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.

Proposed Rules Federal Register

4688

Vol. 66, No. 12

Thursday, January 18, 2001

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.

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

(§ 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 § 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 (§ 20.61);

personnel, medical, and similar files,

the disclosure of which constitutes a

clearly unwarranted invasion of

personal privacy (§ 20.63); and at the

discretion of FDA, interagency or intraagency memoranda or letters, except for

factual information which is reasonably

segregable (§ 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 § 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

§§ 601.50 and 601.51 (21 CFR 601.50

and 601.51). Under §§ 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

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 4689

committee meeting, or other public

workshops or meetings (§ 601.51(d)(1)).

Once a biological license has been

approved, certain information, as

specified in § 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-yetunrecognized 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.

4690 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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.

In 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

4692 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

1While 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.

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.)

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 (§ 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

§§ 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.

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.

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

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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

§ 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 § 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 §§ 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 § 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,

4694 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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, BactoUnidisk, 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.

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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

§ 601.52 entitled ‘‘Availability for public

disclosure of certain data and

information related to human gene

therapy or xenotransplantation’’ and

§ 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 §§ 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 §§ 601.50

and 601.51. The proposed rule would

amend §§ 601.50 and 601.51 to include

language that would reference the

exceptions proposed in § 601.52

regarding the availability for public

disclosure of certain data and

information related to human gene

therapy or xenotransplantation.

Specifically, §§ 601.50(a) and 601.51(a)

would be amended to add the words,

‘‘Except as provided in § 601.52.’’

In addition, FDA is proposing to

amend the § 601.50 section heading and

§ 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 § 601.52

Proposed § 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 § 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 § 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

4696 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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

§ 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

§ 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 § 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 § 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 §§ 20.61, 20.62, 20.63,

20.100, 312.130, 601.50, and 601.51.

Accordingly, proposed § 601.52(b)

would specify that, except as

specifically provided in proposed

§ 601.52, the availability for public

disclosure of data and information

related to human gene therapy or

xenotransplantation shall remain in

accordance with § 601.50 for IND’s for a

biological product.

c. Information for public disclosure.

Proposed § 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 § 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 § 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

§ 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 § 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 § 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 § 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 § 601.52(c)(1) to include

IND safety reports and annual reports,

as provided for in §§ 312.32 and 312.33.

Rather, specific requirements for the

public disclosure of these types of

reports are proposed below in

§ 601.52(c)(7) and (c)(8), respectively.

Under proposed § 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 § 312.23(a)(1)(i) and

(a)(3)(iv)(b), respectively.

Under proposed § 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

§ 312.23(a)(6); proposed § 601.52(c)(4)

would specify that certain elements of

the protocol be available for public

disclosure. Proposed § 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

§ 312.23(a)(6)(iii)(a)); (3) the name and

address of each investigator (submitted

in an IND under § 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 § 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 § 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

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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 § 312.23(a)(6)(iii)(g)). FDA

intends that the term ‘‘investigator’ in

proposed § 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 § 312.3(b). In

proposed § 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 § 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 § 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

§ 312.23. FDA has modified the

language taken from § 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

§ 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 § 601.52(c)(7), FDA

would make IND safety reports, as

provided in § 312.32, and other similar

data and information available for

public disclosure. Under § 312.32,

sponsors of investigational drugs,

including biological drugs, are required

to submit to FDA certain adverse

reaction reports concerning their

product. Under § 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

§ 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 § 601.51(e)(3) are included

in proposed § 601.52(c) to protect the

privacy of patients and health care

workers.

Under § 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

§ 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 § 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 §§ 312.42,

312.38, 312.45, and 312.44, respectively.

Under § 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 § 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 § 601.53

Proposed § 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 § 312.42(b)(6)

provides that a sponsor’s failure to

submit to FDA the data and information

specified in §§ 601.52 and 601.53 that

has been properly redacted under

§ 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

4698 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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 §§ 601.52 and

601.53 is the most efficient means to

accomplish this.

Under proposed § 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 § 601.53(b)(1)

through (b)(5). The sponsor would be

required to include all applicable

information identified as disclosable in

§ 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 § 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 § 601.53(b)(1) would require

submission for public disclosure a

redacted version of the information

defined under § 601.52 to accompany

the original unabridged IND submission.

Proposed § 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 § 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 § 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 § 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 § 601.53(b)(4) would require

submission for public disclosure of a

redacted version of the annual report, in

accordance with § 312.33. Consistent

with § 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 § 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 § 601.53(c) would require

that the sponsor submit the information

identified in § 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 § 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 § 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 § 601.53(a) as

exempt from disclosure (confidential

commercial, trade secret, or personal

information). In addition, under

proposed § 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

§ 20.100(c) by adding a paragraph (43)

that would contain a cross-reference to

the proposed § 601.52 regarding the

availability for public disclosure of

certain data and information submitted

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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 § 312.42(b)(7)

would amend § 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

§ 601.53.

Section § 312.130 contains

requirements regarding the availability

for public disclosure of data and

information in an IND. The proposed

rule would amend § 312.130 by revising

paragraph (b) to include a reference to

proposed § 601.52, in addition to the

existing references to §§ 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 § 601.52 as

contained in the initial IND submission,

amendments documenting changes or

additions to the information defined

under § 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

§ 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

§ 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 § 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

§ 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

4700 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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

(§ 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 § 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 § 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

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 4701

3U.S. Dept of Labor, Bureau of Labor Statistics,

Employer Costs for Employee Compensation, March

1997.

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].

TABLE 1.—ESTIMATES OF COST PER YEAR FOR INDUSTRY-WIDE REDACTION EFFORTS

Type of Redacted Submission

Total Industry

Submissions

per Year

Average Redaction Time/Submission Estimated Industry Cost per Year

New IND1—initial and authorized version 45 24 hours $41,040 [45 x 24 x $38]

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 to Industry $123,880

Average Annual Cost Per Sponsor (147

sponsors)

$843

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

4702 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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 hendralike 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

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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 and

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/critdatalmain.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 § 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 +

4704 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

270x.5 + 90x.5 + 100x20 equals 3,260

hours).

Under § 601.53(c) all submissions

under § 601.53(b) must be readily

separable from the original submission

and clearly marked on each page as

suitable for disclosure. Under

§ 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

§ 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

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

601.53(b), (c), and (d) 147 3.4 505 6.5 3,282

1There 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 § 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:

§ 20.100 Applicability; cross-reference to

other regulations.

* * * * *

(c) * * *

(43) Data and information submitted

related to human gene therapy or

xenotransplantation, in § 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:

§ 312.42 Clinical holds and requests for

modification.

* * * * *

(b) * * *

(7) Clinical hold of any investigation,

as defined in § 601.52 of this chapter,

involving human gene therapy or

xenotransplantation. FDA may place a

proposed or ongoing investigation, as

defined in § 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 § 601.52 of

this chapter, for public disclosure that

complies with the requirements of

§ 601.53 of this chapter.

* * * * *

5. Section 312.130 is amended by

revising paragraph (b) to read as follows:

§ 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 § 314.430 of

Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules 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 §§ 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:

§ 601.50 Confidentiality of data and

information in an investigational new drug

application for a biological product.

(a) Except as provided in § 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:

§ 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

§ 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:

§ 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 §§ 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 §§ 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 § 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

§ 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

4706 Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / Proposed Rules

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:

§ 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 § 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

§ 601.52 at the time of initial IND

submission.

(2) Any amendment documenting

changes or additions to the information

as defined under § 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

§ 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

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 192 and 592

[Docket No. 00N–1396]

RIN 0910–AC15

Premarket Notice Concerning

Bioengineered Foods

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

require the submission to the agency of

data and information regarding plantderived bioengineered foods that would

be consumed by humans or animals.

FDA is proposing that this submission

be made at least 120 days prior to the

commercial distribution of such foods.

FDA is taking this action to ensure that

it has the appropriate amount of

information about bioengineered foods

to help to ensure that all market entry

decisions by the industry are made

consistently and in full compliance with

the law. The proposed action will

permit the agency to assess on an

ongoing basis whether plant-derived

bioengineered foods comply with the

standards of the Federal Food, Drug,

and Cosmetic Act (the act).

DATES: Submit written comments on the

proposed rule by April 3, 2001. Submit

written comments on the information

collection provisions by February 20,

2001.

See section XIV of this document for

the proposed effective date of a final

rule based on this document.

ADDRESSES: Submit written comments

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 provisions to the Office of

Information and Regulatory Affairs,

OMB, New Executive Office Bldg., 725

17th St. NW., rm. 10235, Washington,

DC 20503, Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Regarding human food issues: Linda

S. Kahl, Center for Food Safety and

Applied Nutrition (HFS–206), Food

and Drug Administration, 200 C St.

SW., Washington, DC 20204, 202–

418–3101.

Regarding animal feed issues:

William D. Price, Center for

Veterinary Medicine (CVM) (HFV–

200), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–827–

6652.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background

A. The 1992 Policy

B. Consultations Under the 1992 Policy

and the 1996 Procedures

C. Public Meetings

II. Legal Authority

III. Scope

IV. Definitions

V. Requirement for Premarket Biotechnology

Notice

A. Foods That Are Subject to the

Requirement

B. Origin of Data and Information

C. Timing

VI. Recommendation for Presubmission

Consultation

A. Presubmission Consultation Program

B. Public Disclosure

C. Standard Procedures

VII. Premarket Biotechnology Notice:

Administrative Information

A. Submissions to CFSAN for Use in

Human Food, Animal Feed, or Both

B. Paper Copies

C. Electronic Copies

D. English Language Translations,

Incorporation by Reference, and

Available Guidance Documents

E. Opportunity to Withdraw

VIII. Premarket Biotechnology Notice:

Required Parts

A. Part I: Letter