PeteFree.comGene Therapy Regulation: The Need for Third Party Fiduciaries - Footnotes
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[1] September 17, 1999, Jesse Gelsinger, University of Pennsylvania Human Gene Transfer Protocol #9512-139: Phase I Study of Adenoviral Vector-Mediated Gene Transfer to Liver in Adults with Partial Ornithine Transcarbamylase Deficiency. National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 18 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>.
[2] Availability for Public Disclosure and Submission to FDA for Public Disclosure of Certain Data and Information Related to Human Gene Therapy and Xenotransplantation, 66 Fed. Reg. 4688 (2001) (to be codified at 21 C.F.R. 20, 312, and 601) (proposed Jan. 18, 2001).
[3] Ornithine carbamoyl phosphate (OCT) deficiency is another name for ornithine transcarbamylase (OTC) deficiency. The missing enzyme is necessary for altering l-ornithine to l-citrulline inside mitochondria in the urea cycle. Urea is the major waste product of the metabolism of amino acids. It is produced in the liver, transported to the blood for excretion by the kidneys, and accounts for 90 percent of the nitrogen-containing compounds in urine. When urea cycle enzymes are missing, ammonia builds up in the blood. See generally DORLAND'S ILLUSTRATED MEDICAL DICTIONARY 1190-91 (27th ed. 1988); PAMELA C. CHAMPE & RICHARD A. HARVEY, LIPPINCOTT'S ILLUSTRATED REVIEWS: BIOCHEMISTRY 236 (2nd ed. 1994); and Brendan Lee & John Goss, Long-Term Correction of Urea Cycle Disorders, 138 J. PEDIATRICS S62, S62 (Jan. 2001).
[4] Males have only one X chromosome; women have two. Females have a better chance of receiving a normal allele of the gene for ornithine carbamoyl phosphate enzyme on their second X chromosome to counter-balance some of the negative effects of the defective copy on their first.
[5] Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health: July 12, 2000 19 (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[8] Brendan Lee & John Goss, Long-Term Correction of Urea Cycle Disorders, 138 J. PEDIATRICS S62, S63 (Jan. 2001). Three sodium based drugs provide an biochemical pathway around the block in the cycle created by the missing enzyme. Their coinventor terms them a partial solution at best. National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 18 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>.
[14] Gene therapy is accomplished with vectors that deliver engineered genetic material that either modifies the host's somatic DNA or acts as an independent genetic code (an episome) for the desired material or action.
[15] Foreseeability is a useful legal concept. It means the quality of being reasonably anticipatable. BLACK'S LAW DICTIONARY 660 (7th ed. 1999).
[16] Adenovirus is a non-enveloped, double-stranded DNA virus.
[17] The ideal vector would (1) be easily manufactured, (2) to high purity, (3) target the desired cell type, (4) infect dividing and quiescent cells, (5) integrate into specific chromosomal sites or constitute a stable episome, (6) include manipulable regulatory elements, (7) avoid provoking an immune response, and (8) provide a consistent therapeutic response. National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 6 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>.
[18] Brendan Lee & John Goss, Long-Term Correction of Urea Cycle Disorders, 138 J. PEDIATRICS S62, S65 (Jan. 2001).
[19] Wild-type (unmodified) adenovirus is a disease-causing agent. Consequently, common sense requires that one try to confine it to the tissues that require the engineered gene it will be modified to carry and no others. Similarly, it makes no sense to risk the introduction of the engineered gene into cells that do not require it.
[21] Id. at S65. See 21 C.F.R. §§ 210-226 (2000).
[22] Id. at S65. Unmodified adenovirus causes conjunctivitis, diarrhea, respiratory diseases, and myocarditis. National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 5 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>. First generation adenovirus vectors were usually based on serotypes 2 and 5 and had the E1A gene deleted. E1A was thought to be necessary for the expression of the other adenoviral genes. However, even in E1's absence, there was still low level expression of viral genes. Second generation vectors modified E2 or deleted E2 and E4 genes, but there was little improvement in toxicity. Kazuhiro Oka et al., Recent Advances in Liver-Directed Gene Therapy: Implications for the Treatment of DyslipidemiaI, 11 CURRENT OPINION IN LIPIDOLOGY 179, 181 (Apr. 2000).
[23] National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 6 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>.
[24] Wanda K. O'Neal et al., Toxicity Associated with Repeated Administration of First-Generation Adenovirus Vectors Does Not Occur with A Helper-Dependent Vector, 6 MOLECULAR MEDICINE 179, 180 (Mar. 2000).
[25] Id. at 179. Integration into the host cell genome ideally guarantees that the engineered gene will be produced in daughter cells when the infected cell divides. If the engineered gene is originally present only as an episome operating outside the chromosome, this is less likely to be the case. Consequently, as host cells divide or die, a vector that delivers only episomes will need to be re-administered to maintain the therapeutic effect of the administered gene. If the host immune system has learned to recognize and destroy the vector virus, then the engineered gene will never make it into its target cells and therapy will fail.
[26] Yu Chen et al., Pre-Existent Adenovirus Antibody Inhibits Systemic Toxicity and Antitumor Activity of CN706 in the Nude Mouse LNCap Xenograft Model: Implications and Proposals for Human Therapy, 11 GENE THERAPY 1553, 1553 (Jul. 20, 2000).
[27] Apheresis is a technique in which one or more components of blood are separated from it before transfusing the blood back into the patient. Immunoapheresis does the same thing for a component of the immune system circulating with the blood.
[28] X Ye et al., Transient Depletion of CD4 Lymphocyte Improves Efficacy of Repeated Administration of Recombinant Adenovirus in the Ornithine Transcarbamylase Deficient Sparse Fur Mouse, 7 GENE THERAPY 1761, 1764 (Oct. 2000).
[29] Mikko O. Hiltunen et al., Biodistribution of Adenoviral Vector to Nontarget Tissues after Local In Vivo Gene Transfer to Arterial Wall Using Intravascular and Periadventitial Gene Delivery Methods, 14 FASEB J. 2230, 2231, 2235 (Nov. 2000).
[30] More of the vector is required in order to better saturate the target organ.
[31] Phase I trials study a new drug's pharmacological action, metabolism, and side effects in people. Usually called safety trials, only 20 to 80 patients participate. Phase 2 begins the controlled aspect of the clinical trial and evaluates the drug's effectiveness, common side effects and associated risks. Several hundred patients may take part. Phase 3 examines the drug's overall risk-benefit ratio. Effects in several hundred to several thousand people are studied. 21 C.F.R. 312.21 §§ (a)-(c) (2001).
[32] National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 20-22 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>.
[34] Aspartate transaminase (AST) in one and alanine transaminase (ALT) in the other.
[35] Necrosis means that tissue has been degraded by enzymes following cell death.
[36] Edema occurs when excess fluid builds up in or between tissues. There are many causes.
[37] These are small spaces in the lung tissue where oxygen and carbon dioxide are exchanged between blood and lung.
[38] Renal tubules are an anatomical part of the kidneys. Necrosis occurs when epithelial cells lining the tubules die. "Acute" in medicine means having a short and relatively severe course.
[39] Infarction occurs when a blood vessel is occluded by an air bubble or blood clot. Downstream tissue dies from lack of oxygen.
[40] DIC results from uncontrolled blood clotting. Wholesale coagulation consumes clotting agents like platelets and coagulation factors. DIC therefore manifests as a combination of uncontrolled clotting and hemorrhage. National Institutes of Health: Recombinant DNA Advisory Committee, Minutes of Symposium and Meeting: December 8-10, 1999 8, 22 (visited Apr. 22, 2001) <http://www4.od.nih.gov/oba/rac/meeting.html>.
[41] Cytokines are proteins released by differing cell types upon recognition of something requiring an immune response. They modulate the response, for example, by stimulating other cells to do their part in an attack on foreign cells, viruses, or material.
[42] The Keystone Symposium was held Jan. 6-12, 2001 in Snowbird, Utah. Huntly Collins, U Penn Scientists Discover Reason for Death of Gene-Therapy Teen, PITTSBURG POST-GAZETTE, Jan. 26, 2001, at B-8. Director Wilson declined to comment on the monkey study until the experiment was published in a medical journal. Id. The study had not been published as of April 29, 2001.
[43] Notice the difference between the reaction of mice and monkeys in the experiment IHGT reported to the closed meeting. Id.
[44] The mere fact that it is currently impossible to tell from the publicly accessible record just what testing was done and what it indicated reveals the harm that confidentiality does when oversight is an issue.
[45] See STEPHEN L. WOLFE, MOLECULAR AND CELLULAR BIOLOGY 800 (1993). These mechanisms include (1) rearrangements of V-J or V-D-J elements that form the variable regions of heavy and light chains of antibody molecules, (2) imprecise DNA synthesis in the hypervariable segments of the variable regions, (3) immunoglobulin class switching among heavy chain constant elements, (4) somatic mutations, and (5) random combination of kappa or lambda light chains with heavy chain polypetides during the final assembly of the antibody in question. Id. at 800.
[46] Anaphylactic responses to bee stings, certain foods, latex etc.
[47] Antigens are any substance capable of eliciting an immune reaction. Generally speaking, they are molecular sized components of an invading organism. Given the way in which the "lookout" components of the immune system are produced, this means that although two people will recognize the same virus, it is likely that their immune systems are recognizing different molecular parts of it.
[48] It is unlikely that any protein in the adenoviral vector coat is toxic in small quantities in and of itself. It is more likely that it is capable of triggering a massive response in only a fraction of the population of humans (and monkeys) when given in large doses. This would explain why the other OTC deficient patient, dosed as Gelsinger was, did not die.
[49] Food and Drug Administration: Center for Biologics Evaluation and Research, Warning Letter: James M. Wilson, Director Institute for Human Gene Therapy (Mar. 3, 2000) 5 <http://www.fda.gov/cber> (follow the links beginning with "gene therapy") (an alternative URL is <www.fda.gov/cber/efoi/warning00.htm>). Similar warning letters, dated Nov. 30, 2000, were sent to Wilson's two collaborators, Mark Batshaw and Steven Raper.
[50] The changes involved eliminating the requirement for (1) holding the study if two patients developed mild toxicity, (2) stopping the study if anyone developed Grade III or higher toxicity, and (3) consulting the Institutional Review Board and the FDA when two subjects experienced a Grade II adverse event. Id. at p. 5. Toxicity grading comes from the National Cancer Institute's Common Toxicity Criteria. This is a list of physiological effects and organ/organ system clinical phenomena, each graded on a spectrum from mild to severe. Food and Drug Administration: Center for Drug Evaluation and Research, NCI Common Toxicity Criteria (visited Apr. 29, 2001) <www.fda.gov/cder/oncrefto.htm>.
[51] Id. at 6. These exclusionary criteria had to do with the development of Grade III toxicity that could be attributed to factors in the patients' medical histories.
[52] Id. at 7. In defending its action, IHGT told the FDA that the Grade III toxicities were clinically non-significant. "From the FDA's perspective, these conclusions about the adverse events and your enrollment of subjects at the next higher dose level ignore your verbal agreement to obtain FDA concurrence before beginning a new cohort...There were no obvious pre-existing risk factors in [the subjects] that could account for the adverse events experienced after the infusion of the investigational vector. Your actions demonstrate a disregard for the protocol stopping rules you had agreed to follow that were designed to protect the safety of the study subjects." Id. at 7-8.
[53] Id. at 7. Liver function testing was incomplete. Alanine transaminase, alkaline phosphatase, hematocrit, and platelet tests were averaged. "The annual report, therefore, misrepresented the true nature of the toxicities experienced by these four subjects."
[54] Id. at 8. Monkey study #98-63 ended within a month (Dec. 1998) of the end of the fourth human cohort. IHGT did not report the worrisome results of the monkey tests until Oct. 27, 1999. "The adverse events experienced by each of the four subjects in cohort four was similar to the liver damage experienced by the monkey infused with the vector used in the OTC human study. While several subjects had experienced thrombocytopenia, no subject had yet experienced clear disseminated intravascular coagulation (DIC) prior to the time the monkeys did. The fact that Subject [censored] subsequently developed DIC confirms that, despite your assertion to the contrary, the toxicity experienced by the monkeys did have significant implications for the safety of the OTCD study. You had an affirmative obligation to notify FDA about these results so they could be evaluated." Id. at 8.
[58] Id. at 12. One patient had a pre-infusion plasma ammonia level of 114 micro molar. The protocol had set the top level at less than 70.
[59] Id. at 14. These included complete blood count (CBC), hemoglobin, creatinine, BUN, PT/PTT, and liver enzyme values. Id. at 14-15.
[60] Id. at 16-17. For example, in one case IHGT apparently reported pre-trial lab tests as representing trial results. Id. at 17.
[64] University of Pennsylvania President Judith Rodin, Action by the University of Pennsylvania in Response to the "Report of the Independent Panel Reviewing the Institute for Gene Therapy, 46 UNIVERSITY PENNSYLVANIA ALMANAC 6, 7 (May 30, 2000).
[65] Food and Drug Administration: Center for Biologics Evaluation and Research, Warning Letter: James M. Wilson, Director Institute for Human Gene Therapy (Jul. 3, 2000) 2 <http://www.fda.gov/cber> (follow the links beginning with "gene therapy") (an alternative URL is <www.fda.gov/cber/efoi/warning00.htm>). The IHGT Quality Assurance Unit had not detected, resolved or documented the deficiencies the FDA found when it investigated.
[71] Id. at 7. These included grading the severity of lesions and defining abnormal pathology. A rodent study had similar problems. Rodent laboratory tests were done without defining the normal limits of clinical pathology values. There were no references to published literatures to substitute for the oversight.
[72] Id. at 8. Numerical information has been censored from the letter. It is not possible to determine exactly how many months past expiration the monkey vector was.
[78] Gene Therapy: Is There Oversight for Patient Safety? Hearing Before the Subcommittee on Public Health of the Committee on Health, Education, Labor, and Pensions, 106th Congress (Feb. 2, 2000) (statement of Paul L. Gelsinger) (visited Apr. 30, 2001) <http://www.senate.gov/~labor/hearings/feb020200wt/frist0202/gelsing/gelsing.htm> (a concise exposition of Paul Gelsinger's point of view), and Sally Lehrman, The Gelsinger Story: Part I, 1 GENELETTER (May 1, 2000) <www.geneletter.com> (follow the links under "archives") (a more personal and detailed account of what happened).
[79] Id. (Hearing). "I can see that I was very naive to have been as trusting as I was."
[80] Deborah Nelson & Rick Weiss, Penn Researchers Sued in Gene Therapy Death; Teen's Parents Also Name Ethicist as Defendant, WASHINGTON POST, Sep. 19, 2000, at A03. Arthur Caplan, Penn's director of bioethics, was named because he had advised the research team to use adults [with only partial OTC deficiency] as subjects. His rationale had been that desperate parents of affected infants [more likely suffering from a fuller form of the disease] could not provide true informed consent. Consequently, the protocol was not aimed at terminally ill patients who had run out of options, and the risks it posed to adults who were coping reasonably well with their illness became harder to justify.
[81] Rick Weiss & Deborah Nelson, Penn Settles Gene Therapy Suit; University Pays Undisclosed Sum to Family of Teen Who Died, WASHINGTON POST, Nov. 4, 2000, at A04. Bioethicist Arthur Caplan was released from the suit.
[82] Raul R. Billings, Editorial: A Gene Therapy Death, 1 GENELETTER (Jun. 1, 2000) <www.geneletter.com> (follow the links under "archives").
[83] A recent editorial by two academic physicians gives cautionary advice: "1. Slow down to explore. Discovery is facilitated by an unhurried attitude...2. Read, but not too much...think again before abandoning an investigation merely because someone else says it can't be done or is unimportant. 3. Pursue quality for its own sake...Meticulous testing is a key to generating the kind of reliable information that can lead to new breakthroughs. 4. Look at the raw data...Looking at the raw data provides a check against the automated averaging of unusual, subtle, or contradictory phenomena. 5. Cultivate smart friends...whose attributes are also complementary to your own." David Paydarfar & William J. Schwartz, An Algorithm for Discovery, 292 SCIENCE 13 (6 Apr. 2001).
[84] Sheryl Gay Stolberg, Biomedicine is Receiving New Scrutiny as Scientists Become Entrepreneurs, NEW YORK TIMES, Feb. 20, 2000 <http:www.nytimes.com>. James Wilson, director of IHGT, founded Genovo Inc. He and the University of Pennsylvania own stock. Genovo has rights to commercial development of Wilson's work, and the corporation contributes one-fifth of IHGT's annual $25 million budget. Although NIH funded the Gelsinger study and Genovo had no direct interest in it, the corporation obviously had a substantial interest in Wilson's reputation for success. University rules prevented Wilson from sitting on Genovo's advisory board, and he was not paid for work on the company's behalf. The Gelsinger consent form apparently revealed the Wilson-Genovo connection. Id. See also William F. Raub, Statement by William F. Raub, Ph.D, Deputy Assistant Secretary for Science Policy U.S. Department of Health and Human Services before the Subcommittee on Public Health Committee on Health, Education, Labor, and Pensions United States Senate, May 25, 2000 (May 25, 2000) (visited Apr. 30, 2001) <http://www.fda.gov/opacom/hpchoice.html> (use "T" link to find "testimony").
[85] The irresistible lure of unencumbered research and profit has drawn American drug companies into the third world. Ethical restraints there are marginal or nonexistent, and ethically questionable practices are common. See Joe Stephens, As Drug Testing Spreads, Profits and Lives Hang in the Balance, WASHINGTON POST, Dec. 17, 2000, at A1; Mary Pat Flaherty et al., The Body Hunters: Overwhelming the Watchdogs, WASHINGTON POST, Dec. 18, 2000, at A1; Sharon LaFraniere, The Dilemma: Submit or Suffer, 'Uniformed Consent' Is Rising Ethic of the Drug Test Boom, WASHINTON POST, Dec. 19, 2000, at A1; John Pomfret & Deborah Nelson, In Rural China, A Genetic Motherlode, Harvard-Led Study Mine DNA Riches, WASHINGTON POST, Dec. 20, 2000, at A1; Karen DeYoung & Deborah Nelson, Latin America is Ripe for Trials, and Fraud, Frantic Pace Could Overwhelm Controls, WASHINGTON POST, Dec. 21, 2000, at A1; and Mary Pat Flaherty & Doug Struck, Life by Luck of the Draw: In Third World Drug Tests Some Subjects Go Untreated, WASHINGTON POST, Dec. 22, 2000, at A1.
[86] While in medical school, I noticed that PhD researchers generally did sounder, tighter research than their MD counterparts. I attributed this to a qualitative difference in training and thinking. From my perspective, PhDs had internalized the scientific method and its standards of proof more deeply than the majority of physicians and physician researchers with whom they worked. Part of this difference is due to the fact that the art of medical practice requires intuition, even if only to search the literature for "might be" causation and cures. Patients seen daily are so obviously different from each other in regards to what works and what doesn't, that conscientious doctors are continually fine-tuning treatment in a way for which there is not yet much statistical proof or basis in the literature. This leads to an anecdotal frame of mind, one that recognizes that just because 85 percent of the people are one way doesn't necessarily mean that the patient in the office is not one of the other 15 or fewer percent. Medicine puts a huge premium upon what one has seen, done, and read. That is why teaching hospitals, those bastions of high numbers and variety, are frequently the best resources for those with problems outside the norm. Anecdotes become experiential jewels stored away to await the needs of the right patient. The difference between PhDs and MDs is virtually required by their substantially different trades.
[87] In the conventional medical setting, it is important to remember that not harming the patient is the first priority, followed by doing whatever works to help them get better. This orientation is profoundly different than that required in the Phase I or II research setting, where harming the patient is a very real possibility.
[88] Investigational New Drug Application, 21 C.F.R. §§ 312.1, 312.2, 312.44 (2000) (respectively scope, applicability, and termination). See also William F. Raub, Statement by William F. Raub, Ph.D, Deputy Assistant Secretary for Science Policy U.S. Department of Health and Human Services before the Subcommittee on Public Health Committee on Health, Education, Labor, and Pensions United States Senate, May 25, 2000 (May 25, 2000) (visited Apr. 30, 2001) <http://www.fda.gov/opacom/hpchoice.html> (use "T" link to find "testimony") (reviewing the state of human subject protection in gene therapy trials).
[89] Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health:July 12, 2000, Appendix B (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings"). Fifty-five new INDs were submitted in fiscal 1999 alone.
[91] Id. at Appendix B. The sponsor is the person who takes responsibility for and initiates the clinical investigation. This may be an individual, pharmaceutical company, government agency, or private organization. An investigator is someone who actually conducts the clinical trial. If a team is involved, the investigator is the responsible leader. 21 C.F.R. § 312.3 (2000).
[92] Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health: July 12, 2000, Appendix B (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[93] Amy Patterson, Statement by Dr. Amy Patterson to the Subcommittee on Public Health of the Committee on Health, Education, Labor and Pensions, February 2,2000 (Feb. 2, 2000) (pdf) (visited April 30, 2001) <http://www4.od.nih.gov/oba/rac/documents1.htm> (explaining the NIH role in gene therapy oversight). (The NIH Guidelines for Research Involving Recombinant DNA Molecules are available at <http://www.nih.gov/od/oba>.)
[94] Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health:July 12, 2000, Appendix B (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[96] NIH, NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) (Jan. 2001) §§ III(A), III(C).
[97] Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health:July 12, 2000, Appendix B (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[99] Investigational New Drug Application, 21 C.F.R. §§ 312.23, 312.66 (2000); Institutional Review Boards, 21 C.F.R. § 56.103 (2000).
[100] NIH, NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) (Jan. 2001) § IV(B)(2). The IBC is "charged with conducting an independent assessment of the containment levels required by the NIH Guidelines for the proposed research; assessing the facilities; procedures, practices, and training and expertise of personnel involved in recombinant DNA research; and ensuring compliance with all surveillance, data reporting, and adverse event reporting requirements..." Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health:July 12, 2000, Appendix B (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[101] NIH, NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) (Jan. 2001) § IV(B)(3).
[102] Id. at §§ III(A)-III(D).
[103] See generally Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health:July 12, 2000 (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings"); William F. Raub, Statement by William F. Raub, Ph.D, Deputy Assistant Secretary for Science Policy U.S. Department of Health and Human Services before the Subcommittee on Public Health Committee on Health, Education, Labor, and Pensions United States Senate, May 25, 2000 (May 25, 2000) (visited Apr. 30, 2001) <http://www.fda.gov/opacom/hpchoice.html> (use "T" link to find "testimony"); Amy Patterson, Statement by Dr. Amy Patterson to the Subcommittee on Public Health of the Committee on Health, Education, Labor and Pensions, February 2,2000 (Feb. 2, 2000) (pdf) (visited April 30, 2001) <http://www4.od.nih.gov/oba/rac/documents1.htm>; and Availability for Public Disclosure and Submission to FDA for Public Disclosure of Certain Data and Information Related to Human Gene Therapy and Xenotransplantation, 66 Fed. Reg. 4688 (2001) (to be codified at 21 C.F.R. 20, 312, and 601) (proposed Jan. 18, 2001).
[104] 21 C.F.R. §§ 20.61, 20.62, 20.63, 20.100, 312.130, 601.50, 601.51 (2000). "Because the agency has no mechanism for reliably tracking what information concerning an unapproved, investigational product has been publicly acknowledged, the agency generally provides no information to the public concerning an investigational product..." Availability for Public Disclosure and Submission to FDA for Public Disclosure of Certain Data and Information Related to Human Gene Therapy and Xenotransplantation, 66 Fed. Reg. 4688 (2001) (to be codified at 21 C.F.R. 20, 312, and 601) (proposed Jan. 18, 2001).
[105] The requirement for adverse event reporting is particularly vulnerable to being overlooked by secretive researchers. (Adverse events include illness and death.) After the Gelsinger death, NIH found that 652 of 691 adverse events had not been reported to the agency; these included at least three deaths. Deborah Wilson & Rick Weiss, Earlier Gene Test Deaths Not Reported; NIH Was Unaware of 'Adverse Events', WASHINGTON POST, Jan. 31, 2000, at A1. The FDA, however, found that it was receiving required reports. Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health: July 12, 2000 (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[106] See Raul R. Billings, Editorial: A Gene Therapy Death, 1 GENELETTER (Jun. 1, 2000) <www.geneletter.com> (follow the links under "archives").
[107] Advisory Committee to the Director Working Group on NIH Oversight of Clinical Gene Transfer Research, Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health: July 12, 2000 (visited Jan. 29, 2001) <http://www.hih.gov/obaut/director> (follow links from "key meetings").
[108] The Working Group thought this would (1) ensure the RAC saw a protocol before any subjects were enrolled in it, (2) streamline the approval process, (3) allow IRBs and IBCs to benefit from RAC expertise, (4) maintain the RAC as a forum for public discussion of novel protocols, (5) allow potential and current research subjects access to information, and (6) hold investigators and review agencies more accountable for their actions. Id.
[109] Availability for Public Disclosure and Submission to FDA for Public Disclosure of Certain Data and Information Related to Human Gene Therapy and Xenotransplantation, 66 Fed. Reg. 4688, 4690 (2001) (to be codified at 21 C.F.R. 20, 312, and 601) (proposed Jan. 18, 2001).
[116] The FDA proposals do not change the core definitions of the commercial data the agency is required to protect. 21 C.F.R. § 20.61(a) (2000). "A trade secret may consist of any commercially valuable plan, formula, process, or device that is used for the making, preparation, compounding, or processing of trade commodities and that can be said to be the end product of either innovation or substantial effort. There must be a direct relationship between the trade secret and the productive process." 21 C.F.R. § 20.61(b) (2000). "Commercial and financial information that is privileged or confidential means valuable data or information which is used in one's business and is of a type customarily held in strict confidence or regarded as privileged and not disclosed to any member of the public by the person to whom it belongs." 21 C.F.R. § 20.61(c), (d) (2000). "Data and information submitted or divulged to the Food and Drug Administration which falls within the definition of a trade secret or confidential or financial information are not available to public disclosure." Id. at (c). "A person who submits records to the Government may designate part or all of the information in such records as exempt from disclosure under exemption 4 of the Freedom of Information Act." Id. at (d).
[117] The agency believes it has the legal authority to override confidentiality requirements when doing so is in the public interest. Availability for Public Disclosure and Submission to FDA for Public Disclosure of Certain Data and Information Related to Human Gene Therapy and Xenotransplantation, 66 Fed. Reg. 4688, 4694 (2001) (to be codified at 21 C.F.R. 20, 312, and 601) (proposed Jan. 18, 2001).
[118] See VB, FDA Clamps Down on Gene Therapy, Tissue Banks, Xenotransplants, BIOTECHNOLOGY NEWSWATCH 1 (Feb. 5, 2001) (noting strong objections from the Biotechnology Industry Organization (BIO)); Kim Coghill, FDA Committee Wrestles with Gene Therapy Privacy Issues, 12 BIOWORLD TODAY (Apr. 9, 2001) (reporting on a meeting of the FDA's Biological Response Modifiers Advisory Committee meeting in which Genzyme Corp. and BIO objected to the proposals for disclosure); and Joshua Runyon, Gelsinger Case May Spark New Regulations, DAILY PENNSYLVANIAN, Apr. 16, 2001 (noting that BIO represents nearly 850 companies and academic institutions, that Targeted Genetics opposes disclosing raw data in real time, that Targeted Genetics bought Genovo in 2000, and that its CEO, Stewart Parker, is a board member of BIO.)
[119] See Food and Drug Administration: Center for Biologics Evaluation and Research, Warning Letter: James M. Wilson, Director Institute for Human Gene Therapy (Mar. 3, 2000); Warning Letter: James M. Wilson, Director Institute for Human Gene Therapy (Jul. 3, 2000); and Warning Letter: Mark L. Batshaw, Children's National Medical Center (Nov. 30, 2000) <http://www.fda.gov/cber> (follow the links beginning with "gene therapy") (an alternative URL is <www.fda.gov/cber/efoi/warning00.htm>).
[120] The author is a former law enforcement officer and supervisor.
[121] "Experimental subjects—who are often patients as well—bring limited understanding of genetics and almost limitless, sometimes desperate, hope to the consent process. Researchers, under competitive pressure and also financial pressure from corporate backers, operate under a paternalistic approach to research subjects, asserting professional expertise and arguing experimental necessity while minimizing the right to self-determination—a key aspect of the exercise of autonomy—of their subjects. The result is a greater or lesser degree of ethical effacement...Thus, the real social and legal challenge has become to protect the autonomy of experimental subjects—truly seeing the ethical face of each subject as person—by preserving and enhancing the social safeguards against the powerful systemic pressures to do otherwise." Jeffrey H. Barker, Commentary: Human Experimentation and the Double Facelessness of a Merciless Epoch, 25 N.Y.U. REV. L. & SOC. CHANGE 603, 619-21 (1999).
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