United States: Pro Te: Solutio – Winter 2016

BALANCING THE NEEDS OF SPONSORS AND RESEARCH SITES TO EFFECTIVELY AND EFFICIENTLY NEGOTIATE CLINICAL TRIAL AGREEMENTS

By Kim Coggin

Before a research site begins work on a sponsor-initiated clinical trial, the sponsor and the site should enter into a "clinical trial agreement" or "CTA," to establish the obligations of each party, to convey certain rights to each party, and to allocate risks between the parties. Typically, the sponsor provides its CTA template to the site for review, and the parties will proceed to negotiate the CTA – with each side looking to lock in terms favorable to it.

Each CTA negotiation presents its own unique set of challenges. However, virtually every one will devote significant time to the following issues: ownership and use of trial data, intellectual property, publications, and trial participant injury. Parties often dig in their heels on these provisions without fully understanding these issues or their importance within the context of clinical trial setting. The resulting delays can be detrimental to the parties as well as to the potential trial participants and are both unnecessary and avoidable.

Knowing your bottom-line position, understanding the rationale behind the other side's stance, recognizing the relative importance of the provision to each side, and making reasonable compromises under the circumstances can reduce stalemates, speed up the negotiation process, and get the trial site up and running much more quickly.

Not only that, but savvy sponsors and sites can capitalize on the momentum built during a successful CTA negotiation by using the final negotiated terms as a foundation for drafting a master clinical trial agreement. A master clinical trial agreement, or master CTA, eliminates time consuming negotiations in future trials and gets them running with little to no delay.

RESOLVING COMMON STICKING POINTS IN CLINICAL TRIAL AGREEMENTS

1. OWNERSHIP AND USE OF TRIAL DATA

Ownership of trial data may be addressed in its own separate CTA provision or may be folded into another section, such as confidential information or intellectual property. Regardless of where it is located, ownership and use of trial data are sensitive topics for both sponsors and sites.

The Sponsor's Perspective: It is not uncommon for a sponsor to present the site with CTA language that gives the sponsor exclusive ownership of and unlimited right to use all data related to the site's participation in the trial. From the sponsor's viewpoint, its position is justified because it designed the trial protocol and paid the site for conducting the trial.

The Site's Perspective: The site will often respond that the sponsor is only entitled to own the data specifically contemplated by the protocol (e.g. case report forms (CRFs) and trial-specific test results) and that underlying original source documents, which document the existence of the participant and substantiate the integrity of the trial data collected (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, participant diaries or evaluation checklists, pharmacy dispensing records, and microfilm or magnetic media, x-rays), are the property of the site. Additionally, the site will likely seek to limit the sponsor's use of the trial data. For instance, if the site is a non-profit entity, it may contend that it cannot conduct research on a work-for-hire basis and must be allowed to use trial data, including data that is owned by the sponsor for non-commercial research and education purposes and/or patient care.

The Compromise: Even the sponsor must acknowledge that a request to own all data related to the trial is too broad and reaches beyond what the sponsor actually needs to protect its interests and move the development of its product to the next stage. A properly drafted protocol will require that all necessary data end points be submitted to the sponsor on CRFs. The sponsor does not need the underlying source documents, a fact recognized by the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice (ICH GCP) §8.3.13.

But it may need to audit the source documents at some point in the future, and will likely reserve its right to do so.

With respect to use of the trial data, the site should not object to the sponsor's use of it, provided such use is not prohibited by law and is authorized by the trial participants' informed consent and authorization documents. Similarly, the sponsor's interests are not infringed by granting the site the right to use trial data generated and contributed by the site for internal and non-commercial research, education, and/or patient care. Protection of all such rights is exemplified here:

Any and all information, documents, reports, data, results, and other information generated by Research Site pursuant to the Protocol that are required by the Protocol to be delivered to Sponsor and all copies thereof (collectively, the "Trial Results"), will be the property of Sponsor Subject to Trial Subjects' informed consent and authorization documents, Sponsor may use the Trial Results for any lawful purpose.

Notwithstanding the foregoing, the parties acknowledge and agree that the source documents, as defined in the Good Clinical Practice: Consolidated Guidelines published by the Food and Drug Administration, generated by Research Site and the data contained therein shall not be deemed Trial Results and are the exclusive property of Research Site; provided, however, that Sponsor shall have the right to inspect, audit, and/ or copy the source documents pursuant to this Agreement and subject to the informed consent and authorization documents.

Genetic Data: An Evolving Sub-set of Trial Data. As the field of personalized medicine continues to evolve, the ownership and use of biological specimens and the data derived therefrom pose new challenges to the negotiation of trial data ownership and use. Both sponsors and sites may seek to own and/or use specimens (e.g., blood or tissue samples) and the data derived from such specimens.

It is likely unnecessary for the sponsor to actually own the biological samples as long as the sponsor has the right to use the samples. The site should not object to the sponsor's use of the specimen provided such use does not violate applicable law and is authorized by the informed consent and authorization documents. If the sample is taken pursuant to the protocol, then it is reasonable for the sponsor to limit the site's use of the sample and any data derived therefrom to trial-related purposes. For example:

Sponsor shall have the right to possess, control, retain, store, use and dispose of biologic specimens collected pursuant to the protocol ("Specimens") in accordance with applicable laws and regulations to the extent authorized by the informed consent and authorization documents. Sponsor will own all protocol required data derived from the Specimens ("Specimen Data"). Sponsor will use Specimens or Specimen Data only to the extent not prohibited by applicable law, in accordance with the protocol, and subject to the informed consent form and authorization documents. Research Site will use Specimens and Specimen Data only for purposes of this Trial.

2. INTELLECTUAL PROPERTY OWNERSHIP

Disputes over ownership of trial-related intellectual property are similar to issues regarding ownership of trial data, but focus directly on who owns inventions or discoveries related to the investigational product or the trial in general.

The Sponsor's Perspective: The Sponsors will want broad language through which it owns all inventions, developments, discoveries, or improvements related to the trial or the investigational product.

The Site's Perspective: In the face of such broad language, the site will – almost without fail – object to the sponsor's language for its breadth. Additionally, the site may be unable to give away its intellectual property rights due to its non-profit status.

The Compromise: One way to span the gap between the sponsor and the site is to draft language that provides for site ownership of inventions created solely by the site and for joint ownership of inventions created by both the site and the sponsor. It will also be necessary to include language that gives the sponsor an option to negotiate a license for the site's interest in either or both. For example:

Any inventions or discoveries made by the Research Site in the performance of the Trial that: (i) are improvements, enhancements, or modifications to the Sponsor's Investigational Product; (ii) are new uses specific to the Sponsor's Investigational Product; (iii) incorporate Sponsor Confidential Information; or (iv) are anticipated by the Sponsor's protocols will be the sole property of Sponsor ("Sponsor Invention'')􀀀.

All inventions developed solely by the Research Site that are not sponsor Inventions shall be owned by Research Site ("Research Site Inventions"). All inventions that are not Sponsor Inventions that are developed by one or more employees of both Sponsor and Research Site under this Agreement shall be owned jointly by Sponsor and Research Site ("Joint Inventions")􀀀.

Sponsor shall have, without option fee, a timelimited, first option to negotiate an exclusive, worldwide, compensation-bearing license to any Research Site Invention and Research Site's rights in any Joint Invention. Sponsor shall advise Research Site in writing of its interest in obtaining an exclusive license to any Research Site Invention and/or Research Site's rights in any Joint Invention within sixty (60) days of Sponsor's receipt of notice of Research Site Invention and/or Joint Invention.

3. PUBLICATION RIGHTS

Publication issues most commonly arise between sponsors and academic institutions. Both sponsors and academic institutions want to publish trial results to share information about the clinical trial with the medical community and the public in a timely, accurate, and orderly manner; ensure the safety of the trial participants and the general public; advance science and medicine; meet regulatory obligations and industry guidelines; increase visibility; and promote their reputations within medical and scientific communities and with the general public. However, the independent publication goals of each party can result in a disagreement over CTA language.

The Sponsor's Perspective: The Sponsor prefers narrowly tailored language that ensures protection of its intellectual property and confidential information; facilitates multi-site coordination; safeguards the integrity of trial results, and furthers its competitive advantage.

The Site's Perspective: Sites are primarily focused on contributing to public knowledge; disclosing results for use in future research; and advancing its investigator's professional interests. The site will likely view the sponsor's language as an attempt to limit its academic freedom, interfere with its ability to publish data before other sites, and stymie its efforts to promote transparency and patient safety and education.

The Compromise: The key to resolving opposing interests can be resolved by making reasonable concessions on what information the site can publish, the timing of such publication, and the sponsor's ability to prevent publication of certain information. For example:

Research Site has the right to publish the results that it contributes and generates as a result of its Trial participation with due regard to the protection of Sponsor's Confidential Information provided that any such publication shall be delayed until the earlier of (i) the publication of the multi-center publication; (ii) notice from Sponsor that no multicenter publication will be forthcoming; or (iii) Twelve (12) months after the conclusion of the Trial all sites.

Research Site shall submit any proposed publication to Sponsor at least sixty (60) days before submission for publication. Sponsor will have the right to review and comment upon the publication in order to protect Sponsor Confidential Information and/ or Intellectual Property. Prior to releasing such publication, Research Site will delete Sponsor Confidential Information and Sponsor Intellectual Property. Upon Sponsor's request, publication will be delayed up to ninety (90) additional days to enable Sponsor to secure adequate intellectual property protection. Notwithstanding the foregoing, Sponsor cannot (i) require deletion of result generated and contributed by Research Site; (ii) require deletion of information needed to explain results and their scientific significance; or (iii) require deletions that make the publication incomplete, inaccurate, or misleading.

4. TRIAL PARTICIPANT INJURY

Trial participant injury is generally one of the most heavily negotiated provisions in a CTA. A sponsor is not legally required to cover medical expenses incurred in the treatment of a participant's injuries; however, most sponsors voluntarily agree to some level of reimbursement for medical expenses. While the parties generally agree that the reimbursement should be limited to medical expenses (i.e., not lost wages, pain and suffering, etc.), the sponsor's initial reimbursement offer usually falls short of what the site feels is adequate.

The Sponsor's Perspective: The sponsor's proposed injury reimbursement language usually requires that injury be directly caused by participation in the trial, provides that solely the sponsor will make the determination on causation, excludes certain intervening causes, and establishes a reasonable rate of reimbursement that is consistent with what would be paid outside of the context of the trial. Additionally, in an effort to reduce its financial risk, the sponsor may require that the site seek reimbursement of expenses from private insurers before seeking reimbursement from the sponsor.

The Site's Perspective: The site will likely remind the sponsor that since the sponsor is the ultimate beneficiary of the research, the sponsor's coverage of medical expenses should be as broad as possible. Consequently, the site will balk at narrowly tailored language, at attempts to exclude reimbursement – especially when predicated on the participant's behavior – and at disparate treatment based on the participant's insured status. Additionally, the site may have an issue with the determination of causation being solely the sponsor's call.

The Compromise: Once each side recognizes that the other party has valid and reasonable reasons driving its position on trial participant injury, compromises that serve the needs of both sponsor and site can easily be made. While some provisions will likely require a more thorough benefit/ risk analysis by the sponsor before concessions can be made, e.g., removing the requirement to file insurance and deleting the exclusion related to the trial participant's negligence or failure to follow instructions, the parties should be able to agree to:

  • tie the injury to the trial but make allowances for aggravation of pre-existing injuries;
  • mutual determination on causation or simply remain silent;
  • exclude reimbursement caused by the site's negligence (which is consistent with common law principles of liability); and
  • establish a rate of reimbursement equivalent to what an insurer would pay or negotiate a set flat rate acceptable to both parties.

Notwithstanding the foregoing, it is critical to note that, due to kick-back concerns, the terms agreed upon by the parties in the CTA cannot offer reimbursement beyond what the informed consent document promises to the trial participant.

USE OF AGREED UPON CTA TERMS IN MASTER CLINICAL TRIAL AGREEMENTS

To further reduce CTA negotiation time for future CTAs, sponsors and sites can capitalize on the momentum built during a successful CTA negotiation by using the final negotiated terms as a foundation for drafting a master clinical trial agreement.

A master clinical trial agreement, or MCTA, is an umbrella agreement between the sponsor and site where both parties agree upon a set of contractual terms and conditions for future clinical trials. Establishing a MCTA alleviates the need to re-negotiate the CTA's terms each time a new clinical trial is contemplated. Instead, a short and simple individual trial agreement is executed for each new trial. The individual trial agreement will incorporate the terms of the MCTA and set forth conditions specific to the particular study, such as protocol title, principal investigator name and budget.

While the MCTA will have some unique provisions, such as language describing the use of individual trial agreements and the term of the master agreement, the majority of the provisions should be comparable to the recently completed CTA. The parties may need to renegotiate if the MCTA will apply to a wider range of trial phases/investigational products or if additional levels of institutional review and comment may be required for master agreement. However, the vast majority of the prior language should be able to carry over into the MCTA, keeping negotiation time to an absolute minimum. As a result, trials can get up and running without delay.

CONCLUSION

Sponsors and clinical trial sites have a common interest in quickly negotiating clinical trials. By simply understanding the needs of the other party, recognizing where compromises can be made, and leveraging prior agreed upon language, the parties can effectively and efficiently eliminate CTA sticking points and quickly begin research activities.

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