Good morning, Mr. Chairman and Members of the Committee. Thank you for inviting
the Food and Drug Administration (FDA or the Agency) to participate in this hearing
concerning gene therapy and the Federal government's role in the oversight of this field of medical research. I am Dr. Jay P. Siegel, Director, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration. The Office of Therapeutics Research and Review is the office within FDA responsible for the regulation of gene therapy.
Before I begin, I would like to express, on behalf of the Administration, our continued
concern that gene therapy studies be as safe as possible. As you know, when we recently
discovered potential safety violations with clinical trials being conducted at the Institute
for Human Gene Therapy located at the University of Pennsylvania we took rapid and
appropriate action. We will continue to investigate this situation thoroughly and take
appropriate action to help protect patients participating in gene therapy clinical trials
throughout the country.
Human gene therapy is the administration of genetic material to modify or manipulate the
expression of a gene or to alter the biological properties of living cells. Gene therapy has
the potential to revolutionize the treatment of diseases that currently are incurable or have
inadequate treatments. Cell and gene therapy products constitute an emerging area of
therapeutic intervention that has only existed for just over a decade. The relative
newness and complexity of the science of gene therapy presents considerable challenges
in accomplishing product regulation. Whereas many biotechnology products consist of
single purified proteins and antibodies, these novel therapies combine cells, tissues and
even organs with genetic alterations, novel device delivery systems and use of
specialized growth factors.
The original rationale for gene therapy was to treat genetic diseases by replacing a
nonfunctional, or defective gene. An example of such a disease for which gene therapy
shows promise involves, a genetic error that causes an individual to lack an enzyme
which leads to a condition where the patient cannot mount an immune response to
common infections. This disease, severe combined immunodeficiency, is extremely rare
and has been also called the "bubble baby syndrome."
Currently, gene therapy studies are examining a broad range of potential therapeutic
interventions, including stimulating the body's immune reaction to tumors, inducing new
blood vessels in the heart to alleviate heart attacks, and stopping the replication of HIV
in AIDS patients. There is also renewed emphasis on gene therapies for genetic diseases
such as hemophilia A and B, and cystic fibrosis.
FDA REGULATORY RESPONSIBILITIES
Since the first human gene transfer in the late 1980's, human gene therapy products have
become one of the fastest growing areas of product development under FDA oversight.
In 1993, the Agency published a Federal Register notice which provided clarification
that cell and gene therapies were subject to regulation under the Public Health Service
(PHS) Act and the Federal Food, Drug, and Cosmetic (FD&C) Act.1 Gene therapy products present extraordinarily novel and controversial issues associated with cutting edge medical technology, ranging from the use of mouse and human viruses to produce gene vectors (carriers of genes), to the ethical and social issues involved with the potential for gene alteration in utero and other uses which could affect future generations.
In the five-year period from 1989 to 1993, 48 gene therapy investigational new drug
applications (INDs) were submitted to FDA. In contrast, from the publication of the
1993 Federal Register notice, until January 19, 2000, 240 gene therapy INDs were
submitted to FDA. Of those, 55 were submitted in the most recent Fiscal Year (FY)
1999. There have also been over 800 amendments (e.g., changes to the product, or new
protocols, etc.) to gene therapy INDs submitted each year. The Agency has yet to
receive the first application to license a gene therapy product.
FDA REVIEW PROCESS FOR GENE THERAPY
For any unapproved biological product that is to be tested in humans, an IND must be
filed with FDA. The IND process for gene therapy is the same as it is for other biologic
products. We encourage and recommend meetings between CBER reviewers and
sponsors of a potential INDs for all biological products throughout the product
development process in order to stimulate scientific interchange and clarify FDA
regulatory requirements. Under statutory authority, FDA determines within 30 calendar
days from receipt of an IND whether it is appropriate for the IND to proceed or, if
necessary, to place an IND on clinical hold, in order to protect the safety of human
subjects. This is a difficult task for novel therapies with relatively unknown risks.
Part of the FDA's review of the IND includes a review of the sponsor's proposed or
FDA's recommended stopping rules. The stopping rules are rules in the protocol which
assure that a clinical trial will be stopped if certain adverse events should occur. In
addition, prior to allowing a clinical protocol to proceed under an IND, FDA frequently
requires several modifications to the protocol to ensure that all known safety issues have
been addressed. These might include: changes in manufacturing to ensure purity,
additional laboratory testing of the product, additional animal testing of a product,
exclusion of human subjects who might be at high risk for serious adverse events,
additional safety testing of human subjects, lower starting doses in humans and slower escalation of doses. These modifications to the protocol are intended to lower the risk to
As clinical data accumulate and product development continues, FDA continues to
monitor the IND and may require further changes, for example, when adverse events are
reported. On occasion, or, when information raises concerns regarding the quality of the
investigational product or conduct of the clinical trial, the Agency may perform an
In addition, CBER conducts regulatory research, as needed, to assist in the assessment of
product safety. An example of such regulatory research is the development of assays to
detect the presence of replication competent mouse retrovirus. The development of these
assays are intended to help assure the safety and quality of mouse retroviral vectors used
in gene therapies and therefore lead to marketing of safe products by many firms.
As with all IND studies, an Institutional Review Board (IRB) must review and approve
such studies in advance to ensure the rights and welfare of study participants. The IRB
plays a critical role in the review process, particularly in determining the continuing
adequacy of protocols and with regard to its approval of informed consent forms which
explain the known and potential risks and benefits to human subjects.
Although no product is risk-free, FDA's goal is to minimize the risks by assessing
information on the product and conduct of the clinical trial including the safety reports it
receives from the sponsors of the investigational therapy and similar therapies. It should
be stressed that it is the sponsors and /investigators of clinical trials who conduct the
clinical trials and, therefore, they have primary responsibility to protect the safety of the
patients or individuals participating in the trials. FDA helps assure that
sponsors/investigators are meeting their obligations through the IND review process.
FDA INTERACTIONS WITH NATIONAL INSTITUTES OF HEALTH (NIH)
AND THE RECOMBINANT DNA ADVISORY COMMITTEE (RAC)
In addition to FDA regulation, NIH is actively involved in gene therapy protocols. FDA
has worked closely with NIH and the RAC regarding gene therapy clinical research for
many years and continues to do so. The RAC makes recommendations to NIH on gene
therapy issues (which is discussed at length by in their testimony) and engages in a
public discussion of scientific, safety, ethical, and societal issues related to proposed and
ongoing gene therapy protocols. Also, a CBER representative is an ex-officio member of the RAC and many other CBER staff routinely participate in RAC meetings and a number of RAC subcommittees.
FDA and NIH continue to work together to optimize and streamline Federal regulation
and oversight of human gene therapy research. FDA decides whether individual gene
therapy protocols should proceed after evaluating the information in the IND, while
NIH/RAC conducts the public scientific and ethical review and public discussion of
novel applications of human gene transfer, which are carefully considered during FDA's
review process. FDA and NIH meet regularly to discuss pending gene therapy issues.
The submission process for gene therapy has evolved over the years through a
cooperative effort between FDA and NIH. The current process was reiterated recently in
Dr. Kathryn Zoon's letter dated November 5, 1999, which was sent to all gene therapy
clinical investigators and sponsors and is posted on the FDA website at
www.fda.gov/cber/letters.htm. The letter outlines the current process for submission to CBER of a gene therapy IND and any subsequent adverse event reports. It also describes how that process relates to the submission of gene therapy protocols and adverse event reports to the NIH, Office of Biotechnology Activities (OBA), formerly Office of
Recombinant DNA Activities (ORDA), as required by the NIH Guidelines for Research
Involving Recombinant DNA Molecules (NIH Guidelines). These NIH guidelines only
apply to institutions with NIH-funded research. FDA regulates all research that is subject
to an IND.
REPORTING OF ADVERSE EVENTS
Once the clinical trial has begun, the sponsors and clinical investigators have certain
regulatory responsibilities with respect to reporting adverse events associated with gene
therapy products. These requirements, which are the same as those for any new IND,
specify that any adverse event associated with the use of the study drug that is both
serious and unexpected must be reported to FDA as soon as possible, and no later than
fifteen calendar days of the sponsor receiving the information. Any findings for tests in
laboratory animals that suggest a significant risk for the human subjects must be reported
by the sponsor within the same timeframe. Additionally, an unexpected fatal or life
threatening experience associated with the use of the drug must be reported as soon as
possible by the sponsor but no later than 7 calendar days after the sponsor receives the
information. All other adverse events must be reported in an annual report.
The information provided in the adverse event reports is reviewed by FDA to determine
whether additional actions are warranted to assure the safety of the study participants.
Actions that might be taken by FDA, sponsor, investigator, or IRB could include :
- notifying sponsors with INDs for related or identical products about safety concerns;
- modifying the protocol to include changes in eligibility criteria, changes in dose,
route, and schedule of administration of the product;
- changing the informed consent to disclose new toxicities;
- obtaining additional consent from current study participants to reflect new
- updating the clinical investigator's brochure;
- considering the need for new non-clinical studies; and,
- placing the IND(s) on clinical hold.
When an ongoing study is placed on clinical hold, no new subjects may be recruited to
the study and treated with the investigational therapy; patients already in the study are
taken off the investigational therapy unless specifically permitted to continue by FDA,
based on the particular circumstances of each study.
One of the issues that this Subcommittee has asked us to address is the case involving the
death of a young patient in a gene therapy clinical trial at University of Pennsylvania. As
the Subcommittee knows, this involves an ongoing investigation. In order to ensure that
this investigation is thorough and effective, we are limited in the discussion we can have
today regarding findings that are, necessarily, preliminary. FDA investigators have
concluded an inspection at the University of Pennsylvania. Based upon the FDA
investigators' findings, a notice of inspection observations (FDA Form 483) was issued
to Dr. James Wilson on January 19, 2000, as is often done at the conclusion of an FDA
inspection. The items listed on the FDA Form 483 represent the investigators'
observations concerning potential deficiencies relating to the clinical investigation. In
this case, the investigators' observations listed on the FDA Form 483 pertain to some of
the following issues: informed consent; implementing patient exclusion criteria;
following stopping rules; initiating protocol changes; and, submitting reports of animal
deaths. Based upon the concerns raised regarding the adequacy of the monitoring
program to protect the safety of human subjects, FDA determined it would be prudent to
place all other trials sponsored by Dr. James Wilson and the Institute for Human Gene
Therapy on clinical hold pending demonstration that an adequate monitoring program is
in place. FDA will further evaluate the inspection findings and the sponsor's response to
determine the significance of the observations and if regulatory or additional
administrative action is necessary to achieve corrections. FDA will consider the full
range of options and, if necessary, take further Agency action.
At the December RAC meeting, FDA provided a complete presentation concerning our
adverse event reporting requirements, definitions and procedures.2 This presentation, along with FDA presentations delivered at other forums, should help sponsors and
investigators better understand FDA's requirements with regards to adverse event
reporting. FDA's ex-officio non-voting representative was present at this meeting. FDA
staff also delivered several presentations on the use of adenoviral vectors and the clinical
trial at the University of Pennsylvania. The use of adenoviral vectors was extensively
discussed at the December RAC meeting. At the next RAC meeting in March 2000, the
ad-hoc working group will present and issue a report on the adverse events reported by
investigators using adenoviral vectors. This ad-hoc RAC working group, including
representatives of FDA and NIH, is working together to evaluate the relationship
between adenovirus vectors and the adverse events. FDA hopes this effort may result in
the improvement of human subject safety through the identification of clinical trials that
may need additional monitoring.
In order to protect human subjects and also increase public knowledge of adverse events,
FDA and NIH have taken steps to remind sponsors of their reporting requirements. In
the letter dated November 5, 1999 (noted on page 7), FDA also included information to
the clinical investigators and sponsors reminding them of their responsibilities to report
As of December 1999, FDA has implemented two new Standard Operating Procedures and Policies (SOPP) to notify NIH when FDA has received adverse event reports and protocol changes (SOPP 9110.1 Notification of NIH/Office of Biotechnology Activities (OBA) of Changes in a Gene Therapy Protocol and SOPP 9110.2 Notification of NIH/OBA of FDA's Receipt of Adverse Event Reports to Gene Therapy INDs). These procedures can be found on FDA's website from the Manual of Regulatory SOPP at www.fda.gov/cber/regsopp/regsopp.htm.
With the number of gene therapy IND submissions increasing each year, FDA has
continually evaluated its review and oversight processes, to ensure better human subject
protection, to improve investigator compliance, to improve the quality of submitted
protocols, and to provide additional guidance and standards to facilitate preparation of
INDs. This has been done through educational outreach, conferences, meetings and
CBER staff serves as faculty for a number of educational programs for sponsors and
investigators of INDs. Each year CBER gives numerous presentations on scientific and
regulatory issues and policy as they relate to gene therapy and other biological product
FDA has sponsored or co-sponsored many educational outreach programs, including co-sponsoring three open public Gene Therapy Policy Conferences with NIH that discussed
scientific and ethical issues, such as vector safety, and ethical considerations regarding
prenatal gene therapies, and Gene Therapy Workshops with over 800 people attending
each workshop. During these conferences and workshops, FDA presented information to
sponsors and investigators on FDA requirements, recommendations and policies for gene
therapy INDs. FDA held educational symposia at the 1998 and 1999 annual meetings of
the American Society for Gene Therapy (ASGT) and will expand its symposia at the
ASGT annual meeting in 2000. FDA continues to work with ASGT toward the
development of standard approaches to preclinical toxicology studies and facilities
FDA also partners with many patient groups to provide regulatory and scientific support
at patient group meetings. Such efforts with the Cystic Fibrosis Foundation and with the
National Hemophilia Foundation have contributed to the initiation of a number of gene
therapy trials for those diseases.
FDA reviews annual reports, which include data on patient accrual, adverse events, and
scientific and medical reports. The Office for Protection from Research Risks (OPRR)
and FDA educate the research community on issues related to protecting human research
subjects. Both respond to questions from researchers, IRBs and institutional officials.
FDA and OPRR co-sponsor several workshops annually for the research community.
FDA strives to evaluate and implement measures to improve the conduct of clinical
studies. In addition to the actions mentioned previously, CBER intends to take the
following steps to improve human subject safety:
- Plan to issue a proposed rule on the public disclosure of information regarding clinical trials of gene therapies that would provide more information on gene therapy clinical trials to the public.
- Continue efforts to improve investigator compliance through educational outreach for sponsors and investigators.
- Enhance regulatory research to improve product safety.
- Provide additional guidance for gene therapy products to build upon existing guidance. In this last regard, CBER issued two guidance documents, "Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy" and "Draft Guidance for Industry: Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors."
- Conduct more inspections to increase oversight of gene therapy INDs.
- Encourage sponsors to assess or reassess the adequacy of their monitoring program and to consider obtaining independent monitoring as needed to improve the conduct of their trials and help ensure timely and accurate reporting to oversight bodies.
In the area of gene therapy, it is clear that many exciting innovations are emerging.
While many of these new gene therapy and biotech products may yet have unknown
risks, they also have the potential for tremendous patient benefit. When developing these
new products, sponsors of clinical trials must accept the responsibility to ensure that
participants are not exposed to known unreasonable risks and that the experimental
products are as safe as possible. I have outlined FDA's role in this process and have
briefly mentioned our interactions with NIH. It is critically important that sponsors and
investigators who conduct the clinical trials take the responsibility to assure the safety of
their human subject participants. They must achieve this by using quality controlled
experimental products, by practicing good clinical medicine and also by communicating
accurate information to FDA regarding safety in a timely manner, as required by our
CBER is committed to minimizing the risks to human subjects who participate in clinical
trials, including gene therapy studies, while encouraging the development of promising
new experimental therapies. We will continue to work closely with NIH and others as
appropriate. It is essential that FDA continue to develop the strongest possible science
base so that our reviewers possess the necessary scientific and medical knowledge to
effectively review and evaluate new and increasingly complex investigational biological
products such as gene therapy.
We know that these issues present new and difficult challenges. I believe we have met
these challenges in the past and let me assure the Committee that we will continue to do
so in the future.
1 58 Federal Register 197, October 14, 1993, pp. 53248-53251: Notice: Application of Current Statutory
Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products.
2 The materials presented by FDA at the December 9-10 RAC can be found on the FDA website at www.fda.gov/cber/summaries.
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