This is a response to the document "Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing" [regulations.gov Docket No. FDA-2012-N-0170, FR Doc No: 2012-5476] ( http://www.regulations.gov/#!documentDetail;D=FDA-2012-N-0170-0001 ).
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Response to "Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing" [regulations.gov Docket No. FDA-2012-N-0170, FR Doc No: 2012-5476]
Thank you for the opportunity to provide feeback to "Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing" [regulations.gov Docket No. FDA-2012-N-0170, FR Doc No: 2012-5476]. This response document shall briefly address human subject protections, with special reference to issues identified by U.S. Office of Human Research Protections (OHRP 2011).
Protection of Subject Data
As observed by the U.S. Office of Human Research Protections 'There are no specific data security protections for IRB-reviewed research: regulations require IRBs to determine, for each study, “when appropriate [that] there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.”' (OHRP 2011). The management of subject data is increasingly being outsourced and commercialised by federal agencies. Specific examples involving the National Institute of Allergy and Infectious Diseases [NIAID] include Contract HHSN272-2008-00013C with the EMMES Corporation (OIG 2011b) and Contract N01-AI-15416 With the University of California at San Francisco (OIG 2011c). In 2011, following an investigation by the U.S. Department of Health and Human Services [HHS] Office for Civil Rights [OCR], the University of California agreed to settle potential violations of the Health Insurance Portability and Accountability Act of 1996 [HIPAA] Privacy and Security Rules, after it was uncovered that between 2005-2008, unauthorized employees had repeatedly looked at the electronic protected health information of numerous patients (HHS 2011). It is therefore imperative that the HIPAA Privacy and Security Rules be adopted and applied to clinical trials of FDA-regulated products, with the same applicable penalties for breaches of patient/subject privacy.
Biospecimens and Subject Privacy
Circumcision of male minors, in the absence of a clear and present immediate medical indication, is a controversial practice within the medical profession (KNMG 2010; Smith 2011). Foreskins excised from minors in the absence of a clear and present immediate medical indication, almost invariably present in a normal healthy state, and as such their excision and preservation contributes little to the study of the pathology of disease. Further, the most promising advances in the field of stem cell research, are to be found in cell lines derived from adult sources such as dental pulp stem cells (Authur et al 2008) and bone marrow stem cells (Wada et al 2011), rather than stem cell lines derived from the excised healthy foreskins of minors.
Products derived from foreskins excised en masse from minors in the absence of clear and present immediate medical indications, are frequently utilised in the commercial medical product, and more especially cosmetics industries (Advanced Healing 2011; Ballantyne 2009; LifeCell 2012; Organogenesis 2011; Pitman 2008; SkinMedica 2011). As observed by the U.S. Department of Health and Human Services Office of Human Research Protections, “Changing technology in the field of genomics has dramatically increased the amount and nature of information about individuals that can be obtained from their DNA” (OHRP 2011). Valid concerns therefore exist for the future privacy of children whose healthy tissues are likely to be acquired by commercial interests in the cosmetic and medical product industries - and may be retained indefinitely - due to presently unforeseeable technological advances in the field of genomics.
Doubts exist about the appropriateness of utilising products derived from foreskin and other healthy tissue excised from minors, in the cosmetic and medical product industries, on the basis of exculpatory consent forms signed by parents and legal guardians of minors, and whether it is appropriate for parents and legal guardians to give explicit consent for these purposes.
The provision of information to parents on circumcision consent forms about the storage, transfer, processing, sale or any other use of excised healthy foreskins is unstudied. However, a survey conducted by Schaefer et al (2011) of consent forms from U.S. in vitro fertilization clinics and the provision of information to egg donors of the potential for embryonic research using donated eggs, concluded that “egg donors in the United States, including some who may have a moral objection to research and stem cell research, are not being informed that embryos created with their donated eggs may in fact be used for these purposes”, suggesting the possibility that incomplete information is also being provided to parents about the use of foreskin and other healthy tissue excised from minors.
It is therefore imperative that the FDA mandate that clinical trials for FDA-regulated products must not incorporate the use of foreskin or other healthy tissue excised from minors.
Vulnerable Populations, Overseas Clinical Trials and the Informed Consent of Subjects
As observed by the OHRP (2011) 'Many have called for legislation to extend the Common Rule protections to all research with human subjects conducted in the U.S., regardless of funding source'.
In 2011, the Department of Health and Human Services Office of Inspector General [OIG] published a series of audit reports revealing that throughout the fiscal years 2000-2010, institutes under the aegis of the National Institutes of Health [NIH], did not comply with the time and amount requirements specified in appropriations statutes, in awarding federal contracts to commercial partners, committing the federal government to tens of millions of dollars of expenditure ahead of appropriation of funds from Congress. Specific examples involving NIAID include Contract HHSN266-2006-00015C with NexBio, Inc. (OIG 2011a), Contract HHSN272-2008-00013C with the EMMES Corporation (OIG 2011b), Contract N01-AI-15416 with the University of California at San Francisco (OIG 2011c) and Contract N01-AI-3-0052 with Avecia Biologics Limited (OIG 2011d).
During this time, federal agencies also funded and sponsored research conducted abroad, that would be unlikely to receive ethical approval to be conducted in the United States, incorporating the excision of healthy tissue from subjects in the absence of a clear and present immediate medical indication. Specific examples include NIAIDs sponsorship and funding of ClinicalTrials.gov registered trials NCT00059371 and NCT00425984 (Bailey et al 2007; Gray et al 2007), the methodology, conclusions and ethics of which have been questioned in the professional literature (Boyle & Hill 2011; Green et al 2010). Consent forms for these trials failed to include then known information, from the professional medical literature, about the importance to mens sexual health of the prepuce, frenulum, ridged band and other tissues removed by circumcision (Taylor et al 1996), our understanding of which has grown in the years since (Frisch et al 2011; Sorrells et al 2007).
Of concern, is that the results of the above trials are increasingly being used to justify the en masse circumcision of male minors in the absence of clear and present immediate medical indications, both in the United States and abroad (CDC 2011, Llewellyn 2012).
Clinical trials for FDA-regulated products for the excision of healthy tissue from subjects in the absence of a clear and present immediate medical indication, must be limited to consenting adult subjects and consent forms must contain full and complete information, drawn from the professional medical literature, about the biological functions of the tissue to be excised, and regardless of whether conducted in the United States or abroad, must be conducted according to the provisions of the Common Rule to which clinical trials in the United States must be conducted.
Advanced Healing (2011) Dermagraph Active Living Cells Overview Link http://www.dermagraft.com/about/overview/ Accessed: 2012-01-16. Archived by WebCite at http://www.webcitation.org/64jhakjim
Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S (2008) Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues in Stem Cells. 2008 Jul;26(7):1787-95. Epub 2008 May 22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18499892
Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN, Williams CF, Campbell RT, Ndinya-Achola JO (2007) Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet369(9562),643–656 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17321310
Ballantyne, C (2009) A Cut above the Rest?: Wrinkle Treatment Uses Babies' Foreskins Scientific American 12 February 2009 [Epub] Full-text available at http://www.scientificamerican.com/article.cfm?id=a-cut-above-the-rest-wrin Accessed: 2012-01-18. Archived by WebCite at http://www.webcitation.org/64mLMhvCA
Boyle GJ, Hill G (2011) Sub-Saharan African randomised clinical trials into male circumcision and HIV transmission: methodological, ethical and legal concerns J Law Med. 2011 Dec;19(2):316-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22320006
CDC (2011) Trends in In-Hospital Newborn Male Circumcision - United States 1999-2010 Prepared by Xinjian Zhang, PhD, Sanjyot Shinde, PhD, Peter H Kilmarx, MD, Robert T Chen, MD, Div of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; Shanna Cox, MSPH, Lee Warner, PhD, Div of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion; Maria Owings, PhD, Div of Healthcare Statistics, National Center for Health Statistics; Charbel El Bcheraoui, PhD, EIS Officer, CDC. Morbidity and Mortality Weekly Report (MMWR) Full-text available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a4.htm?s_cid=mm6034a4_w
Frisch M, Lindholm M, Grønbæk M (2011) Male circumcision and sexual function in men and women: a survey-based, cross-sectional study in Denmark Int J Epidemiol. 2011 Oct;40(5):1367-81. Epub 2011 Jun 14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21672947
Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, Sewankambo NK, Wabwire-Mangen F, Bacon MC, Williams CF, Opendi P, Reynolds SJ, Laeyendecker O, Quinn TC, Wawer MJ (2007) Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet369(9562),657–666 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17321311
Green LW, Travis JW, McAllister RG, Peterson KW, Vardanyan AN, Craig A (2010) Male circumcision and HIV prevention insufficient evidence and neglected external validity Am J Prev Med. 2010 Nov;39(5):479-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20965388
HHS (2011) University of California settles HIPAA Privacy and Security case involving UCLA Health System facilities HHS Press Office published 7 July 2011 website Archived at http://liveweb.archive.org/http://www.hhs.gov/news/press/2011pres/07/20110707a.html Retrieved 02 October 2011
KNMG (2010) Non-theraputic circumcision of male minors Royal Dutch Medical Association Full-text available at http://knmg.artsennet.nl/web/file?uuid=579e836d-ea83-410f-9889-feb7eda87cd5&owner=a8a9ce0e-f42b-47a5-960e-be08025b7b04&contentid=77976
LifeCell (2012) AlloDerm Tissue Matrix defined Full-text available at http://www.lifecell.com/alloderm-regenerative-tissue-matrix/95/ Accessed: 2012-01-18. Archived by WebCite at http://www.webcitation.org/64mqrqxmQ
Llewellyn, E (2012) Infant Circumcision: A Tipping Point for HIV Prevention USAIS Frontlines May/June 2012 Full-text available at http://www.usaid.gov/press/frontlines/fl_may12/FL_may12_U5_SWAZILAND.html Accessed: 2012-05-20. Archived by WebCite at http://www.webcitation.org/67nyQ5V2M
OHRP (2011) Regulatory Changes in ANPRM Comparison of Existing Rules with Some of the Changes Being Considered Office of Human Research Protections website Full-text available at http://www.hhs.gov/ohrp/humansubjects/anprmchangetable.html Accessed: 2012-01-16. Archived by WebCite at http://www.webcitation.org/64jh4cWek
OIG (2011a) Appropriations Funding for National Institute of Allergy and Infectious Diseases Contract HHSN266-2006-00015C With NexBio, Inc. (A-03-10-03119) Health and Human Services Office of Inspector General website 21 September 2011 Full-text available at http://oig.hhs.gov/oas/reports/region3/31003119.pdf
OIG (2011b) Appropriations Funding for National Institute of Allergy and Infectious Diseases Contract HHSN272-2008-00013C with the EMMES Corporation (A-03-10-03115) Health and Human Services Office of Inspector General website 31 October 2011 Full-text available at http://oig.hhs.gov/oas/reports/region3/31003115.pdf
OIG (2011c) Appropriations Funding for National Institute of Allergy and Infectious Diseases Contract N01-AI-15416 With the University of California at San Francisco Audit (A-03-10-03120) on the Health and Human Services Office of Inspector General website 10 July 2011 Available at http://oig.hhs.gov/oas/reports/region3/31003120.pdf
OIG (2011d)Appropriations Funding for National Institute of Allergy and Infectious Diseases Contract N01-AI-3-0052 With Avecia Biologics Limited (A-03-10-03117) Health and Human Services Office of Inspector General website 21 September 2011 Full-text available at http://oig.hhs.gov/oas/reports/region3/31003117.pdf
Organogenesis (2011) Apligraf: How Is It Made? Link http://www.apligraf.com/professional/what_is_apligraf/how_is_it_made/ Accessed: 2012-01-16. Archived by WebCite at http://www.webcitation.org/64jhpT91Q
Pitman, S (2008) Babies’ foreskin dubbed as new anti-aging treatment Cosmetic Design Full-text available at http://www.cosmeticsdesign.com/Formulation-Science/Babies-foreskin-dubbed-as-new-anti-aging-treatment Accessed: 2012-01-16. Archived by WebCite at http://www.webcitation.org/64ji8mqbP
Schaefer GO, Sinaii N, Grady C (2011) Informing egg donors of the potential for embryonic research: a survey of consent forms from U.S. in vitro fertilization clinics Fertil Steril. 2011 Dec 22. [Epub ahead of print] Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22196714
SkinMedica (2011) Key Ingredients Link http://www.skinmedica.com/skin-care-products/skin-rejuvenation/tns-recovery-complex#tab2 Accessed: 2012-01-16. Archived by WebCite at http://www.webcitation.org/64jiK7Gdx
Smith JF (2011) The professional imperative for obstetrician-gynecologists to discontinue newborn male circumcision Am J Perinatol. 2011 Feb;28(2):125-8. Epub 2010 Aug 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed?term=20700861
Sorrells ML, Snyder JL, Reiss MD, Eden C, Milos MF, Wilcox N, Van Howe RS (2007) Fine-touch pressure thresholds in the adult penis BJU Int. 2007 Apr;99(4):864-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17378847
Taylor, J.P., A.P. Lockwood and A.J.Taylor The prepuce: Specialized mucosa of the penis and its loss to circumcision Journal of Urology (1996), 77, 291-295 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed?term=8800902
Wada N, Bartold PM, Gronthos S (2011) Human foreskin fibroblasts exert immunomodulatory properties by a different mechanism to bone marrow stromal/stem cells Stem Cells Dev. 2011 Apr;20(4):647-59. Epub 2010 Oct 12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed?term=20712449