国际人类研究外文文献英文

Short communication International human subject research Taking stock in the wake of the Guatemala affair Eli Y Adashi Professor of Medical Science Warren Alpert Medical School Brown University Providence RI USA a r t i c l ei n f oa b s t r a c t Article history Received 1 April 2011 Accepted 5 May 2011 Available online 12 May 2011 The recent unearthing of a US funded study wherein unknowing Guatemalans were exposed to syphilis gonorrhea or chancroid sent shock waves throughout the scientific community Prompted by this revelation the Presidential Commission for the Study of Bioethical Issues has been convened to determine if current standards adequately guard the health and well being of participants in scientifi c studies supported by the Federal Government This communication revisits the statutory and regulatory framework undergirding federally sponsored human subject research and explores its continued relevance in a rapidly globalizing enterprise The emerging patterns are daunting and disconcerting Over half of all clinical trials registered with ClinicalTrials gov http clinicaltrials gov N100 000 are presently conducted in 145 often poorly resourced nations under the jurisdiction of over 2000 international IRBs Review of the operational characteristics of the Offi ce of Human Research Protection the relevant oversight authority reveals it to be underfunded and understaffed and thus unable to discharge its rapidly globalizing responsibilities A review of federally sponsored human subject research by the Presidential Commission now underway could not be timelier 2011 Elsevier Inc All rights reserved Keywords Human Subject Research Presidential Commission for the Study of Bioethical Issues Guatemala Clinical Trials Offi ce of Human Research Protection On October 1 2010 President Obama apologized to his Guatemalan counterpart for a recently unearthed US Government funded study in the course of which between 1946 and 1948 vulnerable Guatemalan populations were intentionally exposed without their knowledge or consent to the causative agents of syphilis gonorrhea or chancroid 1 Prompted by this revelation President Obama instructed the Presidential Commission for the Study of Bioethical Issues to convene a panel of international experts to ensure that when the US government conducts or funds research current rules for research participants protect people from harm or unethical treatment domestically as well as internationally 2 First convened on February 28 2011 3 the panel has its work cut out for it Whatever the agenda there is no avoiding the question many Americans undoubtedly asked could a study akin to the one in question materialize today In one important sense the answer to this query is no 4 In the sixty plus years following the Guatemala affair the US has crafted and enacted a substantive if imperfect regulatory framework designed to safeguard participants in federally sponsored research 5 Against this contemporary backdrop the Guatemala study would have been deemed fl agrantly non compliant for its reliance on vulnerable subjects in the absence of informed consent and its failure to obtain advance group review of the study s risk to benefi t ratio That said a reevaluation of the protection afforded research subjects taking part in federally sponsored studies is both proper and timely After all the mere existence of relevant statutes does not in itself guarantee compliance Moreover regulatory frameworks written decades ago may no longer be up to the task This latter caveat rings especially true for the interna tional clinical trial scene which has been and remains in a Contemporary Clinical Trials 32 2011 605 607 Financial disclosures Dr Adashi declares no confl ict of interest Funding support There is none to declare Warren Alpert Medical School Brown University 101 Dudley Street Providence RI 02905 USA Tel 1 401 863 9037 E mail address Eli Adashi brown edu 1551 7144 see front matter 2011 Elsevier Inc All rights reserved doi 10 1016 j cct 2011 05 001 Contents lists available at ScienceDirect Contemporary Clinical Trials journal homepage dynamic state of uncomfortable fl ux It is the objective of this communication to review the statutory and regulatory framework undergirding federally sponsored human subject research HSR and to explore its continued relevance in a rapidly globalizing research enterprise The statutory and regulatory framework governing federally supported HSR The governance of federally conducted supported or otherwise regulated non exempt HSR in the US or abroad is anchored by the National Research Act of 1974 PL 93 348 implemented by the federal regulations that comprise the Common Rule 5 and overseen by the Offi ce for Human Research Protections OHRP of the Department of Health and Human Services DHHS Pursuant to this regulatory paradigm institutions and organizations seeking federal support for investigator initiated research must fi rst register their Institutional Review Board IRB and fi le a Federalwide Assurance with the OHRP Investigators in turn must submit their research plan to an IRB and to an expert federal panel for peer review prior to the issuance of a grant award Post award oversight by OHRP relies on mandatory incident reporting by IRBs and on selective not for cause surveillance thereof For cause evaluations triggered by allegations fi ndings or concerns of non compliance may if confi rmed result in the imposition of sanctions commensurate with the degree of infraction The globalization of federally supported HSR At the time of this writing the unabated globalization of biomedical research has reached a tipping point whereupon over half of all clinical trials registered with ClinicalTrials gov http clinicaltrials gov N100 000 are conducted beyond the confi nes of the continental US 6 Continental Africa alone is now home to over 2100 clinical trials of which N10 are federally funded 6 Whereas Europe continues to claim a signifi cant proportion 25 of clinical trials 16 occur in Lower Middle Income Countries LMICs whose gross na tional income GNI per capita is 4000 6 7 No longer subscribing to the one institution one IRB construct today s clinical trials constitute international joint ventures involving several often non academic institutions encom passing multiple research sites Faced with these evolving trends the US must strike a careful global balance between its commitment to uncompromising human subject protection and its desire to sustain the pace of research and discovery Challenges to the responsible conduct of HSR in the developing world The decades old domestic IRB system is overworked underfunded and notoriously ineffi cient 8 Applied abroad especially in resource poor settings these same domestic shortcomings stand to be markedly amplifi ed This should hardly come as a surprise After all IRBs or Research Ethics Committees operating in developing countries must grapple with far worse fi nancial and human resource constraints than their developed counterparts Presently close to 700 active international OHRP registered IRBs operate within LMICs An additional 189 hail from the 49 nations constituting the LDCs Least Developed Countries whose annual GNI per capita is 900 7 Financial challenges aside institutions and organizations in developing countries are often hard pressed to constitute a functional Common Rule compliant IRB 46 107 119 orequivalent 5 froma purely local talent pool Skills in demand include but are not limited to study design monitoring and risk assessment 9 Inevitably then questions linger as to the ability of international IRBs to rigorously monitor clinical trials safeguard study subjects and ensure the integrity of the data collected Oversight of international HSR is equally challenged Faced with an ever growing volume of international HSR and an ever expanding IRB universe OHRP has been doing its best to adapt However the rapid proliferation and globali zation of clinical trials may well have stretched if not outgrown OHRP s oversight capacity Currently over 2000 active international IRBs in 145 countries are registered with OHRP With an annual budget of 7 million and a correspondingly modest staff this key Federal agency is operating with the utmost effi ciency commensurate with its means Over the 2000 2010 interval OHRP has issued a total of 7 compliance oversight determination letters to interna tional institutions and organizations Between 1990 and 2007 the annual rate of all including international site visits conducted by OHRP did not exceed 6 per year Instead most evaluations involved the exchange of letters and of supporting documents between OHRP and the grantee institution under scrutiny Inevitably then the oversight capacity of international HSR by OHRP is limited and potentially divorced from on the ground infractions Similar concerns have been raised by the Inspector General of DHHS with respect to oversight exercised by the Food and Drug Administration FDA Although most new drugs seeking FDA approval were the subject of international trials site visits were limited to 0 7 of the locales in question 10 Conclusions Whatever recommendations may be enunciated by the Presidential Commission for the Study of Bioethical Issues eliminating the conduct of federally sponsored HSR in developing countries should not be one Course correction while urgent need not imply the discontinuation of impor tant pursuits once properly conducted There are good reasons for conducting clinical trials abroad Indeed benefi ts can and do accrue to developing countries Interventions designed to address major maladies of developing nations e g malaria must be conducted in context to ensure effi cacy Similar considerations apply to the development of personalized therapeutics forconditions e g non small cell lung cancer the responsiveness of which is ethnically constrained 11 In the not too distant past justice one of the foundational principles of research ethics largely meant excluding vulnerable subjects from research unless their inclusion could be justifi ed Since then however as partic ipation in clinical trials has come to be seen as a benefi t justice has also come to mean inclusion of vulnerable subjects unless their exclusion could be justifi ed With the Guatema lan affair as a catalyst it is our hope that the Presidential Commission for the Study of Bioethical Issues will not lose sight 606E Y Adashi Contemporary Clinical Trials 32 2011 605 607 of this second requirement of justice in the course of its all important pursuit of the fi rst References 1 Reverby SM Normal exposure and inoculation syphilis a PHS Tuskegee doctorinGuatemala 1946 1948 JPolicyHist2011 23 6 28 2 Presidential Memorandum Review of human subjects protection November 24 2010 http www whitehouse gov the press offi ce 2010 11 24 presidential memorandum review human subjects protection 31 March 2011 3 The Presidential Commission for the Study of Bioethical Issues Agenda for Feb 28 March 1 2011 http www bioethics gov meetings 0228