CLINICAL TRIALS: Causality Assessment and Compensation Issues

Transcription

1 CLINICAL TRIALS: Causality Assessment and Compensation Issues Dr YK Gupta Professor and Head, Department of Pharmacology All India Institute of Medical Sciences New Delhi, India

2 Drug Development Process (How to improve R&D productivity: The pharmaceutical industry s grand challenge. Nature Reviews:Drug Discovery 2010;9:203-14)

3 Drug Development Clinical trials Mainstay of drug development process Phase I III : Before marketing authorization Phase IV : Post marketing Pharmacovigilance: throughout the life of a drug

4 Why clinical trials? Required to establish the efficacy and safety of the investigational agent before it can be introduced for general public Adverse event is common occurrence in trials as experience is limited in humans Every drug has its own risk-benefit ratio Protection of human rights is of paramount importance 4

5 Why Regulate Clinical trials For protection of research participants To ensure integrity of scientific data and external validity of trial results To ensure harmonization with international scenario

6 Regulations concerning clinical/biomedical research Contemporary Indian scenario

7 Indian GCP guidelines Good Clinical Practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected, consistent with the principles enshrined in the Declaration of Helsinki and ensures that clinical trial data are credible ( Foreword on Good Clinical Practices for Clinical Research in India)

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9 DRUGS AND COSMETICS ACT Drugs and Cosmetics Act 1940 (as amended upto 05 Dec 2008) deals with powers and provisions An Act to regulate the import, manufacture, distribution and sale of drugs and cosmetics Drugs and Cosmetics Rules 1945 (amended upto 2013) deals with procedures

10 Drugs and Cosmetics Rules 1945 Part X A ( Import or manufacture of new drug for clinical trials or marketing ) consist of following main rules Rule 122-A. Application for permission to import new drug Rule 122D. Permission to import or manufacture fixed dose combination Rule 122DA. Application for permission to conduct clinical trials for New Drug/Investigational New Drug Rule 122DAA. Definition of Clinical trial Rule 122E. Definition of new drug Another example: Part XII Standards Rule 127. List of colours permitted to be used in drugs

11 SCHEDULE Y REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS

12 This image cannot currently be displayed. Twin pivot of regulations Ethics Committee (EC) Informed Consent 12

13 Informed Consent Informed Consent is a decision to participate in research, taken by a competent individual who has received the necessary information; who has adequately understood the information; and who, after considering the information, has arrived at a decision without having been subject to coercion, undue influence or inducement, or Intimidation

14 An audio-video recording of individual subject (including impartial witness, legally acceptable representative, whenever applicable) confirming that the informed consent document has been fully explained and has been well understood and that the subject is voluntarily participating in the clinical study, shall be maintained by the investigator for record

15 Issues with AV recording Privacy and consent for recording Logistics By whom, on what and for how long Recording in large community based studies Illiterate and vulnerable subjects

16 All proposals on biomedical research involving human subjects must be cleared by an Ethics Committee 16

17 Ethics Committee A board or a committee formally designated by an institution to review, approve the initiation conduct periodic review of biomedical research involving humans Independence and Competence A group of men who individually can do nothing but as a group decide that nothing can be done. Fred Allen 17

18 Ethics Committee Composition Total number Minimum quorum Schedule Y Indian GCP ICMR 7 (Chairman from other institution) Non scientific specialist, gender representation, at least 01 independent member 5 (Basic scientist, legal expert, Clinicians, social scientist, lay person) 5-7 (Max 12-15) One philosopher / ethicist / theologian

19 GSR no. 72 (E) dated Rule 122 DD: Registration of Ethics Committee Pertains to approvals for clinical trial protocols EC liable for inspections by CDSCO EC to grant approval and also to carry out review of ongoing trials Mandate of EC expanded and EC to file reports regarding SAEs directly to CDSCO 19

20 CLINICAL TRIALS: Causality Assessment and Compensation Issues Dr YK Gupta Professor and Head, Department of Pharmacology All India Institute of Medical Sciences New Delhi, India

21 SAE assessment and reporting

22 GSR No 53(E) dt 30 Jan 2013 Trial related injury: Adverse effect of inv product Protocol violation, scientific misconduct, negligence by sponsor or investigator!!!! Failure of investigational product to provide intended therapeutic effect, in case the standard care, though available, was not to be provided to the subject as per the clinical trial protocol Use of placebo, in case the standard care, though available, was not to be provided to the subject as per the clinical trial protocol ADR due to concomitant medication Injury to child in utero Any trial related procedure 22

23 How to establish relatedness?? Causality Assessment: The evaluation of the likelihood that a medicine was the causative agent of an observed adverse event

24 Causality Assessment contd Adverse effects are rarely specific for a drug Diagnostic tests are usually absent Rechallenge is rarely ethical Structured and harmonised assessment of causality Precise, uniform and reliable quantitative estimation of relationship likelihood

25 Criteria for assessment Risk factors Challenge Dechallenge (outcome) Rechallenge (outcome) Possible alternative etiological causes Drug level

26 Criteria for assessment Nature (characteristics / mechanism) of the reaction Temporal relationship Previous reports on reported reaction Previous exposure to the drug Lab evidence

27 Methods for assessment Expert opinion Algorithms Probabilistic approaches

28 WHO scale Certain Probable Possible Unlikely Conditional/ Unclassified Unassessable/ unclassifiable

29 Naranjo s scale Questionnaire with 10 questions Answered Yes / No / Unknown Scores range from -1 to +2 Definite ( 9) Probable (5-8) Possible (1-4) Unlikely ( 0)

30 Causality assessment in clinical trials Certain Probable Possible Unlikely Related Not Related 1/9/

31 What if SAE is related Financial compensation for death Financial compensation and free management in case of injuries

32 Compensation issues

33 Compensation: Hindsight 1900 Walter Reed gave $100 for allowing mosquito bites $100 more if subjects contracted viral illness After 1930s Human subjects were routinely paid for participation in research

34 Guidelines on compensation Declaration of Helsinki The protocol should include information regarding.. provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study. ICH GCP Guideline Para 5.8: Compensation to subjects and investigators Para : Written and other information to be given to participants. Indian GCP guidelines Para Compensation for Participation Para Compensation for Accidental Injury

35 Payment to research participants Free treatment of research related injury/reimbursement of such expenses Reimbursement of research related expenses Compensation for research related injury or death??????????????????

36 GSR No 53(E) dt 30 Jan 2013 Insertion of Rule 122 DAB: Compensation in case of injury or death during Clinical trial Injury to the trial subject Free medical management as long as required Trial related injury Medical cost + compensation Trial related death: Compensation to nominee Cost of compensation to be borne by sponsor 36

37 Compensation: Types Tort liability: seeker has to prove fault in court of law No fault

38 What? When? Who? How? And Whom? Of SAE Reporting Who to Whom? When? How? Investigator Sponsor EC Investigator Sponsor EC Appendix- XI format DCGI, EC, Head of Institution, Sponsor DCGI, EC, Head of Institution DCGI [Chairman of Exp. Committee For death case] Initial: <24hrs Full report: within 10 calenda r days 10 calenda r days 21 calenda r days 1/9/

39 New SAE Reporting Process Patient / Relative SAE occurrence Initial Report Final Compensation to be paid Sponsor Sponsor Investigator Sponsor Chairman of EC DCGI Order of Compensation DCGI Analyzed Report *Chairman of Expert Committee DCGI Analyzed Report & Compensation Recommendatio n Investigator Sponsor Chairman of Ethics Committee DCGI *Chairman of Expert Committee Chairman of Ethics Committee 1/9/2015 * In case of Death 39 Sponsor

40 Quantum of compensation Gender Profession Income Age Dependants Concomitant medication Negligence Comorbid conditions Sponsor: Industry V/s Academia Expected survival How do you comprehend this?

41 Quantum of compensation - Factors No- fault basis Age factor: from The Workmen Compensation Act Risk factor: Subjective Base amount: Contemporary and dynamic

42 Quantum of compensation - Factors Two factors: Age factor Risk factor Base amount: Rs 8 lacs Risk Factor Patient Risk 0.5 Terminally ill (survival NMT 6 months) 1 High risk (survival NMT 6-24 months) 2 Moderate risk 3 Mild risk 4 Healthy volunteers; No risk 42

43 Quantum of compensation - Formula Compensation = (8 lacs *Age factor*risk factor)/99.37 Compensation for terminally ill patient of 16 yrs of age: (8 X X 0.5)/99.37 = Approx 9 lacs Compensation for terminally ill patient of 67 yrs of age: (8 X X 0.5)/99.37 = 4 lacs Expected mortality > 90% in 30 days Fixed amount of 2 lacs 43

44 To simplify Age Risk factor Compensation > 65 yrs 4 32 Lacs < 16 yrs Lacs >65 yrs Lacs < 16 yrs Lacs

45 Compensation for injuries A permanent disability Compensation = (DX80XC)/(100X100) Congenital anomaly or birth defect Still birth b) Early death due to anomaly c) No death but deformity which can be fully corrected through appropriate intervention d) Permanent disability (mental or physical) Chronic life-threatening disease Compensation = N x W Reversible SAE in case it is resolved Compensation = 2 x N xw 1/9/

46 Emerging Issues Compensation in Investigator initiated trials? Accreditation of trial sites, ECs and investigators Interpreting foreign trial data for regulatory decisions Compensation on compassionate grounds? 1/9/

47 Thank You