Gene therapy holds the promise of curing disease and improving the quality of life for millions of Americans who suffer from cystic fibrosis, cancer and other illnesses. In fact, today’s newspapers report that gene therapy offered hope for the thousands of Americans who suffer from hemophilia. Hundreds of clinical trials have been initiated over the years as government and private industry have worked together to research numerous ways for this technology to reach its potential.
Gene therapy is subject to greater oversight than virtually all other technology. The FDA, through its statutory role as the regulator of drug development, and the NIH/RAC as the forum for public discussion, have served to protect patients while ensuring that important research moves ahead.
Recently, however, there have been questions raised about the adequacy of this oversight process. The tragic death of a patient in the University of Pennsylvania (UPenn) clinical trial has led to a re-examination of the roles of the FDA and the NIH. Questions have been raised that must be further addressed in order to safely and efficiently move gene therapy research and development into the 21st century:
What should be the respective and appropriate roles of the FDA and OBA/RAC?
What should be the requirements and mechanisms for reporting serious adverse events to FDA and OBA/RAC?
What information should be publicly disclosed?
This paper represents the views of the Biotechnology Industry Organization (BIO) which represents 850 companies, academic institutions and state biotechnology centers engaged in biotechnology research on medicines, diagnostics, agriculture, pollution control and industrial applications. It presents a brief overview of gene therapy technology and its current regulation and oversight. It also recommends clarifications in the roles and responsibilities of the governmental agencies that currently oversee gene therapy trials to ensure that the best balance is achieved between the continued need for patient safety and the future development of these potentially important new therapies.
Gene Therapy Technology
Since the first clinical trial was initiated in 1990, the area of gene therapy has expanded greatly with an increasing number of sponsors and academic researchers conducting human trials. Thousands of patients have now received experimental gene therapies. Target indications for gene therapies include genetic and metabolic diseases, cancer, acquired diseases such as AIDS, and cardiovascular disease. The field of gene therapy continues to focus its efforts on patients with severe and life-threatening diseases who usually have few treatment options or who have failed all current available therapies.
Gene therapy technology is much more complex than replacing a damaged gene or adding a gene to elicit a direct effect. Research identified as gene therapy has evolved to include cancer immunotherapy; angiogenesis; anti-angiogenesis, the destruction of blood vessels supporting tumor growth; and a host of other potential therapeutic interventions. Similarly, the vectors used in gene therapy continue to be refined. In addition to adenovirus vectors, retrovirus, plasmid DNA/lipid delivery systems, adeno-associated virus (AAV), and other technologies are in clinical use.
Gene therapy researchers still face many of the challenges that existed a decade ago: perfection of vector design and delivery to specific sites; control and persistence of expression once delivered to the target site; elimination of negative immune responses to the vector and the gene product; identification of target sites; and disease heterogeneity. Overcoming these obstacles requires on-going modification of the gene delivery system, which contributes to the lengthy development times for these products. However, with continued pre-clinical and clinical development, researchers move toward the establishment of safe and efficacious gene therapy products designed to treat severe and life-threatening disease.
Even after a decade of research and clinical development, many of the gene therapy clinical trials that are active today are in an early stage of development. These early phase studies (Phase I/II) are specifically designed to evaluate the safety of the vector under investigation. These trials continue to be in early development not due to problems establishing a safety profile, but because researchers are exploring their options with indications, routes of administration, dosing regimes, patient populations, combination therapies, and novel vectors. Many studies also are designed to evaluate the maximum tolerated dose, with the expectation that adverse events will occur at some dose level. This approach is standard in any drug development process. In addition, biological markers of activity, not efficacy, are sometimes evaluated in a combination Phase I/II study to evaluate if the vector is having the desired biological effect.
A high level of scrutiny and evaluation has been focused on gene therapies, more so than for almost any other health care technology. Clinical trials undertaken in the US are reviewed by four separate bodies: the Food and Drug Administration (FDA), local Institutional Review Boards (IRB), local Institutional Biosafety Committees (IBC), and the National Institutes of Health’s (NIH) Office of Biotechnology Activities (formerly Office of Recombinant DNA Activities). Most standard drugs and biologics only receive review by the FDA and IRBs.
New product candidates developed by academia and/or industry must meet certain defined standards prior to testing in humans. Before initiating human studies, product candidates are rigorously tested in pre-clinical models to determine initial safety parameters. The FDA is the sole body with statutory authority to regulate gene therapy clinical trials and products.
In order to initiate a clinical trial in the US, an Investigational New Drug Application (IND) must be submitted to FDA. The submission of INDs is a well-defined process that is outlined in the Code of Federal Regulations (CFR). The FDA receives from the sponsor a complete data package that includes all information as required by 21 CFR 312. The FDA directly protects patient safety through thorough evaluation of pre-clinical data, manufacturing data, any available clinical data, and informed consent documents. Each member of the FDA review team brings a wealth of experience and knowledge in their specialty and to the review process in general. All communications and data submissions to the FDA are confidential and the FDA is statutorily bound to up-hold this confidentiality. Through this process sponsors and the FDA develop a collaborative relationship which provides for the development of optimal trial designs and an open discussion about the issues in the development of a product.
In conducting any clinical trial, a sponsor has a statutory obligation under 21 CFR 312 to report adverse events (AE) and serious adverse events (SAE) to the FDA. Serious adverse events are reported to the FDA as either an expedited report (within 7 days after the sponsor’s initial receipt of information on the event for events which are fatal or life-threatening, unexpected and associated with the drug or within 15 days for events which are otherwise serious, unexpected and associated with the drug) or in the IND annual report (a summary of safety experience). One of the responsibilities of the FDA is to monitor and review these on-going safety reports and the safety of gene therapy protocols in general.
IRB and IBC
These local institutions ensure that gene therapy protocols and clinical trial sites take steps to protect patients and health care providers from unnecessary risks. They monitor clinical trials on a local level and are in close contact with investigators. All seven and fifteen day reports sent to the FDA are also sent by sponsors to investigators and forwarded to IRBs. Again, data are kept confidential in an effort to protect patient privacy rights and safety as well as the sponsor’s proprietary technology and/or data.
The NIH Recombinant DNA Advisory Committee (RAC) was established in 1974 as a forum to publicly disclose and debate the ethics and social impact of scientific research involving genetically modified organisms. It was not established pursuant to any statutory mandate. It is an advisory body whose members, who are a mix of lay and scientific community representatives, receive and evaluate applications to conduct gene therapy clinical investigations. The content of these applications and related discussions are open to the public.
The original NIH Guidelines were written in response to the development of recombinant DNA technology and to address scientific uncertainties. At the outset all recombinant DNA experiments were subject to intense scrutiny. BIO supported the role that RAC played during the early development of this technology. It has provided an appropriate public forum for discussion of "cutting edge" scientific issues. Over the past two decades, however, industry and academia have demonstrated that products using recombinant DNA/protein technology are safe and efficacious. A number of these products have had significant impact in patients with severe and life-threatening conditions including cancer, multiple sclerosis and bone marrow transplantation. Over 80 drugs and vaccines developed through biotechnology are on the market today and hundreds of millions of people have benefited from them.
With the passage of time, these RAC guidelines were modified and some functions performed by NIH was ceded to regulatory agencies that had statutory jurisdiction over the relevant trials and products. The RAC continues, however, to request information from entities undertaking clinical trials. The NIH cannot legally compel sponsors to provide it with data and has never had statutory authority to approve, disapprove, or modify clinical trials. However, over the years, many sponsoring companies have voluntarily complied with NIH guidelines and participated in the RAC process.
BIO regards RAC as a group whose primary responsibilities are to:
evaluate the social and ethical issues of gene therapy and related research and
inform past, current, and prospective gene therapy patients and the general public of progress in the field.
Sponsors and the gene therapy community in general, including patient representatives and the press, look to RAC for information and recommendations in these areas. In view of the involvement of OBA/RAC, which makes gene therapy protocols publicly available and publicly reviews proposed gene transfer technologies for clinical trials, gene therapy development remains much more open to public scrutiny than any other form of drug development. This increases public confidence in clinical trials and the willingness of patients to enroll in them.
A New Regulatory Environment
Despite this openness, there are some who argue that more information about adverse events in gene therapy clinical trials should be submitted to the RAC and made public. The investigation of the death of the patient in the clinical trial at UPenn has led to a series of stories in the press that imply that gene therapy is dangerous and that the industry is operating in secret and hiding adverse events. This, according to some, puts the public at risk because the true dangers of gene therapy are not being disclosed.
This pressure for disclosure has culminated in a new proposal from the RAC. Through a proposed amendment to the NIH guidelines, the RAC "clarified" its expectations for access to adverse event reports from institutions and investigators that receive NIH funding. The proposal was published in the Federal Register on November 22, 1999. Under the proposal, NIH would request reporting to the RAC of serious adverse events – whether or not the event was associated with or expected from the intervention – using a specified format and within a specified time frame. It would also request that the reports not contain trade secret or confidential commercial or financial information.
Upon review of this proposal, BIO has the following concerns: the standards outlined for expedited reporting are inconsistent with currently recognized standards; the SAE reporting format is inconsistent with current FDA regulatory standards; the context of disclosure for safety reports by RAC is not defined; and the required disclosure conflicts with current federal confidentiality statutes.
We propose an alternative approach for reporting of adverse event data by sponsors. Our proposal would constitute an agreement between the key federal agencies and industry that will provide the RAC with safety data while ensuring that patient confidentiality and trade secret data is protected.
Our proposal has been agreed to by all the members of BIO engaged in gene therapy research. The proposal sets a standard that all these companies will meet. The substance of the proposal will substantially increase the data that will be transmitted to the NIH and therefore to the RAC. We believe that this will effectively reassure patients and the public regarding the safety and efficacy of gene therapy clinical trials, enhance the ability of researchers to enroll patients in these trials, and enhance the RAC’s role in the process. At the same time, it is consistent with the industry’s FDA obligations and confidentiality rules.
The proposed reporting guideline would inappropriately recommend immediate reporting of unrelated serious adverse events.
According to 21 CFR 312, sponsors are required to notify FDA and all participating investigators of any "serious" and "unexpected" adverse event associated with the use of the drug being tested in the clinical trial within 7 days of notification of the event if the event was fatal or life-threatening, or 15 days for other serious and unexpected associated events. ("associated" refers to reasonable possibility of causation) This process ensures that federal regulators have the information they need to make a timely determination about the progress of a trial and whether patients are in danger. It also ensures that participating investigators are aware of important safety information. If patients are in danger, the FDA has the authority to place a clinical trial on hold or prohibit new enrollments. SAEs that are unrelated to the intervention are reported to FDA as part of the annual IND report submitted by sponsors because there is no imminent safety risk. This reporting structure is applicable to the development process for all drugs and biologics.
The NIH proposal defines "immediate" reporting as no later than 15 calendar days after the adverse event occurred. However, FDA regulations specify that the sponsor must report within 15 calendar days of receiving notification from the investigator that the event has occurred. It is therefore important to acknowledge the distinct and separate responsibilities of an NIH funded investigator and an FDA regulated sponsor of clinical trials.
A reporting system that entails the reporting of all SAEs in an expedited manner is inappropriate and unnecessary. The public is already protected by the immediate reporting of related events that alert FDA and all participating investigators to any dangers to patients in clinical trials. Additionally, the FDA has the mandate at any time during the course of a clinical study to require the sponsor to provide full information and analyses on all observed adverse events. Adverse events may occur during a trial that have nothing to do with the intervention. Public reporting of them, however, in the absence of full contextual information on the investigational agent, can result in premature and potentially misleading perceptions of a product’s profile. This could be detrimental to the development of potentially life-saving new therapies.
The proposal creates another reporting format that is unnecessary and duplicative.
The format for reporting SAEs is well established in federal regulations. 21 CFR describes in detail the process and information to be used by sponsors submitting adverse event reports. To create a new format would simply create additional burdens that would not enhance the understanding of a potentially important safety event.
Since the report requested by NIH would by definition contain trade secret and commercial confidential information and private patient information, the RAC cannot lawfully disclose its contents.
The proposal states that trade secret and confidential information should be removed from the adverse event report sent to NIH. It also requires that patient identifiers be stripped. We appreciate the NIH’s acknowledgement that adverse event reports contain information that cannot lawfully be publicly disclosed. We also appreciate its recognition that disclosure of patient information would violate that individual’s privacy rights and hurt sponsors’ and investigators’ ability to recruit patients into clinical trials.
However, the data and information that would be submitted under the proposal are, by definition, trade secrets and confidential commercial information. Virtually every detail about the design, size, or status of a clinical trial is of potential competitive value. Indeed, FDA explicitly recognizes that adverse events are confidential commercial information. Therefore, the proposal’s requirement of deletion of this information is illogical.
The same argument applies to patient data. BIO is concerned that confidential patient information will still be disclosed because other information in the report will be made public and this information could be used to identify a patient in a clinical trial.
Therefore, the proposal would require reporting of data that would provide the RAC with confidential information that cannot be disclosed. It is well settled law that three federal confidentiality statutes – the confidentiality provisions of the Freedom of Information Act, the federal Trade Secrets Act, and the Federal Food, Drug, and Cosmetic Act – preclude the FDA from publicly disclosing clinical protocols, adverse events, and other confidential commercial and trade secret information in the drug development process. The first two statutes also apply to the NIH. Since the NIH cannot legally apply the same federal statutes to the identical scientific data and information in a completely inconsistent way, if the RAC were to obtain data as contemplated by the proposal, it would not be allowed to disclose them to the public.
Consequently, the proposal has the ironic effect of providing the RAC with data it cannot use to further its mission of public discussion. Thus, the RAC proposal is internally inconsistent. It requires reporting of data for use in a public forum, while acknowledging by its own terms that this data must remain confidential.
BIO Recommendations for Gene Therapy Oversight
Gene therapy is a highly promising technology that has the potential to cure disease and improve the quality of life for thousands of patients. In addition, like other new drugs or biologics under investigation, gene therapy is already strictly regulated. Sponsors of gene therapy clinical trials must comply with federal regulations governing the development of all new drug products. Hundreds of gene therapy clinical trials have been approved over the past decade and thousands of patients have safely received investigational gene therapies.
The FDA regulates clinical trials of gene therapy and has the statutory authority to permit an IND to go into effect or, if necessary, place an IND on clinical hold to ensure safety of human subjects. Under existing federal regulations, serious adverse events are reported in a timely fashion to the FDA. This regulatory oversight role is critical to the FDA’s mission and provides effective protection for the public. BIO believes that only FDA has the scientific expertise needed to review and assess adverse events and that this should remain a statutory responsibility of the FDA. To protect patient confidentiality and because the information in an adverse event report may be of a proprietary nature for the sponsor, the FDA, by law, is not allowed to publicly disclose this information.
BIO continues to support the RAC’s role to publicly discuss the social and ethical implications of new technologies, such as gene therapy. The RAC can and should continue to play a critical role in publicly debating novel scientific and ethical issues associated with certain types of clinical gene therapy research. In this way, the RAC complements the FDA’s regulatory responsibility to oversee the development of individual drug products. However, the RAC should not, and legally may not, publicly disclose confidential commercial and trade secret data and personal patient information relating to gene therapy drugs and clinical trials submitted to it.
As an alternative to the NIH proposal, BIO companies propose the following structure for the future oversight of gene therapy:
The NIH does not have the legal authority to compel adverse event reporting by sponsors of clinical trials using gene therapy. Nonetheless, sponsors agree to voluntarily provide serious, related and unexpected adverse event reports (serious adverse events or SAEs) that are currently sent on an expedited basis to the FDA to the NIH/OBA. Sponsors would also send to RAC the safety data summarized in the IND annual progress report currently provided to FDA. That report contains summaries of all adverse events, whether or not the event was related to the drug in development and an overview of all other adverse events. In this way, OBA and the RAC would have access to adverse event reports at the same time as the FDA.
Thus, within the current scope of NIH guidelines, the RAC should adopt safety reporting guidelines that harmonize with the IND reporting rules and format outlined in 21 CFR 312 and current international standards. As noted, those regulations require sponsors to notify FDA of any serious and unexpected adverse event associated with the use of the drug being tested in the clinical trial within 7 days if the event was fatal or life-threatening, or 15 days for other serious and unexpected events. This process ensures that federal officials have the information they need to make a timely determination about the progress of a trial and whether patients’ safety is in danger. In addition, it protects patients’ privacy rights and maintains the integrity of the drug development process. Harmonization with the FDA requirements would simplify the reporting requirement and would lead to increased compliance.
Coordinating the procedures of the FDA and NIH will also help ensure a discussion between the two agencies as they interpret the data. It is essential that the review and interpretation of submitted safety data be coordinated between FDA and NIH to ensure a single, agreed-upon interpretation of those data. Specifically, if after an initial review, the RAC feels there may be potential safety concerns, we recommend a joint evaluation of the data between the RAC and the FDA. The results of these joint deliberations could form the basis of public discussion at the RAC meeting. Prior to any presentation of the conclusions from this assessment, however, the sponsor should be made aware of the findings, and have the opportunity to provide additional information or comment. Sponsors should also have the opportunity to present data at the RAC meeting.
Although the NIH guidelines and FDA reporting requirements would coincide, the respective roles of the agencies would remain the same. FDA would remain the only agency with regulatory authority and the ability to approve a trial or put a trial on hold. The RAC would maintain its role as an educational advisory body.
Reporting of adverse events to NIH/RAC in addition to FDA is only acceptable to BIO in the case of gene therapy because of the established role that NIH has to oversee novel human gene therapy experiments. Our proposed reporting structure is not applicable to the development process for other drugs and biological products.
The industry’s willingness to provide adverse event data to the RAC is contingent upon an agreement between NIH and industry that would memorialize how the data will be used. OBA would be responsible for ensuring that patient privacy rights are protected and that trade secret data remains confidential. How will the agency carry out that mission? What patient data will become public? How will the RAC ensure that confidential commercial and financial information from companies will not be disclosed? How will the RAC use this data to complement the oversight role of the FDA? We call upon the OBA to develop a proposal that would answer these questions. OBA should work with FDA and industry to develop a process that will provide the RAC with adverse event data it needs to do its job effectively, but also will ensure that this information will be used appropriately. The industry stands ready to work with OBA and FDA on this matter. We look forward to this collaboration.
Once the RAC, FDA, and industry agree to a reporting structure, BIO recommends that the process have a life span of one year. At the end of that year, industry will, in consultation with RAC and FDA, evaluate the system to determine if it should continue or if it needs modification.
The initial promise of gene therapy technology has not yet been realized. Despite the recent tragedy at UPenn, data obtained in gene therapy trials thus far are encouraging, and it is BIO’s belief that gene therapy currently has a good safety profile, as determined by more than a decade of pre-clinical and human clinical data. The biotechnology and pharmaceutical industry involved in gene therapy development fully supports presenting to the public a practical and balanced assessment of the benefits and risks of the technology.
The organizations represented by BIO remain fully committed to providing the resources necessary to fully realize the promise of gene therapy for the treatment of serious medical conditions such as cancer, cardiovascular disease, and genetic and metabolic diseases. It is vital that patients with these conditions have access to novel and innovative therapies. To meet that end, gene therapy research and clinical trials must be regulated in an efficient, thorough, and expeditious manner, in accordance with clear federal statutes and guidelines.