Appendix
M-I-A. Requirements for Protocol Submission
Appendix
M-I-B. RAC Review Requirements
Appendix
M-I-B-1. Initial RAC Review
Appendix
M-I-B-2. Public RAC Review and Discussion
Appendix
M-I-C. Reporting Requirements
Appendix
M-I-C-1. Initiation of the Clinical Investigation
Appendix
M-I-C-2. Additional Clinical Trial Sites
Appendix
M-I-C-3. Annual Reports
Appendix
M-I-C-4. Safety Reporting
Appendix
M-I-C-4-a. Safety Reporting: Content and Format
Appendix
M-I-C-4-b. Safety Reporting: Time frames for Expedited
Reports
Appendix
M-I-C-5. Confidentiality
Appendix
M-I-D. Safety Assessment in Human Gene Transfer
Research
Appendix
M-II. Description of the Proposal
Appendix
M-II-A. Objectives and Rationale of the Proposed
Research
Appendix
M-II-A-1. Use of Recombinant DNA for Therapeutic
Purposes
Appendix
M-II-A-2. Transfer of DNA for Other Purposes
Appendix
M-II-B. Research Design, Anticipated Risks and
Benefits
Appendix
M-II-B-1. Structure and Characteristics of the
Biological System
Appendix
M-II-B-2. Preclinical Studies, Including
Risk-Assessment Studies
Appendix
M-II-B-2-a. Delivery System
Appendix
M-II-B-2-b. Gene Transfer and Expression
Appendix
M-II-B-2-c. Retrovirus Delivery Systems
Appendix
M-II-B-2-d. Non-Retrovirus Delivery/Expression Systems
Appendix
M-II-B-3. Clinical Procedures, Including Research
Participant Monitoring
Appendix
M-II-B-4. Public Health Considerations
Appendix
M-II-C. Selection of the Human Subjects
Appendix
M-III. Informed Consent
Appendix
M-III-A. Communication About the Study to Potential
Participants
Appendix
M-III-B. Informed Consent Document
Appendix
M-III-B-1. General Requirements of Human Subjects
Research
Appendix
M-III-B-1-a. Description/Purpose of the Study
Appendix
M-III-B-1-b. Alternatives
Appendix
M-III-B-1-c. Voluntary Participation
Appendix
M-III-B-1-d. Benefits
Appendix
M-III-B-1-e. Possible Risks, Discomforts, and Side Effects
Appendix
M-III-B-2. Specific Requirements of Gene Transfer
Research
Appendix
M-III-B-2-a. Reproductive Considerations
Appendix
M-III-B-2-b. Long-Term Follow-Up
Appendix
M-III-B-2-c. Request for Autopsy
Appendix
M-III-B-2-d. Interest of the Media and Others in the
Research
Appendix
M-VI. Footnotes of Appendix M
Appendix M applies to
research conducted at or sponsored by an institution that receives any support
for recombinant DNA research from NIH.
Researchers not covered by the NIH Guidelines are encouraged to
use Appendix M (see Section I-C, General Applicability).
The acceptability of
human somatic cell gene transfer has been addressed in several public documents
as well as in numerous academic studies.
In November 1982, the President's Commission for the Study of Ethical
Problems in Medicine and Biomedical and Behavioral Research published a report,
Splicing Life, which resulted from a two-year process of public
deliberation and hearings. Upon release
of that report, a U.S. House of Representatives subcommittee held three days of
public hearings with witnesses from a wide range of fields from the biomedical
and social sciences to theology, philosophy, and law. In December 1984, the Office of Technology Assessment released a
background paper, Human Gene Therapy, which concluded that civic,
religious, scientific, and medical groups have all accepted, in principle, the
appropriateness of gene transfer of somatic cells in humans for specific
genetic diseases. Somatic cell gene
transfer is seen as an extension of present methods that might be preferable to
other technologies. In light of this
public support, RAC is prepared to consider proposals for somatic cell gene
transfer.
RAC will not at
present entertain proposals for germ line alterations but will consider
proposals involving somatic cell gene transfer. The purpose of somatic cell gene transfer is to treat an
individual patient, e.g., by inserting a properly functioning gene into the
subject's somatic cells. Germ line
alteration involves a specific attempt to introduce genetic changes into the
germ (reproductive) cells of an individual, with the aim of changing the set of
genes passed on to the individual's offspring.
The RAC continues to
explore the issues raised by the potential of in utero gene transfer
clinical research. However, the RAC
concludes that, at present, it is premature to undertake any in utero
gene transfer clinical trial.
Significant additional preclinical and clinical studies addressing
vector transduction efficacy, biodistribution, and toxicity are required before
a human in utero gene transfer protocol can proceed. In addition, a more thorough understanding
of the development of human organ systems, such as the immune and nervous
systems, is needed to better define the potential efficacy and risks of human in
utero gene transfer. Prerequisites
for considering any specific human in utero gene transfer procedure
include an understanding of the pathophysiology of the candidate disease and a
demonstrable advantage to the in utero approach. Once the above criteria are met, the RAC
would be willing to consider well rationalized human in utero gene transfer
clinical trials.
Research proposals
involving the deliberate transfer of recombinant DNA, or DNA or RNA derived
from recombinant DNA, into human subjects (human gene transfer) will be
considered through a review process involving both NIH/OBA and RAC. Investigators shall submit their relevant
information on the proposed human gene transfer experiments to NIH/OBA. Submission of human gene transfer protocols
to NIH will be in the format described in Appendix M-I-A, Submission
Requirements for Protocol Submission.
Submission to NIH shall be for registration purposes and will ensure
continued public access to relevant human gene transfer information conducted
in compliance with the NIH Guidelines.
Investigational New Drug (IND) applications should be submitted to FDA in the format described in 21 CFR, Chapter
I, Subchapter D, Part 312, Subpart B, Section 23, IND Content and Format.
Institutional
Biosafety Committee approval must be obtained from each institution at which
recombinant DNA material will be administered to human subjects (as opposed to
each institution involved in the production of vectors for human application
and each institution at which there is ex vivo transduction of
recombinant DNA material into target cells for human application).
Factors that may
contribute to public discussion of a human gene transfer experiment by RAC
include: (i) new vectors/new gene
delivery systems, (ii) new diseases, (iii) unique applications of gene
transfer, and (iv) other issues considered to require further public
discussion. Among the experiments that
may be considered exempt from RAC discussion are those determined not to represent
possible risk to human health or the environment. Full, public RAC review and discussion of a human gene transfer
experiment may be (1) initiated by the NIH Director; or (2) initiated by the
NIH OBA Director following a recommendation to NIH OBA by: (a) three or more
RAC members, or (b) a Federal agency other than NIH. An individual human gene transfer experiment that is recommended
for full RAC review should represent novel characteristics deserving of public
discussion. If it is determined that an
experiment will undergo full RAC discussion, NIH/OBA will immediately notify
the Principal Investigator. RAC members
may forward individual requests for additional information relevant to a
specific protocol through NIH/OBA to the Principal Investigator. In making a determination whether an
experiment is novel, and thus deserving of full RAC discussion, reviewers will
examine the scientific rationale, scientific context (relative to other
proposals reviewed by RAC), whether the preliminary in vitro and in
vivo safety data were obtained in appropriate models and are sufficient,
and whether questions related to relevant social and ethical issues have been
resolved. RAC recommendations on a
specific human gene transfer experiment shall be forwarded to the NIH Director,
the Principal Investigator, the sponsoring institution, and other DHHS
components, as appropriate. Relevant
documentation will be included in the material for the RAC meeting at which the
experiment is scheduled to be discussed.
RAC meetings will be open to the public except where trade secrets and
proprietary information are reviewed (see Section
IV-D-5, Protection of Proprietary Data – Voluntary Compliance). RAC prefers that information provided in
response to Appendix M contain no proprietary data or trade secrets, enabling
all aspects of the review to be open to the public.
Note: Any application submitted to NIH/OBA shall
not be designated as ‘confidential’ in its entirety. In the event that a sponsor determines that specific responses to
one or more of the items described in Appendix M should be considered as
proprietary or trade secret, each item should be clearly identified as
such. The cover letter (attached to the
submitted material) shall: (1) clearly
indicate that select portions of the application contain information considered
as proprietary or trade secret, (2) a brief explanation as to the reason that
each of these items is determined proprietary or trade secret.
Public discussion of
human gene transfer experiments (and access to relevant information) shall
serve to inform the public about the technical aspects of the proposals,
meaning and significance of the research, and significant safety, social, and
ethical implications of the research.
RAC discussion is intended to ensure safe and ethical conduct of gene
transfer experiments and facilitate public understanding of this novel area of
biomedical research.
In its evaluation of
human gene transfer proposals, RAC will consider whether the design of such
experiments offers adequate assurance that their consequences will not go
beyond their purpose, which is the same as the traditional purpose of clinical
investigation, namely, to protect the health and well being of human subjects
being treated while at the same time gathering generalizable knowledge. Two possible undesirable consequences of the
transfer of recombinant DNA would be unintentional: (i) vertical transmission of genetic changes from an individual
to his/her offspring, or (ii) horizontal transmission of viral infection to
other persons with whom the individual comes in contact. Accordingly, Appendices M-I through M-V
request information that will enable RAC and NIH/OBA to assess the possibility
that the proposed experiment(s) will inadvertently affect reproductive cells or
lead to infection of other people (e.g., medical personnel or relatives).
Appendix M will be
considered for revisions as experience in evaluating proposals accumulates and
as new scientific developments occur.
This review will be carried out periodically as needed.
The following documentation
must be submitted (see exemption in Appendix
M-VI-A, Footnotes of Appendix M) in printed or electronic form to
the: Office of Biotechnology
Activities, National Institutes of Health, 6705 Rockledge Drive, Suite 750, MSC
7985, Bethesda, MD 20892-7985 (20817
for non-USPS mail), 301-496-9838, 301-496-9839 (fax), E-mail:
rosenthg@od.nih.gov. NIH OBA will
confirm receipt within three working days after receiving the submission. Investigators should contact OBA if they do
not receive this confirmation.
1. A cover letter on institutional letterhead,
signed by the Principal Investigator(s), that: (1) acknowledges that the
documentation submitted to NIH OBA complies with the requirements set forth in
Appendix M-I-A, Requirements for Protocol Submission; (2) identifies the
Institutional Biosafety Committee (IBC) and Institutional Review Board (IRB) at
the proposed clinical trial site(s) responsible for local review and approval
of the protocol; and (3) acknowledges that no research participant will be
enrolled (see definition of enrollment in Section
I-E-7) until the RAC review process has been completed (see Appendix M-I-B, RAC Review Requirements);
IBC approval (from the clinical trial site) has been obtained; IRB approval has
been obtained; and all applicable regulatory authorizations have been obtained.
2. The scientific abstract.
3. The non-technical abstract.
4. The proposed clinical protocol, including
tables, figures, and relevant manuscripts.
5. Responses to Appendices M-II through M-V, Description
of the Proposal, Informed Consent, Privacy and Confidentiality, and Special
Issues. Responses to Appendices
M-II through M-V may be provided either as an appendix to the clinical protocol
or incorporated in the clinical protocol.
If responses to Appendices M-II
through M-V are incorporated in the clinical protocol, each response must refer
to the appropriate Appendix M-II through M-V.
6. The proposed informed consent document (see Appendix M-III, Informed Consent).
7. Curriculum vitae of the principal investigator(s)
(no more than two pages in biographical sketch format).
Note: A human
gene transfer experiment submitted to NIH OBA should not contain confidential
commercial information or trade secrets, enabling all aspects of the review to
be open to the public.
The initial RAC
review process shall include a determination as to whether the human gene
transfer experiment presents characteristics that warrant public RAC review and
discussion. During the RAC’s initial
review, individual committee members may request additional information
relevant to the protocol. NIH OBA will
immediately notify the Principal Investigator(s) of RAC requests for additional
information. In making a determination
whether an experiment presents characteristics warranting public RAC review and
discussion, reviewers will examine the scientific rationale, scientific
content, whether the preliminary in vitro and in vivo safety data
were obtained in appropriate models and are sufficient, and whether questions
related to relevant social and ethical issues have been resolved. Other factors that may warrant public review
and discussion of a human gene transfer experiment by the RAC include: (1) a new vector/new gene delivery system;
(2) a new clinical application; (3) a unique application of gene transfer;
and/or (4) other issues considered to require further public discussion.
Initial RAC review
shall be completed within 15 working days of receipt of a complete submission
(see Appendix M-I-A, Requirements
for Protocol Submission). At the
end of the 15-day review period, NIH OBA will notify the Principal
Investigator(s) in writing about the results of the RAC’s initial review. Two outcomes are possible: (1) the experiment does not present
characteristics that warrant further review and discussion and is therefore
exempt from public RAC review and discussion; or (2) the experiment presents
characteristics that warrant public RAC review and discussion. Completion of the RAC review process is
defined as: (1) receipt by the
Principal Investigator(s) of a letter from NIH OBA indicating that the
submission does not present characteristics that warrant public RAC review and
discussion; or (2) receipt by the Principal Investigator(s) of a letter from
NIH OBA after public RAC review that summarizes the committee’s key comments
and recommendations (if any).
If a human gene
transfer protocol is submitted less than eight weeks before a scheduled RAC
meeting and is subsequently recommended for public RAC review and discussion,
the review of the protocol by the RAC will be deferred until the next scheduled
RAC meeting. This eight-week period is
needed to ensure adequate time for public notice and comment and thorough
review by the committee members.
No research
participant shall be enrolled (see definition of enrollment in Section
I-E-7) in the human gene transfer experiment until: (1) the RAC review process has been
completed; (2) Institutional Biosafety Committee (IBC) approval (from the
clinical trial site) has been obtained; (3) Institutional Review Board (IRB)
approval has been obtained; and (4) all applicable regulatory authorization(s)
have been obtained.
For a clinical trial
site that is added after the RAC review process, no research participant shall
be enrolled (see definition of enrollment in Section
I-E-7) at the clinical trial site until the following documentation has
been submitted to NIH OBA: (1) IBC
approval (from the clinical trial site); (2) IRB approval; (3) IRB-approved
informed consent document; (4) curriculum vitae of the principal
investigator(s) (no more than two pages in biographical sketch format); and (5)
NIH grant numbers(s) if applicable.
Public RAC review and
discussion of a human gene transfer experiment may be: (1) initiated by the NIH Director; or (2)
initiated by the NIH OBA Director following a recommendation to NIH OBA
by: (a) three or more RAC members; or
(b) a Federal agency other than NIH. In
making a determination whether an experiment presents characteristics
warranting public RAC review and discussion, reviewers will examine the
scientific rationale, scientific content, whether the preliminary in vitro
and in vivo safety data were obtained in appropriate models and are
sufficient, and whether questions related to relevant social and ethical issues
have been resolved. Other factors that
may warrant public review and discussion of a human gene transfer experiment by
the RAC include: (1) a new vector/new
gene delivery system; (2) a new clinical application; (3) a unique application
of gene transfer; and/or (4) other issues considered to require further public
discussion.
After a human gene
transfer experiment is reviewed by the full RAC at a regularly scheduled
meeting, NIH OBA will send a letter summarizing the RAC key comments and
recommendations (if any) regarding the protocol to the NIH Director, the
Principal Investigator, the sponsoring institution, and other DHHS components,
as appropriate. Completion of RAC
review is defined as receipt by the Principal Investigator(s) of a letter from
NIH OBA summarizing the committee’s findings.
Unless NIH OBA determines that there are exceptional circumstances, the
RAC summary letter will be sent to the Principal Investigator(s) within 10 working
days after the completion of the RAC meeting at which the experiment was
reviewed.
RAC meetings will be
open to the public except where trade secrets or confidential commercial
information are reviewed. To enable all
aspects of the protocol review process to be open to the public, information
provided in response to Appendix M should not contain trade secrets or
confidential commercial information. No
application submitted to NIH OBA shall be designated as ‘confidential’ in its
entirety. In the event that an
investigator determines that specific responses to one or more of the items
described in Appendix M should be considered as confidential commercial
information or a trade secret, each item must be clearly identified as
such. The cover letter (attached to the
submitted material) shall: (1) clearly
designate the information that is considered as confidential commercial
information or a trade secret; and (2) explain and justify each designation.
No later than 20
working days after enrollment (see definition of enrollment in Section
I-E-7) of the first research participant in a human gene transfer
experiment, the Principal Investigator(s) shall submit the following
documentation to NIH OBA: (1) a copy of
the informed consent document approved by the Institutional Review Board (IRB);
(2) a copy of the protocol approved by the Institutional Biosafety Committee
(IBC) and IRB; (3) a copy of the final IBC approval from the clinical trial
site; (4) a copy of the final IRB approval; (5) a brief written report that
includes the following information: (a)
how the investigator(s) responded to each of the RAC’s recommendations on the
protocol (if applicable); and (b) any modifications to the protocol as required
by FDA; (6) applicable NIH grant number(s);
(7) the FDA
Investigational New Drug Application (IND) number; and (8) the date of the
initiation of the trial. The purpose of
requesting the FDA IND number is for facilitating interagency collaboration in
the Federal oversight of human gene transfer research.
No research
participant shall be enrolled (see definition of enrollment in Section
I-E-7) at a clinical trial site until the following documentation has been
submitted to NIH OBA: (1) Institutional
Biosafety Committee approval (from the clinical trial site); (2) Institutional
Review Board approval; (3) Institutional Review Board-approved informed consent
document; (4) curriculum vitae of the principal investigator(s) (no more than
two pages in biographical sketch format); and (5) NIH grant number(s) if
applicable.
Within 60 days after the one-year
anniversary of the date on which the investigational new drug (IND) application
went into effect, and after each subsequent anniversary until the trial is
completed, the Principal Investigator (or delegate) shall submit the
information set forth in (a), (b), and (c).
When multiple studies are conducted under the single IND, the Principal
Investigator (or delegate) may choose to submit a single annual report covering
all studies, provided that each study is identified by its OBA protocol number.
(a) Clinical Trial Information. A brief summary of the status of each trial
in progress and each trial completed during the previous year. The summary is required to include the
following information for each trial: (1) the title and purpose of the trial;
(2) clinical site; (3) the Principal Investigator; (4) clinical protocol
identifiers, including the NIH OBA protocol number, NIH grant number(s) (if
applicable), and the FDA IND application number; (5) participant population
(such as disease indication and general age group, e.g., adult or pediatric);
(6) the total number of participants planned for inclusion in the trial; the
number entered into the trial to date; the number
whose participation in the trial was
completed; and the number who dropped out of the trial with a brief description
of the reasons; (7) the status of the trial, e.g., open to accrual of subjects,
closed but data collection ongoing, or fully completed, and (8) if the trial
has been completed, a brief description of any study results.
(b) Progress Report and Data Analysis. Information obtained during the previous
year's clinical and non-clinical investigations, including: (1) a narrative or tabular summary showing
the most frequent and most serious adverse experiences by body system; (2) a
summary of all serious adverse events submitted during the past year; (3) a
summary of serious adverse events that were expected or considered to have
causes not associated with the use of the gene transfer product such as disease
progression or concurrent medications; (4) if any deaths have occurred, the
number of participants who died during participation in the investigation and
causes of death; and (5) a brief description of any information obtained that
is pertinent to an understanding of the gene transfer product’s actions,
including, for example, information about dose-response, information from
controlled trials, and information about bioavailability.
(c) A copy of the updated clinical protocol
including a technical and non-technical abstract.
Principal Investigators must submit, in
accordance with this section, Appendix M-I-C-4-a and Appendix M-I-C-4-b, a written report
on: (1) any serious adverse event that is both unexpected and associated with
the use of the gene transfer product (i.e., there is reasonable possibility
that the event may have been caused by the use of the product; investigators
should not await definitive proof of association before reporting such events);
and (2) any finding from tests in laboratory animals that suggests a
significant risk for human research participants including reports of
mutagenicity, teratogenicity, or carcinogenicity. The report must be clearly labeled as a “Safety Report” and must
be submitted to the NIH Office of Biotechnology Activities (NIH OBA) and to the
local Institutional Biosafety Committee within the timeframes set forth in Appendix M-I-C-4-b.
Principal Investigators should adhere to any
other serious adverse event reporting requirements in accordance with federal
regulations, state laws, and local institutional policies and procedures, as
applicable.
Principal Investigators may delegate to
another party, such as a corporate sponsor, the reporting functions set forth
in Appendix M, with written notification to the NIH OBA of the delegation and
of the name(s), address, telephone and fax numbers of the contact(s). The Principal Investigator is responsible
for ensuring that the reporting requirements are fulfilled and will be held accountable
for any reporting lapses.
The three alternative mechanisms for
reporting serious adverse events to the NIH OBA are: by e-mail to oba@od.nih.gov; by fax to 301-496-9839; or by mail to the
Office of Biotechnology Activities, National Institutes of Health, MSC 7985,
6705 Rockledge Drive, Suite 750, Bethesda, Maryland 20892-7985.
The serious adverse event report must
include, but need not be limited to:
(1) the date of the event; (2) designation of the report as an initial
report or a follow-up report, identification of all safety reports previously
filed for the clinical protocol concerning a similar adverse event, and an
analysis of the significance of the adverse event in light of previous similar
reports; (3) clinical site; (4) the Principal Investigator; (5) NIH Protocol
number; (6) FDA’s Investigational New Drug (IND) Application number; (7) vector
type , e.g., adenovirus; (8) vector subtype, e.g., type 5, relevant deletions;
(9) gene delivery method, e.g., in vivo, ex vivo transduction; (10)
route of administration, e.g., intratumoral, intravenous; (11) dosing schedule;
(12) a complete description of the event; (13) relevant clinical observations;
(14) relevant clinical history; (15) relevant tests that were or are planned to
be conducted; (16) date of any treatment of the event; and (17) the suspected
cause of the event. These items may be
reported by using the recommended Adverse Event Reporting Template available on
NIH OBA’s web site at: http://www4.od.nih.gov/oba/rac/documents1.htm,
the FDA MedWatch forms, or other
means provided that all of the above elements are specifically included.
Reports from laboratory animal studies as
delineated in Appendix M-I-C-4 must be
submitted in a narrative format.
Any serious adverse event that is fatal or life-threatening,
that is unexpected, and associated with the use of the gene transfer product
must be reported to the NIH OBA as soon as possible, but not later than 7
calendar days after the sponsor’s initial receipt of the information (i.e., at
the same time the event must be reported to the FDA).
Serious adverse events that are unexpected
and associated with the use of the gene transfer product, but are not fatal or
life-threatening, must be reported to the NIH OBA as soon as possible, but not
later than 15 calendar days after the sponsor’s initial receipt of the
information (i.e., at the same time the event must be reported to the FDA).
Changes in this schedule are permitted only where,
under the FDA IND regulations [21 CFR 312(c)(3)], changes in this reporting
schedule have been approved by the FDA and are reflected in the protocol.
If, after further evaluation, an adverse
event initially considered not to be associated with the use of the gene
transfer product is subsequently determined to be associated, then the event
must be reported to the NIH OBA within 15 days of the determination.
Relevant additional clinical and laboratory
data may become available following the initial serious adverse event
report. Any follow-up information
relevant to a serious adverse event must be reported within 15 calendar days of
the sponsor’s receipt of the information.
If a serious adverse event occurs after the end of a clinical trial and
is determined to be associated with the use of the gene transfer product, that
event shall be reported to the NIH OBA within 15 calendar days of the
determination.
Any finding from tests in laboratory animals
that suggests a significant risk for human research participants including
reports of mutagenicity, teratogenicity, or carcinogenicity must be reported as
soon as possible, but not later than 15 calendar days after the sponsor’s
initial receipt of the information (i.e., at the same time the event must be
reported to the FDA).
Data submitted in accordance with Appendix M-I-C that are claimed to be
confidential commercial or trade secret information must be clearly labeled as
such. Prior to making its determination
about the confidentiality of data labeled confidential commercial or trade
secret, the NIH will contact the Principal Investigator or delegate to
ascertain the basis for the claim and subsequently will notify the Principal
Investigator or delegate of its final determination regarding the claim.
If NIH determines that the data so labeled
are confidential commercial or trade secret and that their public disclosure
would promote an understanding of key scientific or safety issues, the NIH will
seek agreement from the appropriate party to release such data. Public discussion of scientific and safety
issues raised by data submitted in accordance with Appendix M-I-C is vital to informing
both investigators and human subjects about the safety of gene transfer
research.
To protect the privacy of participants in
gene transfer research, any serious adverse event or annual reports submitted
to NIH OBA must not contain any information that would identify the human
research participants.
A working group of the RAC, the NIH Gene
Transfer Safety Assessment Board, with staff support from the NIH OBA, will: 1)
review in closed session as appropriate safety information from gene transfer
trials for the purpose of assessing toxicity and safety data across gene
transfer trials; 2) identify significant trends or significant single events;
and 3) report significant findings and aggregated trend data to the RAC. It is expected that this process will
enhance review of new protocols, improve the development, design, and conduct
of human gene transfer trials, promote public understanding and awareness of
the safety of human gene transfer research studies, and inform the
decision-making of potential trial participants.
Responses to this
appendix should be provided in the form of either written answers or references
to specific sections of the protocol or its appendices. Investigators should indicate the points
that are not applicable with a brief explanation. Investigators submitting proposals that employ the same vector
systems may refer to preceding documents relating to the vector sequence
without having to rewrite such material.
State concisely the
overall objectives and rationale of the proposed study. Provide information on the specific points that
relate to whichever type of research is being proposed.
For research in which
recombinant DNA is transferred in order to treat a disease or disorder (e.g.,
genetic diseases, cancer, and metabolic diseases), the following questions
should be addressed:
Appendix
M-II-A-1-a. Why is the disease
selected for experimental treatment by means of gene transfer a good candidate
for such treatment?
Appendix
M-II-A-1-b. Describe the natural history
and range of expression of the disease selected for experimental
treatment. What objective and/or
quantitative measures of disease activity are available? In your view, are the usual effects of the
disease predictable enough to allow for meaningful assessment of the results of
gene transfer?
Appendix
M-II-A-1-c. Is the protocol
designed to prevent all manifestations of the disease, to halt the progression
of the disease after symptoms have begun to appear, or to reverse
manifestations of the disease in seriously ill victims?
Appendix
M-II-A-1-d. What alternative
therapies exist? In what groups of
subjects are these therapies effective?
What are their relative advantages and disadvantages as compared with
the proposed gene transfer?
Appendix
M-II-A-2-a. Into what cells will
the recombinant DNA be transferred? Why
is the transfer of recombinant DNA necessary for the proposed research? What questions can be answered by using
recombinant DNA?
Appendix
M-II-A-2-b. What alternative
methodologies exist? What are their
relative advantages and disadvantages as compared to the use of recombinant
DNA?
Provide a full
description of the methods and reagents to be employed for gene delivery and
the rationale for their use. The
following are specific points to be addressed:
Appendix
M-II-B-1-a. What is the structure
of the cloned DNA that will be used?
Appendix
M-II-B-1-a-(1). Describe the gene
(genomic or cDNA), the bacterial plasmid or phage vector, and the delivery
vector (if any). Provide complete nucleotide
sequence analysis or a detailed restriction enzyme map of the total construct.
Appendix
M-II-B-1-a-(2). What regulatory
elements does the construct contain (e.g., promoters, enhancers,
polyadenylation sites, replication origins, etc.)? From what source are these elements derived? Summarize what is currently known about the
regulatory character of each element.
Appendix
M-II-B-1-a-(3). Describe the steps
used to derive the DNA construct.
Appendix
M-II-B-1-b. What is the structure
of the material that will be administered to the research participant?
Appendix
M-II-B-1-b-(1). Describe the
preparation, structure, and composition of the materials that will be given to
the human research subject or used to treat the subject’s cells: (i) If DNA, what is the purity (both in
terms of being a single DNA species and in terms of other contaminants)? What tests have been used and what is the
sensitivity of the tests? (ii) If a
virus, how is it prepared from the DNA construct? In what cell is the virus grown (any special features)? What medium and serum are used? How is the virus purified? What is its structure and purity? What steps are being taken (and assays used
with their sensitivity) to detect and eliminate any contaminating materials
(for example, VL30 RNA, other nucleic acids, or proteins) or contaminating
viruses (both replication-competent or replication-defective) or other
organisms in the cells or serum used for preparation of the virus stock
including any contaminants that may have biological effects? (iii) If co-cultivation is employed, what
kinds of cells are being used for co-cultivation? What steps are being taken (and assays used with their sensitivity)
to detect and eliminate any contaminating materials? Specifically, what tests are being conducted to assess the
material to be returned to the subject for the presence of live or killed donor
cells or other non-vector materials (for example, VL30 sequences) originating
from those cells? (iv) If methods other
than those covered by Appendices M-II-B-1 through M-II-B-3, Research Design,
Anticipated Risks and Benefits, are used to introduce new genetic
information into target cells, what steps are being taken to detect and
eliminate any contaminating materials?
What are possible sources of contamination? What is the sensitivity of tests used to monitor contamination?
Appendix
M-II-B-1-b-(2). Describe any other
material to be used in preparation of the material to be administered to the
human research subject. For example, if
a viral vector is proposed, what is the nature of the helper virus or cell
line? If carrier particles are to be
used, what is the nature of these?
Provide results that
demonstrate the safety, efficacy, and feasibility of the proposed procedures
using animal and/or cell culture model systems, and explain why the model(s)
chosen is/are most appropriate.
Appendix
M-II-B-2-a-(1). What cells are the intended
target cells of recombinant DNA? What
target cells are to be treated ex vivo and returned to the human
subject, how will the cells be characterized before and after treatment? What is the theoretical and practical basis
for assuming that only the target cells will incorporate the DNA?
Appendix
M-II-B-2-a-(2). Is the delivery
system efficient? What percentage of
the target cells contain the added DNA?
Appendix
M-II-B-2-a-(3). How is the
structure of the added DNA sequences monitored and what is the sensitivity of
the analysis? Is the added DNA
extrachromosomal or integrated? Is the
added DNA unrearranged?
Appendix
M-II-B-2-a-(4). How many copies are
present per cell? How stable is the
added DNA both in terms of its continued presence and its structural stability?
Appendix
M-II-B-2-b-(1). What animal and
cultured cell models were used in laboratory studies to assess the in vivo
and in vitro efficacy of the gene transfer system? In what ways are these models similar to and
different from the proposed human treatment?
Appendix
M-II-B-2-b-(2). What is the minimal
level of gene transfer and/or expression that is estimated to be necessary for
the gene transfer protocol to be successful in humans? How was this level determined?
Appendix
M-II-B-2-b-(3). Explain in detail
all results from animal and cultured cell model experiments which assess the
effectiveness of the delivery system in achieving the minimally required level
of gene transfer and expression.
Appendix
M-II-B-2-b-(4). To what extent is
expression only from the desired gene (and not from the surrounding DNA)? To what extent does the insertion modify the
expression of other genes?
Appendix
M-II-B-2-b-(5). In what percentage
of cells does expression from the added DNA occur? Is the product biologically active? What percentage of normal activity results from the inserted
gene?
Appendix
M-II-B-2-b-(6). Is the gene
expressed in cells other than the target cells? If so, to what extent?
Appendix
M-II-B-2-c-(1). What cell types
have been infected with the retroviral vector preparation? Which cells, if any, produce infectious
particles?
Appendix
M-II-B-2-c-(2). How stable are the
retroviral vector and the resulting provirus against loss, rearrangement,
recombination, or mutation? What
information is available on how much rearrangement or recombination with
endogenous or other viral sequences is likely to occur in the human subject’s
cells? What steps have been taken in
designing the vector to minimize instability or variation? What laboratory studies have been performed
to check for stability, and what is the sensitivity of the analyses?
Appendix
M-II-B-2-c-(3). What laboratory
evidence is available concerning potential harmful effects of the transfer
(e.g., development of neoplasia, harmful mutations, regeneration of infectious
particles, or immune responses)? What
steps will be taken in designing the vector to minimize pathogenicity? What laboratory studies have been performed
to check for pathogenicity, and what is the sensitivity of the analyses?
Appendix
M-II-B-2-c-(4). Is there evidence
from animal studies that vector DNA has entered untreated cells, particularly
germ-line cells? What is the
sensitivity of these analyses?
Appendix
M-II-B-2-c-(5). Has a protocol
similar to the one proposed for a clinical trial been conducted in non-human
primates and/or other animals? What
were the results? Specifically, is
there any evidence that the retroviral vector has recombined with any
endogenous or other viral sequences in the animals?
If a non-retroviral
delivery system is used, what animal studies have been conducted to determine
if there are pathological or other undesirable consequences of the protocol
(including insertion of DNA into cells other than those treated, particularly
germ-line cells)? How long have the
animals been studied after treatment?
What safety studies have been conducted? (Include data about the level of sensitivity of such assays.)
Describe the experimental
treatment that will be administered to the human subjects and the diagnostic
methods that will be used to monitor the success or failure of the experimental
treatment. If previous clinical studies
using similar methods have been performed by yourself or others, indicate their
relevance to the proposed study.
Specifically:
Appendix
M-II-B-3-a. Will cells (e.g., bone
marrow cells) be removed from human subjects and treated ex vivo? If so, describe the type, number, and intervals
at which these cells will be removed.
Appendix
M-II-B-3-b. Will human subjects be
treated to eliminate or reduce the number of cells containing malfunctioning
genes (e.g., through radiation or chemotherapy)?
Appendix
M-II-B-3-c. What treated cells (or
vector/DNA combination) will be given to human subjects? How will the treated cells be
administered? What volume of cells will
be used? Will there be single or
multiple experimental treatments? If
so, over what period of time?
Appendix M-II-B-3-d. How will it be determined that new gene
sequences have been inserted into the subject’s cells and if these sequences
are being expressed? Are these cells
limited to the intended target cell populations? How sensitive are these analyses?
Appendix
M-II-B-3-e. What studies will be
conducted to assess the presence and effects of the contaminants?
Appendix
M-II-B-3-f. What are the clinical
endpoints of the study? Are there
objectives and quantitative measurements to assess the natural history of the
disease? Will such measurements be used
in human subject follow-up? How will
subjects be monitored to assess specific effects of the treatment on the
disease? What is the sensitivity of the
analyses? How frequently will follow-up
studies be conducted? How long will
follow-up continue?
Appendix
M-II-B-3-g. What are the major
beneficial and adverse effects of the experimental treatment that you
anticipate? What measures will be taken
in an attempt to control or reverse these adverse effects if they occur? Compare the probability and magnitude of
deleterious consequences from the disease if recombinant DNA transfer is not
used.
Appendix
M-II-B-3-h. If a treated human
subject dies, what special post-mortem studies will be performed?
Describe any
potential benefits and hazards of the proposed gene transfer to persons other
than the human subjects receiving the experimental treatment. Specifically:
Appendix
M-II-B-4-a. On what basis are
potential public health benefits or hazards postulated?
Appendix
M-II-B-4-b. Is there a significant
possibility that the added DNA will spread from the human subject to other
persons or to the environment?
Appendix
M-II-B-4-c. What precautions will
be taken against such spread (e.g., subjects sharing a room, health-care
workers, or family members)?
Appendix
M-II-B-4-d. What measures will be
undertaken to mitigate the risks, if any, to public health?
Appendix
M-II-B-4-e. In light of possible risks
to offspring, including vertical transmission, will birth control measures be
recommended to subjects? Are such
concerns applicable to health care personnel?
Indicate the relevant
training and experience of the personnel who will be involved in the
preclinical studies and clinical administration of recombinant DNA. Describe the laboratory and clinical
facilities where the proposed study will be performed. Specifically:
Appendix
M-II-B-5-a. What professional
personnel (medical and nonmedical) will be involved in the proposed study and
what is their relevant expertise?
Provide a two-page curriculum vitae for each key professional person in
biographical sketch format (see Appendix
M-I-A, Requirements for Protocol Submission).
Appendix
M-II-B-5-b. At what hospital or
clinic will the experimental treatment be given? Which facilities of the hospital or clinic will be especially
important for the proposed study? Will
subjects occupy regular hospital beds or clinical research center beds? Where will subjects reside during the
follow-up period? What special
arrangements will be made for the comfort and consideration of the research
participants. Will the research
institution designate an ombudsman, patient care representative, or other
individual to help protect the rights and welfare of the research participant?
Estimate the number
of human subjects to be involved in the proposed study. Describe recruitment procedures and
eligibility requirements, paying particular attention to whether these
procedures and requirements are fair and equitable. Specifically:
Appendix M-II-C-1. How many subjects do you plan to involve in
the proposed study?
Appendix M-II-C-2. How many eligible subjects do you anticipate
being able to identify each year?
Appendix M-II-C-3. What recruitment procedures do you plan to
use?
Appendix M-II-C-4. What selection criteria do you plan to
employ? What are the exclusion and
inclusion criteria for the study?
Appendix M-II-C-5. How will subjects be selected if it is not
possible to include all who desire to participate?
In accordance with
the Protection of Human Subjects (45 CFR Part 46), investigators should
indicate how subjects will be informed about the proposed study and the manner
in which their consent will be solicited.
They should indicate how the Informed Consent document makes clear the
special requirements of gene transfer research. If a proposal involves children, special attention should be paid
to the Protection of Human Subjects (45 CFR Part 46), Subpart D, Additional
Protections for Children Involved as Subjects in Research.
Appendix
M-III-A-1. Which members of the
research group and/or institution will be responsible for contacting potential
participants and for describing the study to them? What procedures will be used to avoid possible conflicts of
interest if the investigator is also providing medical care to potential
subjects?
Appendix
M-III-A-2. How will the major
points covered in Appendix M-II, Description
of Proposal, be disclosed to potential participants and/or their parents or
guardians in language that is understandable to them?
Appendix
M-III-A-3. What is the length of time
that potential participants will have to make a decision about their
participation in the study?
Appendix
M-III-A-4. If the study involves
pediatric or mentally handicapped subjects, how will the assent of each person
be obtained?
Submission of a human
gene transfer experiment to NIH OBA must include a copy of the proposed
informed consent document. A separate
Informed Consent document should be used for the gene transfer portion of a
research project when gene transfer is used as an adjunct in the study of
another technique, e.g., when a gene is used as a "marker" or to
enhance the power of immunotherapy for cancer.
Because of the
relative novelty of the procedures that are used, the potentially irreversible
consequences of the procedures performed, and the fact that many of the
potential risks remain undefined, the Informed Consent document should include
the following specific information in addition to any requirements of the DHHS
regulations for the Protection of Human Subjects (45 CFR 46). Indicate if each of the specified items
appears in the Informed Consent document or, if not included in the Informed
Consent document, how those items will be presented to potential subjects. Include an explanation if any of the
following items are omitted from the consent process or the Informed Consent
document.
The subjects should
be provided with a detailed explanation in non-technical language of the
purpose of the study and the procedures associated with the conduct of the
proposed study, including a description of the gene transfer component.
The Informed Consent
document should indicate the availability of therapies and the possibility of
other investigational interventions and approaches.
The subjects should
be informed that participation in the study is voluntary and that failure to
participate in the study or withdrawal of consent will not result in any
penalty or loss of benefits to which the subjects are otherwise entitled.
The subjects should
be provided with an accurate description of the possible benefits, if any, of
participating in the proposed study.
For studies that are not reasonably expected to provide a therapeutic
benefit to subjects, the Informed Consent document should clearly state that no
direct clinical benefit to subjects is expected to occur as a result of
participation in the study, although knowledge may be gained that may benefit
others.
There should be clear
itemization in the Informed Consent document of types of adverse experiences,
their relative severity, and their expected frequencies. For consistency, the following definitions
are suggested: side effects that are
listed as mild should be ones which do not require a therapeutic intervention;
moderate side effects require an intervention; and severe side effects are
potentially fatal or life-threatening, disabling, or require prolonged
hospitalization.
If verbal descriptors
(e.g., "rare," "uncommon," or "frequent") are
used to express quantitative information regarding risk, these terms should be
explained.
The Informed Consent
document should provide information regarding the approximate number of people
who have previously received the genetic material under study. It is necessary to warn potential subjects
that, for genetic materials previously used in relatively few or no humans,
unforeseen risks are possible, including ones that could be severe.
The Informed Consent
document should indicate any possible adverse medical consequences that may
occur if the subjects withdraw from the study once the study has started.
The subjects should
be provided with specific information about any financial costs associated with
their participation in the protocol and in the long-term follow-up to the
protocol that are not covered by the investigators or the institution involved.
Subjects should be
provided an explanation about the extent to which they will be responsible for
any costs for medical treatment required as a result of research-related
injury.
To avoid the possibility
that any of the reagents employed in the gene transfer research could cause
harm to a fetus/child, subjects should be given information concerning possible
risks and the need for contraception by males and females during the active
phase of the study. The period of time
for the use of contraception should be specified. The inclusion of pregnant or lactating women should be addressed.
To permit evaluation
of long-term safety and efficacy of gene transfer, the prospective subjects
should be informed that they are expected to cooperate in long-term follow-up
that extends beyond the active phase of the study. The Informed Consent document should include a list of persons
who can be contacted in the event that questions arise during the follow-up
period. The investigator should request
that subjects continue to provide a current address and telephone number.
The subjects should
be informed that any significant findings resulting from the study will be made
known in a timely manner to them and/or their parent or guardian including new
information about the experimental procedure, the harms and benefits
experienced by other individuals involved in the study, and any long-term
effects that have been observed.
To obtain vital
information about the safety and efficacy of gene transfer, subjects should be
informed that at the time of death, no matter what the cause, permission for an
autopsy will be requested of their families.
Subjects should be asked to advise their families of the request and of
its scientific and medical importance.
To alert subjects
that others may have an interest in the innovative character of the protocol
and in the status of the treated subjects, the subjects should be informed of
the following: (i) that the institution and investigators will make efforts to
provide protection from the media in an effort to protect the participants'
privacy, and (ii) that representatives of applicable Federal agencies (e.g.,
the National Institutes of Health and the Food and Drug Administration), representatives
of collaborating institutions, vector suppliers, etc., will have access to the
subjects' medical records.
Indicate what measures will be taken to
protect the privacy of subjects and their families as well as maintain the
confidentiality of research data. These
measures should help protect the confidentiality of information that could
directly or indirectly identify study participants.
Appendix
M-IV-A. What provisions will be made to
honor the wishes of individual human subjects (and the parents or
guardians of pediatric or mentally handicapped subjects) as to whether, when,
or how the identity of a subject is publicly disclosed.
Appendix M-IV-B. What provisions will be made to maintain the
confidentiality of research data, at least in cases where data could be linked
to individual subjects?
Although the
following issues are beyond the normal purview of local Institutional Review Boards,
investigators should respond to the following questions:
Appendix M-V-A. What steps will be taken, consistent with
Appendix M-IV, Privacy, to ensure that accurate and appropriate
information is made available to the public with respect to such public
concerns as may arise from the proposed study?
Appendix M-V-B. Do you or your funding sources intend to
protect under patent or trade secret laws either the products or the procedures
developed in the proposed study? If so,
what steps will be taken to permit as full communication as possible among
investigators and clinicians concerning research methods and results?
Appendix M-VI-A. Human studies in which induction or
enhancement of an immune response to a vector-encoded microbial immunogen is
the major goal, such an immune response has been demonstrated in model systems,
and the persistence of the vector-encoded immunogen is not expected, are exempt
from Appendix M-I, Requirements
for Protocol Submission, Review and Reporting – Human Gene
Transfer Experiments.