Third Party Involvement in
NHLBI-Supported Clinical Trials and Other Population-Based Studies:
Awardee/Contractor Third Party Related Issues
National Heart, Lung, and Blood
Institute National Institutes of Health
Revised: September 30, 2003
On this page:
- Background
- Investigators involved in NHLBI-supported clinical
trials and other population-based studies may find it
advantageous to seek additional support from or other
involvement by industry or other third parties (e.g.,
the VA, CMS, charitable foundations) for the studies
themselves, for substudies, and for ancillary studies.
- The NHLBI generally views favorably support from industry
or other third parties for NHLBI-supported studies,
so long as the primary purpose of a study is not compromised.
However, in all such cases, judgment must be exercised.
Relationships that may be appropriate in some circumstances
may not be in others.
- NHLBI-supported clinical trials are particularly sensitive
because
- The Institutes name is often closely associated
with clinical trials
- They often constitute the final testing and validation
of therapies that are intended for widespread clinical
use
- Involvement of Third Parties
- Third party involvement may entail providing financial
support; participating directly in a study; supplying
study resources; or receiving special access to study
results, data, findings, or intellectual property. Third
party involvement may concern only the original scope
of the study or may extend to enlargements of the scope
or ancillary additions through further procedures, data
collection, or analyses, and may involve one, some,
or all centers in a collaborative clinical trial.
- Examples of types and mechanisms of third party involvement
include:
- In-kind support of materials, e.g., drugs, devices,
reagents
- In-kind support of services, e.g., laboratory
services
- Financial support through a conditional gift to
the NHLBI Gift Fund
- Financial support through a charitable third party
that works in collaboration with the NHLBI and that
manages, accounts for, and distributes funds to
study investigators in accordance with NHLBI program
plans
- Financial support provided directly to an NHLBI-supported
investigator for use in accordance with study plans.
- Third party involvement may be based on an agreement
between
- The NHLBI and a third party (required for Institute-initiated
studies)
- An awardee/contractor and a third party. Note
that awardee/contractor here encompasses
both the direct recipient of an NHLBI assistance
award or contract and any other parties that are
in a subcontracting or other participatory relationship
(e.g., participating clinical unit or central laboratory)
with the recipient.
- Appropriate Involvement
- Although a relationship with a third party can receive
the concurrence of the NHLBI under less restrictive
conditions (as indicated in C.2 below), a relationship
can be expected to receive the concurrence of the Institute,
whenever all of the following conditions are met:
- The third party does not participate in and has
no influence on the governance or conduct of a study,
or in the analysis, interpretation, or reporting
of its results,
- The third party has no access to study results
until after a manuscript has been submitted for
publication or a public presentation has been prepared,
- The third party has no access to study data other
than those that form the basis for published reports
or are available to other qualified members of the
scientific community,
- The third party has no commitments with the study
investigators as to intellectual or tangible property
or other issues that conflict with PHS policy on
grants or contracts (particularly as to reporting,
distribution of unique research resources, inventions,
or commercialization),
- The nature of the third partys support and
the conditions under which it is to be provided
are clearly stated, and
- The third partys involvement neither raises
the appearance of nor creates conflict of interest
issues with the study investigators, the NHLBI,
or its employees.
- In certain circumstances, variations from the above
may be acceptable, e.g.,
- Limited third party participation may be desirable
- In planning a study, developing its protocol,
and planning the analysis of study data. However,
definitive decisions on such matters must remain
with the Institute and the scientific participants
of the trial.
- In investigator meetings.
- In reviewing the final manuscript (see the
footnote of the NHLBI Statement on Private Sector
Involvement in Clinical Trials).
- For some studies, broader third party access to
study data may be permitted and/or required, e.g.,
, in some situations, a third party may be permitted
to appoint a physician or other scientist (who may
be an employee) to review and provide written comments
on near final major manuscript(s) for consideration
by the writing committee. This will only be permitted,
however, if the third party has in place a policy
and process to ensure that both the manuscripts
and their findings will be treated as highly confidential
by the reviewer and by any (very limited number
of) necessary consultants to the reviewer. In particular,
no or minimum communication of such findings should
be permitted "vertically" to higher management within
the organization and none at all should be permitted
"laterally" outside the "scientific" management
path. Included are
- Studies of products in the development or
initial clinical investigative phase.
- Studies of products for which the third party
holds the IND or IDE.
- Studies that for regulatory or ethical reasons,
require communication between the FDA and/or
IRB(s) and the third party.
- Other studies as determined on a case-by-case
basis.
- For studies with other federal agencies and certain
not-for-profit sponsors, greater involvement by
those agencies and sponsors may be appropriate.
- If support from the third party is in the form of
a drug, device, or biologic, the third party will assist
the NHLBI and the investigator(s) in ensuring the greatest
possible care in protecting participants by providing
to the NHLBI and the investigator(s) all information
regarding adverse events reasonably attributable to
the drug, device, or biologic. This information will
be used solely for developing or updating informed consent
forms.
- Information Required by
the NHLBI
- To make informed decisions about third party support
or involvement, the NHLBI requires information about:
- Third party involvement or influence in study
governance and conduct, and in the analysis, interpretation,
and reporting of results.
- Third party access to results, and access to and
ownership of the dataset, and any other commitments
with the third party as to intellectual or tangible
property.
- The nature and any conditions of third party
support.
- The nature of any conflict of interest issues
and their proposed resolution.
- Specific requirements:
- For all clinical trials, the existence of any
financial or other relationships relevant to the
trial (including but not limited to stock ownership
or options, consultancies, honoraria, patent rights,
royalties, business plans, employment relationships,
corporate leadership positions, trustee or speaker
panel roles, and research or other support from
the interested party) of any principal investigators
and other key personnel and the criteria to be used
for potential future investigators must be reported
in detail, and any of them that are unacceptable
to the Institute must be avoided or resolved.
- For other population-based studies, the issues
and sensitivities related to third party involvement
may be less compelling than for clinical trials,
so the limitations on third party involvement for
them may be less restrictive even if a potential
conflict of interest exists. However, each case
must be evaluated separately. For example, few restrictions
may be warranted in agreements related to studies
to validate procedures and reagents.
- Staff Responsibilities:
- Initiation of all contacts with third parties
must be approved by the Division Director and by
the Director, NHLBI, or his designee(s).
- All substantive contacts with third parties by
staff must be reported to the Division Director
and the Director, NHLBI, or his designee(s).
- All substantive contacts with third parties reported
by grantees or awardees must, in turn, be reported
to the Division Director and the Director, NHLBI,
or his designee(s).
- Agreements Made Prior to the Award of a Grant
or Contract
- Investigator-initiated grants
- Third party agreements are initiated, developed,
and implemented by grant applicants.
- Agreements are generally directly between applicants
and third parties.
- Third-party relationships are only a consideration
in the peer review process to the extent that they
relate to scientific and technical merit.
- NHLBI review/concurrence is required for all
grant applications with direct costs in excess of
$500,000 in any year
- If any third party involvement is proposed
in a letter requesting NHLBI acceptance of a
grant application, the appropriateness of the
involvement should be considered as part of
the Institute process to determine whether to
accept an application (see: http://www.nhlbi.nih.gov/funding/policies/500kweb.htm).
- Formal review and recommendation as to appropriateness
of third party relationships is a responsibility
of NHLBI staff and should be part of the overall
pre-award review. Particular attention should
be addressed to any provisions regarding restrictions
on publication, presentation, or public disclosure
of results and on disclosure of risks to participants
in clinical studies.
- a) All restrictions on publication, presentation,
or public disclosure of results, other than
those related to proprietary information,
must be limited in both duration and scope.
- b) No restrictions are permitted on disclosures
to participants of risks that arise during
a study.
- The Director, NHLBI, or his designee(s) must
be involved from the outset in all discussions
and decisions regarding the acceptability of
proposed third party involvements and what additional
terms or conditions may be needed for them to
be acceptable.
- Institute-initiated grants or contracts
- Third party agreements must be initiated, developed,
and implemented by the NHLBI.
- Agreements are between the Institute and third
parties unless Institute solicitations (RFA or RFP)
specify otherwise.
- All agreements for third party involvement in
clinical trials, whether developed and implemented
by the NHLBI or by an awardee or contractor, must
include statements specifying that:
- All restrictions on publication, presentation,
or public disclosure of results, other than
those related to proprietary information, must
be strictly limited as to both duration and
scope.
- No restrictions are permitted on disclosures
to participants of risks that arise during a
study.
- Agreements Made Subsequent to an Award
- Investigator-initiated grants
- Third party agreements are initiated, developed,
and implemented by the grantee.
- Agreements are generally directly between a grantee
and third parties.
- For multi-center studies, the study governance
(e.g., study Steering or Executive Committee) is
generally centrally involved.
- For multi-center studies and clinical networks,
the study governance should address details related
to section D2 as part of its protocol or operations
manual.
- NHLBI review/concurrence
- Formal review and recommendation as to appropriateness
of third party relationships proposed subsequent
to an award.
a) For most investigator-initiated awards, NHLBI
review/concurrence is not required.
b) For investigator-initiated grants that are
converted to cooperative agreements or that
have direct costs in excess of $500,000 in any
year, NHLBI review/concurrence is required and
must be so indicated in the terms and conditions
of an award.
- The Institute should respond in an advisory
capacity to all matters submitted to it for
which NHLBI review/concurrence is not required
by the terms and conditions of the award.
- When NHLBI review/concurrence is required
- a) The Director, NHLBI, or his designee
makes all decisions and provides the Institute
response regarding the acceptability of
proposed third party involvements and what
additional terms or conditions may be needed
for them to be acceptable.
- b) The involvement of a third party in
the governance, conduct, analysis, interpretation,
or reporting of results is a matter of substance
in the conduct of the study and may be a
basis for Institute non-concurrence, depending
upon the nature of the third party and the
nature of its actions and the terms and
conditions of the award.
- All restrictions on publication, presentation,
or public disclosure of results, other
than those related to proprietary information,
that are not strictly limited as to
both duration and scope are grounds
for non-concurrence.
- All restrictions on disclosure to
participants of risks that arise during
a study are grounds for non-concurrence.
- Institute-initiated grants or contracts
- Third party agreements for a parent study must
be developed and implemented by the NHLBI.
- In all cases, scientific considerations must
be the final determinants in any decisions to
seek third party involvement.
- If more than one party can provide the desired
involvement, e.g., provide an appropriate drug
or device, each must be afforded an equal opportunity
to do so.
- By prior agreement through the study governance
and concurrence by the NHLBI, agreement may be between
the awardee and a third party for substudies or
ancillary studies.
- Contact with potential collaborators with commercial
interests should be initiated exclusively through
the study governance and the NHLBI, or in unusual
situations, with their advice and concurrence. Any
preliminary informal contact that raises the topic
should be brought to the study governance promptly.
- The Institutes role depends in part upon
the NHLBI award instrument:
- For contracts and cooperative agreements,
the terms and conditions of the award address
the process and necessary information.
- For grants other than cooperative agreements,
potential third party relationships are governed
by general grants policy. For example, with
a potential third party relationship as outlined
in section C1 above, the grantee would be expected
to consult informally with NHLBI staff and to
report any new third party involvement and major
features thereof in a periodic report. Other
potential third party relationships warrant
consultation with appropriate NHLBI staff.
- In all cases, the involvement of a third party
in the governance, conduct, analysis, interpretation,
or reporting of results must be carefully scrutinized.
- All restrictions on publication, presentation,
or public disclosure of results, other than
those related to proprietary information, must
be limited in both duration and scope.
- All restrictions on disclosure to participants
of risks that arise during a study are grounds
for non-concurrence.
Attachment: NHLBI Statement on
Third Party Involvement in a Clinical Trial -- used in conjunction with
Institute-initiated trials
NHLBI Statement on
Third Party Involvement In Clinical Trials The primary
factors influencing an NHLBI decision to undertake a clinical trial (or the
selection of a drug in a clinical trial) are the scientific opportunity, the
clinical need, and the feasibility of the study. Third party involvement may
increase the feasibility or value of a study. However, scientific merit must
remain the primary determinant in deciding whether to implement a study.
The control of a clinical trial must reside entirely with the Institute and
the scientific participants of the trial. Although third parties may have
limited participatory roles in planning a study, developing its protocol, and
planning the analysis of study data, definitive decisions on such matters must
remain with the Institute and the scientific participants of the trial.
Once a trial is started, data confidentiality must be maintained within
the Institute and the data and safety monitoring board. Except under special
circumstances and by specific prior arrangement, third parties will not have
access to any scientific data prior to their availability to the scientific
community and the general public.* Immediately prior to their
release, results will be made available to cooperating third parties. (During
the conduct of the trial, third parties may be given general information
concerning operational aspects of the study, such as the rate of recruitment,
but they will not receive any of the detailed data on performance that is
provided to the data and safety monitoring board.) In the event that
any adverse effects are encountered which, for legal or ethical reasons, may
require communication with the FDA and/or IRBs, relevant third parties will be
notified. The detailed results of a study will ultimately be made
available to cooperating third parties for use in such purposes as applications
to the FDA and advertising. The advertising might, for example, emphasize the
scientific results of studies, and note, but not emphasize, the relationship
with the NHLBI. However, neither the conduct of the trial nor the results
should be represented as an endorsement by the NHLBI of the drug or product
under study. Appropriate recognition will be given to the private
sector institution's contributory role in the clinical trial.
* For example, in some
situations, a third party may be permitted to appoint a physician or other
scientist (who may be an employee) to review and provide written comments on
near final major manuscript(s) for consideration by the writing committee. This
will only be permitted, however, if the third party has in place a policy and
process to ensure that both the manuscripts and their findings will be treated
as highly confidential by the reviewer and by any (very limited number of)
necessary consultants to the reviewer. In particular, no or minimum
communication of such findings should be permitted "vertically" to higher
management within the organization and none at all should be permitted
"laterally" outside the "scientific" management path.
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