of other site -14 calendar days Evaluated and discussed Medical management of adverse event financial plan for trial related injury

26. V ACCINE TRIALS Contain active or live – attenuated Standard vaccine -if no – community involvement Control groups- Post trial access Certification of vaccination

27. C LINICAL TRIALS WITH SURGICAL PROCEDURES / MEDICAL DEVICES Safe procedures Indian Medical Devices Regulatory Authority (IMDRA)- Health Ministry Indian Standard Institute, Board of Indian Standards, Drug Controller General of India, and Nuclear Medicine Board of the BARC Informed consent as in drug trials Patient information sheet- information on follow-up if withdraw from trial.

28. D IAGNOSTIC AGENTS - USE OF RADIO - ACTIVE MATERIALS AND X- RAYS Participants & investigators are exposed Bhabha Atomic Research Centre, Mumbai Informed consent must- possible genetic damage to offspring & other risk Safety measures Event of death of a participant with radiological implant Done on patients undergoing diagnostic or therapeutic purposes. Substitute Ultrasound Non-radioactive diagnostic agents considered as drugs

29. C LINICAL EVALUATION OF TRADITIONAL AYURVEDA, SIDDHA, UNANI ( ASU ) REMEDIES & MEDICINAL PLANTS “ Operational Guidance: Information needed to support clinical trials of herbal products (2005)” -- - WHO Drugs Controller General of India Categories of drugs Cat I – No Phase I Cat II & III – Phase I -IV

30. E THICAL ISSUE ORGAN TRANSPLANTATION RESEARCH Institutional Committee for Stem Cell Research and Therapy (IC- SCRT) & National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) Centers registration with NAC-SCRT & Equipped institutions No deliberate conception and /or subsequent abortion No research is permitted on the live aborted foetus. Voluntary, informed, written consent from mother 2 stages – 1 st for the abortion 2 nd for donation of tissue from the foetus. Termination of pregnancy for financial or therapeutic benefits Intact embryos or foetuses will not be kept alive artificially Cells obtained from fetuses will not be patented for commercial

31. R EPORTING OF RESULTS OF RESEARCH support ?or contradict ? Cource(s) of funding and sponsors Report explain methodology, how ethical guidelines followed, ethical dilemmas encountered and resolved, etc. No any keep secrete results. Who will? Investigators? Institution? Sponser? Ensure easy availability & accessibility Conflict of interest

32. I NTERACTING WITH MEDIA Avoid dissemination till published No false hopes or expectations or unnecessarily scare raise

33. R IGHTS AND R ESPONSIBILITIES OF P EER R EVIEWERS /R EFEREES Encouraged to improve and advance research Peer reviewer in expertise field Undertaking objectively, impartially and constructively Actual or potential conflicts of personal or professional interest Malpractices in research or violation of ethics

34. P UBLICATION IN SCIENTIFIC JOURNAL Clear consent for publication from participants Confidentiality Authorship - International Committee of Medical Journal Editors (ICJME) Consolidated standards of reporting trials (CONSORT) guidelines

35. R IGHTS & R ESPONSIBILITIES OF E DITORS & P UBLISHERS Ensure that such material is, duly reviewed by referees As journalists & as researcher Fabricated, falsified or plagiarized information - not be entertained After publication - doubt is raised about its ethical status or ethical conduct of the study Misconduct

36. R IGHTS AND R ESPONSIBILITIES OF F UNDERS AND S PONSORS Right to expect progress of work & final report Right to get a copy of ethical guidelines for research Respect ethical guidelines for research & should not expect researchers and institutions to undertake research or conduct it in any way contrary to ethical guidelines.

37. C HALLENGES Use of placebo or standard? Paying researcher: Motivation Or Inducement? Training of IEC members

38. R EFERENCES : World medical association. Medical ethics manual. 2 nd Ed. UK: The World Medical Association Inc; 2009. World Medical Association. Declaration of Helsinki: 2008. Seoul: TheWorld Medical Association Inc; 2008. ICMR. Ethical guidelines For Biomedical research On Human participants. New Delhi: ICMR; 2006. WHO. Operational Guidelines for Ethics Committees That Review Biomedical Research. Geneva: World health organization; 2000. Amnesty International. Ethical codes & declarations relevant to the health professions. 4 th Ed. London: Amnesty international; 2000. CM Francis. Medical Ethics. 2 nd ed. New Delhi: Jaypee brothers, 2004. Ravindran GD. Medical ethics education in India. Indian journal of medical ethics 2008 Jan-Mar;5(1):18-26.