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