H U M A N G E N E THERAPY 2:77-83 (1991) Mary Ann Liebert, Inc., Publishers
Clinical C o n s i d e r a t i o n s in t h e D e s i g n o f P r o t o c o l s for S o m a t i c G e n e
Therapy
FRED D. LEDLEY
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ABSTRACT Despite t w o decades of investigating the potential for somatic gene therapy in curing h u m a n disease, few clinical trials are being proposed. This delay is d u e in part to limitations of existing m e t h o d s for gene transfer a n d to the recognized need to proceed judiciously into this controversial arena. Delay is also caused b y a disjunction between the traditional precedents a n d principles of clinical investigation a n d the procedures instituted to regulate somatic gene therapy. T h e premise of this report is twofold: first, that m o r e extensive clinical investigation of gene transfer technologies w o u l d b e beneficial to patients, medicine, a n d basic science a n d second, that clinical investigations could b e expedited b y appealing to the established experience in clinical investigation without c o m p r o m i s i n g the scientific excellence a n d discipline essential for this highly public process. This report develops a clinical perspective o n potential applications of existing gene transfer technologies a n d the issues involved in developing experimental protocols. T h e initiation of clinical trials should be a p r i m a r y goal of gene therapy research p r o g r a m s .
genetic engineering (Nirenberg, 1967). It has been two decades since research began to establish a technical and social foundaThe development of clinical trials involving somatic gene tion for gene therapy of human disease. During this time there transfer requires consideration of a variety of clinical issues. has been extensive debate about the propriety of gene therapy The ethics and efficacy of somatic gene transfer trials m a y be (Nirenberg, 1967; Friedman and Roblin, 1972; Anderson and largely dependent on the quality of patient selection and Fletcher, 1980; Friedmann, 1983; Surgeon General, 1983; clinical follow-up. T h e success of these trials m a y be depen- O T A , 1984; Walters, 1986; Fletcher, 1990; Murray, 1990; dent not only on the sophistication of the molecular genetic Nelson, 1990), intensive development of methods for gene technologies, but also on the adequacy of surgical, medical, transfer (Friedmann, 1989; Ledley, 1989), and establishment of and even psychosocial support for the patients. Optimal a review process explicitly for evaluating clinical applications clinical trials involving gene transfer require a collaborative (Recombinant D N A Advisory Committee, 1989). However, approach to these problems that draws from the experience there remains an extremely limited body of clinical invesof conventional clinical investigation as well as molecular tigation,1 and clinical investigators remain largely uninvolved in the development of therapeutic applications for this technology. genetics. The absence of clinical investigation does not simply reflect the limitations of existing genetic technologies or the recognized need for caution in embarking on genetic manipulation in INTRODUCTION: CLINICAL INVESTIGATION humans. It also reflects a historical disjunction between the A N D SOMATIC G E N E THERAPY traditional precedents and principles of clinical investigation and the procedures instituted to regulate somatic gene therapy. The T HAS BEEN A QUARTER OF A CENTURY since scientists first initial recognition, that gene manipulation in humans required i called attention to the medical and social implications of special control, dates from the seminal works of Nirenberg
OVERVIEW S U M M A R Y
Howard Hughes Medical Institute, Departments of Cell Biology and Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, T X 77030. [As of January, 1991, only three gene transfer protocols have been approved by the Recombinant Advisory Committee (RAC).
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LEDLEY
(1967) and Friedmann and Roblin (1972). These works were present time. The disparity between in vitro and clinical opporpublished at a time when clinical research itself (and the tunity reflects limitations in both basic and clinical technologies. authority of physicians to serve as regulators of clinical investiBone marrow is generally considered the most likely target for gation) was being critically reexamined and restructured somatic gene therapy (Friedmann, 1989), and extensive re(Beecher, 1968) and a system for review of protocols by search has been directed at introducing genes into pluripotential Institutional Review Boards for H u m a n Research were being stem cells which can be transplanted using conventional clinical mandated (Surgeon General, 1966; Code of Federal Regula- methods. It has proven difficult, however, to transform reliably tions, 1983). The early attempts at gene therapy by Rogers the pluripotential stem cell and to obtain adequate expression of (Rogers, 1971) and Cline (Mercola and Cline, 1980) seemed the transgene in its differentiated progeny. M o r e basic research imprudent and reinforced the notion that a separate process for needs to be done on pluripotential stem cells and mechanisms of regulating gene therapy was needed. A s a result, the standards gene regulation before therapeutic trials involving complete for IRB-regulated clinical investigation and somatic gene ther- replacement of a patient's bone marrow can be performed with apy evolved largely by independent, though parallel paths. confidence. The recent protocols for gene therapy of adenosine The procedures and principles regulating gene therapy are deaminase deficiency (Blaese and Anderson, 1990) circumvent significantly different from the perspectives represented by stem cell biology by targeting genes to differentiated lymphoconventional clinical investigation. For example, while there is cytes, which are more reproducibly manipulated and transextensive debate about the "scientific rationale" for experiments formed. M a n y other cells including hepatocytes, keratinocytes, fibroinvolving gene transfer, less weight is given to the "clinical indications" for clinical trials. It is a paradox that "gene transfer' blasts, myoblasts, and endothelial cells are potential targets for experiments using marker genes with no potential benefit to the gene therapy (Ledley, 1989). These targets m a y present less subject have preceded potentially therapeutic trials of "gene complex problems of differentiation and gene regulation. The therapy.17 Gene transfer experiments are being justified and clinical application of each of these targets, however, is limited evaluated entirely on their basic science merit without reference by the absence of established clinical methods for cellular transplantation. Clinical research will be required to establish to clinical benefit, and they have been approved because they conform to conventional paradigms of basic scientific investiga- the transplantation technologies required for somatic gene thertion. apy of solid organs (Ledley, 1990). The difference is also apparent in the measurement of risk. While the theoretical risks of gene transfer have been subject to The principle of gene transfer as opposed to intense scrutiny, these risks are not always gauged relative to the gene therapy morbidity of the underlying disease states or conventional therapies. There is also little acknowledgement ofthe patient's There are important applications of gene transfer in clinical right to accept personal risks in the interests of potential research which are not truly gene therapy. T h e first clinical benefits—an issue that has achieved particular prominence in protocol to be approved (Anderson et al, 1988; Rosenberg experimental therapy for A I D S . et al, 1990) used gene transfer to "mark" tumor infiltrating The divergent perspectives regulating clinical investigation lymphocytes (TIL). W h e n the marked cells were transplanted and gene therapy lead to considerable tension in the review into patients as part of a conventional cancer immunotherapy process. This dynamic was recognized in an article in The N e w protocol, it was possible to assess engraftment of the marked York Times which described the review of a gene therapy cells independently ofthe patient's clinical course. The principle proposal by the Recombinant Advisory Committee under the of using gene transfer in clinical protocols has been explicitly headline: " M . D . and Ph.D.; Cultures in Conflict" (Angier, approved by the H u m a n Gene Therapy Subcommittee of the Recombinant Advisory Committee which reported: 1990). The premise of this report is that more extensive clinical investigation of gene transfer technology is clinically and scien- The sense of the Subcommittee and outside consultants is tifically appropriate, and that clinical applications of gene supportive ofthe general concept of the use of recombinant transfer could be expedited by appealing to established princivectors in gene transfer procedures for marking somatic ples and precedents of clinical investigation without compromiscells in humans as an aid to the development of important ing the scientific excellence and discipline essential for this new advances in clinical research. Because such proceprocess. This report describes clinical issues involved in the dures are not done primarily to benefit the subject, and m a y implementation of gene transfer, but will not review technical in fact be of no benefit to the individuals involved, aspects of gene delivery and expression which have been proposals to carry out these experiments must be supported by a clear data base demonstrating if a specific procedure reviewed elsewhere. planned is safe and likely to yield knowledge of value. (Recombinant D N A Advisory Committee, 1988)
W H A T SHOULD BE STUDIED? Obstacles to therapeutic investigation Simple genetic defects are commonly corrected in cultured cells using gene transfer technologies. F e w diseases, however, appear to be amenable to "cure" by somatic gene therapy at the
Protocols involving gene transfer can play an important role in the development of gene therapy by providing a venue for testing the efficiency of gene transfer methods, the stability of gene expression, and the safety of retroviral vectors. The intent ofthe Recombinant Advisory Committee ( R A C ) appears to be that methods for gene transfer first be assessed in clinical experi-
C L I N I C A L C O N S I D E R A T I O N S IN S O M A T I C G E N E T H E R A P Y
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ments involving gene transfer in which the patient is not that they have applied gene transfer technologies to classical dependent upon the expression of the recombinant gene before problems of investigative therapeutics and proposed experitrials with therapeutic intent are proposed. ments with direct precedents in the transfusion of select hematological elements, immunotherapy, and enzyme replacement therapy. Consideration of animal models for somatic
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gene therapy There is extensive debate about the nature and extent of animal studies that should precede human investigations. In principle, the efficiency of gene transfer, stability of gene expression, and safety of gene transfer vectors can be demonstrated in animals before proceeding to clinical trials ( O T A , 1984; Recombinant D N A Advisory Committee, 1989). H o w ever, there is a developing consensus that despite the desirability of assessing the therapeutic efficacy of gene therapy in homologous animal models of h u m a n diseases, the paucity of such models (Desnick et al, 1982) and normal phenotypes in some genetically engineered animal models (Finger et al, 1988; McDonald etal, 1988, 1990) makes this requirement unrealistic ( O T A , 1984). It is unclear, however, h o w many animal experiments and in what species are prerequisite for human trials (Anderson and Fletcher, 1980). Are studies in rodents sufficient? Are rabbits, dogs, or pigs more appropriate? Are existing data from nonhuman primates (Cornetta et al, 1990) sufficient? Is it feasible (or ethical) to study all retroviral vectors in nonhuman primates? While animal experiments are useful for assessing specific aspects of gene transfer, there is no data explicitly supporting the contention that animal experiments can presage the outcome, efficacy, or safety of human applications. The details of anato m y , cell biology, genetics, and immunology of other species do not duplicate the vicissitudes of human biology, particularly when considering retroviral vectors whose infectivity, tropism, and pathology is naturally species specific. Controlled data justifying the utility of animal models could be obtained by judicious clinical trials performed in conjunction with ongoing animal experiments. Such studies could ultimately reduce the number, extent, and danger of human investigations by determining h o w to obtain meaningful data from animal experiments. Without a baseline of information from human subjects, the current generation of animal experiments m a y be unnecessary and uninformative, and future clinical trials m a y subject patients to the same risks that animal experiments are designed to avoid.
ISSUES IN T H E CONSTRUCTION OF CLINICAL PROTOCOLS Guidelines for clinical research in gene therapy have been established by the N I H in a document entitled: "Points to Consider in the Design and Submission of H u m a n Somatic Cell Gene Therapy Protocols" (Recombinant D N A Advisory C o m mittee, 1989). Protocols must first be reviewed by local IRB (bioethics) and I B C (biosafety) committees and must meet the standards of conventional clinical research. The protocol is then reviewed by the H u m a n Gene Therapy Subcommittee and Recombinant D N A Advisory Committee of the NIH. These committees serve formally in an advisory capacity to the Director of the N I H w h o must approve all gene transfer or gene therapy proposals. The "Points to Consider . " poses technical questions which are considered by the R A C in its review. The most important questions, however, remain those associated with all clinical investigation: safety, a balance between risk and benefit, patient selection, and the provision of responsible and complete medical care and clinical follow-up. The safety of clinical investigation: issues in patient m a n a g e m e n t
The issue of safety to society must be differentiated from that ofriskto study subjects. The issue of safety involves protecting against any possibility of infectious transmission of recombinant genes. Infectious spread of recombinant viruses has not been observed with the present generation of defective retroviral vectors in laboratory or animal experiments, and the risk of this complication is considered extremely remote. Nevertheless, clinical trials have raised n e w concerns about infectious transmission since recombinant materials will no longer be restricted to facilities meeting containment guidelines (NIH, 1984). "Universal Precautions" are n o w commonly employed with all patients and are considered sufficient to prevent transmission of known pathogens including hepatitis or HIV. The careful implementation of "Universal Precautions" in consultation with Opportunities for clinical investigation of gene therapy nursing and hospital infection control officers should provide There has been extensive discussion about which diseases ample protection against even unanticipated complications and represent ideal models for gene therapy. This discussion has not should ensure that these experiments pose no threat to the been directed primarily at identifying diseases which might be community. Clinical protocols should also exclude individuals ameliorated by gene transfer, but rather has been concerned with with retroviral diseases such as H I V to further minimize any risk identifying a model in which to establish the paradigm that of recombinations. human disease can be "cured" by stable replacement of a defective gene function. The clinical application of gene transfer Ethics, risk, and benefit does not require prior justification ofthe paradigm of therapeutic gene replacement and does not need to be restricted to prototype No governmental or religious study in this country has raised diseases. Gene transfer m a y prove to be a powerful pharmaco- objections to gene therapy involving somatic cells if the intent of logical agent in conventional, allopathic paradigms of medical the research is therapeutic; there is no risk to nonsubjects; therapeutics. Gene transfer m a y also be a powerful adjunct in germ-line manipulation is not involved; the legal, moral, and conventional clinical research. The success ofthe N I H group in spiritual prerogatives of subjects are protected; and principles of pioneering clinical trials of gene transfer reflects, in part, the fact fairness, privacy, confidentiality, and nondiscrimination are
LEDLEY
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80 observed (Walters, 1986; Fletcher, 1990; Murray, 1990; Nelson, 1990). M a n y studies have concluded that somatic gene therapy is ethically the same as transplantation of organs, cells, or artificial devices. Clinical trials designed explicitly for the well-being of the patient break little n e w ground ( O T A , 1984; Walters, 1986). The principal ethical issue is whether individuals can be recruited for protocols entailing uncertainrisksand possibly little benefit—issues that are c o m m o n to all clinical research. Clinical research is safeguarded by the nature of informed consent and the process by which it is elicited (Surgeon General, 1966; Code of Federal Regulations, 1983; Andrews, 1987). This precedent does not require that protocols be completely free of risk, that risk be quantitatively defined, or that benefits be unequivocally established before clinical trials are proposed. The premise of informed consent is that the probability of personal risk does not preclude clinical trials. Rather,risksmust be honestly described, and the patient must be the ultimate arbiter ofthe value ofthe potential benefits and anticipated risks. A Lancet editorial emphasized: " the individual's responsibility and choice, provided it harms no one else, is fundamental to a democratic society" (Anon, 1989). Patient selection is critical to therisk-benefitratio of a clinical protocol. Risk m a y be minimized by preserving conventional therapeutic options in the event that gene therapy proves inadequate. Benefit m a y be enhanced by selecting patients whose clinical condition allows for a meaningful therapeutic response. It is important not to undervalue the potential benefits of experimental therapeutic approaches to genetic disease, most of which remain impervious to conventional therapy (Costa et al., 1985; Hayes etal, 1985). There is no particular ethical value to restricting research to patients with end-stage disease. The standards of safety and ethics are not altered by the severity of a patient's illness or prognosis. The willingness of subjects to participate in research, however, m a y be influenced if the patient's illness alters the apparent value of risk and potential benefit. The importance of follow-up
primary care providers, social workers, geneticists, and psychologists in addition to the clinical investigators. It m a y also be appropriate to establish a registry of patients participating in gene transfer research to ensure that even rare complications are detected as soon as possible and that patients and health care providers can be notified if novel concerns arise in the future. Special issues in pediatrics It is inappropriate to delay research in pediatrics given the exigency of therapy for genetic diseases which represent an increasing fraction of pediatric morbidity and mortality. Moreover, the benefit-risk ratio m a y be more favorable in children w h o generally have discrete rather than degenerative diseases, exhibit greater regenerative capacity, and e m b o d y the potential to live long and productive lives. While particular caution has to be exercised in pediatric research, there are clear guidelines for pediatric investigation with the informed consent of parents or guardians (Andrews, 1987; Jansen, 1978; Code of Federal Regulations, 1983). Pediatric research m a y be proposed if there is "minimal risk" (defined as "risks of harm anticipated in the proposed research are not greater, considering probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests"), if "greater than minimal risk" is balanced by anticipated benefit to the subject, or if there is no benefit to the subject but the risks are "reasonably commensurate" with the patient's disease and significant generalizable knowledge m a y accrue (Code of Federal Regulations, 1983). Thus, the risk of gene transfer in m a n y patients must be compared to those of experimental organ transplantation, investigation of live (attenuated) vaccines, or radiation and chemotherapy for cancer. Follow-up in pediatrics is particularly difficult. It is complicated in childhood and adolescence by the normally poor participation in medical care and the transition from pediatric practitioners to internists. It will be important to establish mechanisms for maintaining follow-up through this period and the period of reproductive activity in young adulthood.
There are medical, scientific, and ethical imperatives to Public concern about somatic gene therapy maintain long-term follow-up of patients w h o participate in clinical trials of somatic gene therapy. F r o m a medical perspec- Two decades of debate over somatic gene therapy have tive, it is likely that there m a y be complications of gene transfer awakened both the expectations and concerns of the public. that need to be identified, diagnosed, prevented, or treated Public concern has perhaps been intensified by the restriction of aggressively. Even normal issues of health care, reproduction, this technology to basic science laboratories and the absence of and psychosocial development m a y be influenced by participa- apparent reference to practical medical therapeutics. Although it tion in gene transfer trials. From a scientific perspective, the is necessary to address principles of the scientific method, efficacy of gene transfer will ultimately have to be determined medical ethics, and public policy cautiously, the dearth of by controlled clinical studies. Long-term follow-up is essential clinical investigation m a y call into question the suitability of to identify complications of gene transfer that contribute to the these principles, foster public skepticism about the therapeutic efficacy of this technology. F r o m an ethical imperative, the potential and safety of somatic gene therapy, and even threaten benefit-risk ratio of any clinical research experiment can be the prestige of medicine and the willingness of society to invest greatly enhanced by the investigator's commitment to identify in genetic technologies. and manage any resulting complications. It m a y indeed be Clinical trials m a y substantially allay public concerns by considered the investigator's obligation to m a k e every possible exhibiting genetic technology in the recognizable context of effort to maintain follow-up of study participants. health and disease and provide a h u m a n face for research that is It is notoriously difficult to achieve efficient, long-term often perceived as threatening, coldly objective, or even amoral. follow-up in clinical research or practice. Protocols involving The public is better able to appreciate success or failure in gene transfer should describe plans for follow-up involving clinical trials than esoteric discussions about safety, social
CLINICAL C O N S I D E R A T I O N S IN S O M A T I C G E N E T H E R A P Y policy, and regulation. Clinical protocols should include specific plans for dealing constructively with public attention and using this attention to instruct the public about genetic disease and the importance of basic laboratory, animal, and clinical investigations.
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Psychosocial aspects of somatic gene therapy Psychosocial dynamics contribute substantially to medical therapeutics and will certainly contribute to the measured success of somatic gene therapy. Even the most deterministic medical interventions can be complicated by the appearance of "non-disease" (Bergman and S t a m m , 1967) or placebo effects (Haegerstam et al, 1982). T h e potential emotional consequences of being subjects to genetic modification, along with the anticipated public attention that m a y attend these protocols, make prior consideration of psychosocial issues particularly important. The ability of patients and families to provide informed consent and to participate fully in somatic gene therapy must be analyzed in the context of established models of reasoned action (Fishbein, 1980) or health beliefs (Becker and M a i m a n , 1975; Mikhail, 1981), their knowledge of gene therapy, sources of information, networks of support, and patterns of control. It will also be important to assess the long-term psychosocial consequences of genetic manipulation on the subject using quantitative measurements of self esteem, well-being, behavior, and psychosocial development.
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several years, an unrealistic time given the rapidly advancing state ofthe technology. General Clinical Research Center ( G C R C ) grants represent an important mechanism for funding clinical trials. Gene transfer projects can be funded from G C R C grants by local scientific advisory committees after approval by the R A C and director of the N I H . Moreover, funds for gene therapy proposals can be requested as part of G C R C applications after approval of local IRB and IBC committees, before approval is obtained from the R A C . O n e corollary to this method of obtaining funding is that the timing of submission of clinical protocols m a y be dictated by G C R C funding cycles. Corporate sponsorship of clinical research raises concerns about proprietary rights, the accessibility to clinical data, the financial interests and objectivity of the investigator, and the applicability of government regulations. The R A C has requested that initial trials not contain proprietary information so as not to interfere with public disclosure. The application and review process The major practical issue in proposing human trials is to observe meticulously the rules of the regulatory progress. The rancorous debates over genetic manipulation have gradually ceded to legal wrangling about rules and regulations. The report by the Office of Technology Assessment ( O T A , 1984) concluded that a societal consensus on somatic gene therapy was probably impossible and noted:
Where there is no agreement on what decision to make, the only alternative is a process for making the decision, and governmental agencies must demonstrate that the process is rational and fair. The development of somatic gene therapy is critically dependent on quality clinical investigation. It is c o m m o n to lament the state of clinical research, its scientific rigor, its level offunding, Legal challenge to details of the review process has become and the level of participation by academic physicians. S o m e of the last bastion of groups opposed to gene transfer in human the concern about proceeding with clinical trials reflects a subjects. Although these challenges do not reflect the mainconcern for the scientific enterprise itself. It has been argued that stream of societal, ethical, or theological thought, they are premature clinical trials could undermine public confidence and predictable and troubling. Investigators and institutions preparsupport for science in general. ing for clinical trials must be prepared to handle legal challenges Exemplary scientific rigor is certainly essential in the design and the controversy and cost these legal maneuvers will engenand performance of clinical research involving gene transfer. der. The involvement of molecular biologists, and the demand for the degree of precision that characterizes molecular biology, will present clinical investigation with a challenge that can only W H E N SHOULD A CLINICAL P R O T O C O L strengthen clinical research in general. In addition, the emersion INVOLVING G E N E TRANSFER of molecular biologists in clinical research will m a k e the basic BE SUBMITTED? scientist more aware of the complex and often counterintuitive realities of medicine, as well as the enormous power of existing There are no absolute impediments to clinical trials involving medical and surgical techniques that m a y be employed in an aspects of somatic gene therapy. Carefully constructed protocols using gene transfer to expedite research in cellular transplantaancillary capacity for gene transfer. The procurement of funding for clinical research involving tion, cellular regeneration, and malignancies might be progene transfer is a potentially limiting problem. It is inappropriate posed, approved, and performed successfully. Therapeutic trials for patients to bear costs of experimental procedures, and of gene therapy involving gene transfer into accessory sites or chimeric engraftment with cells treated with recombinant genes research protocols are generally not covered by third-party providers ( O T A , 1984). Investigator-initiated grants are also might also be proposed and approved, if the design of these unlikely to provide funds for clinical trials ( O T A , 1984). N I H protocols preserves conventional therapeutic options for the guidelines require approval of h u m a n protocols by the R A C , but patient and could provide substantial benefit to patients with before grants are reviewed. Sequential review by local I B C and minimal risks. I R B committees, the R A C , and funding agencies m a y require There is no reason to be reticent about the imperative of The state of clinical investigation and sources offunding
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DESNICK, R.J., PATTERSON, D.F., andSCARPELLI, D.G. (1982). Animal Models of Inherited Metabolic Diseases. (Alan R. Liss Inc., New York). FINGER, S., H E A V E N S , R.P., SIRINATHSINGHJI, D.J., K U E H N , M.R., and D U N N E T T , S.B. (1988). Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch-Nyhan syndrome. J. Neurol. Sci. 86, 203-213. FISHBEIN, M. (1980). A theory of reasoned action: some applications and implications. Neb. Symp. Motiv. 27, 65-116. FLETCHER, J.C. (1990). Evolution of ethical debate about human gene therapy. Human Gene Ther. 1, 55-68. F R I E D M A N N , T. (1983). Gene Therapy, Fact and Fiction. (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). F R I E D M A N N , T. (1989). Progress toward human gene therapy. Science 244, 1275-1278. F R I E D M A N N , T. A., and ROBLIN R. (1972). Gene therapy for human genetic disease. Science 175, 949-52. ACKNOWLEDGMENTS H A E G E R S T A M , G., HUITFELDT, B., NILSSON, B.S., SJOVALL, J., SYVALAHTI, E., and W A H L E N , A. (1982). Placebo in clinical This report was prepared for the "Round Table Group on drug trials—a multidisciplinary review. Methods. Exp. Clin. PharHepatic Gene Therapy" of the Baylor College of Medicine and macol. 4, 261-278. Texas Children's Hospital in considering development of cliniH A Y E S , A., COSTA, T., SCRIVER, C.R., and CHILDS, B. (1985). cal trials. I especially thank Dr. Ralph Feigin, Dr. George Ferry, The effect of mendelian disease on human health II: Response to Dr. William Klish, Dr. Bert O'Malley, and Dr. Savio W o o for treatment. Am. J. Med. Genet. 21, 243-255. encouragement and advise and T a m m y Reid for preparation of JANSEN, A.R. (1978). Research involving children. Pediatrics 62, this manuscript. This work was supported in part by the A C T A 131-136. foundation. Fred D. Ledley is an Assistant Investigator of the LEDLEY, F.D. (1989). 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Points to consider in the design and submission of human somatic cell gene tee. (Reprinted in Human Gene Ther. 1, 327-362, 1990). therapy protocols. Fed. Reg. 54, 36698-36703 (Reprinted in Human C O D E O F F E D E R A L R E G U L A T I O N S (1983). Title 45, Part 46 Gene Ther. 1,93-103, 1990.) Protection of Human Subjects (revised March 8, 1983). C O R N E T T A , K., M O E N , R.C, CULVER, K., M O R G A N , R.A., ROGERS, S. (1971). Gene therapy: A potentially invaluable aid to medicine and mankind. Res. Commun. Chem. Path. Pharm. 2, M C L A C H L I N , J.R., STURN, S., SELEGUE, J., L O N D O N , W., 587-598. BLAESE, R.M., and A N D E R S O N , W.F. (1990). Amphotropic Murine Leukemia Retrovirus is not an acute pathogen for primates. R O S E N B E R G , S.A., A E B E R S O L D , P., C O R N E T T A , K., KASID, A., M O R G A N , R. A., M O E N , R., K A R S O N , E.M., LOTZE, M.T., Human Gene Ther. 1, 15-30. Y A N G , J.C, TOPALIAN, S.L., M E R I N O , M.J., C U L V E R , K., COSTA, T., SCRIVER, C.R., and CHILDS, B. (1985). The effect of MILLER, A.D., BLAESE, R.M., and A N D E R S O N , W.F. (1990). mendelian disease on human health: a measurement. Am. J. Med. Gene transfer into humans—immunotherapy of patients with adGenet. 21, 231-242. vanced melanoma, using tumor-infiltrating lymphocytes modified by clinical investigation in gene therapy. The goal of every laboratory should be to anticipate clinical applications of their technology. This does not mean that protocols should be submitted in haste or that the stringent criteria which regulate the development of clinical protocols should be relaxed. It does mean that investigators should adopt a perspective in which all laboratory experiments are conceived as stepping stones to specific clinical experiments and are constructed using clinically applicable technologies. B y insisting on a clinical perspective for basic research and social discussion, attention will be focused on the substantive problems that remain in proposing clinical protocols, and clinical application of this important technology to patients in need will be facilitated.
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LEDLEY
CLINICAL CONSIDERATIONS IN SOMATIC GENE THERAPY
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retroviral gene transduction. New. Engl. J. Med. 323, 570-578. Address reprint requests to: S U R G E O N G E N E R A L . (1966). U S Public Health Service, Public Dr. Fred Ledley Policy Order N o 129. Investigation Involving Human Subjects, Department of Cell Biology Including Clinical Research. Requirements for Review to Insure the Baylor College of Medicine Rights and Welfare of Individuals. O n e Baylor Plaza S U R G E O N G E N E R A L (1983). President's Commission for the study Houston, T X 77030 of ethical problems in medicine and biomedical and behavioral research. Splicing life (U.S. Government Printing Office, Washington DC). W A L T E R S , L. (1986). The ethics of human gene therapy. Nature 320, Received for publication January 14, 1991; accepted after revision January 26, 1991. 225.
Clinical C o n s i d e r a t i o n s in t h e D e s i g n o f P r o t o c o l s for S o m a t i c G e n e
Therapy
FRED D. LEDLEY
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ABSTRACT Despite t w o decades of investigating the potential for somatic gene therapy in curing h u m a n disease, few clinical trials are being proposed. This delay is d u e in part to limitations of existing m e t h o d s for gene transfer a n d to the recognized need to proceed judiciously into this controversial arena. Delay is also caused b y a disjunction between the traditional precedents a n d principles of clinical investigation a n d the procedures instituted to regulate somatic gene therapy. T h e premise of this report is twofold: first, that m o r e extensive clinical investigation of gene transfer technologies w o u l d b e beneficial to patients, medicine, a n d basic science a n d second, that clinical investigations could b e expedited b y appealing to the established experience in clinical investigation without c o m p r o m i s i n g the scientific excellence a n d discipline essential for this highly public process. This report develops a clinical perspective o n potential applications of existing gene transfer technologies a n d the issues involved in developing experimental protocols. T h e initiation of clinical trials should be a p r i m a r y goal of gene therapy research p r o g r a m s .
genetic engineering (Nirenberg, 1967). It has been two decades since research began to establish a technical and social foundaThe development of clinical trials involving somatic gene tion for gene therapy of human disease. During this time there transfer requires consideration of a variety of clinical issues. has been extensive debate about the propriety of gene therapy The ethics and efficacy of somatic gene transfer trials m a y be (Nirenberg, 1967; Friedman and Roblin, 1972; Anderson and largely dependent on the quality of patient selection and Fletcher, 1980; Friedmann, 1983; Surgeon General, 1983; clinical follow-up. T h e success of these trials m a y be depen- O T A , 1984; Walters, 1986; Fletcher, 1990; Murray, 1990; dent not only on the sophistication of the molecular genetic Nelson, 1990), intensive development of methods for gene technologies, but also on the adequacy of surgical, medical, transfer (Friedmann, 1989; Ledley, 1989), and establishment of and even psychosocial support for the patients. Optimal a review process explicitly for evaluating clinical applications clinical trials involving gene transfer require a collaborative (Recombinant D N A Advisory Committee, 1989). However, approach to these problems that draws from the experience there remains an extremely limited body of clinical invesof conventional clinical investigation as well as molecular tigation,1 and clinical investigators remain largely uninvolved in the development of therapeutic applications for this technology. genetics. The absence of clinical investigation does not simply reflect the limitations of existing genetic technologies or the recognized need for caution in embarking on genetic manipulation in INTRODUCTION: CLINICAL INVESTIGATION humans. It also reflects a historical disjunction between the A N D SOMATIC G E N E THERAPY traditional precedents and principles of clinical investigation and the procedures instituted to regulate somatic gene therapy. The T HAS BEEN A QUARTER OF A CENTURY since scientists first initial recognition, that gene manipulation in humans required i called attention to the medical and social implications of special control, dates from the seminal works of Nirenberg
OVERVIEW S U M M A R Y
Howard Hughes Medical Institute, Departments of Cell Biology and Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, T X 77030. [As of January, 1991, only three gene transfer protocols have been approved by the Recombinant Advisory Committee (RAC).
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LEDLEY
(1967) and Friedmann and Roblin (1972). These works were present time. The disparity between in vitro and clinical opporpublished at a time when clinical research itself (and the tunity reflects limitations in both basic and clinical technologies. authority of physicians to serve as regulators of clinical investiBone marrow is generally considered the most likely target for gation) was being critically reexamined and restructured somatic gene therapy (Friedmann, 1989), and extensive re(Beecher, 1968) and a system for review of protocols by search has been directed at introducing genes into pluripotential Institutional Review Boards for H u m a n Research were being stem cells which can be transplanted using conventional clinical mandated (Surgeon General, 1966; Code of Federal Regula- methods. It has proven difficult, however, to transform reliably tions, 1983). The early attempts at gene therapy by Rogers the pluripotential stem cell and to obtain adequate expression of (Rogers, 1971) and Cline (Mercola and Cline, 1980) seemed the transgene in its differentiated progeny. M o r e basic research imprudent and reinforced the notion that a separate process for needs to be done on pluripotential stem cells and mechanisms of regulating gene therapy was needed. A s a result, the standards gene regulation before therapeutic trials involving complete for IRB-regulated clinical investigation and somatic gene ther- replacement of a patient's bone marrow can be performed with apy evolved largely by independent, though parallel paths. confidence. The recent protocols for gene therapy of adenosine The procedures and principles regulating gene therapy are deaminase deficiency (Blaese and Anderson, 1990) circumvent significantly different from the perspectives represented by stem cell biology by targeting genes to differentiated lymphoconventional clinical investigation. For example, while there is cytes, which are more reproducibly manipulated and transextensive debate about the "scientific rationale" for experiments formed. M a n y other cells including hepatocytes, keratinocytes, fibroinvolving gene transfer, less weight is given to the "clinical indications" for clinical trials. It is a paradox that "gene transfer' blasts, myoblasts, and endothelial cells are potential targets for experiments using marker genes with no potential benefit to the gene therapy (Ledley, 1989). These targets m a y present less subject have preceded potentially therapeutic trials of "gene complex problems of differentiation and gene regulation. The therapy.17 Gene transfer experiments are being justified and clinical application of each of these targets, however, is limited evaluated entirely on their basic science merit without reference by the absence of established clinical methods for cellular transplantation. Clinical research will be required to establish to clinical benefit, and they have been approved because they conform to conventional paradigms of basic scientific investiga- the transplantation technologies required for somatic gene thertion. apy of solid organs (Ledley, 1990). The difference is also apparent in the measurement of risk. While the theoretical risks of gene transfer have been subject to The principle of gene transfer as opposed to intense scrutiny, these risks are not always gauged relative to the gene therapy morbidity of the underlying disease states or conventional therapies. There is also little acknowledgement ofthe patient's There are important applications of gene transfer in clinical right to accept personal risks in the interests of potential research which are not truly gene therapy. T h e first clinical benefits—an issue that has achieved particular prominence in protocol to be approved (Anderson et al, 1988; Rosenberg experimental therapy for A I D S . et al, 1990) used gene transfer to "mark" tumor infiltrating The divergent perspectives regulating clinical investigation lymphocytes (TIL). W h e n the marked cells were transplanted and gene therapy lead to considerable tension in the review into patients as part of a conventional cancer immunotherapy process. This dynamic was recognized in an article in The N e w protocol, it was possible to assess engraftment of the marked York Times which described the review of a gene therapy cells independently ofthe patient's clinical course. The principle proposal by the Recombinant Advisory Committee under the of using gene transfer in clinical protocols has been explicitly headline: " M . D . and Ph.D.; Cultures in Conflict" (Angier, approved by the H u m a n Gene Therapy Subcommittee of the Recombinant Advisory Committee which reported: 1990). The premise of this report is that more extensive clinical investigation of gene transfer technology is clinically and scien- The sense of the Subcommittee and outside consultants is tifically appropriate, and that clinical applications of gene supportive ofthe general concept of the use of recombinant transfer could be expedited by appealing to established princivectors in gene transfer procedures for marking somatic ples and precedents of clinical investigation without compromiscells in humans as an aid to the development of important ing the scientific excellence and discipline essential for this new advances in clinical research. Because such proceprocess. This report describes clinical issues involved in the dures are not done primarily to benefit the subject, and m a y implementation of gene transfer, but will not review technical in fact be of no benefit to the individuals involved, aspects of gene delivery and expression which have been proposals to carry out these experiments must be supported by a clear data base demonstrating if a specific procedure reviewed elsewhere. planned is safe and likely to yield knowledge of value. (Recombinant D N A Advisory Committee, 1988)
W H A T SHOULD BE STUDIED? Obstacles to therapeutic investigation Simple genetic defects are commonly corrected in cultured cells using gene transfer technologies. F e w diseases, however, appear to be amenable to "cure" by somatic gene therapy at the
Protocols involving gene transfer can play an important role in the development of gene therapy by providing a venue for testing the efficiency of gene transfer methods, the stability of gene expression, and the safety of retroviral vectors. The intent ofthe Recombinant Advisory Committee ( R A C ) appears to be that methods for gene transfer first be assessed in clinical experi-
C L I N I C A L C O N S I D E R A T I O N S IN S O M A T I C G E N E T H E R A P Y
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ments involving gene transfer in which the patient is not that they have applied gene transfer technologies to classical dependent upon the expression of the recombinant gene before problems of investigative therapeutics and proposed experitrials with therapeutic intent are proposed. ments with direct precedents in the transfusion of select hematological elements, immunotherapy, and enzyme replacement therapy. Consideration of animal models for somatic
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gene therapy There is extensive debate about the nature and extent of animal studies that should precede human investigations. In principle, the efficiency of gene transfer, stability of gene expression, and safety of gene transfer vectors can be demonstrated in animals before proceeding to clinical trials ( O T A , 1984; Recombinant D N A Advisory Committee, 1989). H o w ever, there is a developing consensus that despite the desirability of assessing the therapeutic efficacy of gene therapy in homologous animal models of h u m a n diseases, the paucity of such models (Desnick et al, 1982) and normal phenotypes in some genetically engineered animal models (Finger et al, 1988; McDonald etal, 1988, 1990) makes this requirement unrealistic ( O T A , 1984). It is unclear, however, h o w many animal experiments and in what species are prerequisite for human trials (Anderson and Fletcher, 1980). Are studies in rodents sufficient? Are rabbits, dogs, or pigs more appropriate? Are existing data from nonhuman primates (Cornetta et al, 1990) sufficient? Is it feasible (or ethical) to study all retroviral vectors in nonhuman primates? While animal experiments are useful for assessing specific aspects of gene transfer, there is no data explicitly supporting the contention that animal experiments can presage the outcome, efficacy, or safety of human applications. The details of anato m y , cell biology, genetics, and immunology of other species do not duplicate the vicissitudes of human biology, particularly when considering retroviral vectors whose infectivity, tropism, and pathology is naturally species specific. Controlled data justifying the utility of animal models could be obtained by judicious clinical trials performed in conjunction with ongoing animal experiments. Such studies could ultimately reduce the number, extent, and danger of human investigations by determining h o w to obtain meaningful data from animal experiments. Without a baseline of information from human subjects, the current generation of animal experiments m a y be unnecessary and uninformative, and future clinical trials m a y subject patients to the same risks that animal experiments are designed to avoid.
ISSUES IN T H E CONSTRUCTION OF CLINICAL PROTOCOLS Guidelines for clinical research in gene therapy have been established by the N I H in a document entitled: "Points to Consider in the Design and Submission of H u m a n Somatic Cell Gene Therapy Protocols" (Recombinant D N A Advisory C o m mittee, 1989). Protocols must first be reviewed by local IRB (bioethics) and I B C (biosafety) committees and must meet the standards of conventional clinical research. The protocol is then reviewed by the H u m a n Gene Therapy Subcommittee and Recombinant D N A Advisory Committee of the NIH. These committees serve formally in an advisory capacity to the Director of the N I H w h o must approve all gene transfer or gene therapy proposals. The "Points to Consider . " poses technical questions which are considered by the R A C in its review. The most important questions, however, remain those associated with all clinical investigation: safety, a balance between risk and benefit, patient selection, and the provision of responsible and complete medical care and clinical follow-up. The safety of clinical investigation: issues in patient m a n a g e m e n t
The issue of safety to society must be differentiated from that ofriskto study subjects. The issue of safety involves protecting against any possibility of infectious transmission of recombinant genes. Infectious spread of recombinant viruses has not been observed with the present generation of defective retroviral vectors in laboratory or animal experiments, and the risk of this complication is considered extremely remote. Nevertheless, clinical trials have raised n e w concerns about infectious transmission since recombinant materials will no longer be restricted to facilities meeting containment guidelines (NIH, 1984). "Universal Precautions" are n o w commonly employed with all patients and are considered sufficient to prevent transmission of known pathogens including hepatitis or HIV. The careful implementation of "Universal Precautions" in consultation with Opportunities for clinical investigation of gene therapy nursing and hospital infection control officers should provide There has been extensive discussion about which diseases ample protection against even unanticipated complications and represent ideal models for gene therapy. This discussion has not should ensure that these experiments pose no threat to the been directed primarily at identifying diseases which might be community. Clinical protocols should also exclude individuals ameliorated by gene transfer, but rather has been concerned with with retroviral diseases such as H I V to further minimize any risk identifying a model in which to establish the paradigm that of recombinations. human disease can be "cured" by stable replacement of a defective gene function. The clinical application of gene transfer Ethics, risk, and benefit does not require prior justification ofthe paradigm of therapeutic gene replacement and does not need to be restricted to prototype No governmental or religious study in this country has raised diseases. Gene transfer m a y prove to be a powerful pharmaco- objections to gene therapy involving somatic cells if the intent of logical agent in conventional, allopathic paradigms of medical the research is therapeutic; there is no risk to nonsubjects; therapeutics. Gene transfer m a y also be a powerful adjunct in germ-line manipulation is not involved; the legal, moral, and conventional clinical research. The success ofthe N I H group in spiritual prerogatives of subjects are protected; and principles of pioneering clinical trials of gene transfer reflects, in part, the fact fairness, privacy, confidentiality, and nondiscrimination are
LEDLEY
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80 observed (Walters, 1986; Fletcher, 1990; Murray, 1990; Nelson, 1990). M a n y studies have concluded that somatic gene therapy is ethically the same as transplantation of organs, cells, or artificial devices. Clinical trials designed explicitly for the well-being of the patient break little n e w ground ( O T A , 1984; Walters, 1986). The principal ethical issue is whether individuals can be recruited for protocols entailing uncertainrisksand possibly little benefit—issues that are c o m m o n to all clinical research. Clinical research is safeguarded by the nature of informed consent and the process by which it is elicited (Surgeon General, 1966; Code of Federal Regulations, 1983; Andrews, 1987). This precedent does not require that protocols be completely free of risk, that risk be quantitatively defined, or that benefits be unequivocally established before clinical trials are proposed. The premise of informed consent is that the probability of personal risk does not preclude clinical trials. Rather,risksmust be honestly described, and the patient must be the ultimate arbiter ofthe value ofthe potential benefits and anticipated risks. A Lancet editorial emphasized: " the individual's responsibility and choice, provided it harms no one else, is fundamental to a democratic society" (Anon, 1989). Patient selection is critical to therisk-benefitratio of a clinical protocol. Risk m a y be minimized by preserving conventional therapeutic options in the event that gene therapy proves inadequate. Benefit m a y be enhanced by selecting patients whose clinical condition allows for a meaningful therapeutic response. It is important not to undervalue the potential benefits of experimental therapeutic approaches to genetic disease, most of which remain impervious to conventional therapy (Costa et al., 1985; Hayes etal, 1985). There is no particular ethical value to restricting research to patients with end-stage disease. The standards of safety and ethics are not altered by the severity of a patient's illness or prognosis. The willingness of subjects to participate in research, however, m a y be influenced if the patient's illness alters the apparent value of risk and potential benefit. The importance of follow-up
primary care providers, social workers, geneticists, and psychologists in addition to the clinical investigators. It m a y also be appropriate to establish a registry of patients participating in gene transfer research to ensure that even rare complications are detected as soon as possible and that patients and health care providers can be notified if novel concerns arise in the future. Special issues in pediatrics It is inappropriate to delay research in pediatrics given the exigency of therapy for genetic diseases which represent an increasing fraction of pediatric morbidity and mortality. Moreover, the benefit-risk ratio m a y be more favorable in children w h o generally have discrete rather than degenerative diseases, exhibit greater regenerative capacity, and e m b o d y the potential to live long and productive lives. While particular caution has to be exercised in pediatric research, there are clear guidelines for pediatric investigation with the informed consent of parents or guardians (Andrews, 1987; Jansen, 1978; Code of Federal Regulations, 1983). Pediatric research m a y be proposed if there is "minimal risk" (defined as "risks of harm anticipated in the proposed research are not greater, considering probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests"), if "greater than minimal risk" is balanced by anticipated benefit to the subject, or if there is no benefit to the subject but the risks are "reasonably commensurate" with the patient's disease and significant generalizable knowledge m a y accrue (Code of Federal Regulations, 1983). Thus, the risk of gene transfer in m a n y patients must be compared to those of experimental organ transplantation, investigation of live (attenuated) vaccines, or radiation and chemotherapy for cancer. Follow-up in pediatrics is particularly difficult. It is complicated in childhood and adolescence by the normally poor participation in medical care and the transition from pediatric practitioners to internists. It will be important to establish mechanisms for maintaining follow-up through this period and the period of reproductive activity in young adulthood.
There are medical, scientific, and ethical imperatives to Public concern about somatic gene therapy maintain long-term follow-up of patients w h o participate in clinical trials of somatic gene therapy. F r o m a medical perspec- Two decades of debate over somatic gene therapy have tive, it is likely that there m a y be complications of gene transfer awakened both the expectations and concerns of the public. that need to be identified, diagnosed, prevented, or treated Public concern has perhaps been intensified by the restriction of aggressively. Even normal issues of health care, reproduction, this technology to basic science laboratories and the absence of and psychosocial development m a y be influenced by participa- apparent reference to practical medical therapeutics. Although it tion in gene transfer trials. From a scientific perspective, the is necessary to address principles of the scientific method, efficacy of gene transfer will ultimately have to be determined medical ethics, and public policy cautiously, the dearth of by controlled clinical studies. Long-term follow-up is essential clinical investigation m a y call into question the suitability of to identify complications of gene transfer that contribute to the these principles, foster public skepticism about the therapeutic efficacy of this technology. F r o m an ethical imperative, the potential and safety of somatic gene therapy, and even threaten benefit-risk ratio of any clinical research experiment can be the prestige of medicine and the willingness of society to invest greatly enhanced by the investigator's commitment to identify in genetic technologies. and manage any resulting complications. It m a y indeed be Clinical trials m a y substantially allay public concerns by considered the investigator's obligation to m a k e every possible exhibiting genetic technology in the recognizable context of effort to maintain follow-up of study participants. health and disease and provide a h u m a n face for research that is It is notoriously difficult to achieve efficient, long-term often perceived as threatening, coldly objective, or even amoral. follow-up in clinical research or practice. Protocols involving The public is better able to appreciate success or failure in gene transfer should describe plans for follow-up involving clinical trials than esoteric discussions about safety, social
CLINICAL C O N S I D E R A T I O N S IN S O M A T I C G E N E T H E R A P Y policy, and regulation. Clinical protocols should include specific plans for dealing constructively with public attention and using this attention to instruct the public about genetic disease and the importance of basic laboratory, animal, and clinical investigations.
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Psychosocial aspects of somatic gene therapy Psychosocial dynamics contribute substantially to medical therapeutics and will certainly contribute to the measured success of somatic gene therapy. Even the most deterministic medical interventions can be complicated by the appearance of "non-disease" (Bergman and S t a m m , 1967) or placebo effects (Haegerstam et al, 1982). T h e potential emotional consequences of being subjects to genetic modification, along with the anticipated public attention that m a y attend these protocols, make prior consideration of psychosocial issues particularly important. The ability of patients and families to provide informed consent and to participate fully in somatic gene therapy must be analyzed in the context of established models of reasoned action (Fishbein, 1980) or health beliefs (Becker and M a i m a n , 1975; Mikhail, 1981), their knowledge of gene therapy, sources of information, networks of support, and patterns of control. It will also be important to assess the long-term psychosocial consequences of genetic manipulation on the subject using quantitative measurements of self esteem, well-being, behavior, and psychosocial development.
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several years, an unrealistic time given the rapidly advancing state ofthe technology. General Clinical Research Center ( G C R C ) grants represent an important mechanism for funding clinical trials. Gene transfer projects can be funded from G C R C grants by local scientific advisory committees after approval by the R A C and director of the N I H . Moreover, funds for gene therapy proposals can be requested as part of G C R C applications after approval of local IRB and IBC committees, before approval is obtained from the R A C . O n e corollary to this method of obtaining funding is that the timing of submission of clinical protocols m a y be dictated by G C R C funding cycles. Corporate sponsorship of clinical research raises concerns about proprietary rights, the accessibility to clinical data, the financial interests and objectivity of the investigator, and the applicability of government regulations. The R A C has requested that initial trials not contain proprietary information so as not to interfere with public disclosure. The application and review process The major practical issue in proposing human trials is to observe meticulously the rules of the regulatory progress. The rancorous debates over genetic manipulation have gradually ceded to legal wrangling about rules and regulations. The report by the Office of Technology Assessment ( O T A , 1984) concluded that a societal consensus on somatic gene therapy was probably impossible and noted:
Where there is no agreement on what decision to make, the only alternative is a process for making the decision, and governmental agencies must demonstrate that the process is rational and fair. The development of somatic gene therapy is critically dependent on quality clinical investigation. It is c o m m o n to lament the state of clinical research, its scientific rigor, its level offunding, Legal challenge to details of the review process has become and the level of participation by academic physicians. S o m e of the last bastion of groups opposed to gene transfer in human the concern about proceeding with clinical trials reflects a subjects. Although these challenges do not reflect the mainconcern for the scientific enterprise itself. It has been argued that stream of societal, ethical, or theological thought, they are premature clinical trials could undermine public confidence and predictable and troubling. Investigators and institutions preparsupport for science in general. ing for clinical trials must be prepared to handle legal challenges Exemplary scientific rigor is certainly essential in the design and the controversy and cost these legal maneuvers will engenand performance of clinical research involving gene transfer. der. The involvement of molecular biologists, and the demand for the degree of precision that characterizes molecular biology, will present clinical investigation with a challenge that can only W H E N SHOULD A CLINICAL P R O T O C O L strengthen clinical research in general. In addition, the emersion INVOLVING G E N E TRANSFER of molecular biologists in clinical research will m a k e the basic BE SUBMITTED? scientist more aware of the complex and often counterintuitive realities of medicine, as well as the enormous power of existing There are no absolute impediments to clinical trials involving medical and surgical techniques that m a y be employed in an aspects of somatic gene therapy. Carefully constructed protocols using gene transfer to expedite research in cellular transplantaancillary capacity for gene transfer. The procurement of funding for clinical research involving tion, cellular regeneration, and malignancies might be progene transfer is a potentially limiting problem. It is inappropriate posed, approved, and performed successfully. Therapeutic trials for patients to bear costs of experimental procedures, and of gene therapy involving gene transfer into accessory sites or chimeric engraftment with cells treated with recombinant genes research protocols are generally not covered by third-party providers ( O T A , 1984). Investigator-initiated grants are also might also be proposed and approved, if the design of these unlikely to provide funds for clinical trials ( O T A , 1984). N I H protocols preserves conventional therapeutic options for the guidelines require approval of h u m a n protocols by the R A C , but patient and could provide substantial benefit to patients with before grants are reviewed. Sequential review by local I B C and minimal risks. I R B committees, the R A C , and funding agencies m a y require There is no reason to be reticent about the imperative of The state of clinical investigation and sources offunding
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DESNICK, R.J., PATTERSON, D.F., andSCARPELLI, D.G. (1982). Animal Models of Inherited Metabolic Diseases. (Alan R. Liss Inc., New York). FINGER, S., H E A V E N S , R.P., SIRINATHSINGHJI, D.J., K U E H N , M.R., and D U N N E T T , S.B. (1988). Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch-Nyhan syndrome. J. Neurol. Sci. 86, 203-213. FISHBEIN, M. (1980). A theory of reasoned action: some applications and implications. Neb. Symp. Motiv. 27, 65-116. FLETCHER, J.C. (1990). Evolution of ethical debate about human gene therapy. Human Gene Ther. 1, 55-68. F R I E D M A N N , T. (1983). Gene Therapy, Fact and Fiction. (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). F R I E D M A N N , T. (1989). Progress toward human gene therapy. Science 244, 1275-1278. F R I E D M A N N , T. A., and ROBLIN R. (1972). Gene therapy for human genetic disease. Science 175, 949-52. ACKNOWLEDGMENTS H A E G E R S T A M , G., HUITFELDT, B., NILSSON, B.S., SJOVALL, J., SYVALAHTI, E., and W A H L E N , A. (1982). Placebo in clinical This report was prepared for the "Round Table Group on drug trials—a multidisciplinary review. Methods. Exp. Clin. PharHepatic Gene Therapy" of the Baylor College of Medicine and macol. 4, 261-278. Texas Children's Hospital in considering development of cliniH A Y E S , A., COSTA, T., SCRIVER, C.R., and CHILDS, B. (1985). cal trials. I especially thank Dr. Ralph Feigin, Dr. George Ferry, The effect of mendelian disease on human health II: Response to Dr. William Klish, Dr. Bert O'Malley, and Dr. Savio W o o for treatment. Am. J. Med. Genet. 21, 243-255. encouragement and advise and T a m m y Reid for preparation of JANSEN, A.R. (1978). Research involving children. Pediatrics 62, this manuscript. This work was supported in part by the A C T A 131-136. foundation. Fred D. Ledley is an Assistant Investigator of the LEDLEY, F.D. (1989). 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Y A N G , J.C, TOPALIAN, S.L., M E R I N O , M.J., C U L V E R , K., COSTA, T., SCRIVER, C.R., and CHILDS, B. (1985). The effect of MILLER, A.D., BLAESE, R.M., and A N D E R S O N , W.F. (1990). mendelian disease on human health: a measurement. Am. J. Med. Gene transfer into humans—immunotherapy of patients with adGenet. 21, 231-242. vanced melanoma, using tumor-infiltrating lymphocytes modified by clinical investigation in gene therapy. The goal of every laboratory should be to anticipate clinical applications of their technology. This does not mean that protocols should be submitted in haste or that the stringent criteria which regulate the development of clinical protocols should be relaxed. It does mean that investigators should adopt a perspective in which all laboratory experiments are conceived as stepping stones to specific clinical experiments and are constructed using clinically applicable technologies. B y insisting on a clinical perspective for basic research and social discussion, attention will be focused on the substantive problems that remain in proposing clinical protocols, and clinical application of this important technology to patients in need will be facilitated.
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