Navigating the differences between Investigator-Initiated v. Sponsor-Initiated Clinical Trials – What are the special contract and administration issues to be aware of?

NCURA Western Regional Conference April 5, 2011 – Denver, CO

Clinical Trial Agreement Specific Terms & Conditions – Top 10

• Definition of Sponsor-Initiated Trial

• Definition of Investigator-Initiated Trial

• HIPAA & Access to study records

• Study Data

• Inventions

• Compliance

• Debarment

• Good Clinical Practices

• Indemnification & Subject Injury

• Publications with respect to multi-center trials

• Record Retention

• Payment

Sponsor-Initiated Trial

• The investigation to be undertaken is an FDA Phase I, II, III, or IV drug study or an FDA-regulated medical device study.

• Preclinical studies are specifically excluded.• A sponsor provides its proprietary product and study protocol

to the University for the investigation.• The cost of the trial conducted according to the sponsor's

protocol is fully funded by the sponsor and is not supported in whole or in part with other funds, including Federal funds.

• Sponsor holds the IND/IDE.• Sponsor assumes all liability under the study.

Investigator-Initiated Trial

• The investigation to be undertaken is an FDA Phase I, II, III, or IV drug study or an FDA-regulated medical device study.

• Preclinical studies are specifically excluded.• A sponsor might provide its proprietary product to the

University for the investigation.• The cost of the trial conducted according to the PI's protocol

might be partially or fully funded by the sponsor.• The University/Investigator hold the IND/IDE.• Liability is shared depending on whether the sponsor provides

study drug/device.

HIPAA & access to study records

• HIPAA – “Health Insurance Portability & Accountability Act” (Federal Law).

• CMIA – “Confidentiality of Medical Information Act” (California Law).

• Regulates who can access personally identifiable information of a study subject from a medical record .

• Because the University is a “hybrid” organization and subject to both HIPAA and CMIA – Office of General Counsel (OGC) has crafted standard language for use in research agreements.

• Of note the sponsor and its representatives should not have access to patient personally identifiable information when the study is Investigator-Initiated. It is not permitted unless the sponsor holds an IND or IDE.

HIPAA & access to study records

Sample HIPAA Clause – Sponsor-Initiated Trial:

"Sponsor's representative provided access to source records for the purpose of monitoring or auditing the Study will not make a record of or disclose direct identifiers of any Study subject (including the Subject's name, street address, telephone, social security, medical record, or health plan beneficiary numbers). In the event that copies of the original source records are to be made, the Sponsor's representative must redact all direct identifiers of the Study subject prior to copying or assure that such identifiers have been redacted prior to taking the source documents off site."

HIPAA & access to study records

Sample HIPAA Clause – Investigator-Initiated Trial:

“Sponsor has no legal right to review source documents under HIPAA. If Sponsor requires access to source documents, then Sponsor must reimburse University to redact the subject’s identifiable information from records prior to Sponsor’s inspection of such redacted source documents. Such disclosure is authorized without securing the subject’s authorization."

Study Data

Study Data is:

• The data generated in the conduct of the study as compiled on the case report form (“CRF”); and

• Any reports (including but not limited to written reports, x-rays, lab reports) required to be generated and delivered to the sponsor pursuant to the protocol.

• For Investigator-Initiated studies – recommend that University only supply a report on the aggregate data.

Study Data

Study Data is NOT:

• Everything generated in the course of the study;• Patient Medical Records; or• Source documents.

Study Data

Sample Clause – Sponsor-Initiated Trial:

“All case report forms and the data as compiled therein and any reports required to be generated by the University in the course of conducting the Trial pursuant to the Protocol and delivered to Sponsor (“Study Data") shall be the property of Sponsor, which may utilize the Study Data for any lawful purpose.”

Study Data

Sample Clause – Investigator-Initiated Trial:

“DATA: The University shall own all Study data. Nothing herein shall prevent University from using or sharing information and data generated hereunder for ordinary research and educational purposes of a university. Company may, upon prior notice and at reasonable times, access Study data in whatever form available, however, consistent with applicable law, individual subject identifiers shall not be made available to Company. If Study data must be redacted for the purpose of allowing Company access, then Company agrees to reimburse University for the cost of generating such redacted reports.”

Inventions

Inventions are:

• Patentable intellectual property conceived and reduced to practice in the performance of the Protocol under the CTA.

Inventions

Inventions are NOT:

• Know-how, copyrightable works, data, etc.• “Intellectual property conceived or reduced to practice using

the study drug” (and other variations of this phrase).

InventionsSample Clause – Sponsor-Initiated Trial:• Definition of Inventions

“Inventorship of all inventions shall be determined in accordance with U.S. Patent Law. Developments or discoveries first conceived and reduced to practice under this Agreement and in the direct performance of the Protocol that necessarily use or incorporate Sponsor's Study Material and/or proprietary information shall be defined as “Study Inventions”.

• Ownership of Inventions“To the extent that Institution is legally able to do so, and to the extent Sponsor has authored the study protocol to be conducted under this agreement, and has designed and structured the manner in which the work is to be conducted, all rights and interest in Study Inventions shall be the sole property of Sponsor. In instances in which Sponsor desires to secure protection on such inventions, the Investigator will cooperate, at Sponsor’s expense for all out-of-pocket costs, with the Sponsor for the purpose of filing and prosecuting patent applications, the cooperation to include the execution of any and all lawful papers which may be deemed necessary by Sponsor for the filing and prosecution of applications and for assignment of the same to Sponsor, including all declarations, oaths, specifications, and instruments of assignments for filing and recordation in the U.S. and foreign patent offices.”

• If federal funding may be involved“Sponsor acknowledges that Federal regulations such as the Bayh-Dole Act, the Tax Reform Act of 1986, and the NIH Guidelines for Sharing Research Resources may also affect the range and scope of rights that may be granted to sponsors. The parties mutually acknowledge that the United States government, as a matter of statutory right under 35 U.S.C. 200-212, may hold a nonexclusive license and certain other rights under patents or inventions made as a consequence of research whose funding includes funds supplied by the United States government. In the event the United States government has such rights or in the future is found to have such rights with respect to all or any new inventions or discoveries, any license contemplated under this Agreement, even if termed an “exclusive” license shall be understood to be subject to the rights of the United States government, without any effect on the parties' remaining obligations, as set forth in the license or in this Agreement.”

InventionsSample Clause – Investigator-Initiated Trial:• Use standard research agreement IP language

“University agrees to communicate in writing and in confidence to Sponsor all patentable inventions which are conceived and reduced to practice by University, in the direct performance of the Study (“Inventions”). Inventorship of Inventions will be determined in accordance to U.S. patent law. Ownership of such Inventions shall vest in the party to whom the inventor has an obligation of assignment.”

• If federal funding may be involved Sponsor acknowledges that Federal regulations such as the Bayh-Dole Act, the Tax Reform Act of 1986, and the NIH Guidelines for Sharing Research Resources may also affect the range and scope of rights that may be granted to sponsors. The parties mutually acknowledge that the United States government, as a matter of statutory right under 35 U.S.C. 200-212, may hold a nonexclusive license and certain other rights under patents or inventions made as a consequence of research whose funding includes funds supplied by the United States government. In the event the United States government has such rights or in the future is found to have such rights with respect to all or any new inventions or discoveries, any license contemplated under this Agreement, even if termed an “exclusive” license shall be understood to be subject to the rights of the United States government, without any effect on the parties' remaining obligations, as set forth in the license or in this Agreement.

• Additionally the University can offerFallback – offer (1) NERF for research and development purposes (or to make, use or sell the sponsor’s study drug – requires review and approval by KAA); and/or(2) option for exclusive license to Inventions.

Compliance

Compliance – Debarment – Good Clinical Practices• Clinical trials are subject to various Code of Federal Regulation

provisions including but not limited to:– 21 CFR 50 (Protection of Human Subjects);– 21 CFR 54 (Financial Disclosure by Investigators);– 21 CFR 56 (IRBs);– 21 CRF 312 (Investigational New Drug Application);– 21 CFR 314 (Applications for FDA Approval to Market A

New Drug); and– 21 CFR 812 (Investigational Device Exemptions).

Compliance

21 CFR 312

• Essentially covers the legal/regulatory responsibilities of Sponsors and Investigators.

• Definitions of note

– “Sponsor” for the purpose of the FDA does NOT mean the “funder” of the study.

– “Sponsor means a person who takes responsibility for and initiates a clinical investigation.” A sponsor can be a company, AMC or individual. (See 312.3 for full definition)

– “Investigator means an individual who actually conducts a clinical investigation.” (See 312.3 for full definition)

– “Sponsor-Investigator means an individual who both initiates and conducts an investigation.” Therefore, when our PIs conduct Investigator-Initiated Trials this definition and all the responsibilities that go with it apply.

– “Contract Research Organization (CRO)” – basically run a study for a sponsor – a middle man.

Debarment

• Basically a “good standing” requirement, which if a person or entity has been debarred then any data submitted in support of a New Drug Application (“NDA”) may not be acceptable and could jeopardize the sponsor’s right to market their product.

• Applies to anyone providing services on the trial so could expand to more than our agents and employees.

• Of note only required to “certify” to the FDA not “warrant.”

Debarment

Sample Clause:

“DEBARMENT. Institution hereby certifies that neither it nor its employees performing work under this Agreement are disqualified as clinical investigators under the provisions of 21 C.F.R.§ 312.70, or excluded from participation in any Federal health care program as defined in 42 U.S.C. 1320a-7b(f) ("Federal Health Care Program"). In the event that during the term of this Agreement, the Institution or its employees or agents becomes disqualified or excluded, Institution shall notify Sponsor promptly.”

Good Clinical Practices “GCP”

• Generally GCP is an internationally accepted ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials.

• We adhere to version promulgated by the FDA in the Federal

Register.

Good Clinical Practices “GCP”

Sample Compliance Provision:

“COMPLIANCE. Institution agrees to perform the Study in accordance with all applicable federal, state and local regulations. (for drug studies add: pertaining to investigational drugs, including but not limited to, the regulations set forth in The United States Food and Drug Administration ("FDA") Form 1572, 21 CFR Parts 50, 54 and 56, and such FDA Good Clinical Practice (GCP) requirements as may be published by the FDA from time to time). In order that Sponsor may fulfill its certification and other financial disclosure obligations under 21 CFR Part 54 to the FDA and such other laws and regulations as may from time to time be or become applicable with respect hereto, the Principal Investigator and each Subinvestigator, as specified in Form 1572, shall provide such financial disclosures to Sponsor as Sponsor may request, on such forms as Sponsor may supply or as Sponsor may approve. During the time the Study is being conducted and for one (1) year thereafter, the Principal Investigator and each Subinvestigator shall update such forms promptly and provide same to Sponsor as may be requested by Sponsor or whenever any material change occurs in the information disclosed by a previous form. Upon termination of the Study, the Principal Investigator shall dispose of or return the Study Material as directed by Sponsor, and at Sponsor's expense.”

Good Clinical Practices “GCP”

Additional language for device trials:

“If the Study will be used in support of an FDA investigational device exemption (IDE) application, then, in addition to all other provisions of this Agreement, the requirements of this Section shall apply. The Institution will ensure that Principal Investigator and all employees perform the Study in accordance with 21 CFR Section 812, including, but not limited to, Sections 812.25, 812.100, 812.110, 812. 140, 812.145, and 812.150, and with the investigational plan as defined in Section 812.25, and with all conditions of approval imposed by the reviewing IRB or FDA. The Principal Investigator shall supervise all testing of the device involving human subjects. Upon termination of the Study, the Principal Investigator shall dispose of or return the device as directed by Sponsor, and at Sponsor's expense, unless such disposal or return would jeopardize the rights, safety or welfare of a subject.”

Indemnification & Subject Injury

• Standard University considerations for indemnification (e.g. “…in proportion to and to the extent that…”)

• Certain carve outs generally allowed:– Claims arising out of University’s negligence or willful acts;– University’s failure to follow the protocol or written instructions of the

sponsor; and– University’s failure to comply with applicable federal, state and local laws.

• Certain carve outs NOT allowed:– We do NOT bill the subject’s insurance – the primary payer must be the

trial sponsor.– We do NOT carve out for Subjects inability to follow the protocol when

not under the PI’s supervision.

Indemnification & Subject Injury

• Subject Injury – University policy requires that a sponsor reimburse the university for the reasonable necessary costs associated with the medical care provide when a clinical trial subject is injured as a result of their participation in the study. For a Sponsor-Initiated Trial this requirement is absolute unless the Chancellor has provided a waiver.

• For Investigator-Initiated Trials, subject injury is not required from the funding sponsor if the study drug/device is FDA approved.

Indemnification & Subject Injury

• Sample Clause – Subject Injury (w/carve outs):

“Institution policy requires that research subjects be provided any and all medical treatment reasonably necessary for any injury sustained as a result of participation in the Trial. Company agrees that it will reimburse Institution for the reasonable costs it incurs in providing reasonably necessary medical treatment to human subjects who are injured as a result of a the study drug or a research procedure performed in accordance with the Protocol; provided, however, that the Company shall not be obligated to reimburse the Institution for such costs to the extent the injury is caused by: (i) a deviation from the Protocol by Institution or Investigator; (ii) the negligence or intentional malfeasance of the Investigator or the Institution; or (iii) the natural progression of the underlying disease of the Trial patient.”

Publications

Multi-Center Publications:• Later stage trials are conducted at multiple sites and many times the trials

are also international.• University will agree to a reasonable delay - “holdback” period to allow

the sponsor to publish the multi-center results first.• However, if no multi-center publication within 12 months (maximum w/o

approval 18, anything longer requires VCR approval) then University can publish its data subject to normal review and request to delete sponsor Confidential Information or an additional time limited delay to file patents.

• Of note:– Trial registration is now a legal requirement.– For multi-center trials, authorship usually conditioned on size of enrollment

and other considerations.

Publications

Sample Clause – Multi-Center Publication: “If this is a multicenter Study, Institution agrees to publish the results of this Study cooperatively and not

prior to publication of the results of the multicenter Study. However, if no multicenter publication has occurred within twelve (12) months of the close of this Study at Institution, Institution shall have the right to publish independently the results of this Study subject to the review procedure set forth herein.

Institution will submit to Sponsor all proposed publications, papers, and any other written disclosure of data or information resulting from the Study, at least thirty (30) days prior to submission for publication, for the purpose of Sponsor's identification of Confidential Information subject to the Institution's obligation of confidentiality hereunder. Sponsor will immediately notify the Institution in writing of such information disclosed in the proposed publication and the Institution will delete such Confidential Information before submission for publication.

At the written request of the Sponsor, Institution shall withhold submission for an additional period of up to sixty (60) days in order to allow Sponsor time to file patent applications or take other action to secure the proprietary rights in Inventions disclosed in the publication.

In addition to the publication provisions herein, Institution may also use Clinical Trial Results for internal, non-commercial research and academic purposes, and in connection with patient care.”

Records Retention

• Of note because a sponsor may need to check source/patient medical records to validate/verify information.

• 21 CFR 312.62 specifically outlines the investigator’s responsibility, which is for 2 years following the date a marketing application is approved or if no application filed, then 2 years after the investigation is discontinued

• Not appropriate to “turn-over” records to a sponsor – instead we would require the sponsor pay us a per subject fee to store the records

Bonus Material

Payment terms for Investigator-Initiated Trials– Recent trends are to ensure that payment is made for services

provided at fair market value.• May no longer be a good idea to just bill set amounts as

milestones tied to either time or patient enrollment.• Seeing Sponsors requesting payments back for “unspent” funds as

opposed to “unearned.”• Tip – develop an internal budget that lays out costs based on

visits/procedures + fixed fees + contingent fees, then development payment schedule.

Presenter Contact Information

Helene Orescan, JD DirectorDavid Geffen School of Medicine at UCLA

Clinical Trials Contract Unit10911 Weyburn Avenue, 3rd Floor

Los Angeles, CA 90095(O) 310-794-0137 (F) 310-794-8902

horescan@mednet.ucla.edu

Thierry Musy-Verdel, JD | Industry Contracts Officer Industry Contracts Division | Office of Sponsored Research

University of California, San Francisco 185 Berry Street, Suite 4603

San Francisco, CA 94143-1016 (94107 for Express Mail) v. 415.514.8226 | f. 415.348.1498

thierry.musyverdel@ucsf.edu