federal oversight of gene therapy research

Although nuclear transfer techniques, to date, do not utilize recombinant DNA technologies, they do involve genetic manipulation and thus are reviewed and approved through the mechanisms

CHAPTER 13

Federal Oversight of Gene Therapy

Research

THOMAS F KRESINA, PH.D.

BACKGROUND

Federal oversight of biomedical research is an evolving regulatory activity of the federal government Federally supported research is regulated by the federal gov-ernment in the context of animal care and their humane use, as well as for the safe and ethical use of humans in clinical trials For experimental protocols that utilize animals, approval is required by the Institutional Animal Care and Use Committee (IACUC) The IACUC is a committee formed at the local institutional level com-prised of scientists, clinical researchers, institutional officials, and lay and commu-nity representatives/leaders It is the mission of the IACUC to review and approve all experimental protocols involving animal use In a similar fashion, research pro-tocols involving human use are required to receive review and approval by the Insti-tutional Review Board (IRB) The IRB composition and approval procedure is directed by federal law (Protection of Human Subjects, Title 45 Code of Federal Regulations Part 46) and enforced by the Office for the Protection from Research Risks (OPRR) In order to highlight emphatically the role and authority of OPRR,

as well ensure the protection of individuals in clinical trials, the OPRR has recently been elevated from an office at the National Institutes of Health (NIH) to a standing office of the Department of Health and Human Services

Research protocols involving recombinant deoxyribonucleic acid (DNA) mole-cules provide additional risks and thus have additional review and approval require-ments A brief historical account of federal regulation is presented along with current regulatory requirements as well as potential future changes in review and approval procedures

303

An Introduction to Molecular Medicine and Gene Therapy Edited by Thomas F Kresina, PhD

Copyright © 2001 by Wiley-Liss, Inc ISBNs: 0-471-39188-3 (Hardback); 0-471-22387-5 (Electronic)

As research advances provide new and exciting experimental techniques and protocols, the increasing risks in application of these technological advances need

to be addressed Already, sheep, cows, and primates have been cloned using nuclear transfer techniques (see Chapter 2) However, cloning using nuclear transfer techniques is not “new.” The first experiments in nuclear transfer occurred in frogs in 1952 At that time, using the nuclei of tadpoles transferred into frog eggs, scientists raised cloned tadpoles and even adult frogs.The cloning was taken in stride because of the use of embryonic nuclei Indeed such studies have continued and advanced for 45 years without controversy Recent embryonic cloning work was published in 1996 when lambs were reported cloned from embryos In the case of Dolly, modifications in the previously successful protocols resulted in the ability

to clone using an adult cell, a mammary cell reprogrammed to “dedifferentiate,” and thus permitting the development of an adult animal Thus, the field entered the era of nonembryonic cloning In March, 1997, scientist in the United States announced the cloning of primates from embryonic cells using nuclear transfer These techniques have an obvious extension of cloning humans, and that has startled the research and lay communities alike Quickly, 10 days after the adult cell cloning study was announced, President Clinton announced a ban on federal funds to support research on cloning of humans He also requested the private sector to refrain from such research The president went on to urge Congress

to prohibit by law the cloning of humans Three months later in June, 1997, the National Bioethics Advisory Commission concluded that, at this time, it is “morally unacceptable for anyone in the public or private sector, whether in research or clinical setting, to attempt to create a child using somatic cell nuclear transfer cloning” (see Suggested Readings) However, this has not stopped mavericks from announcing the attempt to open “Cloning Clinics” in Chicago or elsewhere These clinics would be a for-profit venture with the noble cause of providing an option of parental cloning for infertile couples Such announcements have created a public outcry and sent elected officials at both the state and federal levels scrambling to establish laws prohibiting the use of cloning technology Thus, in the future, federal or local law may supercede or modify the Food and Drug Administration (FDA) jurisdiction over all recombinant DNA research (which included cloning) in the United States and its territories (see below) This is likely because the frontier continues to rapidly move forward in high profile

Although nuclear transfer techniques, to date, do not utilize recombinant DNA technologies, they do involve genetic manipulation and thus are reviewed and approved through the mechanisms established for gene therapy protocols This procedure continues to evolve over time and comprises submission to the Office

of Recombinant DNA Activities (ORDA)—now a component of the Office of Biotechnology Activities—as well as some form of federal review and/or approval

by the NIH and the FDA In recognition of the expanding complexity of genetic manipulation in research, the NIH established in November, 1999, the Office of Biotechnology Activities, which monitors and coordinates research in recombinant DNA, gene transfer, genetic testing, and xenotransplantation

OFFICE OF BIOTECHNOLOGY ACTIVITIES

As part of the Office of Science Policy at the National Institutes of Health, the Office

of Biotechnology Activities is comprised of the Recombinant DNA and Gene Transfer Committee and two advisory committees of the Department of Heath and Human Services (DHHS)—the Secretary’s Advisory Committee on Genetic Testing and the Secretary’s Advisory Committee on Xenotransplantation The Secretary’s Advisory Committee on Genetic Testing (SACGT) was chartered in June, 1998, in response to recommendations of two working groups commissioned jointly by the NIH and the Department of Energy (DOE) for the Human Genome Project The SACGT grew out of the identified need for broad-based public policy development

to help address the benefits and challenges of genetic knowledge and genetic testing The SACGT advises DHHS and the NIH on all aspects of the development and use

of genetic tests, including the complex medical, ethical, legal, and social issues raised

by genetic testing The committee wrestles with issues such as the development of genetic testing guidelines These include criteria regarding the risks and benefits

of genetic testing, assisting institutional review boards (see below) in reviewing genetic testing protocols in both academic and commercial settings, the ade-quacy of regulatory oversight of genetic tests, provisions for assuring the quality

of genetic testing laboratories, the need for mechanisms to track the introduc-tion of genetic tests to enable accuracy and clinical effectiveness over time to

be evaluated, and safeguarding the privacy and confidentiality of genetic informa-tion and preventing discriminainforma-tion as well as stigmatizainforma-tion based on genetic information

The Secretary’s Advisory Committee on Xenotransplantation (SACX) was char-tered in July, 1999, and is being formulated The committee will consist of 15 voting members, including the chair Members are currently being recruited from author-ities knowledgeable in such fields as xenotransplantation, epidemiology, virology, microbiology, infectious diseases, molecular biology, veterinary medicine, immunol-ogy, transplantation surgery, public health, applicable law, bioethics, social sciences, psychology, patient advocacy, and animal welfare Of the appointed members, at least one shall be a current member of the Xenotransplantation Subcommittee of the Food and Drug Administration Biologic Response Modifiers Advisory Com-mittee and at least one shall be a current member of the Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee This is a newly formed advisory committee of the DHHS/NIH because DHHS has

a vital role in safeguarding public health while fostering the development of promis-ing strategies to treat tissue destruction, organ failure and other public health needs The SACX will consider the full range of complex scientific, medical, social, and ethical issues and the public health concerns raised by xenotransplantation These include ongoing and proposed protocols, and making recommendations to the sec-retary of DHHS on policy and procedures The recommendations of the committee will facilitate efforts to develop an integrated approach to addressing emerging public health issues in xenotransplantation

The Recombinant DNA and Gene Transfer Division of OBA monitors scientific progress in basic and clinical research involving DNA and human gene transfer A component of this monitoring is performed by the Recombinant DNA Advisory Committee

OFFICE OF BIOTECHNOLOGY ACTIVITIES 305

RECOMBINANT DNA ADVISORY COMMITTEE

In response to a report by the Committee on Recombinant DNA Molecules, estab-lished by the National Academy of Sciences in 1974, the DHHS chartered a com-mittee to establish biological and physical containment practices and procedures for recombinant DNA research.The document generated by this committee became the basis for a set of guidelines to be used for the safe conduct of recombinant DNA research The guidelines became known as “The NIH Guidelines for Research Involving Recombinant DNA Molecules” or the NIH Guidelines The original DHHS committee developed into the NIH Recombinant DNA Advisory Commit-tee or RAC This action was based on the recommendation of the 1982 President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research The commission’s report entitled “The Social and Ethical Issues of Genetic Engineering with Human Beings (Splicing Life)” explicitly stated that “the NIH should extend its purview over recombinant DNA research beyond environmental” (containment) “issues to human gene therapy.”Thus, a Human Gene Therapy Committee was formed comprised of federal and nonfederal scientists and clinicians, lay individuals, and ethicists.This committee merged with the DHHS

char-tered committee to form the NIH RAC (Recombinant DNA Advisory Committee).

The RAC, in its original form, constituted a 25-member committee charged with the responsibility of reviewing and approving all research protocols involving human use and recombinant DNA molecules Investigators, developing protocols utilizing human gene transfer for marking, nontherapeutic, and therapeutic studies, were required to utilize the NIH Guidelines Thus, investigators were required to specify the research practices to be utilized for the constructing and handling of recombinant DNA molecules as well as organisms and viruses containing recombi-nant DNA molecules Compliance with the NIH Guidelines was mandatory for all recombinant DNA research within the United States and its territories Human gene transfer protocols were to be submitted in the format described in Appendix M

of the NIH Guidelines entitled “Points to Consider in the Design and Submission

of Protocols for the Transfer of Recombinant DNA Molecules into the Genome of One or More Human Subjects.” The Points to Consider apply to any protocol con-ducted at or sponsored by an institution that receives any support for recombinant DNA research from NIH

Based on the 1984 background study entitled “Human Gene Therapy” by the Office of Technology Assessment, the RAC was directed to consider for approval only somatic gene therapy protocols The directive was based on the civic, religious, scientific, and medical community acceptance in principle of the appropriateness of gene therapy for somatic cells in humans for specific diseases Somatic gene therapy was and is seen as an extension of current experimental therapeutic methods and potentially preferable to other elaborate technologies Factors considered in the RAC review included the use of new vectors or new gene delivery systems, appli-cation to new diseases, unique appliappli-cation of gene transfer, and other issues that would require public attention and debate, such as unique ethical situations The RAC recommendation, approval or disapproval, of a specific protocol is transmit-ted to the director of the NIH The director provided a concurrence or nonconcur-rence on the recommendation and forwarded the decision to the commissioner of the FDA In 1993, protocols involving human gene transfer were also required to

be simultaneously submitted to the FDA for Investigational New Drug (IND)

approval using the identical format The first gene therapy protocol was a cancer gene marking study entitled “The Treatment of Patients with Advanced Cancer Using Cyclophosphamide, Interleukin-2 and Tumor Infiltrating Lymphocytes.” The protocol received RAC approval on October 3, 1988, and NIH approval on March

2, 1989 Roughly 10 years later, as of May 1999, ORDA lists 313 protocols having been received and under review or having been reviewed (Table 13.1)

Amended Federal Oversight

On July 8, 1996, the director of the NIH proposed an amendment to the NIH Guide-lines This amendment modified the federal oversight of gene therapy research It was proposed that in order to enhance NIH mechanisms for scientific and ethical oversight of DNA recombinant activities, the RAC would be discontinued and all approval responsibilities for recombinant DNA activities involving human gene transfer would be relinquished to the FDA Thus, the FDA would retain statutory authority for authorizing IND The enhancement of NIH oversight of human gene therapy research was proposed via various mechanisms Most notably, a series of

RECOMBINANT DNA ADVISORY COMMITTEE 307 TABLE 13.1 Human Gene Transfer Protocols Received by

NIH as of 5/99

Infectious diseases

Monogenetic diseases

Ornithine transcarbamylase deficiency 1

Other diseases

Cancer therapy

Prodrug/HSV-TK and ganciclovir 30

Cell marking studies 34

Therapeutic protocols 277

Gene Therapy Policy Conferences would be initiated and intended to augment the quality and efficiency of public discussion of the scientific merit and ethical issues relevant to gene therapy clinical trials These conferences would assemble individ-uals with scientific, ethical, and legal expertise to discuss and formulate policy on single topic issues The conference policy statements would be submitted to the director of the NIH and, furthermore, made available to the DHHS agencies such

as the FDA and the Office for Protection from Research Risks for implementation The initial Gene Therapy Policy Conference occurred on September 11, 1997, and was entitled “Human Gene Transfer: Beyond Life Threatening Disease.” The agenda included the scientific prospects for trait enhancement through gene therapy, assess-ing long-term safety and efficacy, the conceptual, ethical, and social issues of treat-ment versus enhancetreat-ment, as well as to delineate the distinction between treattreat-ment and gene enhancement Summaries of past Gene Therapy Policy Conferences and future agendas can be found at the Office of Biotechnology Activities home page www.nih.gov/od/oba

On November 22, 1996, the NIH director published a document entitled “Notice

of Proposed Action under the NIH Guidelines for Research Involving Recombi-nant DNA Molecules.” This document detailed the retention of the RAC but mod-ifying its roles and responsibilities The RAC retains the function of a charted advisory committee to the director of NIH, but no longer has approval/disapproval protocol It now meets quarterly to discuss novel human gene transfer experiments, identify novel scientific and ethical issues, and advise the NIH director on modifi-cations to the NIH Guidelines The RAC is now comprised of 15 members, with at least 8 members knowledgeable in molecular genetics, biology, or recombinant DNA research and at least 4 members knowledgeable in applicable legal aspects, public attitudes, and environmental safety issues and public health In addition, RAC members co-chair the Gene Policy Conferences

CURRENT REVIEW AND APPROVAL PROCESS

Based on the scientific scope of the developed protocol, a review process has been established and is required for all protocols involving DNA/RNA molecules, gene therapy, nucleic acids, or nuclear transfer As shown in Table 13.2, the original review process required public review, RAC review, approval by the NIH, and/or FDA and institutional approval As shown in Figures 13.1 and 13.2, an initial linear process is now being streamlined to allow for concurrent review to provide investigators minimal time between submission of the protocol for review and initiation of the experimental protocol This streamlined approval process may now take a backseat

to a rigorous approval process due to the recent disclosure of adverse events in human gene therapy clinical studies (see below) However, regardless of whether a linear process or concurrent process of review, a non-novel protocol requires both FDA and institutional approval prior to initiation

FDA Approval

The FDA has defined gene therapy as “a medical intervention based on modifica-tion of the genetic material of living cells.” Cells may be modified ex vivo for

sub-CURRENT REVIEW AND APPROVAL PROCESS 309 TABLE 13.2 Summary of Review Procedures Required for Recombinant DNA

Protocols Prior to Initiation of Study

Consolidated simultaneous Some protocols Triage Yes Yes review

FIGURE 13.1 Path for approval for a protocols that involves human/animal use and rDNA.

sequent administration or may be altered in vivo by gene therapy products given directly to the subject When the genetic manipulation is performed ex vivo on cells and subsequently administered to the patient, this is considered a form of somatic cell therapy The genetic manipulation may be intended to “prevent, treat, cure,

diagnose, or mitigate disease or injury in humans” [Federal Register 58(197):53248–

53251] As noted above, the Center for Biologics Evaluation and Research (CBER) has the authority within the FDA to review gene therapy protocols (Table 13.3)

FIGURE 13.2 Proposed non-linear, concurrent review of protocols that involve human/ animal use and rDNA.

TABLE 13.3 Protocols Received by NIH and Pending

Review as of 5/99

Cancer

Coronary artery disease 1a

aSubmission not complete (2 in vitro protocols in cancer).

CBER has produced documents to address somatic gene therapy They include documents entitled “Points to Consider in Human Somatic Cell and Gene Therapy”

as well as an Addendum to this document “Points to Consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications” and “Guidance for

Indus-try for the Submission of ChemisIndus-try, Manufacturing, and Controls Information for

a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use.” The original Points to Consider document focused on ex vivo somatic gene therapy, while the addendum provides additional guidance based

on current information regarding regulatory concerns for production, testing, and administration of recombinant vector for gene therapy with a particular emphasis

on in vivo administration It also provides a brief outline of information needed for IND applications for gene therapy, regulatory issues related to all classes of vector products for gene therapy, preclinical issues for safety evaluation in animals, and regulatory handling of modifications in vector preparations Although each new bio-logical requires an independent IND submission, if related vectors are made or

“minor” modifications are generated, an argument can be provided for the inclu-sion of the products as a panel and thus be described in the context of an amend-ment to the original IND application Alternatively, the vectors could be described

in master files if intended for multiple IND submissions This simplifies the submis-sion process by not filing redundant materials

The Points to Consider document for plasmid DNA vaccines was produced in December, 1996, and outlines the CBER approach to regulation of plasmid DNA vaccines In addition, product consideration for an IND submission is presented as well as considerations for plasmid DNA vaccine modifications, the use of adjuvants and devices for vaccine delivery, and preclinical immunogenicity and safety evalu-ations CBER and the Center for Drug Evaluation and Research (CDER) also provide guidance to industry on the context and format of the Chemistry, Manu-facturing and Controls (CMC) Section of a Biologics License Application

A final document of note is the FDA Information Sheets for the Institutional Review Board’s (IRB’s) and Clinical Investigators This document provides IRB operations and clinical investigation requirements including the use of drugs, bio-logicals, and medical devices in clinical investigations Guidance is provided on cooperative research, foreign clinical studies, study recruitment, payment to research subjects, and informed consent among other topics These documents provide guidance clinical trial design and development

MOVING TOO FAST IN A FIELD OF PROMISE

A startling and sobering event occurred in 1999, in the field of gene therapy research, and initiated a series of further events and revelations That event was the initial death of a patient in an experimental clinical trial involving gene therapy Investigators at the FDA found numerous violations of federal research regulations and shortcomings in the protection of human subjects in the execution of the clin-ical research This resulted in the FDA placing a “clinclin-ical hold” or halting all research at the University of Pennsylvania’s Institute for Human Gene Therapy Further government hearings and investigations of the gene therapy research field revealed that a total of 731 adverse events had occurred in human studies involv-ing gene therapy Of these only 39 had been originally reported as required by law Six hundred and fifty two adverse events involved studies using adenovirus as the vector while 40 adverse events were belatedly reported for all other vectors Inves-tigators who receive approval from the FDA to initiate a human gene transfer

MOVING TOO FAST IN A FIELD OF PROMISE 311

protocol must report any serious adverse event immediately to the local IRB (see below), Institutional Biosafety Committee, Office of Protection from Research Risks (OPRR), NIH/ORDA, and FDA The form and information required is pre-sented as Table 13.4 The apparent lack of compliance with this law has resulted in

an Executive Order published by President Clinton on February 9, 2000, requiring the FDA and NIH to review all federally regulated gene therapy research for com-pliance with federal law

An additional issue arose on February 12, 2000, related to patient safety in gene therapy clinical research In an apparent oversight in quality control of vector con-struction (see Appendix), a report surfaced by a clinical researcher of possible viral contamination of a vector preparation used in a cancer pediatric protocol.The inves-tigator reported the possible contamination by pathogenic human immuodeficiency virus (HIV) and/or hepatitis C virus of a viral vector preparation administered to patients in the protocol The investigator immediately notified the parents of the participants of the possible contamination, halted the clinical trial, and notified gov-ernment oversight Further PCR studies are needed to definitively establish conta-mination These events show the risks of experimental gene therapy research that must be realized by all and specifically presented to the patient as part of the overall informed consent process

INSTITUTIONAL REVIEW OF RECOMBINANT DNA RESEARCH

Research involving human subjects and human use, sponsored and not necessarily performed by an institution in the United States, is subject to approval by an IRB and the Institutional Biosafety Committees (IBC) The IRB is a review committee constituted locally and acts on behalf of the sponsoring institution to protect poten-tial research subjects The IRB balances the competing interests of the medical researcher with loyalty to science and society and the individual patient with a focused interest in personal health The underlying task of the IRB is to discern the relative risk to a patient of an experimental protocol Thus, the IRB balances the potential risk to the patient due to adverse effects of the protocol against the poten-tial gain to society through increased medical knowledge

IRBs grew out of a mandate from the National Commission for the Protection

of Human Subjects of Biomedical and Behavioral Research Statutory authority has come from the Code of Federal Regulations (CFAR) Title 21, CFR part 50,

1981, and (DHHS) Title 45 CFR part 46 1983 The latter Code of Federal Regula-tions was a component of The Public Health Service Act as amended in 1985 and

1993 Part 46 of the code is entitled “Protection of Human Subjects” and provides the basic federal policy for the protection of human research subjects The policy defines the code of conduct for research that includes the confidentiality of patient data and identity Each institution sponsoring research is required to provide the DHHS assurance that the institution does and will continue to comply with terms and conditions of the Public Health Service Act This assurance includes a state-ment of principles governing the institution for the protection of rights and welfare

of the human subjects enrolled in research protocols conducted at the sponsoring institution, the establishment of the IRB and continued review of the research