Tag Archives: SEAS IMPROVE-IT Dr. Allen Taylor NEJM Heart.org FierceBiotech SEAS cancer signal letter Peto Califf Questions Schering August 17 2009

A More Modern (PI Independent) Version of a Pharma Sponsored Clinical Trial Agreement


To round out the trilogy, started yesterday here, and here, I offer this — the preferred, more balanced and modern version of the Study data ownership, control and publication provisions — in a Pharma Co. sponsored clinical trial agreement. I may yet lay out some SEC analysis, to explain why changes to those rules aren’t needed — so long as PIs preserve their independence, and universities do the same, when negotiating clinical trial agreements. To the preferred model clauses, then:

. . . .3. PROPRIETARY RIGHTS

Definitions

Data. “Data” is defined as all data, results, conclusions and observations arising from this Study, elements of which may be duplicated within the [Pharma Co.] Sponsor Deliverables (as defined below) and the Original Source Documents (as defined below). All Data shall be promptly and fully disclosed by University and/or Principal Investigator to [Pharma Co.] Sponsor.

New Inventions or Discoveries. “New Invention or Discovery” shall mean any invention or discovery conceived or reduced to practice during and as part of the Study performed pursuant to this Agreement. [The terms “conceived” and “first reduced to practice” shall be given the meaning of those terms as they appear in 35 U.S.C. §102 (g).]

Original Source Documents. “Original Source Documents” is defined as the original of all medical records, hospital records, clinical and patient charts, laboratory notes, pharmacy dispensing records, recorded data from automated instruments, microfiches, photographic negatives, microfilm or magnetic media, X-rays and other diagnostic images, and other records generated and maintained by the pharmacy, laboratories and medico-technical departments of University. University shall at all times retain ownership of all Original Source Documents generated by University.

Sponsor-Initiated Protocol Study. “Sponsor-Initiated Protocol Study” is defined as a Study for which all material provisions of the Protocol have been developed by [Pharma Co.] Sponsor, or its agents and provided to University or the Principal Investigator.

Sponsor-Deliverable. “Sponsor-Deliverables” is defined as all case report forms and any other report required by the Protocol and prepared as part of this Study by [Pharma Co.] Sponsor.

All Sponsor-Deliverables shall be the property of [Pharma Co.] Sponsor .

All Data arising from this Study shall be the sole property of University. [Pharma Co.] Sponsor shall have, upon Study completion, or termination, the right to freely utilize such Data resulting from this Study for any and all legal purposes (consistent with the scope of the informed consent and HIPAA authorization given by the Study Subjects). University hereby grants [Pharma Co.] Sponsor a non-exclusive, royalty free, worldwide license, to use all such Data.

All rights, title and interest in and to any inventions representing a reduction to a practice of a [Pharma Co.] Sponsor’s prior conception as expressed in the Protocol or other written records of [Pharma Co.] Sponsor, the know-how evident thereto, and any patent applications and resultant patents derived therefrom shall be the exclusive property of [Pharma Co.] Sponsor (“Sponsor IP”).

With the exception of the Sponsor IP, [the PI and University] will retain title to any patent or other intellectual property rights in New Inventions or Discoveries made solely by their respective employees in the course of the Study. New Inventions or Discoveries made jointly by University and Sponsor shall be jointly owned by the parties.

For New Inventions or Discoveries developed solely by University, the University or its designee, consistent with the University’s technology transfer policies, will offer [Pharma Co.] Sponsor the first option to enter into a royalty-bearing license agreement to obtain an exclusive, royalty-bearing license to all rights in such New Invention or Discovery, which must be exercised within sixty (60) days of Sponsor’s receipt of notice of such invention. If [Pharma Co.] Sponsor licenses such an invention, [Pharma Co.] Sponsor shall pay University a reasonable royalty as determined by the commercial value of such invention. In the event [Pharma Co.] Sponsor fails to exercise its right of first refusal within this sixty (60) day period, University shall be free to license such inventions to third parties on terms no less favorable than those offered to [Pharma Co.] Sponsor.

University shall promptly notify [Pharma Co.] Sponsor and shall assist [Pharma Co.] Sponsor in gaining patent protection for the New Invention or Discovery, if applicable. [Pharma Co.] Sponsor shall reimburse University for all reasonable expenses incurred thereby, provided University has given reasonable written notice prior to incurring such expenses. Any patent application shall be filed, maintained and prosecuted by [Pharma Co.] Sponsor or its designee. University shall retain a royalty-free, irrevocable right to continue using the Invention or Discovery solely for its internal, non-commercial use. . . .

5. PUBLICATIONS

University and/or Principal Investigator shall have the right to publish the results of the Study. Prior to submission for publication of any manuscript, poster, presentation, abstract or other written or oral material describing the results of the Study, the University and/or the Principal Investigator shall provide [Pharma Co.] Sponsor thirty (30) days to review a manuscript and fifteen (15) days to review any poster presentation, abstract or other written or oral material which describes the results of the Study for the sole purpose of determining if any patentable information is disclosed thereby. If [Pharma Co.] Sponsor requests in writing, the University and/or the Principal Investigator shall withhold any publication or presentation an additional sixty (60) days solely to permit [Pharma Co.] Sponsor to seek patent protection and to remove any Confidential Information from all publications.

Inclusion of the University and/or Principal Investigator in the authorship of any multi-center publication will be based upon substantial contribution to the design, analysis, interpretation of data, drafting and/or critically revising any manuscript(s) derived from the Study. The University and the Principal Investigator agree that if a Study is part of a multi-center study, any publication by the University and/or Principal Investigator of the results of the Study conducted at University shall not be made before the first multi-center publication. In the event there is no multi-center publication within twelve (12) months after a Study has been completed or terminated at all Study sites, and all data has been received, University shall have the right to publish its results from the Study, subject to the notice requirements described above. . . .

7. CHANGES TO THE PROTOCOL AND ON-GOING STUDY MONITORING

A. If generally accepted standards of Good Clinical Practice (“GCP”) as defined in the ICH Guideline for Good Clinical Practice and in 21 U.S. Code of Federal Regulations (“C.F.R.”) Parts 50, 54, 56, and 312 relating to the safety of Subjects require a deviation from any Protocol, these standards will be followed. Any party who becomes aware of the need for a deviation from the Protocol will immediately inform the other party to this Agreement of the facts causing the deviation as soon as the facts are known to the party. In addition, Principal Investigator will promptly inform University’s institutional review board (“IRB”) of the deviation.

B. [Pharma Co.] Sponsor may also, from time to time, make changes to any Sponsor-Initiated Protocol. Any such changes may not be implemented before approval by the University’s IRB. If these changes will affect the cost of the Study, University will provide Sponsor with a written estimate of the change in Study cost and Sponsor will remunerate University for any increase in cost.

C. [Pharma Co.] Sponsor agrees to notify University (through the Institution’s IRB, with a copy to the Institution’s Principal Investigator) promptly of any findings, whether such results are final or part of an interim analysis, of which [Pharma Co.] Sponsor becomes aware which may affect the safety or medical care of Study participants or their willingness to continue as participants, alter the risk/benefit ratio of the Study, or alter the conduct of the Study. The IRB shall be responsible for communicating such results and possible effects to the Subjects in an appropriate manner. During the Study and at the conclusion of the Study, [Pharma Co.] Sponsor will continue to inform Institution of observed Study Drug/Device effects so Institution, if appropriate can inform Subjects.

D. Upon the written request of the University’s IRB or the Principal Investigator, [Pharma Co.] Sponsor shall provide to University’s IRB copies of any data safety monitoring reports related to the Study, including any reports of any independent data safety monitoring committees.

E. [Pharma Co.] Sponsor shall have the right, upon reasonable notice and during regular business hours, to audit the Principal Investigator’s conduct of the Study. [Pharma Co.] Sponsor shall provide a copy of the outcome of any such audit to the Principal Investigator and to the University’s IRB. Upon the written request of the University’s IRB or the Principal Investigator, [Pharma Co.] Sponsor shall provide to University’s IRB copies of any data safety monitoring reports related to the Study, including any reports of any independent data safety monitoring committees. . . .

If IMPROVE-IT (and/or SEAS and SHARPS) were being conducted under an agreement such as the above [generally modeled after the University of Pittsburgh’s current Clinical Trial Agreement form — but with some subtle, yet substantial modifications by your erstwhile editor(!)], Dr. Califf would have been able to provide his interim data, knowing that the same would not be disclosed at a hastily-convened press conference (PR damage control event), or aggregated, then disclosed, unless required by applicable law. He and the University would also own the data — the Study results, and retain an unfettered right to publish even a null result.

The parties (Schering-Plough, Merck and Duke) have not disclosed the clinical trial agreement(s) governing IMPROVE-IT, so there is no way to know which of these two competing forms control IMPROVE-IT. The old, pro-Pharma Co. Sponsor version, or the above, more modern and balanced one.

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Pharma Sponsored Clinical Trials Agreements, Reconsidered. . . .


This is Part Two, to this companion piece, of yesterday. It deals with more weedy details — in the hope of avoiding “the next iceberg” — the next highly-orchestrated early-release of partial top-line studies data, a la the July 2008 SEAS-style press event. So to get right to it, then:

In many clinical trials agreement forms signed prior to 2006 (such as the one likely signed by Duke, Dr. Califf and Merck-Schering-Plough), the corporate sponsor may hold great sway over what happens with data from a given study. In fact, in many of these older agreements, the corporate sponsor (referred to as “Pharma Co.”, below) may own the data, outright.

It is then possible, that under the IMPROVE-IT clincial trial acreement, Dr. Califf (and by extension, Duke University) possessed no right to “say no” to Merck/Schering-Plough’s interim use of the data — even if all Merck and Schering-Plough wanted the early access to study data for was to butress a claim that the cancer signal data in SEAS was spurious. In other words, even if Schering-Plough solely sought the data for PR or Investor Relations purposes.

To be clear, safety should always be paramount, but assuming Dr. Califf was adequately monitoring his IMPROVE-IT patient-data-sets for cancer signals (and we have no reason to suspect he wasn’t) — then he was, in some fashion, made an unwitting shill, at the July 21, 2008 SEAS (highly orchestrated) press event, primarily because his clinical trial agreement did not afford him enough independence from (Pharma Co.) sponsor-influence. Here is a typical version of the relevant older, pro-sponsor contract clause:

. . . .INVENTIONS AND DATA

Pharma Co. shall exclusively own all rights, title and interests (collectively “Rights”) in and to any inventions, data (including Study results and any clinical specimens or samples obtained from Subjects), discoveries, know-how, patents, copyrights, moral rights, trade and service marks, and trade secrets and other intellectual property, including but not limited to inventions, discoveries and technology relating to the Investigational New Drug or otherwise generated by the Study (collectively, the “Discoveries”). The Study Center and the Researchers hereby irrevocably transfer and assign any and all their Rights in any such Discoveries to Pharma Co.. The Discoveries will be the sole property of Pharma Co. and Pharma Co. will have the right to determine the treatment of any Discoveries, including the right to keep them as trade secrets, to file and execute patent applications on it, to use and disclose it without prior patent application, to file copyright and trademark applications on it or its own name, or to follow any other procedure Pharma Co. deems appropriate. . . .

Note also that the above clause would allow the Pharma Co. permanently to prevent publication of a null result, for example. All the Pharma Co. need say was that all data comprised “trade secrets“, and was thus immune from publication (and any other disclosure) by the university or the Principal Investigator(s).

Some other time, I will outline a more modern, and independent version of these sorts of clinical trial agreement clauses, but upon reflection, this clause (in part) could have contributed significantly to Dr. Califf’s feeling “forced” (by Merck and Schering-Plough) to disclose (at least three years’ prematurely) the top-line IMPROVE-IT trial data, perhaps even directly to agents of M/SP, rather than an ad hoc committee of his PI peers, in strict-confidence. Such a strictly confidential “PIs only” disclosure could have been conditioned upon a covenant preventing M/SP from using it for [remature PR purposes.

I may post more on this, if readers’ interest, or developments, warrant.