Acoustic Separation and Biomedical Research: Lessons from Indian Regulation of Compensation for Research Injury

Drugs and Cosmetics (First Amendment) Rules (2013) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 53(E).

See, e.g., Parliament of India, “Department-Related Parliamentary Standing Committee on Health and Family Welfare, Fifty-Ninth Report on the Functioning of the Central Drugs Standard Control Organisation (CDSCO) May 8, 2012” available at <http://164.100.47.5/newcommittee/reports/EnglishCommittees/Committee%20on%20Health%20and%20Family%20Welfare/59.pdf> (last visited February 18, 2015): At 1–2 (Noting the importance of medicines in India and calling for a greater focus on patient safety); It should be noted that in many circumstances, countries considering tightening regulatory requirements may need to be concerned about a race to the bottom: Namely that foreign investors may simply seek a more lax or favorable regulatory climate elsewhere.

See, e.g., Levine R. J. Holder A. R. , “Legal and Ethical Problems in Clinical Research.” Clinical Research and Regulatory Affairs 7, no. 6 (1989): 315–370;.

see also President's Commission for the Study of Bioethical Issues, “Moral Science: Protecting Participants in Human Subjects Research,” available at <http://bioethics.gov/node/558> (last visited February 18, 2015).

“Responsible Research: A Systems Approach to Protecting Research Participants,” Institute of Medicine, available at <http://www.iom.edu/Reports/2002/Responsible-Research-A-Systems-Approach-to-Protecting-Research-Participants.aspx> (last visited February 18, 2015).

Dan-Cohen M. , “Decision Rules and Conduct Rules: On Acoustic Separation in Criminal Law,” Harvard Law Review 97, no. 3 (1984): 625.

Id., at 629–630.

Jesani A. , “New Regulations on Compensation for Injury and Death in Drug Trials,” Indian Journal of Medical Ethics 10, no. 2 (2013): 76–79.

Mukherjee S. , “Compensation Conundrum,” Perspectives in Clinical Research 3, no. 1 (2012): 4–7.

See, e.g., Pandya M. Desai C. , “Compensation in Clinical Research: The Debate Continues,” Perspectives in Clinical Research 4, no. 1 (2013): 70–74;.

see also “Ethical Guidelines for Biomedical Research on Human Participants,” available at <http://www.icmr.nic.in/ethical_guidelines.pdf> (last visited February 18, 2015).

see Stone K. , “India Clamps Down On Clinical Trials Oversight,” available at <http://pharma.about.com/od/Government_IP/a/India-Clamps-Down-On-Clinical-Trials-Oversight.htm> (last visited February 18, 2015).

Mukherjee , “Compensation Conundrum” supra note 7;.

See also Pike E. R. , “In Need of Remedy: US Policy for Compensating Injured Research Participants,” Journal of Medical Ethics 40, no. 3 (2014): 182–85, at 184;.

see also Bhan A. , “Clinical Trial Ethics in India: One Step Forward, Two Steps Back.” Journal of Pharmacology & Pharmacotherapeutics 3, no. 2 (2012): 95–97.

See, e.g. Admin, “Over 2,000 Died during Drug Trials in Last 4 Years, Only 22 Received Compensation,” available at <http://health.india.com/news/over-2000-died-during-drug-trialsin-last-4-years-only-22-received-compensation/> (last visited February 18, 2015).

“Indian Parliament Comes Down Hard on Cervical Cancer Trial,” available at <http://news.sciencemag.org/asiapacific/2013/09/indian-parliament-comes-down-hard-cervical-cancer-trial> (last visited February 18, 2015);.

Buncombe A. , “‘A Heaven for Clinical Trials, a Hell for India’: Court Orders Government to Regulate Drugs Testing by International Pharmaceutical Companies,” The Independent, available at <http://www.independent.co.uk/news/world/asia/a-heaven-for-clinical-trials-a-hell-for-india-court-orders-government-to-regulate-drugs-testing-by-international-pharmaceutical-companies-8849461.html> (last visited February 18, 2015);.

Buncombe A. Lakhani N. , “Without Consent: How Drugs Companies Exploit Indian ‘Guinea Pigs,”’ The Independent, available at <http://www.independent.co.uk/news/world/asia/without-consent-how-drugs-companies-exploit-indian-guinea-pigs-6261919.html> (last visited February 18, 2015).

London A. J. , “A Non-Paternalistic Model of Research Ethics and Oversight: Assessing the Benefits of Prospective Review,” Journal of Law, Medicine & Ethics 40, no. 4 (2012): 930–44, at 933. London states that “an unfair division of social resources occurs when a group of stakeholders contribute resources to a joint enterprise for the purpose of sharing expected benefits, but more advantaged parties are able to shape the collaboration so as to secure a disproportionate share of the benefits.”.

See, Parliament of India, “Department-Related Parliamentary Standing Committee on Health and Family Welfare, Fifty-Ninth Report on the Functioning of the Central Drugs Standard Control Organisation (CDSCO) May 8, 2012,” supra note 2;.

see, e.g., Bhan A. , “Clinical Trial Ethics in India,” supra note 8;.

Jesani A. , “New Regulations on Compensation for Injury and Death in Drug Trials,” supra note 2;.

Press Trust of India, “Only 45 of 2,868 Clinical Trial Deaths Compensated since 2005,” Business Standard India, March 5, 2013, available at <http://www.business-standard.com/article/pti-stories/only-45-of-2-868-clinical-trial-deaths-compen-sated-since-2005-113030500403_1.html> (last visited February 18, 2015);.

Vaidyanathan G. , “Failings Exposed at India's Drug Regulator,” Nature, May 18, 2012 available at <http://www.nature.com/news/failings-exposed-at-india-s-drug-regulator-1.10668?nc=1397868291471> (last visited February 18, 2015);.

Cressey D. , “India Shakes up Rules on Clinical Trials,” Nature, August 21, 2012 available at <http://www.nature.com/news/india-shakes-up-rules-on-clinical-trials-1.11223?nc=1386066851805> (last visited February 18, 2015).

Parliament of India, “Department-Related Parliamentary Standing Committee on Health and Family Welfare, Fifty-Ninth Report on the Functioning of the Central Drugs Standard Control Organisation (CDSCO) May 8, 2012,” supra note 2;.

Drugs and Cosmetics (First Amendment) Rules (2013) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 53(E) § 2. (i)(5).

See the Indian Parliament website, available at, <http://164.100.47.4/newlsbios_search/NewAdvsearch.aspx> (last visited February 18, 2015).

See also Dhar A. , “Bill to Make Biomedical, Health Research Ethical,” The Hindu, September 19, 2013, available at <http://www.thehindu.com/todayspaper/tp-national/bill-to-make-biomedical-health-research-ethical/article5143738.ece.> (last visited February 18, 2015).

See Pike E. R. , “Recovering from Research: A No-Fault Proposal to Compensate Injured Research Participants,” American Journal of Law and Medicine 38, no. 1 (2012): 9–62, at 39–42.

See, e.g., “WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects,” October 19, 2013, available at <http://www.wma.net/en/30publications/10policies/b3/> (last visited February 18, 2015).

What counts as a “research related” injury is a subject that is ripe for further definition. There are some countries that use the term broadly to refer to any injury that is sustained during the subject's research participation. Other countries require the injury to be causally related to the subject's research participation. See, e.g., President's Commission for the Study of Bioethical Issues, “Moral Science: Protecting Participants in Human Subjects Research,” available at <http://bioethics.gov/node/558> (last visited February 18, 2015), Appendix V (listing international compensation requirements).

45 C.F.R. 46.116(a)(6) See “Moral Science,” supra note 15.

It should be made clear that the rules contain not only the much noted provisions governing compensation for research related injuries, but also broader regulatory requirements for the biomedical research industry. See generally GSR 53(E) supra note 1;.

see also Drugs and Cosmetics (Second Amendment) Rules (2013) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 63(E), available at <http://cdsco.nic.in/writereaddata/GSR%2063(E)%20dated01%20.02.2013.pdf> (last accessed February 18, 2015).

see also Drugs and Cosmetics (Third Amendment) Rules (2013) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 72(E) at <http://cdsco.nic.in/writereaddata/G.S.R%2072%28E%29%20dated%2008.02.2013.pdf> (last visited May 23, 2013).

See also Sunstein C. R. , “On the Expressive Function of Law.” University of Pennsylvania Law Review 144, no. 5 (May 1996): 2021, 2022–2025.

Singh J. A. , “India's Regulatory Reforms on Compensation for Clinical Trial Injuries and Deaths: Urgent Need for Revisiting,” Indian Journal of Medical Ethics 10, no. 3 (2013): 195–197.

Sugarman J. , “India's New Policy to Protect Research Participants,” BMJ 347, no. 2 (2013): f4841–f4841.

see, e.g., Mahalingam K. , “Critical Condition,” Outlook Business, March 1, 2014, available at <http://business.outlookindia.com/article_v3.aspx?artid=289527> (last visited February 18, 2015).

It should be noted that narrow tailoring cannot be thought to cure all of India's regulatory ills. There is always the possibility that research sponsors will seek out other countries that have less strict regulatory requirements in which to conduct their research. This should not be seen as a reason not to regulate because there is a point at which unregulated or irresponsibly conducted research would reduce trust in the research enterprise and lead to little or no public benefit. See, e.g., London, supra note 10, at 932–933. Concerns about a hypothetical “race to the bottom” should not deter policy-makers from attempting to create an ethically justified policy tailored to meet the needs of their population.

Moderation has also been suggested on other grounds: See Singh J. A. , “India's Regulatory Reforms on Compensation for Clinical Trial Injuries and Deaths: Urgent Need for Revisiting,” Indian Journal of Medical Ethics 10, no. 3 (2013): 195–97.

See, e.g., Sunstein C. R. , “On the Expressive Function of Law,” supra note 18;.

see also Dan-Cohen “Decision Rules and Conduct Rules,” supra note 4.

See Pike E. R. , “In Need of Remedy: US Policy for Compensating Injured Research Participants.” Journal of Medical Ethics 40, no. 3 (March 1, 2014): 182–85, 182 (relying on beneficence as the source of a duty of risk minimization but coming to a similar conclusion).

Joffe S. Miller F. , “Bench to Bedside: Mapping the Moral Terrain of Clinical Research,” Hastings Center Report 38, no. 2 (2008): 30–42, at 36.

See, e.g., President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, “Compensating for Research Injuries: The Ethical and Legal Implications of Programs to Redress Injured Subjects,” (1982): 58–60.

See Shah S. K. , “Outsourcing Ethical Obligations: Should the Revised Common Rule Address the Responsibilities of Investigators and Sponsors?” Journal of Law, Medicine & Ethics 41, no. 2 (2013): 397–410, at 407.

See President's Commission, “Compensating for Research Injuries,” supra note 24.

This concept contains elements of both causation and risk theory. Hart H. L. A. Honoré T. , Causation in the Law, 2nd ed. (Oxford, UK: The Clarendon Press, 1985): At 64–65, 284–290 (observing that a cause is one factor among many necessary factors that is abnormal in the course of our thinking about what ordinarily would have happened in a particular situation, and noting that considerations of whether an injury is within the risk intended to be guarded against may provide a limit on causal analysis. It is possible, in this context, that this could include all physical injuries, but it might exclude emotional or mental injuries of a less predictable variety.).

Childress J. F. , “Compensating Injured Research Subjects: I. The Moral Argument,” The Hastings Center Report 6, no. 6 (1976): 21.

Id.

See Henry L. M. , “Moral Gridlock: Conceptual Barriers to No-Fault Compensation for Injured Research Subjects,” Journal of Law, Medicine & Ethics 41, no. 2 (2013): 411–23, at 417.

See also Levine R. J. Holder A. R. “Legal and Ethical Problems in Clinical Research,” Clinical Research and Regulatory Affairs 7, no. 6 (1989): 315–70, 328;.

Mariner W. K. , “Compensation for Research Injuries,” in Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies (Washington, D.C.: National Academies Press, 1994): 116 (discussing distributive justice in similar terms).

See Henry , id., at 413. (Reparative Justice is “a form of corrective justice intended to make an injured party whole again, but while compensation counteracts a loss or harm that may not be due to any wrongdoing, reparations ‘repair’ an injury to one party that is wrongfully caused by another.”).

Research participation creates benefit whether or not the intervention being studied is shown to be effective. Even negative results are valuable because they contribute to the scientific literature and guide future research.

See Pike , “Recovering from Research: A No-Fault Proposal to Compensate Injured Research Participants,” supra note 14;.

see also Henry , “Moral Gridlock,” supra note 29.

G.S.R. 53(E), supra note 1.

Id.

Id.

Whether ultimate financial responsibility for such misconduct should rest with the sponsor may be an open question. In some circumstances, it might be appropriate to allow the sponsor to proceed against the individual who committed the misconduct in an effort to recoup its losses. The sponsor may be held responsible under a theory similar to that of respondeat superior, wherein the principal is held accountable for the wrongs of his agent, but not because he bears any particular moral culpability. See Hart H. L. A. Honoré T. , Causation in the Law, 2nd ed. (Oxford, UK: The Clarendon Press, 1985): 64–65.

See supra, section B.

The extent of ancillary care obligations to trial participants is too broad a topic to be fully discussed here. At the moment, it is sufficient to say that care not related to injuries incurred because of research participation falls into the category of an ancillary care obligation and not a definition of a compensable research related injury. See Belsky L. Richardson H. S. , “Medical Researchers' Ancillary Clinical Care Responsibilities,” BMJ: British Medical Journal 328, no. 7454 (2004): 1494–1496. Such an obligation is not properly included in the duty of nonmaleficence because it is not clear that research sponsors have any obligation to minimize risks that do not stem from research participation.

Singh J. A. , “India's Regulatory Reforms on Compensation for Clinical Trial Injuries and Deaths: Urgent Need for Revisiting,” Indian Journal of Medical Ethics 10, no. 3 (2013): 195–97.

See Hart Honoré , supra note 36, at 34–35, describing explanatory analysis of causes.

See Wendler D. Emanuel E. J. Lie R. K. , “The Standard of Care Debate: Can Research in Developing Countries Be Both Ethical and Responsive to Those Countries' Health Needs?” American Journal of Public Health 94, no. 6 (June 2004): 923–928, at 923–924.

See id.

See id., at 924.

What is “necessary” in this situation is, of course, not uncontroversial. A full exploration of the concept of necessity is, however, not needed in order to explore the issues related to causation and the standard of care addressed here.

See Wendler , “The Standard of Care Debate,” supra note 41, at 927.

Id., at 927. The authors define those terms as follows: “(1) scientific necessity: Investigators must use less than the worldwide best methods to answer the scientific question posed by the trial; (2) relevance for the host community: Answering the scientific question posed by the trial will help address an important health need of the host community; (3) sufficient host community benefit: The trial will produce a fair level of benefit for the host community; and (4) subject and host community nonmaleficence: Subjects and the host community will not be made prospectively worse off than they would be in the absence of the trial.”.

It should be acknowledged that many still view the short course AZT trials as controversial. I do not intend to make a broad foray into the ethics of placebo controlled research here, but rather limit my comments to the question of whether a person can be said to have been injured in a way that warrants compensation by receiving standard of care treatment.

See London A. J. , “The Ambiguity and the Exigency: Clarifying ‘Standard of Care’ Arguments in International Research,” The Journal of Medicine and Philosophy 25, no. 4 (2000): 379–397. Examining distinctions between the de facto and de jure local standards of care, and arguing that a broad conception of clinical equipoise might help to define what standard of care may ethically be given to trial participants.

See supra section B.

See, e.g., Slack C. Stobie M. Milford C. Lindegger G. Wassenaar D. Strode A. IJsselmuiden C. , “Provision of HIV Treatment in HIV Preventive Vaccine Trials: A Developing Country Perspective,” Social Science & Medicine 60, no. 6 (2005): 1197–1208. It should be noted that this scenario is distinct from that in which a participant in the control arm of a study is receiving standard of care treatment, but must undergo additional procedures that are solely for research purposes and do not have clinical benefit. If a participant is injured due to a procedure performed solely for research purposes, both care and compensation are appropriate.

See, e.g., Joffe S. Miller F. , “Bench to Bedside: Mapping the Moral Terrain of Clinical Research,” supra note 23, 36–37.

G.S.R. 53(E)2(i)(5)(e), supra note 1 requiring compensation for “adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol.” This rule might be subject to an exception where the subject is injured due to an unforeseen interaction between the concomitant medication and the drug or device being studied.

See, e.g., Joffe S. Miller F. , “Bench to Bedside: Mapping the Moral Terrain of Clinical Research,” supra note 23, 36–37.

These types of injury cannot be said to be “caused” by research. Other systems of compensation commonly bar compensation for injuries incurred in this way. See, e.g., New Zealand Accident Compensation Act 2001, (2001).

see also Health Research Council of New Zealand, “Guidelines on Ethics in Health Research,” 2005, available at <http://www.hrc.govt.nz/news-and-publications/publications/ethics-and-regulatory> (last visited February 18, 2015).

In some circumstances, it could be reasonable to draw a bright line rule for no-fault compensation in case of any injury or death that occurs during research. The benefits of such an approach (easy administration) are outweighed in this case by its cost. By removing the causation element of research related injuries, regulators would expose sponsors to unpredictable and potentially exorbitant compensation costs. Such a bright line rule might also provide less incentive for research sponsors to engage in proactive risk minimization activities because risk minimization alone would not necessarily reduce the sponsor's financial burden.

Chaudhury R. R. , “Report of the Prof. Ranjit Roy Chaudhury Expert Committee to Formulate Policy and Guidelines for Approval of New Drugs, Clinical Trials and Banning of Drugs,” (2013) available at <http://cdsco.nic.in/writereaddata/Report_of_Dr_Ranjit_Roy.pdf> (last visited February 18, 2015).

See also Drugs and Cosmetics (Third Amendment) Rules (2014) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 292(E) available at <http://cdsco.nic.in/writereaddata/1Draft%20Rules%20on%20compensation.pdf> (last visited February 18, 2015).

See “Actions on the Recommendations of Prof. Ranjit Roy Chaudhury Expert Committee to Formulate Policy and Guidelines for Approval of New Drugs, Clinical Trials and Banning of Drugs,” available at <http://cdsco.nic.in/writereaddata/Action_RR_Choudhury_Committee__06.11.2013.pdf>(last visited February 18, 2015): 6–8.

See also G.S.R. 292 (E) supra note 55.

Whether the ethics review committees and licensing authorities are the best choice of independent expert decision makers in this context remains an open question. See Sugarman , “India's New Policy to Protect Research Participants,” supra note 19. Nonetheless, the recognition of the need for an independent expert decision maker is a step in the right direction that allows the government to take advantage of the benefits of acoustic separation.

Drugs and Cosmetics (Sixth Amendment) Rules (2014), Galette of India, Part II - Section 3 - Subsection (i) G.S.R. 889 (E), available at <http://www.cdsco.nic.in/writereaddata/Notificatiohn%20on%20Compensation%20on%20clincial%20trial%20(1).pdf> (last visited March 4, 2015).

“Draft Formula to Determine the Quantum of Compensation In Case Of Trial Related Injury (Other Than Death)” available at <http://www.cdsco.nic.in/writereaddata/uploaded_for_website__1_FINAL2014.pdf> (last visited February 18, 2015).

See Dan-Cohen , “Decision Rules and Conduct Rules,” supra note 4 at 630.

Id., at 629–630.

Id.

See Id., at 632–635.

Id.

See id.

Id., at 626.

Id., at 634–636.

See, e.g., Rubin E. L. , “Law and Legislation in the Administrative State,” Columbia Law Review 89 (1989): 369–426, at 382–383.

See id., at 383–385 Edward L. Rubin has characterized these rules further as being either “transitive” or “intransitive” depending on whether they are merely internal directives aimed at guiding agency action (intransitive) or directly speaking to those who are to be regulated (transitive). If applied to Dan-Cohen's framework, conduct rules may be (or should be) highly transitive – they should pass through the agency and be acted upon by the regulated parties – while decision rules may be highly intransitive because they are intended solely to guide agency conduct. Intransitive rules have higher degrees of acoustic separation, and this is acceptable within the norms governing legal frameworks, because they are not intended to guide public conduct. The lack of public notice of the law's content therefore does not run afoul of due process or other fairness considerations.

See London, “A Non-Paternalistic Model of Research Ethics and Oversight,” supra note 10.

See Drugs and Cosmetics (Third Amendment) Rules (2014) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 292(E), supra note 55.

For example, in the past, India's research industry has faced robust criticism over non-payment to individuals who were injured or killed due to participation in biomedical research. Reporting on the mechanism of compensation was less developed than reporting on the fact of injury and non-payment. See, e.g., India, “Only 45 of 2,868 Clinical Trial Deaths Compensated since 2005,” supra note 9.

Buncombe Lakhani , “Without Consent,” supra note 9.

See, e.g. Rubin , supra note 67.

This is a vital part of the informed consent process. See Emanuel E. J. Wendler D. Grady C. , “What Makes Clinical Research Ethical?” JAMA 283, no. 20 (2000): 2701–2711, at 2706.

See Rubin , “Law and Legislation in the Administrative State,” supra note 67, at 406.

See Dan-Cohen , “Decision Rules and Conduct Rules,” supra note 4, at 648–651 (discussing the implications of acoustic separation for the definition of criminal offenses in relation to common morality).

Admittedly, the United States falls far behind many other high income countries because it does not have a national compensation requirement for research related injuries. See, 45 C.F.R. 46.116(a)(6).

See also Kulkarni A. Bhatt A. , “Causality Assessment: A Causality of Compensation?” Perspectives in Clinical Research 4, no. 4 (2013): 196–198.

Drugs and Cosmetics (Third Amendment) Rules (2014) Gazette of India, Part II – Section 3 – Sub-section (i) G.S.R. 292 (E), available at <http://cdsco.nic.in/writereaddata/1Draft%20Rules%20on%20compensation.pdf> (last visited February 18, 2015).

see Drugs and Cosmetics (Sixth Amendment) Rules (2014), supra note 57.