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Protecting Human Research Subjects

Statement of

William A. Raub, Ph.D
Deputy Assistant Secretary for Science Policy
Department of Health and Human Services


the Subcommittee on Public Health
Senate Committee on Health, Education, Labor, and Pensions

May 25, 2000


Good morning, Mr. Chairman and members of the Subcommittee. I am William Raub, Deputy Assistant Secretary for Science Policy for the Department of Health and Human Services (HHS). I appreciate this opportunity to discuss HHS efforts to protect human research subjects throughout our programs and, in particular, to enhance oversight of human gene transfer research. Accompanying me today are Dr. Kathryn Zoon, Director of the Center for Biologics Evaluation and Research, Food and Drug Administration (FDA) and Dr. Lana Skirboll, Director, Office of Science Policy, National Institutes of Health (NIH).

On February 2, during an earlier hearing before this Subcommittee, colleagues from FDA and NIH described efforts then underway at the two agencies to address issues arising in the aftermath of the death of a patient at the University of Pennsylvania as a result of an experimental gene transfer intervention. Our testimony today is intended, in part, to update the Subcommittee on continuing efforts to foster compliance with FDA and NIH requirements associated with human gene transfer research. But our testimony also is intended to extend the discussion to issues associated with the protection of human research subjects in general.

We do this for two reasons. First, we have no cause to believe that gene transfer research is inherently more dangerous than other types of experimental clinical intervention. On the contrary, in recent years, clinical research generally has become even more complex - which, in turn, has engendered a new degree of complexity in the accompanying ethical, safety, and conflict-of-interest considerations. To focus exclusively on human gene transfer research in the face of this broad-based trend would be a disservice both to research subjects and the patients who ultimately may benefit from well-designed and carefully conducted clinical trials.

Second, notwithstanding the many successes over the years in protecting human research subjects from undue and undisclosed risks, we recognize that the protection system itself needs to be enhanced. In this regard, we agree with the finding of the HHS Inspector General that Institutional Review Boards (IRBs) - the central elements of the system - generally have difficulty fulfilling their fundamental responsibilities because many of them are overworked and few have been accorded the necessary authority and resources by their parent institutions. These findings have been reinforced over the last two years by a series of inspections by the HHS Office for Protection from Research Risks (OPRR) - several of which resulted in complete or partial cessation of human subjects research at certain research institutions until corrective actions were taken and approved by OPRR. We therefore feel confident that human gene transfer research will benefit in important ways from efforts to enhance human subjects protection across the board.

President Clinton's concern that public uncertainty about the safety of clinical trials could discourage participation in clinical trials and undermine the progress science has made toward developing new methods to detect, treat, and prevent disease prompted his request late last year that HHS develop a plan to ensure that mandatory safeguards for individuals participating in clinical trials are upheld. In response, on May 23, HHS Secretary Donna E. Shalala announced several new efforts designed to improve protection for human research subjects; to strengthen oversight of all medical research, including human gene transfer research; and to reinforce clinical researchers' responsibility to comply with regulatory requirements. I would like first to give you some background to put the Administration's announcement into historical context. Then, I would like to briefly describe the elements of the Secretary's initiative and discuss recent developments specific to the oversight of human gene transfer trials.


A Brief History of U.S. Regulatory Efforts to Protect Human Research Subjects

Dramatic advances in treatment and prevention of disease have been achieved through research carried out by universities, pharmaceutical and biotechnology companies, and government laboratories and clinics. A crucial part of this research involves the voluntary participation of human subjects in clinical trials to test promising but, in some cases, potentially risky new therapies -- such as gene transfer. Therefore, Federal policy for all research involving human subjects aims to obtain the benefits of new knowledge while protecting subjects against possible abuse or harm.

For more than 50 years, inspired by the principles embodied in the Nuremberg Code, HHS agencies have been committed to protecting individuals from possible abuse or harm in clinical trials and to ensuring that prospective and enrolled participants understand the potential risks and potential benefits, if any, of being a research subject. In the 1960s, for example, amendments to the U.S. Food, Drug and Cosmetic Act established requirements that, at a minimum, people must consent to participating in an experimental therapy. A 1967 FDA policy clarified the procedure further to ensure that informed consent be obtained in writing.

During the 1970s, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research furthered protections with recommendations for the establishment of IRBs, oversight committees that are responsible for ensuring that people who agree to participate in studies understand the nature of the research and willingly consent to participate. In 1972, OPRR was created as part of NIH to ensure the safety and welfare of people who participate in research sponsored by HHS. In 1974, HHS first published regulations protecting human subjects in research. In 1981, these regulations were revised. At the same time, FDA harmonized its regulations with those of HHS as much as possible.

In 1991, 17 agencies of the federal government implemented essentially identical regulations, collectively known as the Common Rule, requiring regular review of proposed and ongoing research to help ensure protection for human research subjects. The rule emphasizes the need for willing consent by prospective and enrolled subjects, based on their understanding of the potential risks and the potential benefits, if any, associated with their participation.

Oversight of Research Involving Human Subjects

Within HHS, responsibility for protection of human research subjects is shared among the OPRR, the FDA, the NIH, and the other funding agencies. OPRR has overall responsibility for ensuring the safety of individuals who participate in HHS-sponsored research. FDA must approve all clinical trials aimed at testing a new drug, biological product, or medical device - including the associated approaches to human subjects protection. NIH requires that research it funds be in compliance with the OPRR-approved assurance for the institution where the research is to be conducted. NIH also develops and maintains the NIH Guidelines for Recombinant DNA Research (NIH Guidelines) and convenes the Recombinant DNA Advisory Committee (RAC), which provides additional oversight and public discussion of human gene transfer research - including whatever ethical issues may be involved.

Within the research community, special oversight committees, known as institutional review boards (IRBs), are responsible for ensuring compliance with the Common Rule and any other applicable regulations related to the protection of human research subjects. Oversight of the informed consent process is a central duty of IRBs. This informed consent process requires that potential participants be given an explanation of purposes of the research, the expected duration of the subject's participation, a description of the procedures to be followed and their potential risks and benefits, if any, and identification of any procedures that are experimental. Research institutions, such as academic health centers, and sponsors of research regulated by FDA, such as pharmaceutical, device, and biotechnology companies, have the ultimate responsibility to ensure that clinical investigators adhere to informed consent requirements.

OPRR has the primary responsibility for developing and implementing the policies, procedures, and regulations to protect human subjects involved in HHS-sponsored research. In carrying out its mission, OPRR has set up formal agreements with more than 4,000 federally-funded universities, hospitals, and other medical and behavioral research institutions in the United States and abroad. These agreements, called "assurances", outline each institution's commitment to conduct its research projects in compliance with the Common Rule and other applicable requirements to protect individuals involved in these projects from undue and undisclosed risks.

In accordance with these assurances, each institution sets up one or more IRBs. The membership of an institution's IRB typically includes physicians, scientists, patient representatives and others who agree to oversee the human subjects research being conducted at the institution. Federal regulations require that each IRB include at least one non-scientist and at least one individual not affiliated with the institution.

OPRR provides guidance to IRB members as well as to scientists and research administrators on the complex ethical issues relating to the involvement of human subjects in medical or behavioral research. The office conducts national educational workshops and provides on-site, technical assistance to institutions conducting HHS-sponsored research.

In addition to its educational activities, OPRR also has a regulatory role. OPRR monitors and evaluates an institution's compliance with the rules governing research subjects. If complaints or concerns arise regarding an institution's oversight practices, OPRR has the authority to investigate and, if necessary, require corrective action or even suspend human subjects research at an institution until the problems are resolved. OPRR is currently involved in 163 open investigations and has undertaken more than 30 site visits since 1993 to various institutions to review compliance with their oversight process.

Last year, the Advisory Committee to the Director of NIH recommended that the OPRR be relocated to the Office of the Secretary to enhance its stature, underscore its independence from the funding agencies, and foster its increased effectiveness. The Committee also recommended that a public advisory council be established to provide broad scientific and ethical guidance to the relocated OPRR. Secretary Shalala accepted the committee's basic recommendation and soon will reassign the human subjects protection functions of the OPRR to the new unit within the Office of Public Health and Science within the Office of the Secretary. The Secretary also expects to announce the appointment of the director for the new office this summer.

Complementing the role of OPRR, FDA has oversight responsibility for all clinical trials and their respective IRBs, including IRBs in industry-sponsored trials. FDA must review the design of all clinical trials designed to test a new medical product before those trials may begin. FDA monitors adverse events during clinical trials and can suspend trials when problems arise and, where indicated, take action to disqualify non-compliant investigators. Each year, FDA inspectors review the activities of approximately 600 clinical investigators and 250 to 300 IRBs.

Oversight of Human Gene Transfer Research

Human gene transfer research is overseen jointly by FDA and NIH. Recent reports of gene transfer trials that provided insufficient human subject protections and involved apparently significant financial conflicts of interest underscored the urgency of taking additional steps to protect human research subjects in these trials. As a result, in March 2000, HHS announced two new initiatives: gene transfer research sponsors now are required to submit monitoring plans in advance to FDA; and NIH and FDA have initiated a series of gene transfer safety symposia.

FDA stepped up its inspections of ongoing gene transfer studies; and NIH enhanced efforts to ensure compliance with the NIH Guidelines and initiated a program of not-for-cause site visits to awardee institutions to promote compliance with award conditions, including safety requirements associated with gene transfer research. These efforts are resulting in additional oversight to that which IRBs already provide. Also, NIH and FDA are working to strengthen and streamline their collaborative efforts to monitor gene transfer trials. And, in recent months, FDA has issued warning letters to several gene transfer researchers for failure to comply with federal guidelines for clinical research, to fully inform participants of its risks and benefits, or to report adverse events promptly. I will discuss some of these efforts in more detail later.


As the number of research projects and study volunteers increases and clinical research becomes ever more complex, the integrity of research must be maintained. Recognizing the need to enhance human subject protections, President Clinton requested that HHS take steps to ensure that critical medical research proceeds in a manner that protects the safety of those making the research possible. In response, Secretary Shalala announced on May 23, 2000 several new efforts designed to improve human research subject safety, to further strengthen government oversight of all medical research, and to reinforce clinical researchers? responsibility to follow federal guidelines. The initiative involves the following five components:

  • education and training
  • informed consent
  • improved monitoring
  • conflicts of interest
  • civil money penalties

I will summarize each component in the order listed.

Education and Training. HHS will undertake an aggressive effort to improve the education and training of clinical investigators, IRB members, and associated IRB and institutional staff. NIH will require research bioethics training and human subjects research training for all clinical investigators receiving NIH funds; such training already is required for NIH clinical investigators. To build on this first step taken by NIH, FDA and OPRR will work together in the coming months to develop a set of aggressive educational standards for required training that ensure all of the researchers under their jurisdiction are properly informed of their roles and responsibilities. Also, OPRR will require institutions, as part of their formal assurance agreements with OPRR, to ensure that their IRB administrators and members will have taken appropriate training before assuming IRB duties. These requirements will be a condition of the NIH awards process and the OPRR assurance process.


Ensure that informed consent has been obtained and is being maintained appropriately. HHS will release guidance this June stating that research institutions and sponsors are expected to conduct an audit of participant records and safety protocols to determine that informed consent has been obtained and is being maintained in accordance with Federal regulations. For particularly risky or complex clinical trials, such as those using highly toxic substances or being performed on vulnerable populations such as children, IRBs will be expected to take additional measures, such as directly observing the informed consent process.

Reconfirming informed consent after any significant trial-related event that may affect a subject's willingness to participate. This June, HHS will direct investigators to reconfirm informed consent of participants after a significant event that may have implications for the safety of participants, such as the unexpected death or serious illness of a trial participant or a patient in a clinical trial using similar scientific techniques that is determined to be related to their participation in the trial. This re-confirmation of informed consent must be obtained in writing and documented in subject records.

Initiate a systematic public review of the informed consent process. This summer, HHS will conduct a widespread review, including consumer advocates, members of the research community, industry representatives, and other interested parties, of the informed consent process with the goal of taking prompt action to strengthen current protections. This process will explore the best way to ensure that subjects are informed of the potential risks and benefits of study participation.

Improved Monitoring. With the explosion of potential new therapies and new avenues of research, IRBs are increasingly strained to fulfill even their basic responsibilities. To improve their ability to monitor ongoing clinical trials, NIH will require that investigators submit Clinical Trial Monitoring Plans for smaller-scale early research trials (Phase I and Phase II) to the NIH for review and will expect investigators to also submit them to the responsible IRB to ensure that the IRB receives the results of study monitoring as frequently as necessary to help ensure subjects' protection. NIH already requires Phase I and Phase II investigators to have such plans. In addition, NIH already requires that Data and Safety Monitoring Boards (DSMBs) be established for all large-scale (Phase III) trials and that these Boards share their summary reports of adverse events observed during the trials with the responsible IRB. Also, for research on medical products intended to be marketed, FDA will issue guidelines delineating the relationship between DSMBs and IRBs; defining when DSMBs should be required and when they should be independent; and discussing responsibilities, confidentiality issues, operational issues, and membership qualifications.

OPRR is streamlining its assurance procedures for research institutions -- thereby making more resources available for monitoring and education both at the institutions and within OPRR. In addition, NIH has issued new guidance allowing grant applicants to defer IRB review of proposed research protocols until after completing the initial phase of NIH peer review but before final funding approval. Previously, NIH required that indication of IRB review and approval be included with all grant applications, even though fewer than half of all applications submitted to NIH are actually funded.

Conflicts of Interest. FDA and NIH already require disclosure of potential financial conflicts of interest to appropriate officials. However, in the wake of statutes passed in the early 1980s to promote technology transfer, individual academic researchers -- and even academic institutions themselves -- now are involved in commercial ventures. These developments have created new ethical and conflict-of-interest considerations of which research subjects should be appropriately apprised. To this end, NIH will issue additional guidance to clarify current Public Health Service regulations regarding conflicts of interest, which will apply to all NIH-funded research. This will set the stage for HHS-sponsored public discussions this summer to find new ways to manage financial conflicts of interest so that research subjects are neither misled nor coerced and to do more toward ensuring that research results are analyzed and presented objectively. Based on these public forums, NIH and FDA will work together to develop new guidance for the medical research community - addressing, for example, what information should be disclosed to potential participants, institutional officials, sponsors, FDA, and NIH, where applicable.

Civil Monetary Penalties. The Administration will send legislation to the Congress providing FDA with new authority to levy civil monetary penalties of up to $250,000 for researchers and up to $1 million for institutions for repeated violation of current Federal regulations. While FDA can currently issue warning letters or impose regulatory sanctions that halt research until problems are rectified, financial penalties give the agency additional tools to sanction those who do not follow Federal regulations. NIH, OPRR and FDA will work more closely together to enforce and target existing penalties where warranted.


Joint Efforts by FDA and NIH

FDA and NIH are working together to ensure effective communication between the two agencies as they jointly oversee human gene transfer research. For example, as previously reported to this Subcommittee, an NIH effort late last year to examine the safety of adenoviral vectors uncovered significant under-reporting of hundreds of serious adverse events to NIH. The failure of investigators to report serious adverse events to NIH is not acceptable and will not be allowed to recur. However, their delinquency with regard to NIH rules does not mean that they were delinquent in their obligations toward FDA. On the contrary, a joint FDA/NIH analysis showed that adverse events in human gene transfer research were appropriately reported to the FDA and in a timely manner, as required by FDA regulations.

FDA and NIH also are working together to streamline requirements applicable to human gene transfer trials. For example, FDA has put into place Standard Operating Procedures and Policies by which FDA notifies NIH of the receipt of serious adverse event reports and amendments to gene transfer protocols. This newly instituted process provides a backup system for ensuring investigator compliance with serious adverse event reporting requirements.

NIH and FDA are co-sponsoring and/or participating in a variety of educational outreach programs to ensure that all investigators, sponsors, and institutions involved in gene transfer research understand the guidelines and regulations concerning gene transfer clinical trials. This afternoon, the NIH will be participating in a satellite training broadcast sponsored by the FDA for clinical investigators regarding clinical trials in gene transfer research. Also today, NIH staff will participate in a conference sponsored by the American Industrial Hygiene Association on the Federal and local institutional oversight of gene transfer research. At the upcoming annual meeting of the American Society of Gene Therapy in June 2000, NIH and FDA will co-chair an educational session on the oversight of human gene transfer research.

FDA has a long history of participating in meetings of the NIH-hosted Recombinant DNA Advisory Committee (RAC), which is a central part of the oversight of human gene therapy trials; a FDA representative is an ex-officio member of the RAC and many other FDA staff routinely participate in RAC meetings and a number of RAC working groups. In addition, FDA participated in or co-sponsored Gene Therapy Policy Conferences. FDA and NIH staff have regularly scheduled meetings at both the working and management levels to discuss gene therapy protocol issues and policies.

This past March, NIH and FDA announced a joint effort to convene Gene Transfer Safety Symposia. These symposia, which will be held approximately four times a year, will bring together leading experts in gene transfer research in a public forum and give them an opportunity to discuss medical and scientific data germane to their specialties. The open sharing and analysis of medical and scientific data from gene transfer research should inform the field and enhance patient safety. The first safety symposium was sponsored by the NIH in March 2000 and focused on the preclinical safety and toxicity profile of a new class of adenoviral vectors (internally deleted, helper dependent adenovirus), which have been recently developed and proposed for clinical use. NIH is sponsoring a second safety symposium on cardiovascular gene transfer research in June 2000.


Since the February hearing, FDA has stepped up its oversight of ongoing human gene transfer trials. Three of these studies are noteworthy in that they are subjects of FDA investigation for apparent non-compliance with applicable rules. Because all three cases remain open, we cannot discuss them in detail today. However, I can report briefly regarding the circumstances of each trial and what FDA has learned from them and from its reviews of other human gene therapy trials.

University of Pennsylvania

As FDA reported in its previous testimony before this Subcommittee, upon learning of the death of a patient in a clinical trial at the Institute for Human Gene Therapy (IHGT), FDA took several actions, including placing the clinical trial on hold. This meant that no additional subjects could be enrolled or treated in the clinical trial for the duration of the hold. FDA investigators then conducted an inspection of the clinical trial, which utilized an investigational adenovirus vector for the gene intended to correct Ornithine Transcarbamylase Deficiency (OTCD).

A notice of inspectional observations (Form FDA 483) was issued on January 19, 2000, at the close of the inspection. The observations regarding the adequacy of oversight and monitoring of this clinical trial raised concerns that similar deficiencies might exist in the conduct of other clinical trials under the sponsorship of IHGT or its Director, Dr. James Wilson, M.D.. Therefore, FDA placed the other related investigational new drug applications (INDs) on clinical hold in order to avoid exposing the human subjects in those clinical trials to a significant and unreasonable risk. These trials remain on hold pending demonstration that an appropriate oversight and clinical monitoring program is in place.

Next, FDA issued a Warning Letter to IHGT based on information obtained during the inspection. The Warning Letter cited the failure of IHGT to maintain an effective IND with respect to its trials. Maintaining an effective IND is important because an IND is the primary and formal mechanism by which a sponsor engages FDA in the clinical trial. Absent accurate, complete, and updated information to an IND, FDA has less than full ability to assess the progress and the problems occurring during the course of the trial.

The Warning Letter also stated that IHGT failed to fulfill the general responsibility of a sponsor, which included not having adequate standard operating procedures for the conduct of clinical studies and not providing the clinical investigators with the information needed to conduct the clinical trials properly. Further, IHGT failed to monitor the conduct of the OTCD study and, in particular, failed to ensure that only eligible human subjects were enrolled and failed to ensure that the clinical investigators provided complete and accurate information to the responsible IRB.

IHGT provided a response to the Form FDA 483 and a partial response to the Warning Letter. The clinical trials, however, remain on clinical hold pending a complete and adequate response to the issues involving the oversight of clinical trials and responses to the other requests for information. Further, the inspection on the IHGT clinical trial and the lack of prompt reporting to FDA via the IND of certain animal testing results led FDA to initiate an inspection of the animal testing facility at the University of Pennsylvania where the gene therapy product was tested prior to use in human subjects. FDA's inspection, conducted in February, found significant deviations from the good laboratory practice (GLP) regulations concerning the conduct of such trials.

In the course of the IHGT investigation, FDA also inspected the IRB at the University of Pennsylvania because this IRB was involved with the oversight of the IHGT clinical trials. The University IRB has voluntarily undertaken necessary corrective actions.

Baylor/St. June Childrens Hospital

On February 4, just two days after the previous hearing before this Subcommittee, FDA learned about the possible contamination of a master viral bank used to manufacture the adenoviral vector lot used in a gene therapy product given to approximately 20 children enrolled as human subjects in clinical trials sponsored by Dr. Laura Bowman at St. Jude Children's Research Hospital - Memphis, Tennessee and Dr. Malcolm Brenner at Baylor College of Medicine - Houston, Texas. FDA immediately placed the three INDs associated with the two sponsors on clinical hold.

The researchers at St. Jude and Baylor were conducting clinical trials on children enrolled as human subjects with relapsed or refractory neuroblastoma (a cancer of the nervous system). The experimental therapy involved using neuroblastoma cells modified with an adenoviral gene therapy vector prepared from the same master viral bank.

After the lead researcher moved to Baylor, the remaining principal researcher at St. Jude conducted a quality control examination of the gene therapy product. The examination revealed that the master viral bank used in the manufacture of the gene therapy product had never been properly tested for HIV-1, the virus that causes Acquired Immunodeficiency Syndrome (AIDS), and Hepatitis C Virus (HCV), a virus that can cause potentially serious liver damage and sometimes death. Researchers at St. Jude sent the material to a contract laboratory for polymerase chain reaction (PCR) testing to determine whether genetic material associated with these viruses was present in the samples. The PCR test, while very sensitive, has a high incidence of false positives (indicating the presence of viral sequences where none exists) unless this test is performed with rigorous quality control and precise laboratory technique. The initial results came back as positive for both HIV-1 and HCV. Although these test results were not definitive, this situation presented a potentially grave health risk for the individuals who had received this investigational treatment, as well as deep concern on the part of their families. If these first test results were accurate, the individuals treated with the product derived from the master viral bank may have been unknowingly exposed to these infectious agents.

FDA was notified of these test results late on a Friday afternoon. By the following Monday, FDA scientists had developed a testing plan and begun its implementation. The remaining supplies of the gene therapy material were very small. These supplies were obtained from St. Jude and Baylor in order to conduct independent testing in FDA laboratories. Using state-of-the-art methodologies, FDA scientists tested each sample by conducting triplicate runs with two separate assays. The samples tested negative, indicating that the master viral bank was negative for both HIV-1 and HCV.

The ability of FDA scientists to conduct timely and accurate testing was crucial to the success of the investigation. The involvement of FDA scientists who were knowledgeable of and experienced in PCR detection of both HIV-1 and HCV using small amounts of samples allowed FDA to provide test results back to each of the clinical sites within seven days of receipt of their sample material. The negative test results provided enormous relief to those individuals who received this material and their families.

Based on the concerns raised in association with the potential viral contamination issue, FDA investigators initiated an inspection of the study being conducted at St. Jude Children's Hospital; the investigation was concluded on February 18, 2000. The inspection revealed inadequate testing of the master viral bank and the use of research grade materials not intended for use in clinical trials. In response, St. Jude established significant new quality assurance measures to address FDA observations and to respond to Office of Protection of Research Risks (OPRR's) concerns involving this gene therapy trial and a bone marrow transplant program not regulated by FDA. The response was adequate to address FDA's concerns. Because of the relationship of the product and the investigator at Baylor, FDA also initiated an inspection of the clinical investigator at Baylor on March 1, 2000. On March 3, 2000 FDA investigators issued a Form FDA 483 and concluded the inspection at Baylor College of Medicine. The inspection revealed minor deficiencies, which were corrected by the sponsor of the clinical trial.

St. Elizabeth's Hospital

Jeffrey M. Isner, M.D., at St. Elizabeth's Medical Center of Boston, has been conducting gene therapy research using genes called vascular endothelial growth factors VEGF and VEGF-2. The VEGF genes are being studied for their potential to stimulate the growth of new blood vessels - a process called angiogenesis - in people with various forms of cardiovascular disease and peripheral vascular disease.

These studies have been ongoing since 1998. FDA put some of these trials on clinical hold in February 2000, due to failure of the sponsors to develop an assay for VEGF-2 levels in the blood of treated subjects. Such an assay is needed in order to evaluate the potential relationship of serious adverse events such as hypotension with the VEGF-2 gene product.

FDA investigators conducted an inspection of VEGF clinical trials at St. Elizabeth's; the investigation was concluded on March 22, 2000. Based upon the inspectional findings, FDA issued a Warning Letter to Dr. Isner in his capacity as principal clinical investigator on April 28, 2000, citing a series of violations including: enrollment of ineligible patients; failure to follow the approved protocol; and failure to protect the welfare of subjects under his care. Dr. Isner now has the responsibility to provide a detailed response to the Warning Letter and to comply with specific requests for information or data.


The FDA reviews of these and other human gene transfer studies identified instances of shortcomings in the following areas:

  • eroded adherence to requirements or standards of informed consent;
  • lack of investigator adherence to good clinical practices and current Federal requirements, including failure to report adverse events properly;
  • lack of adequate quality control and quality assurance programs for the gene therapy products used in clinical trials;
  • an IRB process that is in jeopardy;
  • conflict of interest issues, such as when an investigator also functions as a sponsor;
  • lack of public access to safety and efficacy data from high-risk clinical trials;
  • limited range of enforcement options for Federal authorities to address failure to adhere to FDA regulations and requirements;
  • inadequate resources to meaningfully address the above concerns;
  • need for improved coordination among FDA, NIH, and OPRR; and
  • poor understanding by investigators and institutions of the FDA and NIH roles in gene therapy oversight.

We note that OPRR/NIH independently has identified essentially the same issues through its oversight activities and that the vast majority of these shortcomings are not unique to human gene therapy. Instead, these findings reinforce the need to enhance protection for human research subjects across the board.

NIH Activities

NIH's role in the oversight of human gene transfer research is unique. NIH's oversight of gene transfer research consists of three interrelated components: the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines); the Recombinant DNA Advisory Committee (RAC); and ensuring public access to information about gene transfer research. The NIH Guidelines set forth standards and principles for the conduct of human gene transfer trials and requirements for the submission of protocols and adverse event reports to the NIH. They apply to investigators conducting gene transfer research that is either funded by the NIH or carried out at an institution that receives NIH support for recombinant DNA research of any type. Institutions, principally through Institutional Biosafety Committees (IBCs), are responsible for ensuring that all recombinant DNA research is conducted in accord with the NIH Guidelines. The RAC recommends changes in the NIH Guidelines in light of advances in the knowledge about the science and safety of gene transfer research. It conducts public review and discussion of the scientific, safety, and ethical issues of novel gene transfer protocols. It explores in-depth complex scientific and ethical issues raised by the continuing progress of the research by convening Gene Therapy Policy Conferences, which can also yield important consensus recommendations that guide the field.

After a protocol is registered with the NIH Office of Biotechnology Activities.(OBA), it is forwarded to the 15-member RAC for a preliminary review to determine whether the protocol raises novel and/or unresolved scientific, safety or ethical issues. Novel protocols will undergo in-depth review and public discussion by the RAC. After review, the RAC's recommendations are forwarded to the principal investigator, Institutional Review Board (IRB) and IBC, and FDA.

NIH is committed to ensuring full compliance with the NIH Guidelines. To this end, since this Subcommittee's last hearing on gene transfer research, OBA staff have written to every principal investigator who ever registered a human gene transfer protocol with NIH to reiterate the requirements of the NIH Guidelines and to request that investigators provide OBA with any information that has not been submitted previously in accordance with the NIH Guidelines. To ensure that every principal investigator fully understands the NIH request and is moving expeditiously to submit the required information to OBA, every principal investigator also is being contacted directly by telephone.

In addition, as part of a new NIH grants compliance program, OBA is conducting a series of not-for-cause site visits to NIH-funded institutions in order to assess the level of investigator and institutional understanding of NIH rules. These site visits are not investigations or audits. Rather, they provide a forum for NIH staff to meet with directors of sponsored research, other research administrators responsible for ensuring institutional compliance with the NIH Guidelines, clinical gene transfer researchers, administrators and members of Institutional Biosafety Committees, and IRB administrators and members. Discussions focus on institutional and investigator roles and responsibilities, training and education, and policies and procedures for ensuring compliance with NIH requirements for human subject research in general and gene transfer, in particular. The first three site visits took place in March.

Several efforts are underway to clarify, streamline, and harmonize NIH and FDA requirements for adverse event reporting as well as to improve NIH's oversight of gene transfer trials:

  • Earlier this year, a working group of the Advisory Committee to the Director, NIH (ACD), composed of individuals from outside the Federal government, was established to conduct a review of NIH's role in the oversight of clinical gene transfer research. The working group is scheduled to present its report at the June 8, 2000, ACD meeting. After considering the report of the working group, the ACD will make recommendations to the NIH Director regarding ways to strengthen NIH's oversight of human gene therapy research.
  • Furthermore, an ad hoc RAC working group on adverse event reporting and the ACD working group are formulating recommendations regarding the extent and type of serious adverse event data that should be reported to the NIH.
  • NIH has established a working group to assess the feasibility and utility of creating one or more national Data and Safety Monitoring Boards (DSMB) for gene transfer clinical research.
  • Also, NIH has made substantial progress on the development of an interactive web-based database of gene transfer trials, which both the general public and the scientific community will be able to access and use with ease. The completed database will include core information on each protocol, including trial site, principal investigator, disease under study, vector being used for the gene transfer, and information regarding clinical outcomes.

Since the first gene transfer experiment in 1989, approximately 400 clinical trials registered with the NIH and more than 4,000 patients have participated in gene therapy studies. Approximately 89 percent have been Phase I studies designed to assess safety and toxicity; 10 percent are Phase II studies which assess safety and efficacy and generally involve a larger number and a more diverse population of patients; and 1 percent of the trials have progressed to Phase III efficacy studies. Gene transfer trials target a range of diseases, including cancer, HIV infection, cystic fibrosis, and hemophilia - recently we have seen for the first time evidence of successful treatment of a disease using gene transfer.


Mr. Chairman, we welcome the continuing interest of this Subcommittee in human gene transfer research specifically and in medical research in general. HHS reaffirms its commitment to protecting human research subjects in all areas and to working actively with the research community and the Congress on a program of continuing improvements toward that end.

(Hypertext updated by jch 2000-JUL-21)