Third Party Involvement in NHLBI-Supported Clinical Trials and Other Population-Based Studies: Awardee/Contractor Third Party Related Issues

Background
1. 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.
2. 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.
3. NHLBI-supported clinical trials are particularly sensitive because
  1. The Institute's name is often closely associated with clinical trials
  2. They often constitute the final testing and validation of therapies that are intended for widespread clinical use
Involvement of Third Parties
1. 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.
2. Examples of types and mechanisms of third party involvement include:
  1. In-kind support of materials, e.g., drugs, devices, reagents
  2. In-kind support of services, e.g., laboratory services
  3. Financial support through a conditional gift to the NHLBI Gift Fund
  4. 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
  5. Financial support provided directly to an NHLBI-supported investigator for use in accordance with study plans.
3. Third party involvement may be based on an agreement between
  1. The NHLBI and a third party (required for Institute-initiated studies)
  2. 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
1. 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:
  1. 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,
  2. 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,
  3. 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,
  4. 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),
  5. The nature of the third party's support and the conditions under which it is to be provided are clearly stated, and
  6. The third party's involvement neither raises the appearance of nor creates conflict of interest issues with the study investigators, the NHLBI, or its employees.
2. In certain circumstances, variations from the above may be acceptable, e.g.,
  1. Limited third party participation may be desirable
    1. 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.
    2. In investigator meetings.
    3. In reviewing the final manuscript (see the footnote of the NHLBI Statement on Private Sector Involvement in Clinical Trials).
  2. 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
    1. Studies of products in the development or initial clinical investigative phase.
    2. Studies of products for which the third party holds the IND or IDE.
    3. Studies that for regulatory or ethical reasons, require communication between the FDA and/or IRB(s) and the third party.
    4. Other studies as determined on a case-by-case basis.
  3. For studies with other federal agencies and certain not-for-profit sponsors, greater involvement by those agencies and sponsors may be appropriate.
3. 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
1. To make informed decisions about third party support or involvement, the NHLBI requires information about:
  1. Third party involvement or influence in study governance and conduct, and in the analysis, interpretation, and reporting of results.
  2. 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.
  3. The nature and any conditions of third party support.
  4. The nature of any conflict of interest issues and their proposed resolution.
2. Specific requirements:
  1. 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.
  2. 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.
3. Staff Responsibilities:
  1. Initiation of all contacts with third parties must be approved by the Division Director and by the Director, NHLBI, or his designee(s).
  2. All substantive contacts with third parties by staff must be reported to the Division Director and the Director, NHLBI, or his designee(s).
  3. 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
1. Investigator-initiated grants
  1. Third party agreements are initiated, developed, and implemented by grant applicants.
  2. Agreements are generally directly between applicants and third parties.
  3. Third-party relationships are only a consideration in the peer review process to the extent that they relate to scientific and technical merit.
  4. NHLBI review/concurrence is required for all grant applications with direct costs in excess of $500,000 in any year
    1. 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/research/funding/500k-costs.htm).
    2. 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.
    3. 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.
2. Institute-initiated grants or contracts
  1. Third party agreements must be initiated, developed, and implemented by the NHLBI.
  2. Agreements are between the Institute and third parties unless Institute solicitations (RFA or RFP) specify otherwise.
  3. 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:
    1. 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.
    2. No restrictions are permitted on disclosures to participants of risks that arise during a study.
Agreements Made Subsequent to an Award
1. Investigator-initiated grants
  1. Third party agreements are initiated, developed, and implemented by the grantee.
  2. Agreements are generally directly between a grantee and third parties.
  3. For multi-center studies, the study governance (e.g., study Steering or Executive Committee) is generally centrally involved.
  4. 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.
  5. NHLBI review/concurrence
    1. 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.
    2. 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.
    3. 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.
2. Institute-initiated grants or contracts
  1. Third party agreements for a parent study must be developed and implemented by the NHLBI.
    1. In all cases, scientific considerations must be the final determinants in any decisions to seek third party involvement.
    2. 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.
  2. 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.
  3. 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.
  4. The Institute's role depends in part upon the NHLBI award instrument:
    1. For contracts and cooperative agreements, the terms and conditions of the award address the process and necessary information.
    2. 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.
  5. In all cases, the involvement of a third party in the governance, conduct, analysis, interpretation, or reporting of results must be carefully scrutinized.
    1. 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.
    2. 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.