NCI Cooperative Research and Development Agreements

December 1, 2000

The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute(NCI) currently sponsors more than 160 Investigational New Drug applications

ABSTRACT: The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute(NCI) currently sponsors more than 160 Investigational New Drug applications(INDs), and is involved in approximately 1,600 active protocols. It is alsocurrently involved in more than 50 collaborative agreements with pharmaceuticalcompanies. These agreements consist of cooperative research and developmentagreements (CRADAs) and clinical trials agreements (CTAs). A CRADA is a detailedcontract between the NCI and a pharmaceutical company for the clinicalco-development of an investigational agent, and may include preclinicaldevelopment that stipulates terms for a broader scope of research than thatcovered by a CTA. The CTEP/Investigational Drug Branch is currently involved ina number of oxaliplatin (Eloxatin) protocols under the CRADA program. [ONCOLOGY14(Suppl 11):27-29, 2000]

Introduction

The Cancer Therapy Evaluation Program(CTEP) of the National Cancer Institute (NCI) Division of Cancer Treatment andDiagnoses sponsors approximately 160 Investigational New Drug applications(INDs), and is involved in approximately 1,600 active protocols. It reviewsabout 500 new protocols and enrolls more than 33,000 patients annually intoongoing studies. The CTEP has over 9,900 registered investigators, works withapproximately 2,000 institutions, and presently, is involved in more than 50collaborative agreements with pharmaceutical companies.

The therapeutic agents being studied in these programs aredeveloped at the NCI, funded by NCI grants, and submitted by universities, otheracademic or research institutions, or pharmaceutical companies. The CTEP isinvolved currently in the domestic development program for oxaliplatin(Eloxatin).

CooperativeResearch and Development Agreements and Clinical Trials Agreements

Collaboration between the NCI and institutions or pharmaceuticalcompanies occurs through cooperative research and development agreements(CRADAs) and clinical trials agreements (CTAs). These differ in importantrespects. Clinical trials agreements are most appropriate for collaboration whenthe collaborator has a strong patent position, has completed the preclinicalstudies and IND-directed toxicology required for IND filing, and is supplyingonly the formulated agent to be used in the clinical study protocols (with nofurther development of the agent being intended). Clinical trials agreements arenot covered by congressional legislation, and no funding is provided for theirexecution. For rapid implementation, these agreements can be approved and signedby a divisional director at the NCI.

In contrast, a CRADA is a detailed agreement between the NCI anda pharmaceutical company for the co-development of an agent that stipulatesterms for a much broader scope of research, usually encompassing preclinicaldevelopment. Cooperative research and development agreements were created bycongressional legislation as a result of the Federal Technology Transfer Act.Their implementation requires National Institutes of Health (NIH) subcommitteereview and approval, and their execution allows the NIH to receive financialsupport for research from the collaborator.

Characteristics of CRADAs

Many potential advantages are associated with collaborating withthe CTEP in the development of promising investigational agents, includingregulatory expertise. The NCI has been involved in studies that have led to morethan 60% of the current indications for cancer for all agents licensed by the USFood and Drug Administration (FDA).

Other advantages include the ability to evaluate investigationalanticancer agents in a wide variety of tumor types and disease settings and toexpedite trials through the extensive Cooperative Groups clinical trialsnetworks. In this evaluation process, all data on a particular agent are madeavailable exclusively to the NCI collaborator for the agent.

During the application process, either the NCI or thecollaborator can submit the initial IND. A filed IND may cross-reference an INDor master file held by the NCI or collaborator. All information in the NCI INDis shared fully with the collaborator, and manufacturing data can be heldconfidential.

Protocol Development

The activity of the CTEP in the collaboration with thepharmaceutical company begins with discussions of the development plans for theinvestigational agent, including an exchange of information about sponsoredstudies. Thereafter, the CTEP is active in developing protocols, monitoringstudies, and providing the pharmaceutical company with access to data. Protocoldevelopment is typically initiated by receipt of a protocol letter of intentfrom an investigator to perform a particular study, or by requests from the CTEPfor protocol letters of intent. Proposals are reviewed by the CTEP ProtocolReview Committee and sent to the pharmaceutical company with an invitation toprovide comments, after which a consensus review is performed by the NCI. Thefinal CTEP-approved protocol with all amendments is subsequently forwarded tothe pharmaceutical company at the time of submission to the FDA.

In its role as an IND sponsor, the CTEP attends pre-INDmeetings, writes and files INDs, monitors adverse drug reactions, submits annualprogress reports for each clinical trial sponsored under an IND, sends revisionsto FDA letters and phone inquiries, and participates in joint NCI/FDA-sponsoredconferences. With regard to study monitoring, the CTEP assumes responsibilityfor monitoring and reporting to the FDA. For pivotal trials, specialarrangements can be made between the NCI and a pharmaceutical sponsor to permitadditional or complementary sponsor auditing.

Guidelines for NCI-Sponsored Trials

The general guidelines for NCI-sponsored trials are as follows.The NCI oversees a drug master file for the standard procedure involved inclinical trials of investigational agents. It reviews and approves all protocolsand is responsible for ensuring that all investigators adhere to the protocoland FDA regulations. It also ensures confidentiality of data and that applicabletransfer limitations per the CRADA are observed. Issues regarding ownership ofinvestigator data and intellectual property are written into the agreement. TheNCI is responsible for ensuring that such agreements are enforced. Any access totrial data is provided by the NCI and the collaborating company (or companies).

IssuesRaised by Pharmaceutical Companies

The general issues raised by pharmaceutical companies regardingNCI-sponsored trials include patent rights, publication procedures, data rights,timely access to data, and control of the development of an investigationalagent. Patent rights usually arise in the context of the use of patents filed byan individual investigator who has developed a particular method ofadministering an agent or combination of agents. The NCI policy permitsmodification of the funding agreement with an "Intellectual Property Optionto Collaborator" statement. This offers the right of first negotiation tothe company supplying the investigational agent in cases in which an inventionusing that agent arises.

With regard to NCI publications, the collaborator(s) is given 30days to review manuscripts prior to submission to ensure that no confidential orproprietary information is released; an additional 30 days for review can berequested in cases in which patent filings are involved. No editorial commentson manuscripts are accepted.

Clinical Trials Data

Clinical trials data that are generated in NCI-sponsored trialsare made available exclusively to the NCI, the FDA, and the collaborator. TheNCI is currently implementing a new informatics system designed to improve thespeed with which data are made available to collaborators. At present,approximately 98% of data requested by the CTEP from collaborators are availablewithin 3 to 4 weeks of each quarterly due date; continual improvements areexpected in the time required for data collection and availability.

The CTEP is also implementing applications that will allowelectronic filing of adverse event data to the NCI, and in turn, to the FDA, aswell as electronic protocol submission to the NCI of standard formats of phaseI, II, and III trials. As noted, there is joint control of development, with thedevelopment process of the investigational agent being a collaborative andnatural effort between the NCI and the pharmaceutical company.

Collaboration Requirements

A number of documents detailing the requirements forcollaborations in addition to providing information on collaborations areavailable to collaborators (or potential collaborators). One provides sectionsof standard language required in any NCI-sponsored protocol covering issues suchas access of new investigational agents to women and minorities, filing ofregulatory information, and investigators’ responsibilities in conducting thestudy and handling data and potential publications.

The "Terms of Award Option to Collaborator" documentis in the funding agreement of all institutions involved in clinical trials ofinvestigational agents. The "Sponsored Research Agreement" documentoutlines the basic procedures for investigators collaborating directly with thepharmaceutical company and provides language that does not conflict with NCIfunding agreements. Finally, the "Collaborative Clinical Development ofInvestigational Anticancer Agents With the NCI" document is a notebook thatcontains detailed information on the Cancer Therapy Evaluation Program modelagreements, and other documents pertinent to successful collaboration with theNCI.

OxaliplatinStudies Under the CRADA Program

The NCI is currently participating in a number of clinicalstudies of oxaliplatin, a new cytotoxic agent from the diaminocyclohexaneplatinum family. Further information on the oxaliplatin clinical trialssponsored under the CRADA agreement are listed and described on the followingwebsites: http://cancertrials.nci.nih.gov/and http://cancernet.nci.nih.gov/.