Testimony of H. Stewart Parker

Good morning. I am Stewart Parker, CEO of Targeted Genetics Corporation, a biotechnology company based in Seattle, Washington. I am testifying on behalf 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.

I very much appreciate the opportunity to participate in this discussion related to oversight of gene therapy.

Before I proceed, I would like to again express my sympathy to the family of Jesse Gelsinger, for the loss of their son and family member. I can only imagine the pain they have endured.

Violations Cannot Be Tolerated

We in the industry were surprised and deeply disturbed to read recent reports of regulatory violations at the Institute of Human Gene Therapy at the University of Pennsylvania. These violations have led to the FDA halting all gene therapy trials underway there. If these or any other violations occurred, this behavior absolutely cannot be tolerated, and penalties should be imposed to the full extent of the law. I am certain that my colleagues in the industry, as well as in gene therapy academia agree with me.

Overview

As all entrepreneurs must do, I want to get right to the bottom line:

• Gene therapy has great potential to provide treatments to the millions of Americans who suffer from genetic diseases. This research must go forward.
• Biotechnology companies expect and welcome science-based regulation from the FDA for gene therapy clinical trials, as we do for all other drug development.
• BIO has made a concrete offer to the RAC that will provide it with the information necessary to fulfill its role as a body that discusses overriding policy and ethical questions related to new technology. This proposal is attached.

Gene Therapy's Promise

I would like to discuss gene therapy, a field that has great potential to provide treatments for both acquired and inherited diseases. The field of gene therapy is focused on finding ways to introduce genes into cells in order to correct a cell malfunction, to add a new function to a cell, or, in the case of cancer, to add a gene to a cancer cell that causes that cell to die. A variety of different types of gene delivery systems are used to deliver genes into target cells. Some systems are made from modified viruses, which appear to be very efficient at getting genetic information into cells. There are many different types of viral based systems, each of which has its own characteristics and safety profile. Nonviral, or synthetic gene delivery systems are also used, each of which, again, has its own unique profile. The goal is to match the appropriate delivery system with the gene, the target cell and the disease, in order to develop effective therapeutics.

There has been tremendous excitement about the prospects of finally knowing all the genes that make up the human being. Gene therapy allows us to actually put that knowledge to work, by creating products out of these genes. There are about 5000 genetic diseases including hemophilia, Huntington's disease and cystic fibrosis. For patients with these diseases and others, gene therapy offers hope that finally these diseases can be efficiently controlled or cured.

Recent reports indicate that this hope is well placed. For example, several gene therapy products have demonstrated safety and have begun to demonstrate efficacy in cancer clinical trials. In addition, recent studies in France have shown that infants suffering from Severe Combined Immunodeficiency Disease (SCID) have had their immune systems completely restored by gene therapy.

Targeted Genetics

My company, Targeted Genetics, is a gene therapy company formed in 1992 as a spinout of Immunex Corporation. We currently are developing a number of products, in clinical and preclinical trials, for the treatment of cystic fibrosis, cancer, rheumatoid arthritis, cardiovascular disease, and hemophilia, using both viral and nonviral delivery systems. Phase I and Phase II clinical data from our lead products, tgAAV-CF, for the treatment of cystic fibrosis, and tgdccE1A, for the treatment of cancer, while preliminary, are promising. Our first presentation to the NIH Recombinant DNA Advisory Committee (RAC) was in 1991, and we have had continued and significant interactions with the RAC.

Having been the first employee of Immunex Corporation, in 1981, I have spent the bulk of my biomedical career developing new technologies, and attempting to translate cutting edge science into new therapeutics. I feel I can speak on behalf of an industry that is trying to overcome technical hurdles and develop products in a sound, responsible manner - products that have potential to treat a vast number of diseases.

Regulatory and Oversight System Changes

While gene therapy research and development must advance to help the millions of Americans who suffer from serious and often fatal diseases, it is imperative that the technology, like all drug therapy, goes forward safely. Consequently, I would like to discuss regulatory oversight of gene therapy, especially the reporting of data from clinical trials. BIO has developed a position paper on this issue, which is available on its website: www.bio.org.

Let me be clear about our position. BIO welcomes and expects strict oversight of our research and development activities by the FDA. Science based oversight by the FDA is both important and welcomed, particularly for new technologies. Indeed, commercial acceptance of our products depends on our ability to show that these products have met rigorous testing criteria, as is the case for all therapeutic products. BIO has consistently lobbied for additional resources for the FDA, so that it can perform its oversight responsibilities even more effectively.

Moreover, our industry welcomes a public discussion about the ethical and social implications of specific applications of biotechnology. Toward that end, the guidance and input from interactions with the RAC have also been important.

We believe that the regulatory body governing individual human clinical trials, the FDA, does a very effective job overseeing patient safety. The industry has been extremely impressed with the scientific expertise and caliber of FDA reviewers with whom we have interacted. I think it is important to remember that the development process for turning a gene into a therapeutic product carries with it the same sorts of stringent requirements and testing standards as those for any other therapeutic product. Due to its knowledge of the drug development process, FDA is well suited to the task of overseeing trials involving individual gene therapy products.

We also believe the RAC is an entity that is effective in organizing public discussion of any overriding policy issues related to gene therapy. The RAC reporting standards, as currently written, provide an effective opportunity for RAC members, and society, to be alerted to any safety and ethics issue that could be encountered. It is my view that compliance by academic researchers with these reporting standards warrants additional review.

Industry takes its compliance with FDA regulatory requirements extremely seriously. Why? For a company, the penalties for noncompliance, as well as the implications of noncompliance with FDA guidelines are so severe that the result could be the end of the company itself. Even the receipt of a simple warning letter can so damage a company's credibility that its products are not accepted, its stock may fall dramatically, and its financial and commercial development partners and potential partners may walk away. It is not only a legal requirement and ethical imperative but also an essential business practice to comply with all FDA regulations at all times.

Proposals Regarding Adverse Event Reporting

In November of last year, the NIH proposed an expanded review system related to adverse events in gene therapy trials, designed to improve safety by requesting more safety reports from gene therapy clinical trials. Many observers, including several members of the RAC, were concerned that this proposal was impractical and would not result in increased safety. It is important to remember that federal law already requires that companies sponsoring clinical trials for gene therapy, as well as other drugs, provide comprehensive adverse event reports to the FDA. Therefore, the only issue here is whether these same reports should be submitted to an additional entity, the RAC.

BIO proposed an alternative approach for reporting of adverse event data to the RAC by sponsors. This proposal is designed to provide the maximum safety information without compromising patient confidentiality or a company's legitimate proprietary data. Under the BIO proposal, the RAC would receive reports of adverse events from company sponsors in addition to the reports it receives from investigators. The BIO plan would provide this information to the RAC as well as to the FDA.

Our proposal has been agreed to by all the members of BIO engaged in gene therapy research. The proposal sets a new high standard that all these companies must meet. This proposal will substantially increase the data that will be transmitted 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.

Let me be clear. Under the BIO plan, the RAC would receive company reports on safety in addition to the investigator reports the RAC already receives under current reporting guidelines.

There are three likely scenarios to be addressed: (1) research that is industry funded and not taking place at an NIH-funded institution; (2) research that is industry funded but is taking place at an NIH-funded institution; and (3) research funded by NIH with or without industry involvement.

This is how our plan would work in these three situations:

Scenario 1: The reporting rules for companies we propose and describe below would apply. The RAC would receive adverse event reports from companies in harmonization with FDA requirements.

Scenarios 2 and 3: In these scenarios, the existing NIH reporting guidelines for academic investigators would apply. In addition, as described in our proposal, companies would provide adverse event reports to the RAC that are currently only provided to the FDA.

Therefore, in any scenario, the RAC would receive data about gene therapy clinical trials.

BIO Recommendations for Gene Therapy Oversight

Specifically, BIO companies propose the following structure for the future oversight of gene therapy:

Sponsoring companies 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 only provided to FDA. In this way, OBA and the RAC would have access to adverse event reports simultaneously with 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. 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 .

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. The results of these 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.

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 developing a mechanism to ensure that patient privacy rights are protected and that commercial development information 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 in some untimely or wholly inappropriate manner? 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 and we offer any and all assistance they may require.

These issues should be resolved for investigator-reported data as well. Our concerns about patient confidentiality and the publication of commercial information also apply in these situations.

OBA should work with FDA, industry, and investigators 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.

Conclusion

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 a rigorous but efficient manner, in accordance with clear federal statutes and guidelines.

We believe that existing FDA and NIH rules provide strong safety oversight for gene therapy products. BIO companies are proposing to provide the RAC with additional data under appropriate circumstances. We look forward to working with both FDA and NIH, as well as Senators and Members of Congress on a proposal that will protect patients while promoting gene therapy.

Thank you for the opportunity to provide these comments. I'll be happy to answer any questions you have.