[Printable PDF]
[Federal Register: January 18, 2001 (Volume 66, Number 12)]
[Proposed Rules]
[Page 4688-4706]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18ja01-28]
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Proposed Rules
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.
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[[Page 4688]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 312, and 601
[Docket No. 00N-0989]
Availability for Public Disclosure and Submission to FDA for
Public Disclosure of Certain Data and Information Related to Human Gene
Therapy or Xenotransplantation
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the biologics licensing regulations regarding confidentiality of
information. The amendments would add provisions that would make
available for public disclosure, and require submission for public
disclosure of, certain data and information related to human gene
therapy or xenotransplantation. The proposed regulation would apply
specifically to the areas of human gene therapy and xenotransplantation
because these areas of clinical research have the potential for unique
public health risks and modification of the human genome. The proposed
rule would provide for public disclosure of certain data and
information related to an investigational new drug application (IND),
to provide an opportunity for public education on, and discussion and
consideration of, public health and safety issues. In addition, the
proposed rule would require sponsors of clinical trials on human gene
therapy or xenotransplantation to submit to FDA for public disclosure
certain data and information that has been redacted to remove or
obscure all information defined as confidential commercial or trade
secret, or names and other personal identifiers of patients and certain
other third parties.
DATES: Submit written comments on this proposed rule on or before April
18, 2001. Submit written comments on the information collection
provisions by February 20, 2001.
ADDRESSES: Submit written comments on this proposed rule to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Submit written comments on the
information collection requirements to Wendy Taylor, FDA Desk Officer,
Office of Information and Regulatory Affairs, Office of Management and
Budget (OMB), New Executive Office Building, 725 17th St. NW.,
Washington, DC 20503, Attn: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Steven F. Falter, Center for Biologics
Evaluation and Research (HFM-17), Food and Drug Administration, 1401
Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background Information
A. Current FDA Policies Regarding Disclosure of Information
FDA regulations in part 312 (21 CFR part 312) provide procedures
that govern the use of investigational new drugs, including new
biological drugs, in humans. Under part 312, the sponsor of a clinical
study in humans must submit to FDA an IND which provides specific
information regarding the investigational new drug and the clinical
study. The IND must be authorized by FDA and approved by the local
institutional review board (IRB) before the clinical study may begin.
The provisions of this rulemaking do not alter the procedures specified
in part 312 for submission of an IND. A manufacturer requesting
approval to market a biological product in interstate commerce must
submit a biologics license application (BLA) to FDA before the product
may be introduced into interstate commerce (42 U.S.C. 262). Among other
things, the BLA contains information and data resulting from the
clinical studies performed under an IND (Sec. 601.2 (21 CFR 601.2(a))).
All information and data concerning the product, including those
submitted in applicable IND's and in the BLA, are held by FDA in a
biological product file (see definition of "biological product file"
in Sec. 601.51(a) (21 CFR 601.51(a)) throughout the lifetime of the
product.
The general requirements related to disclosure of information for
all types of commodities regulated by FDA and for all types of
documents are provided in part 20 (21 CFR part 20). Under these
regulations, certain categories of information are exempt from
mandatory disclosure. The categories of information relevant to human
gene therapy and xenotransplantation clinical trials that have
historically been exempt from public disclosure include trade secrets
and commercial or financial information which is privileged or
confidential (Sec. 20.61); personnel, medical, and similar files, the
disclosure of which constitutes a clearly unwarranted invasion of
personal privacy (Sec. 20.63); and at the discretion of FDA,
interagency or intra-agency memoranda or letters, except for factual
information which is reasonably segregable (Sec. 20.62).
Specific requirements for the availability for public disclosure of
data and information in an IND, including those IND's relating to
biological drug products, are included in Sec. 312.130. FDA's policy
for the confidentiality of data and information contained in an IND for
a biological product and in a biological product file is provided in
Secs. 601.50 and 601.51 (21 CFR 601.50 and 601.51). Under Secs. 601.50
and 601.51, and consistent with the other referenced disclosure
regulations, FDA has not routinely publicly disclosed any data or
information contained in an IND or a pending biological product file.
FDA has not even acknowledged the existence of the IND or a pending
biologics license application, unless its existence has previously been
publicly acknowledged. Because the agency has no mechanism for reliably
tracking what information concerning an unapproved, investigational
product has been publicly acknowledged, the agency generally provides
no information to the public concerning an investigational product,
including information concerning any IND or pending BLA submissions,
and refers the public to the sponsor of the IND or the pending
biological license for further information. In some cases, FDA may
publicly disclose selected portions of safety and effectiveness data,
such as summary information for consideration at an open session of a
Federal advisory
[[Page 4689]]
committee meeting, or other public workshops or meetings
(Sec. 601.51(d)(1)). Once a biological license has been approved,
certain information, as specified in Sec. 601.51(e), concerning the
approved product and the clinical investigation of the product may be
publicly disclosed.
B. Issues Related to Human Gene Therapy and Xenotransplantation
As a result of rapid advances in molecular biology, genomics,
immunology, and transplant biology, new classes of biological
therapeutics are being developed with the goal of providing future
treatment options for genetic disease, cancer, and organ failure. Novel
therapeutic approaches currently under consideration include the areas
of human gene therapy and xenotransplantation. Human gene therapy and
xenotransplantation are being proposed to treat genetic diseases such
as cystic fibrosis, cardiovascular insufficiency, metabolic diseases
such as diabetes, neurologic diseases such as Parkinson's and
Huntington's disease, cancer, acquired immune deficiency syndrome
(AIDS), and organ failure.
1. Definitions
Human gene therapy is defined as the administration of genetic
material to modify or manipulate the expression of a gene product or to
alter the biological properties of living cells for therapeutic use.
Cells may be modified ex vivo for subsequent administration to the
subject or altered in vivo by gene therapy products given directly to
the subject. Human gene therapy includes, but is not limited to,
autologous or allogeneic bone marrow stem cells modified with a viral
vector, intramuscular or intravascular injection of a therapeutic
plasmid deoxyribonucleic acid (DNA) or a therapeutic viral vector,
ribozyme technology, and use of sequence specific oligonucleotides to
correct a genetic mutation. For the purposes of this regulation, gene
therapy is not intended to include the administration of viral or
cellular products (e.g., blood or unmodified bone marrow), or their
derivatives, that do not contain genetic material that has been
specifically engineered into the product for therapeutic purposes.
While prophylactic vaccines, including plasmid DNA vaccines and
genetically modified viral vector vaccines, and some replication
competent viruses are excluded under this regulation from the gene
therapy definition, they are similar in nature to gene therapy
products. Issues relevant to gene therapy products, such as vector
integration and biodistribution, also apply to prophylactic vaccines.
Therefore, the agency requests comment on whether such products should
be included under this rulemaking to allow information related to these
products to be available for public disclosure.
The use of antisense oligonucleotides to block gene transcription
is not intended to be included under gene therapy; however, as noted
above, the use of sequence specific oligonucleotides to correct a
genetic mutation would be included. The proposed mechanism of action of
sequence specific oligonucleotides is to irreversibly change, insert,
or delete a single base in the genome of a cell. This raises questions
of whether base changes may result in mutations that may cause cancer,
or express an immunogenic protein or have other adverse health affects.
In addition, their use in vivo raises issues of activity in tissues
other than the target and the risk of gonadal biodistribution leading
to germ line changes.
Xenotransplantation refers to any procedure that involves the
transplantation, implantation, or infusion into a human recipient of
either: (1) Live cells, tissues, or organs from a nonhuman animal
source; or (2) human body fluids, cells, tissues, or organs that have
had ex vivo contact with live nonhuman animal cells, tissues, or
organs. The live cells, tissues, or organs used in xenotransplantation
are referred to as xenotransplantation products. Xenotransplantation
products include those from transgenic or nontransgenic animals, as
well as combination products that contain xenotransplantation products
in combination with drugs or devices. These include, but are not
limited to, porcine fetal neuronal cells, encapsulated porcine islet
cells, encapsulated bovine adrenal chromaffin cells, baboon bone
marrow, and external liver assist devices employing porcine liver, or
porcine hepatocytes. Nonliving biological products or materials from
animals, such as porcine heart valves and porcine insulin, are not
classified as xenotransplantation products for the purposes of this
rulemaking.
2. Public Health Issues
While human gene therapy offers great promise for improving the
lives of patients with serious, life-threatening diseases and
disorders, there are several risks inherent in its use as a medical
intervention. These risks include the inadvertent infection of
patients, and potentially their contacts, with replication competent
virus present in gene therapy vector preparations. For example,
infection with type C murine retroviruses, which could contaminate
retroviral vector preparations, is known to cause a range of diseases
in animals including spongiform encephalopathy, anemia, and neoplastic
disease. In addition, these risks include the risk of infection with
novel infectious agents generated by recombination in vivo, the
consequences of which are unknown; the risk of insertional mutagenesis
through disruption of the normal genetic sequence, resulting in altered
gene expression; and the risk of inadvertent modification of the
patient's germline and its effect on future offspring.
Although xenotransplantation provides a potential approach to
address the shortage of human organs and for treatment of disease, the
use of xenotransplantation products raises concerns about possible
infection of the recipient and, subsequently, the public at large with
both known and as-yet- unrecognized infectious agents. Experience with
human allograft transplantation has demonstrated the potential for
transmissibility of infections from donor to recipient through
transplants (Refs. 1 to 3). The direct contact resulting from
implantation of a xenotransplantation product into a recipient, with
the associated disruption of anatomical barriers and the
immunosuppression of the recipient, may facilitate interspecies
transmission of xenogeneic infectious agents. The potential for
subsequent transmission of a xenogeneic infectious agent from the
recipient to the recipient's close contacts, and propagation through
the general human population, is an additional risk and a recognized
public health concern.
Insertional mutagenesis is a risk potentially associated with the
infection of xenotransplant recipients and their close contacts and the
general population with xenogeneic retroviruses. In addition to
potential horizontal transmission of infectious agents from the
recipient of a xenotransplantation product to the recipient's contacts,
there is concern regarding vertical transmission of infectious agents
from the recipient to progeny during gestation (e.g., transmission from
mother to fetus of infectious agents across the placenta or during
parturition). Vertical transmission of xenogeneic infectious agents
could result in the development of infectious disease in progeny. In
addition, vertical transmission of xenogeneic viruses can result in
insertional mutagenesis with disruption of normal human development or
integration into the germline resulting in transmission to future
generations.
[[Page 4690]]
Thus, human gene therapy and xenotransplantation investigative
approaches individually pose: (1) Risks that extend beyond the
individual (e.g., public health risks, including the potential for the
transmission of infectious agents from the recipient to the public at
large); and (2) risks of inadvertent modification of the germline
(alterations of the genetic material of the progeny). Moreover, these
approaches may also be used in combination (e.g., xenotransplantation
products genetically modified before implantation), resulting in
complex questions and issues for consideration and discussion prior to
and during human clinical trials.
3. Public Education and Informed Consent Issues
Human gene therapy and xenotransplantation investigations call for
additional mechanisms to provide the public access to clinical trial
information relevant to the assessment of risks and benefits, and to
informed consent. Special care is needed to ensure that individual
subjects understand the experimental nature of the procedures and their
known and unknown risks and burdens. Human gene therapy and
xenotransplantation require the evaluation of risks to third parties
such as health care workers, close contacts of the recipient, and the
community. The informed consent process should address the need for
long-term surveillance and post-mortem analysis and potential
infectious disease risks to recipients and their contacts.
These investigative approaches raise new challenges for the local
review bodies responsible for ensuring the safe and ethical conduct of
this research. Local IRB's are responsible for reviewing biomedical and
behavioral research involving human subjects, to protect the rights of
human subjects (45 CFR part 46, Protection of Human Subjects, and 21
CFR part 56, Institutional Review Boards). Institutional Biosafety
Committees (IBC's) are responsible for reviewing and overseeing basic
and clinical research conducted at their institutions. The IBC assesses
the safety of the research and identifies any potential risk to public
health or the environment (section IV-B-2 National Institutes of Health
(NIH) Guideline for Research Involving Recombinant DNA Molecules). This
proposed rule would provide a mechanism for public access to human gene
therapy and xenotransplantation clinical trial information and for
public education, informed discussion and participation that can form a
foundation for safe and ethical research in these innovative areas.
The proposed rule would enhance the development of related Federal
initiatives that provide for public access to clinical trial
information through national data bases: There are also a number of
Internet sites sponsored by associations, clinical centers or academic
institutions, and nonprofit organizations that provide public access to
similar types of clinical trial information. Examples include: Center
Watch Clinical Trials Listing Service at http://www.centerwatch.com, a
resource both for patients interested in participating in clinical
trials and for research professionals; http://www.HealthAtoZ.com, a
search engine for health and medical Internet resources; the Musella
Foundation for brain tumor research and information, at
http://www.virtualtrials.com; the National Alliance of Breast Cancer
Organizations, at http://www.nabco.org, which,
in an effort to increase
awareness of clinical trials, lists brief descriptive summaries of
clinical trials in the National Cancer Institute Physician Data Query
(NCI PDQ) data base; the University of Michigan, at http:// www.cancer.med.umich.edu, which lists clinical trials at the University
of Michigan Cancer Center (UMCC) and supplies links to external
clinical trials and resources; the former Surgeon General C. Everett
Koop's Internet site, at
http://www.drkoop.com, which allows the public to browse through a
listing of therapeutic areas where volunteers are being sought for
clinical trials; Biotechnology Industry Organization, a trade
association, at http://www.bio.org, which lists press releases and
industry news, and provides links to patient groups and professional
medical societies; and http://www.investor.biospace.com, which has not
only a biotechnology search engine that links to hundreds of companies,
but also extensive information on the latest technologies and clinical
trials, as a basis for investment. The proposed rule should facilitate
the development of similar data bases, either publicly or privately
sponsored, with information concerning the study of gene therapy and
xenotransplantation. As provided under section 113 of the Food and Drug
Modernization Act of 1997 (Public Law 105-115), NIH, through its
National Library of Medicine, has created a national clinical trials
data base at http://clinicaltrials.gov to provide patients, family
members, and other members of the public with current information about
clinical research studies.
4. Basis for Disclosure
Historically, public disclosure of information with regard to human
gene therapy and xenotransplantation has assisted FDA in performing its
duties and has benefitted the public. The categories of information
that may be made publicly available by FDA as a result of this
disclosure rule include information currently made public by other
Federal agencies in connection with advisory committee meetings or
other public workshops or meetings, and through general commercial
disclosure.
The NIH Office of Biotechnology Activities (OBA; formerly the
Office of Recombinant DNA Activities) administers the Recombinant DNA
Advisory Committee (RAC). This committee was established in October
1975, in response to concerns about the potential public health risks
and environmental hazards posed by recombinant DNA research, as well as
the significant ethical, legal, and societal issues associated with
this emerging technology. The RAC has met quarterly in open public
session to discuss these issues and, since the first human gene
transfer clinical trial was proposed in 1988, the committee has
publicly reviewed selected human gene transfer clinical trial
protocols. The minutes of RAC discussions of human gene transfer
clinical trials and related issues are accessible to the public via the
OBA website (http://www.nih.gov/od/oba/index.htm). RAC review and
public discussions provide an important mechanism for receiving public
input into Federal policy development and for making the public aware
of potential toxicities and adverse events associated with gene
transfer products. As one example, when a participant in a cystic
fibrosis gene transfer clinical trial required intensive care treatment
for an acute adverse event suffered shortly after administration of an
adenoviral gene transfer product, the investigator was invited to
discuss the occurrence with other experts in the field at the next
public RAC meeting. This public discussion and analysis facilitated
both dissemination of important information about this toxicity and
enhanced understanding of its pathogenesis, thereby contributing to the
safety of patients in other gene therapy trials.
NIH also collects information on gene transfer studies and makes it
available to the public. Appendix M of the "NIH Guidelines for
Research Involving Recombinant DNA Molecules" (Ref. 4) requires that
investigators provide specific information for the purposes of protocol
registration, RAC review, and
[[Page 4691]]
potential public discussion, and that this information should not
contain confidential commercial information or trade secrets, enabling
all aspects of RAC review to be open to the public. The required
information includes scientific and nontechnical abstracts, the
informed consent document, statements on privacy and confidentiality,
reports of serious adverse events, protocol amendments, and annual
followup reports. Public disclosure of this information has facilitated
progress and has contributed to improved patient safety in the field of
human gene transfer by providing public access to clinical trial
information, rapid dissemination of adverse event information, and
summary information regarding outcomes of gene therapy clinical trials
and adverse events.
All investigators receiving any NIH funds for basic and/or clinical
research involving recombinant DNA molecules, and all investigators
affiliated with institutions receiving any NIH funds for basic and/or
clinical research involving recombinant DNA molecules, must comply with
the NIH Guidelines. The NIH Guidelines also apply to collaborations
between NIH-funded or affiliated researchers and privately funded
investigators. In addition, commercial sponsors not affiliated with a
NIH-funded institution have voluntarily submitted materials to OBA for
RAC review. Therefore, the general practice in the field of human gene
transfer has been to submit to NIH, OBA the information required under
NIH Guidelines with the understanding that the information will be
available for RAC review and potentially public discussion. This
suggests that the information specified in Appendix M is not generally
considered to be proprietary and that its disclosure does not impede
commercial development.
The categories of information that would be disclosed as a result
of this rulemaking include information that generally has been made
public for xenotransplantation protocols. Sponsors of
xenotransplantation IND's have publicly disclosed information regarding
the scope of xenotransplantation clinical trials and the development of
public health safeguards through: (1) Open public sessions of the
Xenotransplantation Subcommittee of the Biologics Response Modifiers
Advisory Committee (BRMAC) for the Center for Biologics Evaluation and
Research (CBER), FDA (December 17, 1997, June 3 and 4, 1999, and
January 13, 2000), and (2) Public Health Service (PHS) sponsored public
workshops, including the workshop entitled "Developing U.S. Public
Health Policy in Xenotransplantation," January 21 and 22, 1998, at
which xenotransplantation clinical trials under FDA IND's were
summarized by the sponsor or by a sponsor's designee. Transcripts of
these meetings can be found on the CBER Internet site at http://
www.fda.gov/cber. At these public meetings, FDA scientists and others
presented data demonstrating that porcine endogenous retroviruses could
be activated and could infect human cells in vitro, and the
implications of these data for porcine xenotransplantation product
development and regulation were discussed. Based on these discussions,
the BRMAC concurred with FDA's decision to place all porcine
xenotransplantation clinical trials on clinical hold. During these
meetings, FDA publicly discussed testing requirements and results
needed by manufacturers in order to address and remove the clinical
hold, and allowed sponsors of porcine xenotransplantation IND's the
opportunity to present testing strategies, assuring the industry of
consistency in regulation. The public as well was assured that Federal
oversight was being conducted in a responsible manner.
Information related to the categories of information FDA proposes
to disclose is available through publicly accessible filings to the
Securities and Exchange Commission (SEC). The Securities Act of 1933
requires that investors receive financial and other significant
information concerning securities being offered for public sale. In an
annual filing, a company must provide a comprehensive overview of its
business. This includes a description of ongoing research programs
including discussion of clinical study safety and efficacy results,
disclosure of investigational sites and the investigators involved,
plans for product development and commercialization, and financial
information. This information may be found on the SEC Internet site at
http://www.sec.gov/edgarhp.htm.
n addition, voluntary disclosure of information regarding clinical
trials of unapproved products and therapies by individual sponsors over
the Internet has become widespread. Company Internet sites often
provide this information in the form of descriptive summaries of
clinical trials, press releases, recruitment opportunities for
patients, investment opportunities, and general awareness material.
Thus, information of the kind FDA proposes to disclose concerning
clinical trials on human gene therapy and xenotransplantation is
already widely disclosed. This disclosure has not impeded commercial
development of these products. In addition, the agency considers public
disclosure of data and for information from human gene therapy or
xenotransplantation clinical trials essential for public education, and
for informed discussion and consideration of the public health and
safety risks associated with the use of these investigational
therapies.
II. Overview of Proposed Rule
A. Scope
The scope of this proposed rule is limited to disclosure of
information related to human gene therapy and xenotransplantation.
Confidential commercial information, such as information regarding
commercial licensing agreements or the identification of suppliers,
trade secret manufacturing information, names and other personal
identifiers of patients and, except as specifically provided in the
regulations, names and personal identifiers of third parties, such as
physicians, hospitals, etc., and, at FDA's discretion, interagency or
intra-agency memoranda and letters would not be disclosed. FDA is
proposing only to disclose certain information necessary to ensure a
continued mechanism for public education and input, which FDA believes
is essential to the evaluation of the public health impact of these new
technologies. FDA believes that these categories of information have
not been considered to be proprietary, since they have been made
publicly available through various mechanisms and their disclosure has
not impeded commercial development. The public expects the current
level of information disclosure and public review to continue in the
areas of human gene therapy and xenotransplantation where there is
potential risk to the public health.
The categories of information related to an IND that would be
disclosed under this regulation include: (1) Product and patient safety
data and related information, including results from preclinical and
clinical studies and tests that demonstrate the safety and/or
feasibility of the proposed procedures; (2) the name and address of the
sponsor; (3) the clinical indications to be studied; (4) the protocol
for each planned study, to include a scientific abstract and a
nontechnical abstract, a statement of the objectives, purpose, and
rationale of the study, the name and address of each investigator, the
name and address of the official contacts of each local review body as
appropriate (IRB, IBC) and dated copies of approval by each group, the
criteria for patient selection and
[[Page 4692]]
exclusion, an estimate of the number of patients to be studied, a
description of the treatment that will be administered to patients, and
the clinical procedures, laboratory tests, or other measures to be
taken to monitor the safety and effects of the drug in human subjects
and to minimize risk; (5) written informed consent forms; (6)
identification of the biological product(s) and a general description
of the method of production, including a description of product
features that may affect patient safety; (7) IND safety reports; (8)
information submitted to FDA in the annual report; (9) the regulatory
status of the investigation, the date of such action, and the reason
for such action; and (10) other relevant data and information that the
Director, CBER, determines are necessary for the appropriate
consideration of the public health and scientific issues, including
relevant ethical issues, raised by human gene therapy or
xenotransplantation.
To facilitate public disclosure of this information, FDA proposes
to require sponsors of human gene therapy and xenotransplantation
clinical trials to submit to FDA the information defined above upon
submission of: (1) The initial IND, (2) any amendment documenting
changes or additions to the IND, at the time the amendment goes into
effect, (3) IND safety reports, and (4) annual reports. FDA is not
proposing to require the submission of any new information not
previously submitted as part of the IND process. For example, FDA is
not proposing that all variations and updates of informed consent forms
be submitted to FDA for public disclosure; however, under the proposed
rule, FDA would disclose any sample informed consent forms generally
submitted with an initial IND submission.
The agency requests comment on whether this rulemaking should apply
to information as defined above that is submitted in a BLA. Public
disclosure of information in a BLA would provide a continuation of the
availability of information for public disclosure up until the time of
license approval. A disadvantage would be the amount of documentation
that would be required to be submitted in order to support this
initiative.
The proposed provisions of this rulemaking do not alter the
procedures specified in part 312 for submission of an IND. However,
with regard to clinical holds of an IND (Sec. 312.42), FDA would be
able to place a human gene therapy or xenotransplantation investigation
on clinical hold if the sponsor does not submit to the agency the
redacted version of data and information for public disclosure, or if
the redacted version submitted is incomplete or not properly redacted.
B. Legal Authority
The proposed regulation would make available for public disclosure
specified safety and effectiveness information submitted in support of
an IND \1\ involving either a human gene therapy or xenotransplantation
protocol. This information, discussed thoroughly in section II.C of
this preamble, includes protocols, criteria for patient selection and
exclusion, summary results of preclinical and clinical studies of the
investigational article, a summary of the treatment that will be
administered and the measures that will be taken to minimize risk to
human subjects, safety reports, informed consent documentation, and
information concerning the regulatory status of the product, such as
whether it is on clinical hold and the reason for the hold. While such
information relating to human gene therapy protocols has routinely been
made available to the public through the NIH RAC process for the last
20 years, FDA regulations have consistently provided that similar
information submitted to FDA as part of an IND is not publicly
available. (See Secs. 601.50 and 601.51.) This proposed rule is an
attempt to harmonize these approaches for public review of important,
new, but potentially hazardous and controversial, therapies. In this
way, FDA will be able to more fully participate in existing and future
venues for obtaining educated public input and discussion that could
inform the agency's deliberations. The agency believes that there is
great benefit in having human gene therapy and xenotransplantation
products scrutinized, as they are being developed, by individuals with
a wide variety of perspectives, including scientists from different
disciplines, biomedical ethicists, patient advocacy organizations, and
the general public, because of the unique blend of proposed benefit as
well as potential risk to society that these products possess.
Investigations of these types of products raise serious ethical and
scientific issues, and, therefore, the decisionmaking process should be
as transparent and fully informed as possible.
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\1\While human gene therapy and xenotransplantation protocols
are generally regulated by CBER as biological products, it is
possible that some of these products may be combination products
consisting of biological components, drug components, and device
components. The same rules of disclosure will apply to the drug or
device components of combination products under the same theories
discussed later in this section.
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The proposed rule would formalize the existing practice of making
certain specified types of safety and effectiveness information in
IND's for human gene therapy and xenotransplantation publicly
available. Such disclosure is necessary in order to protect the public
health by informing the research community and the public of the nature
and the hazards of the proposed research and by permitting comment on
the merits of the proposed research.
The Freedom of Information Act (FOIA), 5 U.S.C. 552, generally
provides that Federal agencies must disclose information in their files
to the public on request. FOIA is designed to make federal agency
records or information available to the public. The Supreme Court has
stated that, "The basic purpose of [the] FOIA is to ensure an informed
citizenry, vital to the functioning of a democratic society, needed to
check against corruption and to hold the governors accountable to the
governed." (See NLRB v. Robbins Tire & Rubber Co., 437 U.S. 214, 242
(1978).) The statute provides nine exemptions and three law enforcement
exclusions that agencies may use to protect specific categories of
information from disclosure (5 U.S.C. 552(b)). These exemptions are the
only basis for withholding information requested by the public under
the FOIA \2\ and are discretionary, not mandatory. (See Chrysler Corp.
v. Brown, 441 U.S. 281 (1979).) One of these exemptions is particularly
relevant to this proposed rule and the disclosure of information in
applications to investigate and market human gene therapy and
xenotransplantation products.
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\2\ It should be noted here that section 301(j) of the act
prohibits the public disclosure of information, obtained under
certain sections of the act, "concerning any method or process
which as a trade secret is entitiled to protection." (See 21 U.S.C.
331(j).) In addition, the so-called Federal Trade Secrets Act also
contains certain restrictions on the public disclosure of trade
secret and confidential commercial information. The Trade Secrets
Act does provide for the disclosure of confidential commercial
information where such disclosure is "authorized by law." (See 18
U.S.C. 1905.)
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Exemption 4 of the FOIA protects trade secrets and confidential
commercial information from public disclosure. (See 5 U.S.C.
552(b)(4).) While trade secret information, narrowly defined as secret,
commercially valuable information related to manufacturing methods or
processes, is present in all IND's and biological product files,
including those subject to this proposed rule, this
[[Page 4693]]
proposal will not affect the confidentiality of such information, and
therefore it will not be discussed. Confidential commercial information
is defined under exemption 4 as "commercial or financial information
obtained from a person and privileged or confidential." Each element
of the definition must be satisfied for information to be confidential
commercial information entitled to protection under exemption 4.
Historically, much of the data and information submitted in IND's
and unapproved biological product files has been considered
confidential commercial information. (See Public Citizen Health
Research Group v. FDA, 704 F.2d 1280 (D.C. Cir. 1983); R & D
Laboratories, Inc. v. FDA No. 00-CV-0165 (D.D.C. Sept. 7, 2000).) FDA's
general information disclosure regulations define confidential
commercial information, and provide that information submitted to FDA
that falls within this definition is not disclosable. (See 21 CFR
20.61.) Further, the regulations that apply to the submission of IND's
and biological product files define the contents of these applications
as confidential commercial information generally exempt from disclosure
and, indeed, even prohibit the agency from acknowledging the existence
of an application (prior to approval) if it has not already been
publicly disclosed. (See 21 CFR 312.130, 601.50, and 601.51.) The
regulations provide different rules for disclosure after an approval
letter has been sent, and when the application has been terminated,
abandoned, or otherwise no longer has commercial value.
The agency is exercising its legal authority to promulgate new
regulations that will make explicit and will formalize the
circumstances and means by which certain safety and effectiveness
information in these special types of applications will be made
available for public disclosure. Such a change is especially warranted
when, as here, the change is being made in large part to reflect the
actual environment in which human gene therapy and xenotransplantation
applications exist.
As has been discussed elsewhere in this preamble (in section I.B,
Issues Related to Human Gene Therapy and Xenotransplantation), sponsors
of IND's pertaining to human gene therapy have publicly disclosed the
types of information covered by this proposed rule for many years as
part of the process overseen by the RAC. Likewise, there has been
widespread practice in the field of xenotransplantation to make
publicly available a great deal of information concerning details of
trials of xenotransplantation products during public advisory committee
meetings and workshops sponsored by FDA and by the U.S. PHS.
Information that is publicly disclosed by its owner cannot be
confidential within the meaning of the FOIA and, as a result, can be
made available for public disclosure by FDA. (See CNA Fin. v. Donovan,
830 F.2d 1132, 1154 (D.C. Cir. 1987).) The fact that these types of
information cannot be considered confidential is the principal basis
for issuing this proposed rule.
This proposed rule contains the public disclosure procedures the
agency will apply to the safety and effectiveness information in human
gene therapy and xenotransplantation applications that has historically
been treated as confidential commercial information by the agency.
These procedures will follow the consistent practice in the fields of
human gene therapy and xenotransplantation of making such information
available to the public. It is important to note that while certain
safety and effectiveness data and information will be publicly
available under this proposed rule, FDA does not intend to disclose the
full reports of safety and effectiveness on the basis of which the
product may be approved. FDA believes that, prior to approval of a
biological product file, the full reports constitute confidential
commercial information, as they traditionally have under the agency's
regulations, and should not be released. (See 21 CFR 601.51(d).)
However, under Sec. 601.51(e), all safety and effectiveness data and
information do become publicly available after a license is issued, and
this practice will not be changed by this proposal.
In addition to the full reports, the agency also wishes to make
clear that it will continue its current policy of not releasing
confidential commercial information that is contained in a human gene
therapy or xenotransplantation IND or unapproved biological product
file. Examples of confidential commercial information that may exist in
these applications would include information concerning licensing
agreements and information identifying suppliers. This information
ordinarily will remain confidential under exemption 4 unless it has
already been publicly disclosed by the sponsor. Such business-related
information is also not the type of information that FDA believes
should be disclosed to further the public discussion and evaluation of
human gene therapy and xenotransplantation trials. In addition, this
proposed rule will not affect the rules governing the disclosure of
personal medical and other similar information, the disclosure of which
would cause an unwarranted invasion of personal privacy. (See 21 CFR 20.63.)
Based on the authorities discussed, the agency proposes to require
sponsors of IND's related to human gene therapy and xenotransplantation
to disclose certain specified safety and effectiveness data and
information. This proposal will formalize and codify the existing
practice in these fields under which these data and information have
been publicly disclosed by their sponsors. Disclosure is especially
necessary regarding these new, important, and also controversial
technologies so that the research community and the public can be
assured of the safety of conducting clinical trials of these products.
This proposal would require the sponsors of human gene therapy or
xenotransplantation IND's to submit to FDA publicly available versions
of information FDA requires in such IND's. The purpose of this
requirement is to facilitate FDA's efforts to make important
information concerning human gene therapy and xenotransplantation IND's
available to the public in a timely and efficient manner. Sponsors
would have to redact the information from IND submissions specified in
proposed Sec. 601.53. Sponsors would redact trade secrets, confidential
commercial information, such as licensing agreements and suppliers, and
names and other personal identifiers of patients and, except as
specifically provided in the regulations, names and personal
identifiers of third parties, such as physicians, hospitals, etc. (See
Secs. 20.61 and 20.63.) It would not be necessary for sponsors to
redact the vast majority of the information in human gene therapy and
xenotransplantation IND's since, as described in this proposal, such
information would be publicly disclosable.
The proposed rule would also specify that FDA may place a human
gene therapy or xenotransplantation investigation on clinical hold if
the sponsor has not submitted to the agency a redacted and thus
disclosable version of the required IND information that complies with
the requirements of proposed Sec. 601.53. A sponsor must properly purge
its redacted version of trade secrets, confidential commercial
information, and names and other personal identifiers and, except as
specifically provided in the regulations, names and personal
identifiers of third parties, such as physicians, hospitals,
[[Page 4694]]
etc. Section 505(i)(3) of the act authorizes FDA to prohibit a sponsor
of an investigation from conducting that investigation if FDA
determines that the drug involved represents an unreasonable risk to
the safety of persons who are the subjects of the clinical
investigation, or if there are other reasons that FDA has established
by regulation for which the agency may issue a clinical hold. FDA
recognizes that errors in redacting may occur and will provide sponsors
with an opportunity to correct such errors. However, FDA will have the
enforcement authority to place a human gene therapy and
xenotransplantation investigation on clinical hold if resolution is not
reached on any discrepancies found by FDA in the redacted versions, or
if a redacted version is not submitted at all by the sponsor. As
described in this proposal, it is important for proposed and ongoing
human gene therapy and xenotransplantation investigations to be the
subject of public education, discussion, and consideration in order for
all relevant issues, including safety, to be explored.
As stated above, FDA has tentatively concluded that the information
that would be disclosed as a result of this rulemaking is, in fact,
already being made public through a variety of mechanisms, and
therefore cannot be considered confidential. As such, it does not
constitute confidential commercial (or trade secret) information within
the meaning of FOIA Exemption 4.
However, FDA's issuance of this proposed rule is authorized even if
the information to be disclosed could be considered confidential
commercial information covered by Exemption 4 and within the scope of
protection of the Trade Secrets Act (18 U.S.C. 1905). That statute
prohibits the disclosure of confidential commercial or trade secret
information, except as "authorized by law." Because agency
regulations that specifically provide for the disclosure of such
information can supply the requisite legal authorization for release of
the information for purposes of the Trade Secrets Act, that statute
would not present a bar to any of the disclosures contemplated by this
proposed rule. (See, e.g., CNA Financial Corp., 830 F.2d 1132, 1138-
1139 (D.C. Cir. 1987)).
The broad rulemaking authority conferred on FDA by Congress under
the act (21 U.S.C. 201 et seq.) permits the agency to amend its
regulations as contemplated by this proposed rule.
Section 505(i) of the act (21 U.S.C. 355(i)) gives FDA the
authority to issue regulations imposing conditions on the investigation
of new drugs. In addition to prescribing certain mandatory conditions,
that section further provides that the agency may impose "other
conditions" as necessary "relating to the protection of the public
health." (21 U.S.C. 355(i)). This language was added to the act as
part of the Drug Amendments of 1962 (Public Law 87-781) to make it
"clear that the conditions prescribed in the [bill] are not the sole
conditions that may be imposed for the protection of public health."
H.R. Conf Rep. No. 2526, at 20 (1962), reprinted in 1962 U.S.C.C.A.N.
2927, 2929. Legislative history relating to these amendments also
indicates that one purpose of the bill was to make "information on
drugs * * * more readily available to physicians and the general
public." (S. Rep. No. 1744, at 1 (1962), 1962 U.S.C.C.A.N. 2884).
FDA's broad discretion in adopting regulations under this language has
been upheld by the courts. (United States v. Garfinkel, 29 F.3d 451
(8th Cir. 1994)).
The proposed amendments to FDA's regulations are within FDA's
statutory discretion in imposing conditions on products under
development to promote the public health. The public health often is
served not only by collection of research data and information, but
also by disclosure of such information. (See e.g., Dole v. United
Steelworkers of America, 494 U.S. 26, 28 (1990)).
The proposed rule would serve several significant public health
goals. It would enhance the ability of patients with serious and
life- threatening diseases and others seeking information about emerging
therapies to obtain critically important information from FDA about the
existence of clinical trials in which they might participate, about
possible safety problems associated with the products they are taking,
and about the regulatory status of applications pending before the
agency.
As an aftermath of recent problems in clinical trials involving
gene therapy products, FDA and NIH have launched two new initiatives to
further strengthen the safeguards for individuals enrolled in clinical
studies for gene therapy. One initiative, the Gene Therapy Clinical
Trial Plan, would ensure: That sponsors meet their obligation to
adequately monitor the clinical trials for which they are responsible;
that there is appropriately independent oversight of such clinical
trials; and that there is an increased level of government oversight,
through increased inspection frequency and review of sponsors'
monitoring plans and other clinical trial practices. Under the other
initiative, FDA and NIH will, several times per year, convene Gene
Transfer Safety Symposia to provide a critical forum with experts in
gene transfer for the sharing and analysis of medical and scientific
data from gene transfer research. FDA and NIH support will also be
provided for professional organizations and academic centers to hold
safety conferences focused on gene therapy. These safety symposia and
educational outreach efforts are intended to guide the conduct of
current clinical trials and enhance the design of future gene transfer
trials to maximize public safety.
The ready availability of information concerning clinical trials
involving gene therapy is essential to the success of these efforts.
For example, such information would be discussed at the government's
safety symposia, may be made available for other scientific discussions
and to the general public, and would be used in evaluating current gene
therapy practices, including sponsor monitoring and informed consent
standards. Likewise, FDA intends to continue to sponsor and support
government, professional, and academic conferences related to
xenotransplantation. Thus, FDA believes that the disclosure of
information contained in INDs related to gene therapy and
xenotransplantation trials is essential to patient safety and
appropriate informed consent.
In addition to section 505(i), section 701(a) of the act (21 U.S.C.
371(a)) gives FDA general rulemaking authority to issue regulations for
the efficient enforcement of the act. A regulation issued under section
701 of the act will be sustained as long as it is reasonably related to
the purposes of the act. (United States v. Nova Scotia Food Prod.
Corp., 568 F.2d 240, 246 (2d Cir. 1977)). Section 903(b) of the act (21
U.S.C. 393(b)) explicitly states that the mission of FDA includes the
promotion and protection of the public health. It has long been
recognized by the courts, including the Supreme Court, that the primary
purpose of the act is the protection of public health (United States v.
An Article of Drug, Bacto-Unidisk, 394 U.S. 784, 798 (1969)). As a result,
FDA's rulemaking authority under section 701(a) of the act has
been broadly construed to uphold a wide variety of the agency's
rulemaking activities intended to protect the public health. (See e.g.,
National Ass'n of Pharmaceutical Mfrs. v. FDA, 637 F.2d 877 (2d Cir.
1981)) (current good manufacturing practice regulations);
Pharmaceutical Mfrs. Ass'n v. FDA, 484 F. Supp. 1179 (D. Del. 1980)
(rule requiring disclosure of drug side effects to patients); American
Frozen Food Inst.
[[Page 4695]]
v. Mathews, 413 F. Supp. 548 (D.D.C. 1976) (rule establishing common
and usual names for certain nonstandard foods to provide consumers with
relevant buying information), aff'd, 555 F.2d 1059 (D.C. Cir. 1977);
National Nutritional Foods Ass'n v. Weinberger, 376 F. Supp. 142
(S.D.N.Y.) (rule requiring that certain vitamin preparations be
restricted to prescription sale and be labeled accordingly), aff'd, 512
F.2d 688 (2d Cir. 1975)), cert. denied, 423 U.S. 827 (1975). FDA
believes that its rulemaking authority under section 701(a) of the act
supports the amendments proposed here because they advance public
health goals concerning gene therapy and xenotransplantation studies.
FDA is also proposing to issue this new regulation under the
authority of section 361 of the Public Health Service Act (PHS Act) (42
U.S.C. 264). Under section 361 of the PHS Act, FDA may make and enforce
regulations necessary to prevent the introduction, transmission, or
spread of communicable diseases between the States or from foreign
countries into the States. (See sec. 1, Reorg. Plan No. 3 of 1966 at 42
U.S.C. 202 for delegation of section 361 of the PHS Act authority from
the Surgeon General to the Secretary, Health and Human Services; see 21
CFR 5.10(a)(4) for delegation from the Secretary to FDA.) Intrastate
transactions may also be regulated under section 361 of the PHS Act.
This proposed regulation is part of a regulatory program that will
further the goal of preventing the introduction, transmission, or
spread of communicable disease. For this regulatory system to be
effective in preventing the spread of disease, FDA must be able to
regularly make publicly available information regarding these
experimental procedures. By providing sponsors, clinical investigators,
patients and their families, and the general public with access to the
types of information proposed in this rule, FDA will be able to more
rapidly identify and react appropriately to newly discovered or
understood risks in order to prevent the spread of communicable disease.
Studies in the areas of gene therapy and xenotransplantation are
conducted to explore the potential for considerable benefits. However,
use of these procedures, particularly in the case of
xenotransplantation, poses potential risks for the transmission of
infectious disease. Infectious disease public health concerns focus not
only on the transmission of known zoonoses, but also on the
transmission of infectious agents as yet unrecognized. The disruption
of natural anatomical barriers and immunosuppression of the recipient
increase the likelihood of interspecies transmission of xenogeneic
infectious agents. An infectious agent may pose risks if it can infect,
cause disease in, and transmit among humans, or if its ability to
infect, cause disease in, or transmit among humans remains inadequately
defined. The public availability of information this proposed rule
envisions will permit public attention to any emerging risks associated
with these experimental techniques, early detection and definition of
which will permit the agency and sponsors to take steps to prevent or
minimize the introduction of communicable disease.
An additional concern is that these infectious agents could
subsequently be transmitted from the patient to family members and
other close contacts of the patients, to health care personnel, and to
other members of the public. Because the potential risk of transmission
of infectious disease extends beyond the patient receiving the
treatment, it is vital that the public, as well as the patient, be
informed and educated about potential infectious disease risks and
methods for reducing those risks. Close contacts should understand the
uncertainty regarding the risks of xenogeneic infections, behaviors
known to transmit infectious agents from human to human (e.g.,
unprotected sex, breast feeding, intravenous drug use with shared
needles, and other activities that involve potential exchange of blood
or other body fluids) and methods to minimize the risk of transmission.
Close contacts of recipients also need to know about the importance of
reporting any significant unexplained illness through their health care
provider to the research coordinator at the institutions where the
xenotransplantation was performed. This broader concern for the spread
of communicable disease is reflected in the proposed requirements
providing for public disclosure. While informed consent procedures may
try to address these educational needs, the public release and
discussion of information that this proposed rule calls for is also
necessary to ensure that all those potentially at risk have the
information to manage these risks and so avoid or minimize the spread
of communicable disease.
For all the above reasons, to promote and protect the public
health, FDA is proposing to issue this proposed rule providing for
public disclosure of certain information relating to gene therapy and
xenotransplantation.
C. Discussion of the Proposed Rule
The proposed rule would create a new Sec. 601.52 entitled
"Availability for public disclosure of certain data and information
related to human gene therapy or xenotransplantation" and Sec. 601.53
entitled "Submission to FDA of certain data and information related to
human gene therapy or xenotransplantation for public disclosure." In
addition, conforming amendments are proposed to Secs. 20.100, 312.42,
312.130, 601.50, and 601.51. The provisions of this rulemaking do not
alter the procedures specified in part 312 for submission of an IND.
The proposed regulations are discussed below.
1. Sections 601.50 and 601.51
Part 601 (21 CFR part 601) sets forth provisions that govern the
licensing of biologic products by the FDA. Existing procedures and
requirements regarding confidentiality of data and information
contained in IND's for biological products or biologics license
applications are described in Secs. 601.50 and 601.51. The proposed
rule would amend Secs. 601.50 and 601.51 to include language that would
reference the exceptions proposed in Sec. 601.52 regarding the
availability for public disclosure of certain data and information
related to human gene therapy or xenotransplantation. Specifically,
Secs. 601.50(a) and 601.51(a) would be amended to add the words,
"Except as provided in Sec. 601.52."
In addition, FDA is proposing to amend the Sec. 601.50 section
heading and Sec. 601.50(a) to replace the word "notice" with
"application" to be consistent with other current regulations
regarding investigational new drugs, i.e., part 312.
2. Proposed Sec. 601.52
Proposed Sec. 601.52 would set forth the requirements regarding the
availability for public disclosure of certain data and information
related to human gene therapy or xenotransplantation. These provisions
would define the therapies and scope of the proposed regulation, and
describe the types of data and information related to human gene
therapy and xenotransplantation that may be disclosed by FDA.
a. Definitions. Proposed Sec. 601.52(a) would include definitions
of human gene therapy and xenotransplantation that are consistent with
existing agency policy and guidance regarding these therapies. Proposed
Sec. 601.52(a)(1) would define "human gene therapy" to mean the
administration of genetic material in order to modify or manipulate the
expression of a gene
[[Page 4696]]
product or to alter the biological properties of living cells for
therapeutic use. FDA interprets this definition to include both the ex
vivo and in vivo modification of cells. Proposed Sec. 601.52(a)(2)
would define "xenotransplantation" to mean any procedure that
involves the transplantation, implantation, or infusion into a human
recipient of either: (a) Live cells, tissues, or organs from a nonhuman
animal source, or (b) human body fluids, cells, tissues, or organs that
have had ex vivo contact with live nonhuman animal cells, tissues, or
organs. This definition of xenotransplantation does not include the use
of products that are nonliving, acellular products such as porcine
heart valves, porcine insulin, or bovine serum albumin. The definition
also does not include non-animal cells and tissues, such as bacteria
and plant cells.
Because the terms "human gene therapy" and
"xenotransplantation" are not currently used elsewhere in the
regulations, FDA is proposing that, for the convenience of the user,
the definitions be included in proposed Sec. 601.52. If, in the future,
additional regulations are issued using these terms, FDA intends to
move these definitions to the section of the regulations which
currently includes definitions of other terms applicable to biological
products (21 CFR 600.3).
b. Scope. Proposed Sec. 601.52(b) would describe the scope of the
proposed regulation. Consistent with the use of the terms "human gene
therapy" and "xenotransplantation," FDA intends that the proposed
rule apply to the procedures, not specific products used in the
therapies, although data and information regarding a product may be
disclosed as proposed in Sec. 601.52(c). FDA intends with this broadly-
defined scope that the proposed regulation apply to any experimental
use of human gene therapy and xenotransplantation, although the
immediate impact of the proposed regulation would be on investigational
products. For example, the proposed regulations would apply to any use
of gene therapy or xenotransplantation in clinical studies in humans,
including use of a licensed gene therapy or xenotransplantation product
with an experimental drug or device being clinically studied for use in
a gene therapy or xenotransplantation procedure.
FDA believes it is not necessary to disclose for purposes of public
education and discussion all the information which may be included in
an IND. Except as specifically provided in the proposed rule, FDA
intends that information regarding human gene therapy or
xenotransplantation investigations will continue to be held
confidential, consistent with existing regulations in Secs. 20.61,
20.62, 20.63, 20.100, 312.130, 601.50, and 601.51. Accordingly,
proposed Sec. 601.52(b) would specify that, except as specifically
provided in proposed Sec. 601.52, the availability for public
disclosure of data and information related to human gene therapy or
xenotransplantation shall remain in accordance with Sec. 601.50 for
IND's for a biological product.
c. Information for public disclosure. Proposed Sec. 601.52(c) would
specify the types of data and information related to human gene therapy
or xenotransplantation that the FDA may make available for public
disclosure. The types of information listed in proposed Sec. 601.52(c)
are already required for submission under existing regulations (parts
312 and 601) as part of an IND or BLA or as a supplement to a BLA.
Under proposed Sec. 601.52(c)(1), FDA would make product and
patient safety data and related information related to human gene
therapy and xenotransplantation available for public disclosure. This
proposed provision is similar to existing requirements in
Sec. 601.51(e)(1), which require that all safety and effectiveness data
and information contained in a biological product file be made
available for public disclosure immediately after a license has been
issued. The proposed provisions in Sec. 601.52, however, would extend
this throughout the entire product development process for a product
related to human gene therapy or xenotransplantation. The proposed rule
further specifies in Sec. 601.52(c)(1) that for the purposes of this
proposed regulation, product and patient safety data and related
information include results of preclinical and clinical studies and
tests that demonstrate the safety and/or feasibility of the proposed
procedures. In addition, FDA proposes in Sec. 601.52(c)(1) to identify
some of the types of product and patient safety data and related
information that would be disclosed to the public that are particularly
relevant or specific to human gene therapy and xenotransplantation.
These types of product and patient safety data and related information
are: (1) Analysis in animals, humans, or in vitro systems of gene
transfer, expression, and persistence; (2) vector biodistribution; (3)
evidence for immune response/anergy; (4) biological activity; (5)
results of product safety testing including test results for known
xenogeneic and human infectious agents and replication competent virus;
(6) qualification of source herd, individual source animal, and source
organ/tissue/cells for xenotransplantation in humans; and (7)
information on monitoring or prevention of potential health risks to
the recipient, close contacts, and health care workers. FDA does not
intend this to be an exclusive list. In all cases, names and other
personal identifiers of patients and, expect as specifically provided
in the regulations, names and other personal identifiers of third
parties, such as physicians or hospitals, would be removed.
Furthermore, FDA does not intend product and patient safety data and
related information under proposed Sec. 601.52(c)(1) to include IND
safety reports and annual reports, as provided for in Secs. 312.32 and
312.33. Rather, specific requirements for the public disclosure of
these types of reports are proposed below in Sec. 601.52(c)(7) and
(c)(8), respectively.
Under proposed Sec. 601.52(c)(2) and (c)(3), FDA would make the
name and address of the sponsor and the clinical indications to be
studied available for public disclosure. The sponsor name and address
and the indications to be studied are types of information that are
consistent with information already required for submission to FDA in
an IND under Sec. 312.23(a)(1)(i) and (a)(3)(iv)(b), respectively.
Under proposed Sec. 601.52(c)(4), FDA would make the protocol for
each planned study available for public disclosure. A study protocol is
required for submission in an IND under Sec. 312.23(a)(6); proposed
Sec. 601.52(c)(4) would specify that certain elements of the protocol
be available for public disclosure. Proposed Sec. 601.52(c)(4)(i)
through (c)(4)(vi) would describe the following specific elements of
the protocol to be available for public disclosure: (1) A scientific
abstract and a non-technical abstract; (2) a statement of the
objectives, purpose, and rationale of the study (submitted in an IND
under Sec. 312.23(a)(6)(iii)(a)); (3) the name and address of each
investigator (submitted in an IND under Sec. 312.23(a)(6)(iii)(b)); (4)
the name and address of the official contacts of each local review body
as appropriate (IRB (submitted in an IND under
Sec. 312.23(a)(6)(iii)(b)), and IBC (NIH Guidelines for Research
Involving Recombinant DNA Molecules, revised April 1998)) and dated
copies of each committee's approval of the study; (5) the criteria for
patient selection and exclusion and an estimate of the number of
patients to be studied (submitted in an IND under
Sec. 312.23(a)(6)(iii)(c)); and (6) a description of the treatment that
will be administered to patients and the clinical procedures,
laboratory tests, or
[[Page 4697]]
other measures to be taken to monitor the safety and effects of the
drug in human subjects and to minimize risk (similar to that submitted
in an IND under Sec. 312.23(a)(6)(iii)(g)). FDA intends that the term
"investigator' in proposed Sec. 601.52(c)(4)(iii) include "sponsor-
investigators" (individuals who have the responsibility for both the
development and clinical investigation of the product) as well as
"investigators," both of which are defined in existing Sec. 312.3(b).
In proposed Sec. 601.52(c)(4)(iv), FDA intends to make available for
public disclosure the dated copies of the IRB's and IRC's approval of
the proposed clinical study to identify when the IRB or IBC assumed
responsibility for the continued review and approval of the IND.
Under proposed Sec. 601.52(c)(5), FDA would make sample informed
consent forms available for public disclosure. FDA proposes to provide
public access to human gene therapy and xenotransplantation clinical
trial information relevant to informed consent to promote public
education, discussion, and consideration of the unique challenges that
these novel therapies present to assuring adequate informed consent, as
discussed previously in this proposed rule.
Under proposed Sec. 601.52(c)(6), FDA would make the identification
of the biological product(s) and a general description of the method of
production, including a description of product features that may affect
patient safety, available for public disclosure. This proposed
provision contains types of information that are required for
submission to FDA in an IND under Sec. 312.23. FDA has modified the
language taken from Sec. 312.23 to reflect information needs related to
human gene therapy and xenotransplantation and specifies that only a
"general" description of the production method would be made
available, excluding trade secret information. FDA does, however,
propose to further specify in Sec. 601.52(c)(6) that the identification
and description would include the following types of information, as
applicable: (1) The vector name and type; (2) gene insert; (3)
regulatory elements and their source; (4) intended target cells; (5)
source of cells, tissues, or organ(s); (6) method used to prepare the
vector containing cells; (7) method used to procure and prepare cells,
tissues, or organ(s) for xenotransplantation; (8) purity of cells; (9)
adventitious agent testing; (10) description of the delivery system;
(11) ancillary products used during production; (12) herd colony and
individual source animal health maintenance and surveillance records;
and (13) biological specimens to be archived from source animals. These
types of information are consistent with information that is already
submitted to and publicly disclosed by OBA for human gene therapy.
Under proposed Sec. 601.52(c)(7), FDA would make IND safety
reports, as provided in Sec. 312.32, and other similar data and
information available for public disclosure. Under Sec. 312.32,
sponsors of investigational drugs, including biological drugs, are
required to submit to FDA certain adverse reaction reports concerning
their product. Under Sec. 601.51(e)(3), information concerning these
adverse experience reports, excluding names and other identifiers of
patients, health care facilities, and physicians, may be publicly
disclosed after the licensure of the product. Under proposed
Sec. 601.52(c)(7), such adverse experience reports and other safety
reports related to an investigational product could be publicly
disclosed at any time throughout the lifetime of the product. The same
limitations for disclosure included in Sec. 601.51(e)(3) are included
in proposed Sec. 601.52(c) to protect the privacy of patients and
health care workers.
nder Sec. 601.52(c)(8), FDA would make information submitted in
the annual report available for public disclosure. Sponsors must submit
to FDA annual reports of the progress of the investigations as required
under Sec. 312.33. FDA proposes that the following types of information
relevant to human gene therapy and xenotransplantation be included, as
applicable, in the annual report submitted by the sponsor to FDA for
public disclosure: (1) Evidence of gene transfer, gene expression in
target cells, and biological activity; (2) assessment of immune
response; (3) analysis of biodistribution; (4) significant preclinical
and clinical toxicities; (5) evidence of infection by agents associated
with the products; (6) adverse experiences; (7) number of subjects who
died during participation in the investigation, with the cause of death
for each subject and the status of autopsy requests; and (8) any
available post mortem evidence of gene transfer, biodistribution,
specifically including gonadal distribution. In all cases, names and
other personal identifiers of patients and, except as specifically
provided in the regulations, names and other personal identifiers of
third parties, such as physicians or hospitals, would be removed.
Under proposed Sec. 601.52(c)(9), FDA would make the regulatory
status of the investigation, the date of a regulatory action, and the
reason for an action available for public disclosure in order to
identify to the public the current regulatory status of a clinical
investigation. For example, FDA would disclose that an investigation is
on clinical hold, or that an IND is inactive, withdrawn, or terminated.
Additional information regarding the procedures and criteria for
placing an investigation on clinical hold, withdrawal of an IND,
inactive status for an IND, and IND termination may be found in
Secs. 312.42, 312.38, 312.45, and 312.44, respectively.
Under Sec. 601.52(c)(10), FDA would make available for public
disclosure other relevant data and information that the Director, CBER,
determines are necessary for the appropriate consideration of the
public health and scientific issues, including relevant ethical issues
raised by human gene therapy or xenotransplantation. This proposed
provision is included because the investigational nature of these
therapies and the continuing evolution of the science surrounding these
therapies renders FDA unable to anticipate all of the types of
information related to human gene therapy and xenotransplantation that
may warrant public education, discussion, and consideration. Examples
of other relevant data that FDA may disclose could, under certain
circumstances, include the details of a test used to determine
eligibility for trial entry or autopsy or biopsy information. However,
in general, FDA intends to release only the information specifically
identified in this proposed rule, except in unique conditions or
circumstances. Proposed Sec. 601.52(c)(10) would provide that other
relevant data and information may be approved for disclosure only by
the Director of CBER.
3. Proposed Sec. 601.53
Proposed Sec. 601.53 would require sponsors of human gene therapy
and xenotransplantation clinical trials to submit to FDA for public
disclosure a redacted version of certain data and information. These
provisions would specify when and what types of submissions to make to
FDA in a redacted version for public disclosure, and the requirements
for identifying and certifying these submissions.
Furthermore, proposed Sec. 312.42(b)(6) provides that a sponsor's
failure to submit to FDA the data and information specified in
Secs. 601.52 and 601.53 that has been properly redacted under
Sec. 601.53(a) is a basis for FDA placing the investigation on clinical
hold. FDA recognizes that errors in redacting may occur and will
provide sponsors with an
[[Page 4698]]
opportunity to correct such errors. However, FDA will have the
enforcement authority to place a human gene therapy and
xenotransplantation investigation on clinical hold if resolution is not
reached on any discrepancies found by FDA in the redacted versions, or
if a redacted version is not submitted at all by the sponsor. It is
important that FDA has the specific authority to place a human gene
therapy or xenotransplantation investigation on clinical hold if the
sponsor has not submitted required data and information to FDA in a
form that FDA can make publicly available in a timely and efficient
manner. As previously described in this proposal, due to the unique
nature of human gene therapy and xenotransplantation, public
participation in the consideration of proposed and ongoing clinical
studies of such therapies is crucial. In order for such public
education, discussion, and consideration to take place and be
meaningful, FDA must be able to make all relevant and publicly
disclosable data and information available to the public as soon as
practicable. The agency has determined that having sponsors submit
redacted versions that comply with proposed Secs. 601.52 and 601.53 is
the most efficient means to accomplish this.
Under proposed Sec. 601.53(a), FDA would require the sponsor of an
IND to submit to FDA for public disclosure a redacted version of the
types of submissions identified in Sec. 601.53(b)(1) through (b)(5).
The sponsor would be required to include all applicable information
identified as disclosable in Sec. 601.52 and redact all information
considered confidential as trade secret, names and other personal
identifiers of patients and, except as specifically provided in the
regulations, names and personal identifiers of third parties, such as
physicians, hospitals, etc., and certain confidential commercial
information, such as information regarding commercial licensing
agreements or the identification of suppliers. Sponsors would be
permitted to redact either by removing or obscuring the information
exempt from disclosure.
Proposed Sec. 601.53(b)(1) through (b)(5) would list the types of
submissions that the sponsor would be required to submit to FDA in
duplicate and as a redacted version for public disclosure. FDA believes
this information should be available for public disclosure as soon as
possible and therefore, would require under this paragraph that the
redacted version be submitted to FDA concurrently with the original
unabridged submission or at the specific time points noted.
Proposed Sec. 601.53(b)(1) would require submission for public
disclosure a redacted version of the information defined under
Sec. 601.52 to accompany the original unabridged IND submission.
Proposed Sec. 601.53(b)(2) would require submission for public
disclosure a redacted version of any amendment documenting changes or
additions to the information defined under Sec. 601.52 that occur
either during the IND review process or after the IND goes into effect.
FDA recognizes that some amendments may require negotiation with FDA
and subsequent revision by the sponsor. As such, FDA would require that
the redacted version of any amendment be submitted at the time the
amendment goes into effect.
Proposed Sec. 601.53(b)(3) would require submission for public
disclosure of a redacted version of any IND safety report at the time
of submission of the original report to FDA. Sponsors are required
under Sec. 312.32 to notify FDA in a written IND safety report of any
serious and unexpected adverse experiences associated with the use of
their drug no later than 15 days after the sponsor's initial receipt of
the information. FDA believes that the timely availability of adverse
experience information is essential for public education and informed
discussion and consideration of the health and safety issues presented
by the experiences.
Proposed Sec. 601.53(b)(4) would require submission for public
disclosure of a redacted version of the annual report, in accordance
with Sec. 312.33. Consistent with Sec. 312.33, sponsors would be
required to submit, within 60 days of the anniversary date that the IND
went into effect, a redacted version of the annual report.
Under proposed Sec. 601.53(b)(5), a sponsor would be required to
submit for public disclosure a redacted version of other information
upon specific request of the Director, CBER. For example, FDA may
request that the sponsor submit information regarding a test used to
determine eligibility for trial entry. This proposed provision is
included because due to the investigational nature of these therapies
and the continuing evolution of the science surrounding these
therapies, FDA is not able to anticipate all of the types of
information related to human gene therapy and xenotransplantation that
may warrant public education, discussion, and consideration. However,
in general, FDA does not intend to request information not identified
in this proposed rule, except for unique conditions or circumstances.
Proposed Sec. 601.53(c) would require that the sponsor submit the
information identified in Sec. 601.53(b) in duplicate, in a form
readily separable from the nonredacted or original unabridged version
or submission and clearly marked as suitable for public disclosure on
each page of the submission. This proposed provision would enable FDA
to identify and provide this information more rapidly to the public and
would help assure that only appropriate information is disclosed to the
public.
Proposed Sec. 601.53(d) would require that any copyrighted material
be included in a single appendix to the submission and listed in a
bibliography in the redacted version. The proposal would specify that
any copyrighted material whose copyright is not owned by the applicant
shall not be included in any other section of the redacted version. FDA
is including this provision to facilitate timely release of the
redacted version on the Internet. In response to an FOIA request,
copyrighted materials can be included in the response. However, with
regard to posting on the Internet, copyrighted material must be
redacted prior to electronic disclosure as this is not considered a
"fair use" of copyrighted material. Therefore, FDA would not release
the appendix containing copyrighted materials as part of the redacted
version on the Internet, but may release the bibliography of materials
included in the appendix.
Proposed Sec. 601.53(e) would require that redacted versions be
accompanied by the statement specified to ensure that the sponsor has
redacted only the information identified in Sec. 601.53(a) as exempt
from disclosure (confidential commercial, trade secret, or personal
information). In addition, under proposed Sec. 601.53, the sponsor must
include a declaration that the statement is true and correct, under
penalty of perjury.
4. Conforming Amendments
The proposed rule would make conforming amendments to parts 20 and
312. Part 20 describes the procedures and policy regarding the
availability and disclosure of information to the public. Section
20.100 lists the cross-references to other sections of title 21 CFR
that contain requirements on the availability of specific categories of
FDA records and how these records are handled upon a request for public
disclosure. The proposed rule would amend Sec. 20.100(c) by adding a
paragraph (43) that would contain a cross-reference to the proposed
Sec. 601.52 regarding the availability for public disclosure of certain
data and information submitted
[[Page 4699]]
to FDA related to human gene therapy or xenotransplantation.
Part 312 describes the procedures and requirements that govern the
use of investigational new drugs, including provisions for submission
to and review by FDA of IND's. The provisions of this rulemaking do not
alter the procedures specified in part 312 for submission of an IND.
Section 312.42, among other things, lists the grounds for which FDA may
impose a clinical hold of an investigation. Proposed Sec. 312.42(b)(7)
would amend Sec. 312.42 by adding an additional basis for clinical hold
for human gene therapy and xenotransplantation investigations. Under
this proposal, FDA could place a human gene therapy or
xenotransplantation investigation on clinical hold if the sponsor has
not submitted to the agency a redacted version for public disclosure
that complies with the requirements of Sec. 601.53.
Section Sec. 312.130 contains requirements regarding the
availability for public disclosure of data and information in an IND.
The proposed rule would amend Sec. 312.130 by revising paragraph (b) to
include a reference to proposed Sec. 601.52, in addition to the
existing references to Secs. 601.50 and 601.51, when listing the
provisions of this chapter that govern the availability for public
disclosure of all data and information in an IND.
III. Implementation
Under the proposed rule, FDA would require that sponsors of human
gene therapy and xenotransplantation clinical trials submit for public
disclosure a redacted version of the information defined under
Sec. 601.52 as contained in the initial IND submission, amendments
documenting changes or additions to the information defined under
Sec. 601.52 at the time the amendments go into effect, IND safety
reports, and annual reports. The redacted version of these documents
should be submitted to FDA in a form immediately releasable to the
public, and clearly marked accordingly on each page of the submission
as suitable for public disclosure. Acceptable approaches range from
submitting a "marked up" version of the original that obscures the
information which is not to be disclosed, to developing a separate
document that abstracts the needed information for public disclosure
from the original unabridged version submitted to FDA.
Specifically, FDA is proposing that the redacted version of the
information specified in the proposed rule be submitted to FDA
concurrently with the original unabridged IND submission or at the
specific time points noted in the provisions. Sponsors of human gene
therapy and xenotransplantation clinical trials would send an original
and two copies of the original unabridged version of the IND submission
(as required under existing Sec. 312.23(d)) as well as one copy of the
redacted version for public disclosure to FDA's CBER, where they would
be received by the Document Control Center (DCC) to be logged, filed,
and routed for appropriate documentation, review, and approval. DCC
would route the submittals to the appropriate FDA reviewer, where, upon
receipt, the redacted version for public disclosure would be reviewed
for administrative completeness as well as to ensure that the
submitting sponsor has appropriately redacted personal information
regarding patients and third parties prior to release to the public.
Once this review is complete, the redacted version for public
disclosure would be sent to the Dockets Management Branch for public
display where a docket number would be assigned. Each redacted version
for public disclosure submitted to FDA would be tagged with the same
docket number for that IND for reference. FDA is also proposing to make
the redacted versions for public disclosure available to the public
electronically on the Internet site according to the docket number.
In addition, to facilitate timely release by FDA of the redacted
version, FDA is proposing to require that all copyrighted materials
submitted in accordance with Sec. 601.53 be placed in a single appendix
and listed in a bibliography in the redacted version. Should an FOIA
request be received for the data and information specified in
Sec. 601.52, FDA would be able to include a copy of any copyrighted
materials in its response. However, FDA would not be able to publicly
release any copyrighted material on the Internet as electronic posting
of such information is not a ``fair use" of that copyrighted material
and must be redacted prior to electronic release. In this case, FDA
instead would disclose the bibliography of copyrighted materials
contained in the appendix.
FDA encourages, but would not require at this time, sponsors to
submit the redacted version for public disclosure in electronic format.
Pilot programs are currently underway regarding submission of
electronic IND's and BLA's. (See 63 FR 29740 and 29741.) As such, FDA
may, in the near future, implement electronic submission and disclosure
of this information.
Sponsors of human gene therapy or xenotransplantation clinical
trials who submit an initial IND or an amendment to an existing IND on
or after the effective date of the final rule resulting from this
rulemaking would be required to submit a redacted version for public
disclosure in conformance with the rule.
Sponsors of xenotransplantation clinical trials who have submitted
an IND to FDA prior to the effective date of the final rule resulting
from this rulemaking would be required to submit for public disclosure
a redacted version of the information defined under Sec. 601.52,
reflecting all amendments to date, by a date specified in the final
rule. Sponsors of human gene therapy clinical trials who have submitted
IND's or amendments prior to the effective date of the final rule, need
not submit redacted versions. For these IND's or amendments, FDA will
rely on the existing OBA database as a source of the information that
FDA will disclose.
For additional information regarding the proposed effective dates
for the final rule see the end of this preamble.
IV. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
V. Analysis of Impacts and Initial Regulatory Flexibility Analysis
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612)
(as amended by subtitle D of the Small Business Regulatory Fairness Act
of 1996 (Public Law 104-121)), and under the Unfunded Mandates Reform
Act (UMRA) (Public Law 104-4). Executive Order 12866 directs agencies
to assess all costs and benefits of available regulatory alternatives
and, when regulation is necessary, to select regulatory approaches that
maximize net benefits (including potential economic, environmental,
public health and safety, and other advantages; distributive impacts;
and equity). The Regulatory Flexibility Act requires agencies to
analyze whether a rule may have a significant impact on a substantial
number of small entities and, if it does, to analyze regulatory options
that would minimize the impact. The UMRA requires that agencies prepare
a written statement under section 202(a) of UMRA of
[[Page 4700]]
anticipated costs and benefits before proposing any rule that may
result in an expenditure by State, local, and tribal governments, in
the aggregate, or by the private sector, of $100 million (adjusted
annually for inflation) in any one year.
The agency believes that this final rule is consistent with the
principles identified in Executive Order 12866. OMB has determined that
the final rule is a significant regulatory action as defined by the
Executive Order and so is subject to review. Because the rule does not
impose mandates on State, local, or tribal governments, or the private
sector, that will result in an expenditure in any one year of $100
million or more, FDA is not required to perform a cost-benefit analysis
according to the Unfunded Mandates Reform Act. Aggregate impacts of the
rule, and aggregate expenditures caused by the rule, will not approach
$100 million for either the public or the private sector. As discussed
below, because of the limited information that can be used to
characterize the entities that may qualify as small businesses, the
impact on small business establishments is uncertain. FDA has therefore
prepared an Initial Regulatory Flexibility Analysis.
A. Background
In the discussion that follows, FDA will describe the purpose and
requirements of the proposed rule, the estimated number of entities
that will be affected, the estimated cost of compliance with the rule
per IND, and a summary of estimated annual costs to industry.
The purpose of the proposed rule is to make available for public
disclosure and to require submission in redacted version for public
disclosure, certain data and information related to human gene therapy
and xenotransplantation investigations. These areas of clinical
investigation have the potential for unique public health risks and
modification of the human genome. The public health and safety risks
require that FDA be able to make timely disclosures of adverse
outcomes, such as the development of novel infectious agents,
unanticipated alterations of a recipient's germline, and severe
toxicity resulting from the therapy, in order to prevent or contain
further adverse occurrences.
These therapeutic research areas will effectively transform
participating recipients into life-long research subjects. The length
of commitment, coupled with the magnitude of potential risks to the
recipients, their families and community, will present new challenges
for risk assessment and the adequacy of informed consent. As noted
earlier, these investigative approaches raise new challenges for
Institutional Review Boards. The novelty and extent of the risk issues
will call for expanded public access to clinical trial information
relevant to assessment of risks and benefits, and public education and
informed consent. These public information needs can only be addressed
through disclosure of relevant information about the proposed and
ongoing investigations.
The information to come under this disclosure regulation includes:
(1) Product and patient safety data and related information including
results of preclinical and clinical studies and tests that demonstrate
the safety and/or feasibility of the proposed procedures; (2) the name
and address of the sponsor; (3) the clinical indications to be studied;
(4) the protocol for each planned study to include a scientific
abstract and a nontechnical abstract, a statement of the objectives,
purpose, and rationale of the study, the name and address of each
investigator and subinvestigator, the name and address of the official
contacts of each local review body as appropriate (IRB, IBC) and the
dated copies of approval by each group, the criteria for patient
selection and exclusion, an estimate of the number of patients to be
studied, and a description of the treatment that will be administered
to patients, and the clinical procedures, laboratory tests, or other
measures to be taken to monitor the safety and effects of the drug in
human subjects and to minimize risk; (5) the informed consent
documentation; (6) the identification of the biological product(s) and
a general description of the method of production, including a
description of product features that may affect patient safety; (7) the
IND safety reports; (8) the information submitted to FDA in the annual
report; (9) the regulatory status of the investigation, the date of an
action, and the reason for an action; (10) and other relevant data and
information that the Director, CBER, determines are necessary for the
appropriate consideration of the public health and scientific issues,
including relevant ethical issues, raised by human gene therapy or
xenotransplantation. After a license has been issued, all safety and
effectiveness data and information in the biological product file are
immediately available for public disclosure unless extraordinary
circumstances are shown (Sec. 601.51(e)(1)).
The sponsor of an IND involving human gene therapy or
xenotransplantation will be required to submit this information in
redacted version for public disclosure, removing all information that
would be defined as trade secret, or personal information. The redacted
submissions would be as follows:
1. Redacted version of information as defined under Sec. 601.52 at
the time of the initial IND submission.
2. Redacted version of any amendment documenting changes or
additions to the information defined under Sec. 601.52, at the time the
amendment goes into effect.
3. Redacted version of IND safety reports at the time of submission
of the initial report.
4. Redacted version of the annual progress report within 60 days of
the anniversary date that the IND went into effect.
The redacted version would be submitted in a form that is readily
identifiable and separable from the original unabridged submission to FDA.
The proposed rule will affect sponsors of human gene therapy or
xenotransplantation clinical trials. The agency estimates that, at any
one time, a total of 147 sponsors will be affected by the proposed
rule. This includes 134 sponsors that have submitted IND's in the area
of human gene therapy, and an additional 13 sponsors that have
submitted IND's for clinical trials involving xenotransplantation. The
number of new IND's per year in these two research areas has remained
relatively constant at the level of approximately 45 IND submissions
per year, for the past several years.
B. Cost Impact
Certain types of information have a substantial commercial value.
This value may be particularly high for data pertaining to specific
business plans, strategies, or lines of scientific research. The
required disclosure of such information, however, imposes no economic
impact where the relevant data are already available to competitors. As
discussed earlier in this preamble, information that would be disclosed
under this proposed rule is routinely examined and discussed by the
RAC, in the case of gene therapy, and discussed at other public
meetings addressing xenotransplantation issues, or through public
filings with the SEC. Because the information proposed for disclosure
has not been treated as confidential by industry, FDA finds that there
is minimal incremental commercial value associated with the information
that may be disclosed. The agency has, therefore, not attributed
regulatory costs to its disclosure. The
[[Page 4701]]
agency requests public comment on the validity of this view.
The proposed rule will require additional paperwork activities for
affected firms. The primary impact on clinical trial sponsors will be
the requirement for additional staff time to redact IND-related
submissions, throughout the period in which the IND is active. Table 1
of this document provides a summary of the types of submissions that
will be required for public disclosure and the estimated number of such
submissions that FDA expects to receive each year across all active
IND's in the areas of human gene therapy and xenotransplantation. The
estimated time required per redacted submission is also shown in table
1. The numbers of submissions and redaction times are estimated by FDA
staff involved in application review, based on their experience in
recent years, and their familiarity with the content of the IND
packages. The redaction is assumed to be performed by a relatively
senior member of the scientific research staff at a sponsoring
organization. The cost per hour of staff time is estimated to be
approximately $38, based on the Bureau of Labor Statistics estimate of
total hourly compensation for professional white-collar workers in the
private goods-producing and service producing industries.\3\ The
redacted documents listed in table 1 reflect a series of submissions
that would typically occur over several years. Based on FDA's estimate
of the total volume of submissions of each type per year, the agency
estimates that the total cost to the industry will be approximately
$123,880 [$41,040+$5,130+$1,710+$76,000]. This yields an average annual
cost of $843 per sponsor [$123,880/147].
---------------------------------------------------------------------------
\3\ U.S. Dept of Labor, Bureau of Labor Statistics, Employer
Costs for Employee Compensation, March 1997.
Table 1.--Estimates Of Cost Per Year For Industry-Wide Redaction Efforts
------------------------------------------------------------------------
Total Industry Estimated
Type of Redacted Submissions Average Redaction Industry Cost per
Submission per Year Time/Submission Year
------------------------------------------------------------------------
New IND\1\-- 45 24 hours $41,040 [45 x 24
initial and x $38]
authorized
version
IND amendments 270 0.5 hour $5,130 [270 x 0.5 x $38]
IND safety reports 90 0.5 hour $1,170 [90 x 0.5 x $38]
Annual reports 100 20 hours $76,000 [100 x 20 x $38]
------------------------------------------------------------------------
Total Annual Cost $123,880
to Industry
------------------------------------------------------------------------
Average Annual $843
Cost Per Sponsor
(147 sponsors)
------------------------------------------------------------------------
\1\ Investigational new drug application.
C. Benefits
Although human gene therapy offers the promise of more effective
treatment, for diseases ranging from cystic fibrosis to human
immunodeficiency virus (HIV), rapid progress and patient safety in
research requires timely communication of new findings about the
success or risks of candidate strategies. The key to success for any
human gene therapy strategy is attaining a vector that can serve as a
safe and efficient gene delivery vehicle (Ref. 5). In general, human
gene therapy researchers work to maximize efficacy through the
regulation of gene expression over long periods (Ref. 6). Simultaneous
with this goal, researchers attempt to develop vectors and treatment
strategies that will both minimize the patient's immune response (which
counters the therapy) (Ref. 7) and minimize the toxicity of the gene
therapy (Refs. 8 and 9). As different vectors are considered, it is
critical that newly discovered risks be reported to alert other
researchers considering similar vectors or developing therapies to
treat similar conditions.
As described earlier, the importance of timely communication of
risks is clearly demonstrated by the cystic fibrosis patient who
developed an acute adverse event requiring intensive care after
receiving an adenoviral vector. In this case, public discussion of the
adverse event at the RAC meeting facilitated rapid dissemination of
important information about this toxicity, thereby contributing to the
safety of patients in other gene therapy trials.
For xenotransplantation, the disclosure of information is necessary
for public education and more efficient product and recipient tracking.
Communication of risks offers other benefits for recipients of
xenotransplantation products, their families, and their communities.
According to a recent World Health Organization report on
xenotransplantation, "The practice of xenotransplantation carries with
it an unquantifiable risk of xenozoonotic infection and disease.
Measures are required to minimize risk and maximize safety in the
potential use of this technology" (Ref. 10). The level of risk is
particularly difficult to quantify since potential viruses may be
unknown and "silent" in the donor species; that is, they may not be
identified through the currently available battery of screening tests
for known pathogens. In addition, the risk of infection in the
recipient of a xenotransplantation product may be substantially
increased as a result of the immunosuppressive drug therapy
administered to prevent rejection of the transplanted
xenotransplantation product.
New evidence supporting the possibility of this risk is reported in
a recent study (Ref. 11) showing that pig pancreatic islets
transplanted into severely immunodeficient mice produce porcine
endogenous retroviruses (PERV) that can infect human cells that had
been transplanted into the same mice receiving the porcine pancreatic
cells. Although pigs are considered a promising alternative source of
organs for xenotransplantation, this study found that the PERV were
trancriptionally active and infectious cross-species in vivo after
xenotransplantation of the pig tissues. These findings bolster earlier
concerns about PERV infection from pig islet
[[Page 4702]]
xenotransplantation in immunosuppressed human patients.
Recent experience with zoonotic viruses has demonstrated the
potential lethality of these viruses. An example is the 1998 to 1999
outbreak of a hendra-like virus in Malaysia and Singapore (Ref. 12).
Documented cases occurred primarily among adults who had come in close
contact with swine, which also showed signs of the illness. In some
instances, illness in the pigs had occurred 1 to 2 weeks before illness
in the humans. Illness in humans was characterized by 3 to 14 days of
fever and headache followed by drowsiness and disorientation that often
progressed to coma within 24 to 48 hours. During the period September
1998 to April 1999, 229 human cases were reported, 111 of which (48
percent) resulted in death. Although the first cases of human illness
were reported in September 1998, the type and source of infection was
initially unknown, so human exposures continued to occur, with the peak
number of new cases occurring 6 months later, in March 1999. Once the
type of virus was identified, through laboratory testing, and the
source of infection (i.e., exposure to pigs) was serologically
confirmed, public health measures were taken to prevent further
outbreaks.
Ebola hemorrhagic fever is another disease that is transferable
from animals to humans (Ref. 13) and consequently illustrates the
importance of timely tracking of and public communication about
zoonotic viruses. In the period from January to July 1995, a total of
316 persons became ill with hemorrhagic fever in Kikwit, Democratic
Republic of the Congo (DRC) (Ref. 14). During the epidemic, a mortality
rate of 60 to 80 percent was reported among hospital cases. After an
incubation period of approximately 7 days, the early clinical features
of the disease included fever, headache, sore throat, diarrhea and
myalgias, followed by vomiting, worsening diarrhea, oliguria, shock and
death after 7 to 14 days. In May of 1995, the month of peak onset of
new cases, the DRC requested international assistance in investigating
the cause of the outbreak. Laboratory testing by the Centers for
Disease Control and Prevention (CDC) confirmed the presence of the
Zaire subtype of Ebola hemorrhagic fever. Continued investigation and
testing enabled the international team to identify modes of
transmission and to specify the precautions necessary to prevent
further spread of the virus. According to the CDC, prompt laboratory
diagnosis is an essential component of the surveillance needed to
maximize Ebola prevention and control measures (Ref. 15). In this
instance, the lack of early detection and proper management of Ebola
hemorrhagic fever patients resulted in numerous deaths among both
health care personnel and patients (Rollin and Ksiazek, 1998). By
hastening the disclosure of important risk information, the proposed
rule would assist public health agencies and health care providers in
more rapidly identifying and controlling any zoonotic viruses that
might emerge following xenotransplantation.
As of April 1999, the United Network for Organ Sharing (UNOS)
reported a total of 62,443 patients on the waiting list for an organ
transplant. This number far exceeds the total of approximately 20,000
transplants performed each year (Ref. 16). In addition to bolstering
the supply of viable organ transplants, patients may also benefit from
cellular and tissue therapies involving a xenotransplantation product.
Although the potential to fill unmet needs is great, the number of
prospective xenotransplant recipients represents a sizeable population
at potential risk of zoonotic infection. The proposed data disclosures
would help to provide the information needed by the public to
understand, manage, and minimize the risks associated with these
advancing medical technologies.
D. Impact on Small Entities
The agency has only limited information to estimate the number of
small entities conducting clinical investigations of human gene therapy
or xenotransplantation. As indicated in the cost analysis, the overall
number of business entities sponsoring clinical trials is estimated to
be 147. Although a few companies are a part of larger firms, many
others may have annual revenues of less than $5 million, which is the
revenue level that identifies a small business, according to the Small
Business Administration. The estimated cost impact of $843 per sponsor
per year reflects the staff time that would need to be allocated to
produce redacted versions of the specified documents for the purpose of
public disclosure.
The proposed rule offers sponsors considerable flexibility in
implementation by allowing for a range of approaches for preparing a
redacted version. Under the proposed rule, acceptable approaches range
from submitting a ``marked up" version of the original that simply
obscures the information not to be disclosed, to development of a
separate document that abstracts the needed information for the public
from the original unabridged version submitted to FDA. This flexibility
will help to minimize the cost impact.
The agency does not anticipate that the estimated cost will
significantly burden any of the sponsors. However, because of the
limited information available for establishments sponsoring clinical
trials in human gene therapy and xenotransplantation, and its
importance in developing estimates of the small entity impact, the
agency requests detailed comment on the number and type of businesses
sponsoring clinical trials in human gene therapy or
xenotransplantation, and the expected impact of the proposed
requirements on these entities.
In developing the proposed rule, the agency considered but rejected
two alternatives that might impose less burden on small businesses. The
agency found, however, that these alternatives would be less effective
in supporting the advancement of this research, because of unanswered
concerns regarding patient safety and public health. One of the
alternatives considered involved voluntary disclosure by clinical trial
sponsors without a regulatory requirement. This alternative would
reduce costs to industry only if establishments failed to voluntarily
provide the needed information for disclosure. Moreover, while
voluntary provision of this information would be no less burdensome for
industry, it could prove inadequate in protecting public health,
because the agency would have no means of assuring the quality and
consistency of the content of the voluntarily disclosed information, or
the timeliness of its reporting. The disclosure of timely, accurate,
and complete information is critical to an appropriate agency response
to adverse outcomes, including the emergence of novel and potentially
life-threatening infectious agents, or the alteration of the germline
in patients participating in the clinical study. Also, voluntary
disclosure provides no means for the agency to ensure a balanced
dissemination of information on identified risks and benefits. Such
balance is central to an adequate public understanding of the
technologies, and to an informed public discussion of the overall risk
versus benefit to patients and communities.
A second alternative to the proposed rule would require disclosure,
but would have FDA assume the sole responsibility for redaction of
documents submitted by the sponsor. Although this alternative would
reduce the direct cost impact for sponsors, the limited number of
agency staff available to perform this task would introduce the risk of
delay in producing the redacted
[[Page 4703]]
version for public disclosure. This outcome could potentially result in
delaying the research, or delaying the timely public availability of
critical information.
VI. References
The following references have been placed on display in the Dockets
Management Branch and may be seen by interested persons between 9 a.m.
and 4 p.m., Monday through Friday.
1. Eastland, T., "Infectious disease transmission through cell,
tissue and organ transplantation: reducing the risk through donor
selection," Cell Transplantation vol 4. pp. 455-477, 1995.
2. Delmonico, F. L. and D. R. Snydman, "Organ donor screening
for infectious diseases" Transplantation, vol. 65, pp. 603-610,
1998.
3. Regamey, N., M. Tamm, M. Wernil, A. Witschi, G. Thiel, G.
Cathomas, and P. Erb, "Tranmission of human herpesvirus 8 infection
from renal-transplant donors to recipients." New England Journal of
Medicine, vol. 339, pp.1358-1363, 1998.
4. "Guidelines for Research Involving Recombinant DNA
Molecules," Appendix M-Points to Consider in the Design
Submission of Protocols for the Transfer of Recombinant DNA
Molecules into One or More Human Subjects (PTC), http:// www4.od.nih.gov/oba/guidelines.html.
5. Friedmann, T., "Overcoming the Obstacles to Gene Therapy,"
Scientific American, vol. 276, No. 6, pp. 96-101, June 1997.
6. Haberman, R. P., T. J. McCown, and R. J. Samulski,
"Inducible Long-Term Gene Expression in Brain With Adeno-Associated
Virus Gene Transfer," Gene Therapy, vol. 5, No. 12, pp. 1604-1611,
December 1998.
7. Middleton, P. G. and E. W. F. W. Alton, "Gene Therapy for
Cystic Fybrosis: Which Postman, Which Box?" Thorax, vol. 53, No. 3,
pp. 197-199, March 1998.
8. Krisky, D. M., D. Wolfe, W. F. Goins, P. C. Marconi, R.
Ramakrishnan, M. Mata, R. J. D. Rouse, D. J. Fink, and J. C.
Glorioso, "Deletion of Multiple Immediate-Early Genes From Herpes
Simplex Virus Reduces Cytotoxicity and Permits Long-Term Gene
Expression in Neurons," Gene Therapy, vol. 5, No. 12, pp. 1593-
1603, December 1998.
9. Yang, E.Y., D. L. Cass, K. G. Sylvester, J. M. Wilson, and N.
S. Adzick, ``Fetal Gene Therapy: Efficacy, Toxicity, and Immunologic
Effects of Early Gestation Recombinant Adenovirus," Journal of
Pediatric Surgery, vol. 34, No. 2, pp. 235-241, February 1999.
10. Report of WHO Consultation on Xenotransplantation, World
Health Organization, Emerging and other Communicable Diseases
Surveillance and Control, Geneva, Switzerland, pp. 28-30, October
1997.
11. Van der Laan, L. J., C. Lockey, B. C. Griffeth, F. S.
Frasier, C. A. Wilson, D. E. Onions, B. J. Hering, Z. Long, E. Otto,
B. E. Torbett, D. R. Salomon, "Infection by Porcine Endogenous
Retrovirus After Islet Xenotransplantation in SCID Mice," Nature,
vol. 407 (6800), pp. 90-94, September 7, 2000.
12. U.S. Department of Health and Human Services, Centers for
Disease Control, "Outbreak of Hendra-Like Virus--Malaysia and
Singapore, 1998-1999," Morbidity and Mortality Weekly Report, vol.
48, No. 13, April 9, 1999.
13. Rollin, P. E. and T. G. Ksiazek, "Ebola Haemorrhagic
Fever," Transactions of the Royal Society of Tropical Medicine and
Hygiene, vol. 92, pp. 1-2, 1998.
14. Roels, T. H., A. S. Bloom, J. Buffington, G. L. Muhumgu, W.
R. MacKenzie, A. S. Khan, R. Ndambi, D. L. Noah, H. R. Rolka, C. J.
Peters, and T. G. Ksiazek, ``Ebola Hemorrhagic Fever, Kikwit,
Democratic Republic of the Congo, 1995: Risk Factors for Patients
with a Reported Exposure," The Journal of Infectious Diseases, vol.
179 Supplement 1:S92-97, 1999.
15. Centers for Disease Control, "Update: Outbreak of Ebola
Viral Hemorrhagic Fever--Zaire 1995," Journal of the American
Medical Association, vol. 274, No. 5, August 1995.
16. U.S. Facts About Transplantation, UNOS, (c) 1998, http:// www.unos.org/newsroom/critdata__main.htm.
VII. The Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). The title, description, and respondent
description of the information collection provisions are shown below
with an estimate of the annual reporting burden. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing each collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have a practical utility; (2)
the accuracy of FDA's estimate of the burden of the proposed collection
of information, including the validity of the methodology and
assumptions used; (3) ways to enhance the quality, utility, and clarity
of the information to be collected; and (4) ways to minimize the burden
of the collection of information on respondents, including through the
use of automated collection techniques, when appropriate, and other
forms of information technology.
Title: Submission to FDA for Public Disclosure of Certain Data and
Information Related to Human Gene Therapy or Xenotransplantation.
Description: FDA is proposing new regulations to require that
sponsors of IND's involving human gene therapy or xenotransplantation
submit information related to the IND in redacted version for public
disclosure, removing all information that would be defined as trade
secret or personal information whose disclosure would constitute a
clearly unwarranted invasion of privacy, and certain confidential
commercial information. Each submission for public disclosure would be
accompanied by a statement, signed by a responsible person, that the
information has been suitably redacted. FDA would then publicly
disclose the redacted version to provide an opportunity for public
education, discussion, and consideration of public health and safety
issues, as well as consideration of societal and ethical issues.
FDA is also proposing to require that the sponsor submit any
copyrighted material in a single appendix to each redacted version and
any copyrighted material whose copyright is not owned by the sponsor
not be included in any other section of the redacted version. The
proposal would further require that the redacted version include a
bibliography of the copyrighted material contained in the appendix.
This provision would facilitate the timely public disclosure of the
redacted version on the Internet, with the copyrighted information
excluded. Making available copyrighted material on the Internet is not
considered "fair use" of copyrighted material.
Description of Respondents: Sponsors of clinical investigations
involving human gene therapy or xenotransplantation.
FDA has estimated the burden for each provision that describes a
collection of information. The estimates are based on FDA's experience
in reviewing IND submissions and in redacting documents related to an
IND.
Under proposed Sec. 601.53(b), approximately 147 sponsors of
clinical investigations involving human gene therapy (134 sponsors) and
xenotransplantation (13 sponsors) would be required to submit a
redacted version of certain documents under the IND. For all 147
sponsors, these documents include the original IND (45 submissions/
year), amendments to an IND (270 submissions/year), IND safety reports
(90 submissions/year), and annual reports (100 submissions/year) for an
estimated total of 505 submissions/year (45 + 270 + 90 + 100). FDA has
estimated the time necessary to copy and redact each of the above types
of submissions; i.e., IND submission, 24 hours/submission; amendments,
.5 hour/per submission; IND safety reports, .5 hour/submission; and
annual reports, 20 hours/submission. The total burden equals the sum of
the burdens estimated for each type of submission (45x24 + [[Page 4704]]
270x.5 + 90x.5 + 100x20 equals 3,260 hours).
Under Sec. 601.53(c) all submissions under Sec. 601.53(b) must be
readily separable from the original submission and clearly marked on
each page as suitable for disclosure. Under Sec. 601.53(d) of the
proposed rule, sponsors of human gene theraphy and xenotransplantation
clinical studies would be required to submit copyrighted material in a
single appendix to each redacted submission and include in the redacted
version a bibliography of these materials. The hours per response,
therefore, are an average estimate of the total time for redaction of
the document, separation of copyrighted material and preparation of a
bibliography, marking of each page as suitable for public disclosure,
and submission to FDA, as provided in Sec. 601.53(b), (c), and (d). The
information collection burdens associated with the submission of an IND
as provided in part 312 are approved by OMB under OMB control number
0910-0014.
Table 2.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response ----------------------------------------------------------------------------------------------------------------
601.53(b), (c), and (d) 147 3.4 505 6.5 3,282 ----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs and maintenance costs associated with this collection of information.
In compliance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3507(d)), FDA has submitted the information
collection provisions of this proposed rule to OMB for review.
Interested persons may submit comments on the information collection
requirements of this proposal by February 20, 2001, to the Office of
Information and Regulatory Affairs, OMB, New Executive Office Bldg.,
725 17th St. NW., Washington, DC 20503, Attn: Desk Officer for FDA.
VIII. Proposed Effective Dates
FDA proposes that any final rule that may issue based on this
proposal become effective 90 days after the date of its publication in
the Federal Register. On or after that date, sponsors of human gene
therapy or xenotransplantation clinical trials would be required to
submit a redacted version of the data and information specified in the
final rule as part of a submission into an IND. Sponsors may
voluntarily submit a redacted version immediately upon the date of
issuance of the final rule. FDA is proposing, for sponsors of
xenotransplantation clinical trials who have submitted an IND prior to
the effective date of the final rule, that the sponsor submit for
public disclosure a redacted version of the information held under the
IND, to contain the information specified in proposed Sec. 601.52. FDA
invites comment on the length of time after issuance of the final rule
that these sponsors should be provided to submit the redacted
information.
IX. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written comments regarding this proposal by April 18,
2001. Two copies of any comments are to be submitted, except that
individuals may submit one copy. Comments are to be identified with the
docket number found in brackets in the heading of this document. Submit
written comments on the information collection provisions by February
20, 2001. Received comments may be seen in the Dockets Management
Branch between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 20, 312, and 601 be amended as follows:
PART 20--PUBLIC INFORMATION
1. The authority citation for part 20 continues to read as follows:
Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21
U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.
2. Section 20.100 is amended by adding paragraph (c)(43) to read as
follows:
Sec. 20.100 Applicability; cross-reference to other regulations.
* * * * *
(c) * * *
(43) Data and information submitted related to human gene therapy
or xenotransplantation, in Sec. 601.52 of this chapter.
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
3. The authority citation for part 312 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42
U.S.C. 262.
4. Section 312.42 is amended by adding paragraph (b)(7) to read as
follows:
Sec. 312.42
Clinical holds and requests for modification.
* * * * *
(b) * * *
(7) Clinical hold of any investigation, as defined in Sec. 601.52
of this chapter, involving human gene therapy or xenotransplantation.
FDA may place a proposed or ongoing investigation, as defined in
Sec. 601.52 of this chapter, involving human gene therapy or
xenotransplantation on clinical hold if it is determined that:
(i) Any of the conditions in paragraph (b)(1) or (b)(2) of this
section apply; or
(ii) The sponsor has not submitted a redacted version of the data
and information, as specified in Sec. 601.52 of this chapter, for
public disclosure that complies with the requirements of Sec. 601.53 of
this chapter.
* * * * *
5. Section 312.130 is amended by revising paragraph (b) to read as
follows:
Sec. 312.130
Availability for public disclosure of data and information in an IND.
* * * * *
(b) The availability for public disclosure of all data and
information in an investigational new drug application for a new drug
or antibiotic drug will be handled in accordance with the provisions
established in Sec. 314.430 of
[[Page 4705]]
this chapter for the confidentiality of data and information in
applications submitted in part 314 of this chapter. The availability
for public disclosure of all data and information in an investigational
new drug application for a biological product will be governed by the
provisions of Secs. 601.50, 601.51, and 601.52 of this chapter.
* * * * *
PART 601--LICENSING
6. The authority citation for part 601 continues to read as
follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,
241, 262, 263; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C.
355 note).
7. Section 601.50 is amended by revising the section heading and
paragraph (a) to read as follows:
Sec. 601.50 Confidentiality of data and information in an
investigational new drug application for a biological product.
(a) Except as provided in Sec. 601.52, the existence of an IND
application for a biological product will not be disclosed by the Food
and Drug Administration unless it has previously been publicly
disclosed or acknowledged.
* * * * *
8. Section 601.51 is amended by revising the section heading and
paragraph (a) to read as follows:
Sec. 601.51 Confidentiality of data and information in a biologics
license application.
(a) For purposes of this section the biological product file
includes all data and information submitted with or incorporated by
reference in any biologics license application, IND's incorporated in
any such application, master files, and other related submissions.
Except as provided in Sec. 601.52, the availability for public
disclosure of any record in the biological product file shall be
handled in accordance with the provisions of this section.
* * * * *
9. Section 601.52 is added to subpart F to read as follows:
Sec. 601.52 Availability for public disclosure of certain data and
information related to an IND concerning human gene therapy or
xenotransplantation.
(a) Definitions. The following definitions of terms apply to this
section:
(1) Human gene therapy means the administration of genetic material
in order to modify or manipulate the expression of a gene product or to
alter the biological properties of living cells for therapeutic use.
Cells may be modified ex vivo for subsequent administration or altered
in vivo by gene therapy products given directly to the subject.
(2) Xenotransplantation means any procedure that involves the
transplantation, implantation, or infusion into a human recipient of
either: Live cells, tissues, or organs from a nonhuman animal source;
or human body fluids, cells, tissues, or organs that have had ex vivo
contact with live nonhuman animal cells, tissues, or organs.
(b) Scope. Except as otherwise provided in this section, the
availability for public disclosure of data and information related to
human gene therapy or xenotransplantation shall be in accordance with
Secs. 601.50 and 601.51.
(c) Information for public disclosure. FDA will make available for
public disclosure the following types of data and information related
to an IND concerning human gene therapy or xenotransplantation. Names
and other personal identifiers of patients and, except as specifically
provided in this section, names and personal identifiers of and third
party, such as physicians or hospitals, will not be made available for
public disclosure.
(1) Product and patient safety data and related information. For
purposes of this section product and patient safety data and related
information include results of preclinical and clinical studies and
tests that demonstrate the safety and/or feasibility of the proposed
procedures. This may include, but is not necessarily limited to,
analysis in animals, humans, or in vitro systems of gene transfer,
expression, and persistence; vector biodistribution; evidence for
immune response/anergy; biological activity; and results of product
safety testing including testing for known xenogeneic and human
infectious agents and replication competent virus; and qualification of
source herd, individual source animal, and source organ/tissue/cells
for xenotransplantation in humans. Also included is information on
monitoring or prevention of potential health risks to the recipient,
close contacts, and health care workers, such as patient monitoring for
replication competent retrovirus and viral shedding and measures taken
to prevent transmission of infectious disease. The availability for
public disclosure of data and information in an IND safety report or
annual report, as provided under Secs. 312.32 and 312.33 of this
chapter, will be governed by the provisions of paragraphs (c)(7) and
(c)(8) of this section.
(2) The name and address of the sponsor.
(3) The clinical indications to be studied.
(4) A protocol for each planned study, to include:
(i) A scientific abstract and a nontechnical abstract.
(ii) A statement of the objectives, purpose, and rationale of the
study. (iii) The name and address of each investigator.
(iv) The name and address of the official contacts of each local
review body as appropriate (Institutional Review Board, Institutional
Biosafety Committee) and the dated copies of each committee's approval
of the study.
(v) The criteria for patient selection and exclusion and an
estimate of the number of patients to be studied.
(vi) A description of the treatment that will be administered to
patients and the clinical procedures, laboratory tests, or other
measures to be taken to monitor the safety and effects of the drug in
human subjects and to minimize risk.
(5) Written informed consent form(s) as provided in Sec. 50.27 of
this chapter.
(6) Identification of the biological product(s) and a general
description of the method of production, including a description of
product features that may affect patient safety. The information shall
include, as applicable, the vector name and type; gene insert;
regulatory elements and their source; intended target cells; source of
cells, tissues, or organ(s); method used to prepare the vector
containing cells; method used to procure and prepare cells, tissues, or
organs for xenotransplantation; purity of cells; adventitious agent
testing; description of the delivery system; ancillary products used
during production; herd colony and individual source animal health
maintenance and surveillance records; and biological specimens to be
archived from source animals.
(7) IND safety reports, as provided in Sec. 312.32 of this chapter,
and other similar data and information.
(8) Information submitted in the annual report to include, as
applicable, assessment of evidence of gene transfer, gene expression in
target cells, biological activity, immune response, status of autopsy
request and evidence of gene transfer and gonadal distribution upon
autopsy, results from assessment for evidence of infection by agents
associated with the product, adverse experiences, and a list of
subjects who died during participation in the investigation, with the
cause of death for each subject.
(9) The regulatory status of the IND, such as on hold, in effect,
inactive, or
[[Page 4706]]
withdrawn, the dates of these actions, and the reasons for these
actions.
(10) Other relevant data and information that the Director, CBER,
determines are necessary for the appropriate consideration of the
public health and scientific issues, including relevant ethical issues,
raised by human gene therapy or xenotransplantation.
10. Section 601.53 is added to subpart F to read as follows:
Sec. 601.53 Submission of certain data and information related to
human gene therapy or xenotransplantation for public disclosure.
(a) A sponsor of an IND shall submit to FDA for public disclosure
in a redacted version the submissions identified in paragraphs (b)(1)
through (b)(5) of this section. Each submission shall include all
applicable information identified as disclosable in Sec. 601.52, but
shall be redacted to remove or obscure all information considered
confidential as a trade secret, certain confidential commercial
information, such as information regarding commercial licensing
agreements or the identification of suppliers, and names and other
personal identifiers of patients and, except as specifically provided
in this section, names and personal identifiers of any third party,
such as physicians or hospitals, must be redacted.
(b) The following shall be submitted in a suitably redacted version
and in duplicate at the time points noted:
(1) Information as defined under Sec. 601.52 at the time of initial
IND submission.
(2) Any amendment documenting changes or additions to the
information as defined under Sec. 601.52 at the time the amendment goes
into effect.
(3) IND safety reports at the time of submission of the initial
report to FDA.
(4) The annual report, within 60 days of the anniversary date that
the IND went into effect, in accordance with Sec. 312.33 of this
chapter.
(5) Other information upon the specific request of the Director,
CBER.
(c) The submissions identified in paragraph (b) of this section
shall be submitted in a form readily separable from the original
unabridged submission to FDA and clearly marked on each page of the
redacted version as suitable for public disclosure.
(d) Any copies of copyrighted material shall be submitted in a
single appendix to each redacted version. Copyrighted materials whose
copyright is not owned by the applicant shall not be included in any
other section of the redacted versions. A bibliography of copyrighted
materials contained in the appendix shall be included as part of each
redacted version.
(e) Any data or information submitted to FDA as a redacted version
for public disclosure in accordance with paragraph (a) of this section
shall be accompanied by the following statement signed by a responsible
individual:
The information contained herein has been redacted for public
disclosure. The only material removed from these records is:
Confidential commercial or trade secret information exempt from
disclosure under the Freedom of Information Act (5 U.S.C. 552 (b)(4))
and the Food and Drug Administration's implementing regulations (21 CFR
20.61); names and other personal identifiers of patients and, except as
specifically provided in the regulations, names and other personal
identifiers of any third party.
I declare, under the penalty of perjury, that the foregoing is
true and correct.
Dated: December 20, 2000.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 01-1048 Filed 1-17-01; 8:45 am]
BILLING CODE 4160-01-F