Mr. Chairman and Members of the Subcommittee, I am Amy Patterson, the Director of the
Office of Biotechnology Activities at the National Institutes of Health (NIH). The NIH's
oversight of human gene transfer research is embodied in the activities of the Recombinant DNA
Advisory Committee (RAC) and the NIH Guidelines for Research Involving Recombinant DNA
Molecules (NIH Guidelines). Both the role of the RAC and the depth and breadth of the
Guidelines have changed in the last quarter of a century since their inception. The public and
the scientific community have benefited from NIH's oversight and stewardship. I am honored to
appear before the subcommittee today to testify about the role of NIH in supporting gene transfer
research and to describe to you our plans for the future.
Background
Since the advent of genetic engineering over 25 years ago, we have reaped many benefits from
recombinant DNA technology. For example, recombinant DNA technology has made possible
the manufacture of therapeutic proteins, such as human insulin and human growth hormone,
which have widespread clinical application and benefit. Recombinant DNA technology, which
has been integral in the sequencing of the human genome, also is being used to discern the
genetic basis for many diseases and to design some of our most remarkable new treatments.
Gene therapy is a relatively recent, and still experimental, application of recombinant DNA
technology and it has caught the public's attention - not only because of its promise, but also
because of the ethical and social implications of this research.
Clinical research, including human gene therapy research, is not without risk. Research is, by
definition, experimental -- if the outcome were known, the study would not have to be
conducted. Thus, the risks associated with the experimental treatment cannot always be
predicted. For this reason, there exists a comprehensive system of Federal laws, regulations, and
guidelines pertaining to the protection of human subjects in clinical trials. This fall, the tragic
death of Jesse Gelsinger a young man enrolled in a University of Pennsylvania clinical study
for a disorder called partial ornithine transcarbamylase (OTC) deficiency underscored the need
for constant vigilance by researchers, by Federal agencies, and by Institutional Review Boards
(IRBs) and Institutional Biosafety Committees (IBCs) responsible for the oversight and conduct
of clinical gene therapy research. The NIH and the scientific community understand that the
realization of the promise of clinical research in general, and gene transfer research in particular,
is predicated on the public's trust particularly the trust of the patients and families who
volunteer to participate in clinical trials.
What is Gene Therapy and What is its Promise?
Gene therapy encompasses a variety of techniques directed toward therapeutic ends. For
instance, gene therapy may be used to: 1) alter or supplement the function of a mutated gene by
providing a copy of a normal gene; 2) directly alter and/or repair the mutated gene; or 3) provide
a gene that adds missing functions or regulates the expression of other genes. The success of
this technology is dependent upon not only the delivery of genetic material into the target cells,
but also the expression of the gene once it reaches its target site. Both of these requirements
pose considerable technical challenges. With regard to gene delivery to target cells, a variety of
"vectors" have been developed to serve this purpose. Most of these vectors are disabled viruses
which work by delivering genes into certain human cell types, in much the same way as ordinary
viruses infect cells.
Clinical gene transfer research has grown significantly since the first experiment in 1989.
Interest in this arena of research, by both investigators and patients, has grown concomitantly
with our increasing knowledge about disease-related genes. It's helpful to consider the scientific
exploration of gene transfer as focused in two areas: methodologies for gene delivery and gene
expression and specific diseases or conditions. Initially, gene transfer trials targeted either
cancer, infectious diseases or single gene disorders such as cystic fibrosis. Increasingly
however, the trend over recent years in gene transfer is to tackle diseases that involve more than
one gene and are chronic. Prominent examples include heart disease, inadequate blood flow to
the limbs, arthritis, and Alzheimer's. There has been increasing interest in the development of a
broad array of vectors that investigators can choose from in order to best target the diseased cell
type - for instance the use of herpes virus as vectors to the CNS, which can deliver genes to both
dividing and non-dividing cells. Adenoviruses can only infect actively dividing cell populations,
which limits their usefulness in treating diseases of the heart or brain, where the cells are not
actively dividing. There is also considerable and growing interest in the use of other methods
apart from viral or bacterial vectors to deliver genetic material into cells. The use of small
molecules composed of RNA and DNA to directly repair the defective DNA, rather replace the
entire gene, has, for example, been applied in animal studies of sickle cell anemia.
To date, more than 4,000 patients have participated in gene therapy studies. Of the 372 clinical
trials registered with the NIH, 89 percent are Phase I studies are designed to assess safety and
toxicity. Ten percent are Phase II studies which assess safety and efficacy and generally involve
a larger number and a more diverse population of patients. Only 1 percent of the trials (3
protocols) have progressed to Phase III efficacy studies. Thus, most human gene therapy clinical
trials have been focused on safety, rather than efficacy. For this reason, it is perhaps more
accurate to refer to this technology as "gene transfer," rather than "gene therapy, " until there is more evidence for the therapeutic benefit of this technology. NIH currently supports or conducts 157 gene transfer trials for a range of disorders, including cancer and AIDS.
Gene transfer research also has raised uniquely complex scientific, medical, ethical, and social
issues that have warranted special oversight by the public and by the NIH, in particular. For
example, the task of introducing genes into target cells carries with it the risk of inadvertent gene
transfer to reproductive cells (sperm or egg cells), which could result in genetic changes being
passed on to offspring. Similarly, because we can not yet fully control the placement and
expression of the transferred genetic material, gene transfer may also pose unexpected health
risks to the patient. And although the vectors used to transfer genes into cells are disabled
viruses, these viruses may still retain some limited ability to cause disease, thus putting the
patients and their close contacts at risk. Finally, this technology also could be put to
controversial uses, e.g., for the enhancement of basic human traits such as height or hair color,
rather than for the treatment of disease.
NIH Oversight of Clinical Gene Transfer Research
The NIH Guidelines and the Recombinant DNA Advisory Committee (RAC), whose unique role
in this class of research is defined in the NIH Guidelines, are the key tools by which the NIH
oversees gene transfer research. Investigators conducting gene transfer research either funded
by the NIH or carried out at an institution that receives NIH support for recombinant DNA
research of any type are expected to comply with the NIH Guidelines. Failure to comply with
the requirements set forth in the NIH Guidelines can result in the limitation, suspension or
withdrawal of NIH support to the institution. NIH can also impose a requirement for prior NIH
approval of any or all recombinant DNA projects at an institution. [All clinical gene transfer
trials, regardless of funding source or research site, are also subject to Food and Drug
Administration (FDA) regulations (21 CFR 312). The FDA has statutory authority to allow a
gene transfer clinical study to proceed and, if necessary, to place a study on clinical hold in order
to ensure the safety of human subjects.]
How did NIH come to play this unique role in this important arena of clinical research? In the
early 1970s, scientists discovered a way to insert or recombine human and other species of DNA
into bacterial genes, hence the term "recombinant DNA." This advance raised a number of
serious concerns and questions among the public as well as the scientific community about the
potential environmental, ecological, and infectious disease risks of this technology. Recognizing
both the powerful benefits that might emerge from this research and the depth of public concern,
the scientific community issued a self-imposed moratorium on recombinant DNA research and
called for the formation of a national oversight body to ensure public discussion and oversight of
this emerging technology. The RAC was subsequently established by the NIH and with its
advice, NIH formulated the NIH Guidelines, which set forth policies and procedures designed to
maximize the safety of basic recombinant DNA research.
In the 1980s, when it became increasingly apparent that recombinant DNA technology had the
potential to lead to new gene-based treatments for human disease, the NIH established a
subcommittee of the RAC to explore the scientific basis for and safety and ethics of so-called
"gene therapy." Composed of scientists, ethicists, lawyers, and patient advocates, as well as
liaison members from the FDA and the Office for the Protection from Research Risks (OPRR),
among others, the subcommittee developed a new chapter in the NIH Guidelines (Appendix M).
This new chapter delineated the roles and responsibilities of individual research investigators,
NIH-funded institutions, IBCs, the RAC, the NIH Office of Recombinant DNA Activities (now
known as the Office of Biotechnology Activities), and the NIH Director in the conduct of human
gene transfer research. It also provided guidance for optimal design of preclinical and clinical
research and standards for informed consent.
Implementation of the NIH Guidelines
The safe conduct of experiments involving recombinant DNA depends on the individual
conducting such activities. In this regard, it is important to understand what the NIH Guidelines
are and what they are not. The NIH Guidelines constitute an administrative framework in which
safety is an essential and integral goal of research involving recombinant DNA molecules. The
NIH Guidelines cannot anticipate every possible situation. The good judgment of the individuals
conducting clinical research is the key essential to protection of human research subjects. The
NIH Guidelines are intended to assist the Principal Investigator, the institution, the Institutional
Biosafety Committee, the Biological Safety Officer, and the Institutional Review Board in
determining safeguards that should be implemented. The NIH Guidelines will never be complete
or final since all conceivable experiments involving recombinant DNA cannot be foreseen.
Therefore, it is the responsibility of the institution and those associated with it to adhere to the
intent of the NIH Guidelines as well as to its specifics. Each institution (and the Institutional
Biosafety Committee acting on its behalf) is responsible for ensuring that all recombinant DNA
research conducted at or sponsored by that institution is conducted in accord with the NIH
Guidelines.
To this end, the NIH Guidelines require that all investigators governed by the Guidelines submit
a copy of each human gene transfer protocol to the NIH. The Guidelines also delineate, among
other things, the role of the RAC, the requirements for reporting of adverse events to the NIH,
the role of the NIH in ensuring public access to information about human gene transfer trials,
and the role of the Gene Therapy Policy Conferences.
The Role of the RAC
The RAC has several important roles in the oversight of gene transfer research -- both with
regard to the Guidelines themselves and with regard to public review of protocols. In light of
advances in the knowledge about the science and safety of gene transfer research, the RAC
can recommend changes in the NIH Guidelines to the NIH Director. Proposed changes must
be published in the Federal Register for public comment before any final change is made by
the NIH Director. The RAC's most visible role is, however, the public review of gene transfer
clinical protocols. This public review involves an in-depth discussion of the design of the
protocol, preclinical safety data, the informed consent document, and any overarching
scientific, safety or ethical issues relevant to the specific protocol.
During the first five years of human gene transfer research, there were many unanswered
questions regarding the safety of this research. For this reason, every clinical gene transfer
protocol registered with the NIH was required to undergo public RAC review and approval.
Based on its review and discussion and any necessary follow-up with the principal
investigators, the RAC recommended approval to the NIH Director, who then made a final
decision as to whether the protocol could proceed.
By 1995, 149 protocols had been approved by the RAC and over 1,000 patients had been
enrolled in worldwide trials. Many of the potential risks that initially raised public concern
had not materialized. In response to these advances in knowledge, the NIH instituted, on the
RAC's recommendation, a new phase of oversight, by which only protocols deemed novel
were subject to full public RAC review and approval. In making a determination whether an
experiment is novel, and thus warranting full public RAC discussion, reviewers examine the
scientific rationale, whether the preliminary in vitro and in vivo safety data were obtained in
appropriate models and are sufficient, and whether questions related to relevant social and
ethical issues have been resolved. Trials that did not present novel and/or unresolved issues
were exempt from RAC review and approval and were forwarded directly to the FDA for its
review.
In an effort to further expand and re-emphasize the unique role of the RAC in the public
oversight of gene therapy research and, at the same time, cease RAC's duplication of the
regulatory role of the FDA, in July 1996, the NIH Director proposed further changes to the
role of the RAC. After careful consideration of public comment and consultations with a
variety of constituency groups, including scientists, patients, and interested Members of
Congress, the NIH Guidelines were revised in October 1997. Under the current NIH
Guidelines, investigators are still required to submit a copy of the proposed research protocol
to the NIH and to comply with all the policies and procedures, including adverse event
reporting, outlined for the conduct of human gene transfer clinical research set forth in the
NIH Guidelines; the RAC is still required to publicly review all novel protocols. However,
the RAC no longer approves novel protocols. In addition, the RAC focuses more attention on
much needed policy issues regarding the scientific basis for and safety and ethics of, emerging
issues in gene therapy research, by convening Gene Therapy Policy Conferences.
Reporting of Adverse Events
A critical provision of the NIH Guidelines requires investigators to report immediately to the
NIH any serious adverse event that occurs during the course of a gene therapy clinical trial. It
is important to note that the requirement to submit adverse events to the NIH is not contingent
upon whether the RAC does or does not have the authority to approve protocols. It is a
requirement which has, in fact, remained unchanged in the NIH Guidelines since the advent of
clinical gene transfer trials.
A serious adverse event is defined as any expected or unexpected adverse event related or
unrelated to the intervention that results in any of the following outcomes: death, a
life-threatening event, in-patient hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity or a congenital anomaly/birth defect, as well as
important medical events that may require medical or surgical intervention to prevent one of
those outcomes. In the context of a clinical trial, an adverse event can occur for many
reasons and not all of these are related to the treatment, per se. In human gene transfer
research, many of the patients enrolled in the trial already have serious and life-threatening
diseases. Thus, a serious adverse event, or even a death, during the course of a clinical trial
may be the result of the underlying disease, rather than the experimental treatment.
Although the FDA also requires reports of serious adverse events in human gene therapy, the
timing and scope of these reports as well as the processes by which FDA responds to this
information differ from those of the NIH. The NIH's unique role in the reporting of adverse
events is perhaps best exemplified in the actions it took following notification of the death of
Jesse Gelsinger. The investigators performing this trial reported the death to the NIH
immediately, as required, and informed the NIH that they considered the cause of death to be
directly related to the gene transfer. After consulting with the FDA and the RAC Chair, the
NIH immediately notified the RAC, IBCs, OPRR, IRBs, and all principal investigators
conducting gene transfer research. The NIH also requested additional data on a range of pre-clinical and clinical parameters from every registered researcher using adenoviral vectors in
clinical trials the vector used in the study in which Jesse Gelsinger participated. Adenoviral
vectors are used in one quarter of the over 372 gene transfer trials registered with the NIH. A
working group of the RAC was formed immediately to conduct an in-depth analysis of the
data and, if necessary, to develop guidance regarding the continued use of adenoviral vectors
in gene transfer studies.
This working group carried out a comprehensive review of the safety and toxicity data
gathered from over 70 adenovirus-based clinical trials involving more than 1,200 research
subjects and developed a number of preliminary recommendations. They recommended that
human gene transfer research in which adenoviral vectors are being used should proceed, but
with greater caution. In addition, the committee identified several other important needs,
including the development of vector standards and the development of specific criteria for
more uniform patient surveillance and monitoring. The working group emphasized the need
for the RAC to convene more conferences which address the safety and toxicity of gene
transfer, and which enhance the exchange of information among researchers. The RAC will
consider the working group's final recommendations and develop a report of its conclusions
and recommendations regarding the use of adenoviral vectors in human gene transfer
research. As necessary, following a public comment process, the NIH will incorporate any
recommendations into the NIH Guidelines.
Public Access to Data on Human Gene Transfer Research
One of NIH's primary responsibilities in its oversight in this arena is ensuring public access to
data on gene transfer research. Recently, a number of questions have been raised about the
status of the NIH gene transfer trial database, and thus, about whether the NIH was meeting
its goal of making gene transfer trial data public. First and foremost, it is important to
understand that data on all 372 human gene transfer trials registered with the NIH since the
inception of the NIH Guidelines are now, and always have been, publicly available. At each
RAC meeting, a portion of the agenda is devoted to the presentation of clinical gene transfer
trials that have been registered with the NIH and any serious adverse events that have been
reported since the previous meeting. A copy of each new proposal is available to the public at
all times. In fact, the NIH provides a copy of any proposal submitted to the NIH, upon
request by any investigator or member of the public. In addition, the data reviewed at each
RAC meeting are posted on NIH's website www.nih.gov/od/oba/. This includes discussion
of any novel protocols, a list of the trials registered, and any reported serious adverse events.
The website contains core information about each of the gene transfer protocols registered
with the NIH elements such as the protocol title, trial site, principal investigator, disease
under study, and vector being used for the gene transfer. This information exists now and is
widely available on NIH's website.
The NIH has been working diligently to develop an interactive web-based database. The
database is designed to enable users to search for specific variables, analyze aggregate data,
and identify emerging trends in gene transfer research. This task has proven to be highly
complex, particularly in light of the multiple audiences that are expected to use this resource.
Our goal is to develop an electronic resource that both the general public and the scientific
community will be able to easily access and use with regard to current information about
specific protocols, including information about adverse events and developments in gene
transfer research. The first phase of the database will be publicly available by the end of this
year. In subsequent years, we will evaluate the first phase of the database and, as necessary,
refine elements which do not meet user expectations.
Gene Therapy Policy Conferences
Another important function of the RAC, which was instituted in October 1997, is the
convening of Gene Therapy Policy Conferences (GTPCs). GTPCs provide a mechanism for
in-depth exploration of emerging scientific and ethical issues raised by the continuing
progress of the research. GTPCs have been held on three extremely complex issues the
ethical issues associated with the use of gene transfer technology for enhancement purposes,
scientific and safety questions about the use of lentiviral vectors, and the scientific, medical,
and ethical issues associated with prenatal gene transfer. GTPCs help inform the field, the
RAC, and the public about emerging issues, and they can, and indeed have, yielded important
consensus recommendations that guide the field.
Current Efforts to Ensure Appropriate NIH Oversight and Coordination with FDA
The NIH continues to consider new policies and procedures to appropriately ensure that its
oversight of human gene transfer research is conducted efficiently and effectively. There is
always need for improvement: the tragic death of Jesse Gelsinger and subsequent events have
prompted a review of the role of the RAC and NIH in oversight of gene transfer research. In
particular, recent events made it clear that the NIH needs to make some systemic changes to
its oversight of adverse event reporting.
Re-evaluating NIH Oversight of Human Gene Transfer Research
In December 1999, the NIH Director established a working group of the Advisory Committee
to the Director (ACD), NIH, to examine the current NIH framework for oversight and public
discussion of clinical gene transfer research, especially with regard to the roles of the RAC
and the NIH Guidelines. This charge was stimulated, in part, by growing concerns about the
RAC's authority and its role with regard to protocol review.
In the recent past, as a result of differences between FDA's legislated requirement to review
protocols within 30 days of submission to the Agency and the timing of quarterly RAC
meetings, some novel clinical gene transfer trials have proceeded prior to public RAC review.
This means that patients have been enrolled and treated prior to public RAC review. To this
end, the ACD working group is being asked to recommend appropriate changes to the role
and/or functions of RAC that would fully ensure that no patient is treated in a novel human
gene transfer trial prior to public RAC review. The working group will consider options that
have been put forth by the RAC, examine the merits of a return to RAC approval of all novel
protocols, and/or propose another mechanism which would meet this goal.
The ACD working group is being asked to address three additional questions: 1) Are current
NIH mechanisms adequate for coordination of its oversight of clinical gene transfer research
with those of FDA, OPRR, IRBs, and IBCs, 2) Are additional NIH measures needed to
minimize risk associated with clinical gene transfer research, and 3) What should the NIH role
be with regard to reporting, analysis, and public discussion of serious adverse events. The
working group will hold its first meeting this month and will meet again in March, in
conjunction with the RAC, with the goal of submitting final recommendations to the Director,
NIH, in May.
Ensuring Compliance With the Reporting of Adverse Events
The NIH's recent request to the gene transfer research community for data regarding the
safety and toxicity of adenoviral mediated gene transfer revealed that many investigators
governed by the NIH Guidelines have been under-reporting serious adverse events to the NIH.
The adverse events that have been reported to us are quite varied both in the nature of the
clinical events, as well as their cause. By and large, the events are due to progression of
underlying disease, concomitantly administered drugs such as chemotherapy, or are known
effects of some vectors, such as fever. We are deeply concerned about the under-reporting of
serious adverse events to the NIH, and we are taking steps to better understand and to address
this problem expeditiously.
The NIH Guidelines clearly place the responsibility for reporting all serious adverse events on
the investigator and the institution. In addition, every investigator who registers a protocol
with the NIH receives a letter from the NIH reminding them of their obligations under the
NIH Guidelines to report all serious adverse events. Even though these reminders are explicit
and targeted to each investigator, they clearly have not accomplished what we intended.
According to the Guidelines, as a result of non-compliance, the NIH can suspend, limit or
terminate NIH funds for the gene transfer project or for all recombinant DNA research at an
institution. The NIH can choose to impose a requirement for prior NIH approval of any or all
recombinant DNA projects at an institution. We can also conduct site visits to ensure
institutions have the proper processes in place to comply with the Guidelines. To this end, the
NIH Office of Extramural Research will undertake a series of site visits to NIH funded
institutions to assess the level of understanding of NIH rules and to identify any problems
associated with NIH oversight, paying particular attention to compliance with the NIH
Guidelines for Research Involving Recombinant DNA Molecules, as well as to financial
conflicts of interest.
We took several immediate steps. First, we sent a memorandum to institutions conducting
human gene transfer research directing them to review their institutional policies and
procedures for ensuring compliance with the NIH Guidelines and requested that any
institution that found compliance problems notify the NIH. A copy of the memorandum was
sent to IRBs, IBCs, and principal investigators at institutions conducting human gene transfer
studies. We are in the process of reviewing responses to the memorandum and are following
up with institutions, as necessary.
Second, the NIH and the FDA established a new process for sharing information with NIH
and notified the gene transfer research community of this change in a November 5, 1999,
letter. The FDA formalized the process in two new Standard Operating Procedures and
Policies (SOPPs). The SOPPs, which were issued December 7, 1999, institute weekly
notification to NIH of reports of adverse events and any other changes in gene therapy
protocols received by the FDA. While these new SOPPs will enhance our ability to monitor
serious adverse events, in no way will they diminish the responsibility of investigators to
fulfill their reporting requirements to NIH.
Third, a working group of the RAC is reassessing the current requirements for the scope and
timing of reporting of adverse events to the NIH, especially with respect to the current
differences between the adverse event reporting requirements of the NIH and the FDA. The
working group proposal will be discussed at the next RAC meeting in early March.
Fourth, the NIH, with concurrence from the RAC, is taking steps to prevent sponsors from
circumventing public access to adverse event reports by labeling this information proprietary.
The RAC articulated its strong objection to this practice, highlighted the importance of
ensuring patient confidentiality to the greatest extent possible, and recommended changes in
the NIH Guidelines to ensure public access to adverse event reports.
Finally, with regard to whether the change in the approval function of the RAC contributed to
the under-reporting problem, it is important to point out that the Guidelines are promulgated
by the NIH, not by the RAC. Therefore, the RAC's role in protocol approval has no bearing
whatsoever on the obligation of investigators and institutions receiving NIH funds for
recombinant DNA research to comply with any of the requirements set forth in the NIH
Guidelines.
***
Without clinical research, there can be virtually no new diagnostics, new treatments or new
prevention strategies to improve the length and quality of our lives and the lives of our
families. Gene transfer clinical research holds promise to treat or even prevent a wide variety
of human diseases and conditions. It is incumbent upon investigators, funding institutions,
and regulatory agencies to ensure that such research is conducted in as safe and ethical a
manner as possible. If we are to improve the Nation's health through research, we must all
work, in concert, to protect the most important participant in the research endeavor the
patient.
Mr. Chairman, this concludes my statement. The NIH appreciates the opportunity to
participate in the Subcommittee's review of recent events in gene therapy research and the
Federal role in overseeing this promising area of research. I would be pleased to answer any
questions you may have.
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