Legal Resources - Clinical Research Agreement

Throughout the following explanatory notes, “NPC” and “Institution” both mean a nonprofit corporation established under 38 U.S.C. §§ 7361 – 7368 and the term PI is used for Principal Investigator.

All explanatory notes are in italics. Suggested and alternative clauses as well as suggested letters are in regular type.(FTCA)

SAMPLE CLAUSES

1. IDENTIFICATION OF PARTIES & PREAMBLE

This clause serves two important purposes. It identifies that there are only two parties to the Agreement, the Sponsor and the NPC. Although the PI is identified in this clause, neither the PI nor VA is a party to the Agreement (See Clause 15).

The second purpose is to focus on the research-aspect of the Study. Some thirty-five years ago, the IRS determined that clinical testing of drugs purely for the purpose of obtaining FDA approval is part of the commercial marketing process and is not scientific research. This resulted in denial of tax-exempt status for an organization that was found to have been created solely to perform clinical drug testing for various unrelated organizations. The organization could not demonstrate the requisite public benefit of such activity. A subsequent IRS Private Letter Ruling discussed a similar situation and reached a different conclusion. It looked at studies that “involve the search for new or improved methods of treating human afflictions” and stated that these “are concerned with new applications of products or drugs in order to improve the ability to treat various diseases and conditions.” The private letter ruling found such studies to be scientific research.

An NPC is authorized by Federal law “to provide a flexible funding mechanism for the conduct of approved research and education at the [VA] medical center” (emphasis supplied). As a result, the NPC authorizing statute bolsters the position that the work an NPC supports is research, not commercial activity. However, it is still important to have language in the CRA stating the position that the NPC work is research in order to satisfy IRS concerns.

SUGGESTED:

[NPC NAME & ADDRESS] (“Institution”) agrees to participate in a collaborative Clinical Research Agreement sponsored by [SPONSOR NAME & ADDRESS] (“Sponsor”) and conducted by [PI NAME] (“Principal Investigator”). This agreement is entered into as of the last date on the signature page hereof. The parties desire to combine their mutual interests and resources to search for new or improved methods of treating human afflictions.

Institution is a flexible funding mechanism established pursuant to 38 U.S.C. §§ 7361-7368 and as such facilitates research approved by the Department of Veterans Affairs (“VA”) and conducted by employees of [VAMC NAME] (VAMC) and Institution.

The parties agree as follows.

ALTERNATIVE:

This Agreement (“Agreement”) is entered into as of the last date on the signature page hereof and sets forth the terms and conditions and establishes the relationship between [NPC NAME &ADDRESS] (“Institution), a nonprofit corporation affiliated with the Department of Veterans Affairs (VA), and [SPONSOR NAME & ADDRESS] (“Sponsor”) to facilitate research.

Sponsor and Institution desire to combine their mutual interests and resources to search for new or improved methods of treating human afflictions and to collaborate in the performance of a clinical investigation of [VERY BRIEF DESCRIPTION (e.g. – heart disease; diabetes; lung cancer.)]. This Study will be coordinated by [PI NAME] (hereinafter “Principal Investigator”).

The VA, the Institution, and the Principal Investigator possess valuable skills, knowledge, expertise and resources in relation to the field of research identified in the Protocol and desire to further serve the VA patients and the general public through medical research. Institution shall facilitate the conduct of this research, which has been approved by the VA in conjunction with the [VAMC NAME] and shall use all reasonable effort to ensure performance of this Agreement which shall provide maximum benefit to the VA, its veterans and the general public.

The parties agree as follows.

Many Sponsors are unfamiliar with the NPC’s relationship with VA. To help explain this relationship, the following paragraph may be used in an introductory letter to Sponsor:

[NPC NAME] is a nonprofit research corporation established and authorized by sections 7361-7368 of Title 38, United States Code to provide a flexible funding mechanism for the conduct of VA approved research. Our corporation facilitates research conducted by VA and corporation employees at the [VAMC NAME], a Federal facility. Federal law and the relationship between the nonprofit research corporation and VA, necessitate some changes to this Agreement.

2. OWNERSHIP OF PROPERTY

2.1 Inventions [Patent Law]

Executive Order 10096 (1/24/50), as implemented by 37 C.F.R. §§ 501.6 & 501.7, provides that the Government obtains a right in any invention made by any Government employee during working hours, with contribution of Government facilities, equipment, material, funds or information, or which has a direct relation to the duties of the inventor. 37 C.F.R. § 501.6 (a)(1). ~~However the~~ Certain regulations do permit an after-the-fact determination and release of Government rights in some circumstances. 37 C.F.R. §§ 501.6 (a)(2) – (4) & 501.7.

NPCs are encouraged to use the language provided in Paragraph 1 for any clauses addressing intellectual property. Many sponsors will be satisfied with this language.

If in advance of development or disclosure, the sponsor requires explicit ownership of any new intellectual property resulting from the study, or the right of first refusal to license such intellectual property, the following applies:

Commitment of intellectual property ownership developed using VA resources and the first right to license intellectual property in advance of discovery and disclosure can be accomplished through Cooperative Research and Development Agreements (CRADAs) pursuant to 15 U.S.C. §3710a of the Federal Technology Transfer Act or in cooperation with the affiliated university, subject to an approved arrangement under a Cooperative Technology Administration Agreement (CTAA). A CTAA provides that the affiliated university will administer intellectual property developed by dual VAMC and university appointees. This includes the right to determine the licensee for further development and marketing of such intellectual property.

As a result:

1. If the inventor is solely a VA employee, a CRADA must be used to pre-commit ownership and/or licensing of new intellectual property.

2. If the inventor is a dual VA and university employee and the VA medical center has entered into Cooperative Technology Administration Agreements (CTAA) with the affiliated university: OGC has stated that NPCs associated with VAMCs with a CTAA in place should work with the affiliated university to obtain a waiver or an exception to the CTAA, or to obtain permission to give the sponsor the first option to license the intellectual property. [This is consistent with paragraph 2.a. of the June 25, 2004, memo distributed by the Acting CRADO.] This applies whether a clinical research agreement or a CRADA is used for a particular study. Language addressing such situations is contained in some CTAAs. If it is not, the NPC is encouraged to to work with the university to modify the CTAA to make a reasonable accommodation.

3. If the inventor is a dual VA and university employee and the VA medical center has not entered into a CTAA with the affiliated university: The NPC must work with the sponsor and the VA to develop a CRADA in order to make any pre-commitment of ownership and/or licensing rights. The following patent language (effective 10/1/01) is consistent with that order and regulations. This is the current VA‑approved clause (Per VA General Counsel Staff Attorney Centanni’s 10/1/01 e mail: This language appears consistent with VA regulations and policy).

If the Sponsor is hesitant about agreeing to the following suggested language, point out that since regulations do not permit the Government to agree to relinquish ownership rights “up front”, that this inventions language is the next best thing because VA agrees to deal first with Sponsor and negotiate in good faith for a license. This gives the greatest protection to Sponsor consistent with the regulations. As an additional step, Sponsor could obtain an assignment at the present time from the PI. Then, if the PI/inventor later receives a determination under 37 C.F.R. sec. 501.7 relinquishing ownership to her/him, Sponsor will have acquired ownership of Government rights through that assignment from the PI and not merely a license.

Comprehensive information about technology transfer in the VA environment is provided on the VA Technology Transfer web site: http://www.vard.org/tts/entry/entry.htm

SUGGESTED:

Use this paragraph regardless of whether the VA Medical Center has a Cooperative Technology Administration Agreement (CTAA) with its affiliated university. A CTAA allows VA and a university to be joint owners of intellectual property, outlines the handling of the intellectual property, and provides for the sharing of royalty income.

Paragraph 1

Inventions, Discoveries & Ownership of Results. Any information, invention or discovery, innovation, suggestion, idea, communication and report (whether patentable or not) (collectively “Invention”), conceived, reduced to practice, made or developed by Principal Investigator using resources provided by the Department of Veterans Affairs as a result of conducting the Study, are controlled by Federal law (35 U.S.C. §§ 102 & 200-212, 37 C.F.R. Part 501, and 38 C.F.R. §§ 1.650 - 1.663). Such invention resulting from this Study shall be disclosed to both VA and Sponsor, and may be subject to joint ownership by VA and Sponsor.

~~Paragraph 2A~~ ~~[Use this paragraph in addition to Paragraph 1 above when there is no CTAA.]~~

If VA obtains ownership of such Invention arising from research conducted under this Study, Sponsor shall be granted the first opportunity to obtain a license for use of the Invention based on good faith negotiations between the parties. If Sponsor pursues a worldwide and exclusive license, it will be subject to federal regulations published at 37 CFR 404.7. Whether nonexclusive, partially exclusive or exclusive, such license will be subject to the right of the United States to retain an irrevocable, royalty-free right to use the Invention throughout the U.S. Government.

~~Paragraph 2B~~ [Use this paragraph in addition to Paragraph 1 above when there is a CTAA - the only difference between Paragraphs 2A & 2B is that “shall” in the first sentence of Paragraph 2A has been changed to "may" in the first sentence of paragraph 2B.]

If VA obtains ownership of such Invention arising from research conducted under this Study, Sponsor may be granted the first opportunity to obtain a license for use of the Invention based on good faith negotiations between the parties. If Sponsor pursues a worldwide and exclusive license, it will be subject to federal regulations published at 37 CFR 404.7. Whether nonexclusive, partially exclusive or exclusive, such license will be subject to the right of the United States to retain an irrevocable, royalty-free right to use the Invention throughout the U.S. Government.

ALTERNATIVE:

Sometimes, after all is said and done on the inventions language in the Agreement, the Sponsor’s proposed language remains inconsistent with the VA approved language. One solution would be to add the following sentence at the end of the inventions clause you negotiate with Sponsor.

Notwithstanding any other language in this Agreement, any information, invention, discovery, or innovation arising from research conducted under this Study shall be governed by applicable Federal laws and regulations.

Another alternative would be to consider this a deal breaker and decline to enter into an Agreement unless the suggested clause is used.

ADDITIONAL POINT:

A Sponsor may insist on owning all rights "in and to any inventions, enhancements, modifications or improvements of Sponsor’s technology in existence at the effective date of the Agreement" (emphasis supplied). This is consistent with the suggested clause because it merely recognizes Sponsor’s ownership rights in any of the described items up to commencement of the Study.

2.2 Data [Copyright Law]

The U.S. Copyright Act (17 U.S.C. §§ 101 – 810) is Federal legislation enacted by Congress under its Constitutional grant of authority to protect the writings of authors. (Article I, Section 8). Given the scope of the Federal legislation and its provision precluding inconsistent state law, the field is almost exclusively a Federal one (17 U.S.C. sec. 301).

Among the rights included in a copyright is the exclusive right of the owner to reproduce, distribute, perform, display, or license his or her work (17 U.S.C. sec. 106). The owner also receives the exclusive right to produce or license derivatives of his or her work (17 U.S.C. sec. 201(d)). The law specifically provides that copyright protection is not available for any work of the United States Government (17 U.S.C. sec. 105). This means that this work cannot be owned by anyone. A "work of the United States Government" is defined as a work prepared by an officer or employee of the United States as part of that person's official duties (17 U.S.C. sec. 101). Consequently, neither the suggested nor alternative clauses contain any language stating that the Sponsor, Principal Investigator or Government owns the data generated from the Study.

Copyright law prohibits the use of a work "owned" by another without the owner's permission. What does it mean to “own” something? A simple example of ownership of something is when a person can say to the world “keep out or keep your hands off this unless you have my permission” and the Government enforces that claim with a law. Since "works of the United States Government" are not copyrightable (i.e., subject to being owned), one is allowed to prepare derivations of such works without permission (however, one may not use classified Government information without permission in a derivative work). A copyright may then be obtained on the derivative work. In order to copyright a derivative work based on one or more preexisting Government works, a notice for the derivative work must "include a statement identifying, either affirmatively or negatively, those portions " of the later work for which copyright may be claimed (17 U.S.C. sec. 403).

SUGGESTED:

All documents, protocols, data, know-how, methods, operations, formulas, confidential information and materials provided to the Investigator by Sponsor are and shall remain Sponsor’s property.

The Completed Case Reports, the Final Report and other documents resulting from the Study shall also be owned by the Sponsor. Copies of any documents referenced herein shall be returned to Sponsor upon Sponsor’s request within fourteen (14) days of such request. Investigator shall have the right to retain a copy for VA or its researchers as is appropriate, for clinical use of the results of the research contemplated in this Agreement.

Patient records are excluded from any discussion of sponsor ownership of reports, records, etc. generated by the Study.

This language is consistent with the copyright laws discussed above and was approved by General Counsel. Although it addresses ownership of the report forms and other physical documents, it is silent about data ownership. However, it contains no language restricting Sponsor from using the data for any purpose.

If Sponsor wants specific language stating that it is permitted to use the data generated from the research, the following alternative could be used.

ALTERNATIVE:

With the exception of patient records, and subject to the rights of publication described in this Agreement, all case report forms and other reports generated during the course of this Study are Sponsor’s property. All data may be used by Sponsor for any purpose without further financial obligation or restriction. Investigator shall have the right to obtain and use such data in order to publish the Study results, for continuing academic research purpose, and for the treatment and medical care of any Study subject.

2.3 Equipment

If Sponsor furnishes equipment or funds to purchase equipment used in the Study, the Agreement should contain language describing the equipment and its disposition after the Study. Clearly, the Sponsor may retain ownership of the equipment and require its return after Study completion. If Sponsor relinquishes ownership the NPC, not the Principal Investigator, should be given ownership. The NPC would then use the equipment to support other VA-approved research. The NPC should review its Articles of Incorporation and Bylaws to ensure that nothing in those documents prohibits its ownership of the equipment.

SUGGESTED:

The following equipment or funds to purchase it is furnished by Sponsor: _____________

Add “a” or “b” to the above:

a. At the completion of the Study, the equipment will be returned to the Sponsor at its expense.
b. At the completion of the Study the equipment will become the Institution’s property for use in other VA-approved research projects.

3. USE OF NAMES AND LOGOS

The suggested clause is similar to what many NPCs have been using. The alternative clause, while giving Sponsor more flexibility in publicizing basic Study information, still limits the use of VA’s or subjects’ names without consent. Section 2635.702 refers to the ethics regulation that prohibits a Federal employee from using public office for the private gain of self or others, including the appearance of governmental sanction or endorsement.

Sponsors may seek language requiring all publicity requests (e. g. media or financial analysts) be funneled through them. NPCs may agree to such a provision so long as publication rights (See Clause 10) are not diminished.

If a CTAA exists between the VA Medical Center and its affiliated university, the university should be mentioned (See Clause 2.1 for explanation of CTAA).

SUGGESTED:

Sponsor shall not use the name of the Institution, VA or study subjects in any form of public information without the written consent of the entity or person involved. This in no way is intended to restrict free publication in scientific journals.

Neither party shall include the name of the other party in any advertising, sales promotion or other publicity release without the prior written approval of that party.

All advertising and/or endorsements are subject to 5 C.F.R. § 2635.702.

ALTERNATIVE:

Sponsor may use the name of each party, title and purpose of the Study, protocol summary, basic eligibility criteria, study site locations and contact information for normal business purposes and may provide the same information to prospective or actual clinical study participants.

Each party agrees not to use the name of any other party, VA, or participant in the Study, in any advertising or news release or other publication without the prior written consent of the other parties.

All advertising and/or endorsements are subject to 5 C.F.R. § 2635.702.

4. PAYMENTS AND NOTICES

The suggested clause provides for names and addresses where payments and notices are to be sent. The alternative adds language regarding the method and timeliness of the delivery.

SUGGESTED:

PAYMENTS. All payments shall be made only to the Institution and sent to:

Contact Person:

Institution Name:

Address:

Tax ID No.:

NOTICES. All notices given by either party to the other should be sent to:

SPONSOR

Contact Person:

Institution Name:

Address:

INSTITUTION

Contact Person:

Institution Name:

Address:

With copy to:

PRINCIPAL INVESTIGATOR

Name:

Address:

ALTERNATIVE:

PAYMENTS. All payments shall be made only to the Institution and sent to:

Contact Person:

Institution Name:

Address:

Tax ID No.:

NOTICES. All notices required or permitted in this Agreement shall be in writing and shall be deemed given as of: (a) the date if delivered by hand or (b) three business days after it is sent by certified mail, postage prepaid, return receipt requested, and addressed to the party to receive such notice or the Investigator at the address set forth below, or such other address as is subsequently specified pursuant to this notice provision:

SPONSOR

Contact Person:

Institution Name:

Address:

INSTITUTION

Contact Person:

Institution Name:

Address:

With copy to:

PRINCIPAL INVESTIGATOR

Name:

Address:

A party or the Investigator may give notice of change of address to the others by following the provisions of this section.

5. ORDER OF PRECEDENCE

This clause may not be needed in every Agreement. Use this clause only if the Sponsor states that the terms of that the Agreement control language over any inconsistent terms in other documents. The suggested clause accommodates this position while making it clear that the Study Protocol is not affected. Any change to the approved Study Protocol requires the consent of all entities that approved the Protocol (usually the Sponsor, the IRB(s) and the VA R&D Committee).

SUGGESTED:

In the event of a conflict between the terms of this Agreement and any other agreement entered into by the parties, the terms of this Agreement shall prevail. However, the current Protocol will continue to control all clinical and scientific aspects of the Study and will be followed until properly amended.

6. LIABILITY FOR NEGLIGENCE

(Indemnity, Federal Tort Claims Act, Insurance, and Providing Treatment for Research-related Injuries)

6.1 No Reciprocal Sponsor - Institution Indemnity

Institution should not agree to indemnify or hold the Sponsor harmless. This would make the Institution financially liable for any negligence that would otherwise be the Sponsor’s responsibility. In order to protect the Institution from this increased financial liability, Sponsor would have to be made an additional insured under the Institution’s insurance policies. This would be a logistical burden and could significantly increase the cost of the insurance. Consequently, it is recommended that no promise of indemnification be made by either party. The suggested and alternative clauses merely state existing tort (negligence) law.

Institution should never agree that VA will indemnify and hold Sponsor harmless. Clause 6.3 contains language describing the extent of VA’s liability for negligence.

SUGGESTED:

Each of the parties shall retain all the rights and remedies available under applicable federal and state laws. Each of the parties shall be responsible and liable for the negligent acts, errors and omissions of its respective employees, agents and representatives.

ALTERNATIVE:

Institution will be responsible for damages to the extent caused by the negligence of its officers, agents and employees arising from the performance of this Agreement. Sponsor will be responsible for all damages to the extent caused by the negligence of its officers, agents and employees arising from the performance of this Agreement.

6.2 Unilateral Indemnity by Sponsor

If Sponsor offers to indemnify the Institution and Principal Investigator without any reciprocal expectation, the suggested clause should be added at the end of the Sponsor’s indemnity language.

SUGGESTED:

Should the U.S. Government or a Federal employee be named as a party to a lawsuit, Sponsor acknowledges that the U.S. Government is represented by the U.S. Department of Justice in accordance with 28 U.S.C. § 516 and any decision to settle or compromise such a lawsuit will be made by the U.S. Government after consultation with the Sponsor

6.3 FTCA Coverage in Lieu of Insurance

The NPC should have a general liability or office insurance package. However, this would not cover medical malpractice. Some NPCs have acquired medical malpractice insurance at significant cost but many cannot obtain or afford it. There has been some question as to the extent of Federal Tort Claims Act (FTCA) coverage of WOC employees. In late 2003, Congress approved NAVREF’s legislative request that the NPC authorizing statute should be modified to provide explicit FTCA coverage for NPC employees who hold VA appointments (with or without compensation) and work on VA-approved research or education under supervision of a Federal employee. Based upon longstanding practice, the suggested clause states and explains the coverage afforded by Federal Tort Claims Act to the NPC and VA employees performing the Study.

SUGGESTED:

The Department of Veterans Affairs (VA) is part of the executive branch of the United States. The Government is self-insured and does not maintain general liability insurance. In lieu of any insurance, VA’s liability for the negligence of its employees in performing their duties is governed exclusively by the provisions of the Federal Tort Claims Act, 28 U.S.C. §§ 1346(b) & 2671 – 2680 (FTCA). The individuals conducting the Study under this Agreement are employees or agents of the United States acting in furtherance of their duties. Pursuant to the extent provided for in the FTCA, the Government is financially liable and responsible for damages that result from the negligent or wrongful actions of federal employees acting within the scope of their employment. The FTCA generally provides that the Government will intervene in negligence claims brought against its employees and will defend, settle or pay them as appropriate.

The following paragraphs may be used in a letter to explain to the Sponsor why the Institution cannot agree to indemnify and hold it harmless (See Clause 6.1) and the provision of FTCA coverage in lieu of medical malpractice insurance (See Clause 6.3).

The research is conducted at the VA Medical Center by Principal Investigator and other VA employees. Consequently, there is little liability exposure to the Institution. We have been informed by our insurer that this Institution’s premiums would rise substantially if it agreed to indemnify and hold any Sponsor harmless because the only practical way for Institution to implement that promise would be to make the Sponsors an additional insured on the Institution’s policy.

The VA could not agree to an indemnity and hold harmless provision because the Anti‑Deficiency Act forbids a Federal officer or agency from incurring any obligation which subject the United States to contingent and undetermined liabilities. 31 U.S.C. § 1341; 62 Comp. Gen. 361, 364 (1983).

As a result of this, it has been our policy to decline to indemnify and hold sponsors harmless. Because of this position, we think it only fair that we not require any sponsor to make this promise to Institution. Absent any agreement, each entity is responsible for its own negligent acts in accordance with the laws under which each operates.

Even though there may be some Institution employees working as research assistants, they also hold “without compensation” appointments from the VA Medical Center under 38 U.S.C. § 7405(a) (1) (D) and are considered VA employees for tort liability purposes. The Principal Investigator is always a VA employee. The Department of Veterans Affairs (VA) is part of the executive branch of the United States Government. The Government is self-insured and does not maintain general liability insurance. In lieu of insurance, VA’s liability for the negligence of its employees in performing their duties is governed exclusively by the provisions of the Federal Tort Claims Act, 28 U.S.C. §§ 1346(b) & 2671 - 2680. This law generally provides that the Government will intervene in negligence claims brought against its employees and defend, settle or pay them as appropriate.

6.4 Medical Malpractice Insurance

If Institution carries medical malpractice insurance, the carrier may be mentioned but do not state the amount of coverage because this could cause a problem with the carrier. However, for the reasons stated above, Institution should not promise to indemnify and hold the Sponsor harmless.

SUGGESTED:

Institution has medical malpractice insurance covering its employees performing the Study from [NAME OF INSURANCE COMPANY] in limits equal to or in excess of that required by Sponsor.

6.5 Providing Treatment for Research-Related Injuries

Nothing in the Agreement can affect or negate the potential liability of the Sponsor, NPC, or VA to a research subject who may be injured through their individual or joint negligence. The research subject may assert a claim or file a lawsuit based on some alleged negligence by them. Since the NPC’s employees are also covered by the FTCA (provided that they have a VA appointment and are working on VA-approved research under the supervision of a VA employee), any alleged claims of NPC employee negligence would come under FTCA protection. In order to recover money damages under the FTCA, a research subject must prove negligence on the part of a VA employee.

That said, VA has provided an additional remedy that does not depend on fault (negligence). By regulation (38 C.F.R. §17.85), VA medical facilities shall provide necessary medical treatment to a research subject injured as a result of participation in a research project approved by a VA Research and Development Committee and conducted under the supervision of one or more VA employees. Whether or not the Agreement between Sponsor and NPC refers to this regulation, it will apply.

The NPC should consider requesting that Sponsor provide no fault coverage of research-related injuries to research subjects similar to that provided by VA. The following suggested language may be negotiated. It is not a deal breaker since the Medical Care Recovery Act (MCRA) applies regardless of any language in the agreement. If the injury was caused by some negligent act of the Sponsor and VA provides necessary medical treatment, VA is authorized by the MCRA to recover the cost of that treatment from the Sponsor.

SUGGESTED:

Sponsor agrees to provide reimbursement for:

(1) All reasonable and customary costs incurred and associated with the diagnosis of an adverse event involving the Study drug or a Study procedure; and

(2) All reasonable and customary costs incurred for treatment of physical injury to the subject if SPONSOR determines, after consulting with Investigator, that the adverse event was reasonably related to administration of the Study drug or Study; provided, however, that:

(a) the adverse event is not attributable to Investigator’s or any agents’ or employees’ negligence or misconduct;

(b) the adverse event is not attributable to any underlying illness, whether previously diagnosed or not; and

(c) the Study drug or Study procedure was administered in accordance with the Study.

SPONSOR shall have the option of paying the additional costs directly to the provider of the service or to the Institution.

7. SIGNIFICANT ADVERSE EVENTS

New CRA Clause Requiring Reciprocal Notification - In March 2003, it became apparent that most clinical research Agreements fail to require prompt reciprocal notification between the sponsor and the institution of any Study findings that could affect patient safety. PIs are required to report adverse outcomes to the R&D Committee and IRB, which in turn notify the Sponsor and FDA, but CRAs generally do not require the Sponsor to promptly notify the Institution if it discovers problems in the case reports. The result could be a dangerous lag in Institution action to scrutinize or even halt the Study. To address this problem, all future CRAs should contain the AAHRPP compliant clause which was worked out in collaboration with VA Office of Research & Development [ORD]. Both the suggested and alternative clauses are intended by ORD to go beyond what is required by the FDA’s adverse event notification process.

AAHRPP COMPLIANT CLAUSE - highly recommended:

Human Subject Protection. The research to be conducted under this CRADA involves Human Subjects or human tissues within the meaning of 38 C.F.R. Part 16 and all research to be performed under this CRADA will conform to applicable Federal laws and regulations and VHA policies and procedures. Additional information is available from the HHS Office for Human Research Protections (http://www.hhs.gov/ohrp/). Collaborator and VA shall immediately notify each other upon identifying any aspect of the protocol, including information discovered during site monitoring visits, or the study results that may adversely affect the safety, well-being, or medical care of participants, or that may affect the willingness of participants to continue participation in the research, influence the conduct of the study, or that may alter the IRB’s approval to continue the study, VA shall promptly notify the IRB of any such events. When participant safety or medical care could be directly affected by study results, VA will send study participants a written communication about the results.

SUGGESTED:

Patient Safety – Reciprocal Notification: Sponsor and Institution shall immediately notify the other upon identifying any aspect of the protocol or the Study results that may adversely affect patient safety or well-being. Institution shall promptly notify IRB and VAMC officials.

In July 2003, a Sponsor took exception with the above suggested language. Among its objections were: not even FDA requires immediate notification; the term “any aspect of the protocol” was too broadly defined; and, it already had too many reporting requirements. Since the Investigational New Drug (IND) reporting regulation already requires a Sponsor to notify participating investigators as well as the FDA in a written IND safety report of “adverse experiences” and certain other “findings” (both terms are defined in the FDA regulation), it was decided to build on the FDA regulation in crafting a clause for a Sponsor Agreement. This resulted in an agreement between ORD and the objecting Sponsor. The alternative clause reflects this agreed language. Note that the last sentence contains a mutual notification agreement for “any events or concerns that do not meet the definition of adverse event requiring notification." Generally experienced PIs and Sponsors have a sense of what this requires. If a Sponsor balks at this sentence, it is not a deal breaker.

ALTERNATIVE:

Sponsor shall comply with the requirements of 21 C.F.R. § 312.32. Institution and/or Principal Investigator will report adverse events or findings (as defined in section 312.32) of which they become aware to Sponsor so that it may comply with that section’s reporting requirements. Sponsor shall furnish a copy of the IND safety report to Institution at the time it furnishes it to the FDA. Sponsor, Institution and Principal Investigator agree to notify each other of any events or concerns about the safety of the subjects that arise as the study progresses, even if these events or concerns do not meet the definition of an adverse event requiring notification.

8. CONFIDENTIALITY OF SPONSOR GENERATED INFORMATION [FOIA]

Sponsor may share trade secrets or other confidential information with the NPC or PI. Both the suggested and alternative clauses protect this information from disclosure. The clauses also provide that even if release of such information is required by statute or judicial proceedings, Sponsor will be given timely notification before disclosure so it has an opportunity to take legal steps to prevent disclosure.

The suggested and alternative clause do not contain any language stating that the data arising from the study are confidential or that data are owned or exclusively controlled by the Sponsor. If the Sponsor were to keep the data confidential or exercise exclusive control over it, the PI’s right to publish results might be limited. This could result in negative tax consequences for the NPC (See note at Clause 10). Any claim by Sponsor of study data ownership is contrary to the Copyright laws (See Clause 2.2 explanatory note).

Complying with VA’s reporting requirements may put a PI at risk of breach confidentiality clauses contained in agreements with pharmaceutical research sponsors. Click here for discussion of this issue and a sample project data sheet and abstract.

SUGGESTED:

During the term of this Agreement and thereafter, Institution and Principal Investigator shall use all reasonable efforts not to disclose without Sponsor’s written consent any information that Sponsor designates as confidential.

Institution and Principal Investigator will not disclose Sponsor’s confidential information to any person, except the Sub-investigators, members of the Institution Review Board and VA Research and Development Committee, or as required to the Food and Drug Administration, without the prior written consent of Sponsor. However, Institution may disclose Sponsor’s and Principal Investigator’s names, total grant amount, and a general non confidential title of the Study without Sponsor’s consent to VA and in any government report required of the Institution. Institution and Investigator further agree to take all reasonable precautions to prevent disclosure of Sponsor’s confidential information to a third party by the Principal Investigator, Sub‑investigators, the Institutional Review Board or the VA Research and Development Committee.

The provisions of this section do not apply to any information which:

(1) Was known to Institution or Principal Investigator prior to receiving that information either directly or indirectly from Sponsor, or

(2) Is generally known to the public or which becomes generally known to the public through no act or omission on the part of the Institution or Principal Investigator, or

(3) Is disclosed to Institution or the Principal Investigator at any time by a third party who had a legal right to disclose it, or

(4) Is needed for purposes of treating a patient who participated in the Study, or

(5) Is required by law, regulation, governmental or judicial order, or subpoena to be disclosed, provided Institution and/or Principal Investigator shall notify Sponsor immediately upon receiving notice of such required disclosure to permit Sponsor to oppose same by appropriate legal action.

ALTERNATIVE:

(A) During the term of this Agreement, Principal Investigator and Institution may obtain Information from Sponsor that Sponsor identifies as Confidential Information.

(B) The parties agree: (i) that Confidential Information will be used only in connection with performance of this Agreement; (ii) to treat the Confidential Information as it would their own proprietary and confidential information; (iii) to disclose the Confidential Information only to employees or agents of the Institution that agree to be bound by these confidentiality obligations and who need to know such Confidential Information; and, (iv) to take all reasonable precautions to prevent the disclosure of the Confidential Information to any third-party without the prior written consent of Sponsor. However, Institution may disclose Sponsor’s and Principal Investigator’s names, total grant amount, and a general non confidential title of the Study without Sponsor’s consent to VA and in any required governmental report.

(C) Institution and Principal Investigator shall be relieved of all obligations under this Section regarding Confidential Information which: (i) was known to Principal Investigator or Institution prior to receipt hereunder as set forth in written records; or (ii) at the time of disclosure to Institution or Principal Investigator was generally available to the public, or which after disclosure hereunder, becomes generally available to the public, through no fault of the Institution or Principal Investigator; or (iii) is hereafter made available to Institution or Principal Investigator from any third-party having a right to do so; or (iv) is needed for purposes of treating a patient who participated in the Study; or (v) is required by law, regulation, governmental or judicial order ,or subpoena to be disclosed, provided Institution and/or Principal Investigator shall notify Sponsor prior to any such disclosure to permit Sponsor to oppose same by appropriate legal action.

9. ACCESS TO & CONFIDENTIALITY OF PATIENT/SUBJECT RECORDS

[All Confidentiality & Disclosure Laws Except FOIA]

A comprehensive discussion of the laws that apply to privacy and release of information from VA medical records can be found in VHA Handbook 1605.1. The applicable Federal privacy laws and regulations discussed in that Handbook are listed in Part B of this workshop handout. The brief discussion here is only for the purpose of understanding the suggested clause.

For decades VA has released information from an individual’s medical records only with his or her written authorization except where the law permitted release without consent. The HIPAA Privacy Rule, which became applicable to VA on April 14, 2003, placed additional guidelines on the release or sharing of “protected health information” (PHI) as that term is defined in the Rule. Neither the privacy laws nor the Privacy Rule permits the release of medical records/PHI to a Sponsor. In order for such information to be released to a Sponsor, the research subject must give written authorization. The VA Privacy Office has promulgated VA Form 10-5345 (Authorization for Release of Protected Health Information for Research Purposes) that must be used for HIPAA research compliance. This form includes a section that, when properly filled out, will permit release of relevant medical records/PHI to a Sponsor. If the Sponsor intends to store these records beyond the five years required by the Privacy Act, language permitting this should also be included in the authorization (See Clause 12, Document Retention).

You should also be aware that ORD has determined that, for HIPAA purposes, an NPC is not a VA component, a covered entity or a business associate. This means that no information regarding the research subjects may be given to an NPC without written authorization. The ORD informed consent form contains a section for this purpose. Consequently, if the NPC needs PHI for any purpose such as payment of an enrollment fee or travel expense, you must make sure that the informed consent form provides authorization for release of relevant information to the NPC.

The authorization to disclose PHI is prepared as part of the informed consent process attendant to all VA research projects. The PI or the VAMC’s R&D service is responsible for preparing this document. The NPC’s role is limited to insuring that the responsible party is aware of the extent of the relevant PHI that will need to be released to the Sponsor and the NPC.

SUGGESTED:

Upon reasonable notice and at reasonable times during the term of this Agreement, the Principal Investigator and each Sub‑investigator shall permit representatives of Sponsor to examine their respective facilities, to validate case reports against original data in their files, to make copies of relevant records and monitor the work performed hereunder, to determine the adequacy of the facilities and to determine whether the Study is being conducted in compliance with this Agreement, the Protocol, and relevant government requirements. Access to patient health information shall be in compliance with all Federal statutes and regulations relating to privacy.

10. PUBLICATIONS

The International Committee of Medical Journal Editors recently issued revised guidelines for PIs’ participation in the study design, access to data, and control over publication. If the study is investigator initiated, the resulting CRA need not provide for the study design participation since it has already occurred. More frequently, the proposed research project involves drugs that have had an existing study design and an ongoing testing process prior to the proposed CRA between the Sponsor and NPC. With these two circumstances in mind, the suggested and alternative clauses do not provide for the PI’s participation in the study design.

However, the suggested and alternative clauses do provide for the PI’s access to multi center studies’ data and control over publication. Publication is an important aspect of the research process and limitations on the right of the PI or the Institution to freely publish study results (even if no publication is contemplated at initiation of the study) could adversely affect the Institution’s nonprofit tax status. An IRS Revenue Ruling found that commercially sponsored research otherwise qualifying as scientific research under section 501(c)(3) of the IRS Code, constitutes scientific research carried out in the public interest when the results are published in a timely fashion. This is why the suggested and alternative clauses contain language protecting the ability of the PI to have access to the data and control over publication.

Click here for additional guidance on publication issues.

SUGGESTED:

Publications and Presentations. Institution or Principal Investigator may freely publish and disseminate the results of its investigative findings hereunder. The authorship and contents (including scientific conclusions and professional judgments) of any paper submitted shall be determined by the Principal Investigator. Principal Investigator shall provide Sponsor with a copy of the paper(s) prepared for publication at the earliest practicable time, but in any event not less than thirty (30) days prior to their submission to a scientific journal or presentation at scientific meetings and a reasonably detailed summary or abstract of any other oral or written publication not less than thirty (30) days prior to their submission or presentation. Sponsor may comment upon, but may not make any editorial changes to the results and conclusions set forth in the papers. Sponsor personnel shall be acknowledged in accordance with customary scientific practice.

If a multi-center project add:

As this Study is part of a multi-center trial, publications derived from this Study should include input from Principal Investigator, his/her colleagues, other investigators in this trial and Sponsor personnel. Such input should be reflected in publication authorship, and agreement regarding order of authors should be established before writing a manuscript. Investigators interested in participating in writing the manuscript should contact Sponsor. Selection of authors will depend, in part, on their level of enrollment of eligible patients. The authors selected shall have access to all data necessary for publication. VA and its researchers shall be acknowledged in accordance with customary scientific practice in any publication or presentation. Subsequent to the multi-center publication or one year after completion of the Study, whichever occurs first, Principal Investigator and/or his/her colleagues may publish the results of Investigator's part of the Study independently. (Federal Copyright Act of 1976, as amended, 17 U.S.C. § 101, et seq.)

ALTERNATIVE:

Publications and Presentations.

(A)(1) If the Study has been designed as a single-center Study, Principal Investigator shall have the right, consistent with academic standards, to publish or present the results of his/her work performed pursuant to the Study, provided that any proposed publication or presentation (collectively, "Proposed Publication") is first reviewed by Sponsor and in accordance with Section (B).

(A)(2) If the Study has been designed as a multi-center Study, Principal Investigator acknowledges that, due to the limited patient population in its treatment group, the data generated from its individual participation in the Study and evaluation of its individual results, may not be sufficient from which to draw any meaningful scientific conclusions. For these reasons, except as provided below, Principal Investigator will not individually publish or present the results obtained from Principal Investigator’s participation in the multi-center Study. Principal Investigator may, however, upon written notice to Sponsor participate in a joint, multi-center publication of the Study results with other third party principal investigators and/or institutions, provided that the Proposed Publication is first reviewed by Sponsor in accordance with Section (B). The authors of this multi-center publication shall have access to all necessary data. VA and its researchers shall be acknowledged in accordance with customary scientific practice in any publication or presentation. In the event that the multi-center publication has not been completed within one (1) year from the date of the completion or termination of the Study, then notwithstanding the foregoing, Principal Investigator may individually publish a Proposed Publication regarding individual results from the Study, provided that the Proposed Publication is first reviewed by Sponsor in accordance with Section (B).

(B) Sponsor shall complete its review within sixty (60) days after receipt of any Proposed Publication (individual or multi-center) from Principal Investigator. If Sponsor believes that any Proposed Publication contains any information relating to patentable items, the disclosure of such Proposed Publication to any third party shall be delayed for up to ninety (90) days (beyond the review period) to permit the filing of a patent application. Should Sponsor request such a delay, then upon the written request of Principal Investigator, Sponsor shall use its best efforts consistent with reasonable business and scientific practice to expedite the filing of such patent application. However, if at the end of such ninety day period, despite the use of diligent efforts on the part of Sponsor, additional time is necessary or required in order to complete the filing of a patent application, Sponsor may request, and Principal Investigator shall grant, an extension of the period of time within which to file the patent application not to exceed an additional sixty (60) days.

11. COMPLIANCE WITH LAWS, REGULATIONS AND GUIDELINES

Since this research is being performed at a Federal (VA) facility, various Federal laws and regulations relating to research apply. Specifically, 38 C.F.R. Part 16 “Protection of Human Subjects”, details the conduct of medical research in a VA facility and incorporates the FDA regulations by reference. Since all research personnel hold VHA appointments, they are subject to VA laws, regulations and guidelines applicable to research. By providing that the Institution and PI (and by inference all who work on the project under the PI’s direction) will follow all applicable laws etc., the suggested clause is consonant with the duties imposed on VHA appointees. Sponsors may want to include state and local laws since many research entities used by Sponsors are subject to state and local laws. Use of the word “applicable” before “state and local laws” should meet the respective needs and concerns of the parties.

The alternative clause, while still referring generally to all applicable laws, specifies two of these laws and regulations (FDA and VA) and assures Sponsor that professional standards will be met. The final reference to Good Clinical Practices is included because the International Conference on Harmonisation (ICH) and the Declaration of Helsinki, among others, have also promulgated research standards that foreign, primarily European regulators, may follow. These are collectively described by the FDA as “Good Clinical Practice”. The last sentence was added in the alternative because the FDA considers these international standards merely as guidance and does not obligate researchers in this country to follow them.

SUGGESTED:

Institution and Principal Investigator shall comply with all applicable federal, state and local laws, regulations and guidelines.

ALTERNATIVE:

Institution and Principal Investigator shall comply with all applicable federal, state and local laws, regulations and guidelines, including but not limited to (i) the Federal Food Drug and Cosmetics Act, as amended and regulations promulgated thereunder, and (ii) VA regulations relating to the protection of human subjects. Additionally, Institution and Principal Investigator (a) shall comply with generally accepted professional clinical and research standards of care, and (b) will follow Good Clinical Practices to the extent required by the FDA.

12. DOCUMENT RETENTION

Both the suggested and alternative language assure that the study records will be maintained for the term mandated by the Privacy Act. The suggested language merely states VA’s rule for the minimum time that “Veteran, Patient, Employee, and Volunteer Research and Development Project Records – VA” (VA System of Records 34 VA 12) will be retained. This rule provides that these records are held for five years after the completion of the research project and/or final report unless they become part of a patient’s individual medical history file in which case the record would remain for seventy-five years after the last activity of care.

The suggested and alternative clauses mention only the five-year period because a patient’s individual medical file will be held by VA for at least seventy-five years and would not be turned over to a Sponsor for storage/retention.

Since the nature of the study may mandate a retention period longer than five years, the alternative language provides that in such a case Sponsor must timely notify the Institution, arrange for the records transfer, and pay for the additional expense. Since study records are VA records containing Protected Health Information (as that term is defined in the HIPAA Privacy Rule), records transferred to the Sponsor must comply with that Rule as well as with Federal privacy laws and regulations. One method of assuring this compliance would be to make sure that the informed consent document signed by every study participant gives permission for the transfer of these records to the Sponsor for such purpose (See Clause 9 explanatory note).

Note that the term “study records” means the data and information that the Principal Investigator generates by doing the study (i.e. following the Study Protocol). The term does not include the NPC’s administrative records for managing the study funds.

SUGGESTED:

Study records are managed in accordance with the Privacy Act records system notice, currently identified as 34 VA 12, which provides, in part, that records will be retained for five (5) years after the completion of the research project and/or publication of a final report. Study records may be destroyed thereafter in accordance with Privacy Act guidelines.

ALTERNATIVE: