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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI
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When investigators perform clinical trials, two organizations are crucial--the sponsor of the trial and the research base. The next two sections discuss the purposes and features of each. In particular, we describe the role of the DCTD as a sponsor of investigational agent trials; as a sponsor DCTD is responsible for the overall direction of the process of new agent development as well as its practical implementation. Of course, DCTD is not the only sponsor of trials involving new anticancer agents. The activity of private pharmaceutical companies has increased dramatically in recent years. We outline here the basis of the relationship among DCTD, pharmaceutical companies, and investigators supported by DCTD in the conduct of clinical trials. We also discuss the vital role of the research base in support of the investigator. As is the case with all types of research, clinical trials cannot take place without a substantial institutional commitment.
2. The Sponsor
The development of new anticancer agents is a long and complex process, but successes have been significant. The fact that some aggressive neoplasms are now curable with chemotherapy is the best possible evidence that agents with selectivity against cancer can be identified and used effectively. On the other hand, oncologists are well aware that for many common tumors, systemic treatment is unsatisfactory. The motivation to develop better therapy is therefore as powerful as ever. With the increased understanding of the malignant process due to recent and anticipated advances in molecular biology and biochemical pharmacology, there is every reason to expect that the development of new agents will proceed along increasingly rational lines in the future.
The process of new agent development is often divided into preclinical and clinical components. Although this division is operationally useful, it should be recognized that continual interplay and cross-feeding exist between the preclinical and clinical arenas. Evidence of synergy or the effectiveness of combined modality approaches in experimental models, for example, has provided the major motivation for a very large number of clinical trials. The converse is also true; clinical observations have from time to time given rise to new lines of basic investigation.
Historically, one of the most important effectors in the discovery and development of new anticancer agents has been the NCI. The prominence of NCI's role in new cancer agent development has no parallel elsewhere in developmental pharmacology. The justification for such intensive involvement of a Government agency in research and development is clear: Significant improvement of cancer treatment is in the public interest. Only more recently has there been substantial involvement on the part of the pharmaceutical companies. This is in contrast to the impressive role of the private sector in the development of many other classes of agents, such as antibiotics, anti-inflammatory agents, and endocrine agents. Current trends suggest an increasing interest by pharmaceutical companies in anticancer agents. Even so, NCI remains the largest sponsor of research with antineoplastic agents; currently, well over 150 compounds are in various stages of clinical testing; a far greater number are in preclinical development.
As part of this massive effort, NCI funds a clinical trials network that includes Cooperative Groups, new agent development contractors, and other investigators at Cancer Centers and University hospitals. More than 10,000 investigators from approximately 2,000 institutions participate in this effort.
In the United States, clinical research with experimental agents is carefully regulated. The ultimate authority for assuring the safety of the public in matters relating to investigational agents and medical devices rests with the Food and Drug Administration (FDA). FDA regulations, which are specific implementations of the Food, Drug, and Cosmetic Act, define the terms under which clinical work with experimental agents may proceed. Because these regulations have the force of law, they must be heeded by all those involved in clinical trials with investigational agents, including NCI, pharmaceutical companies, and investigators. An organization or individual that assumes legal responsibilities for supervising or overseeing clinical trials with investigational agents is termed a sponsor. In the United States, the DCTD and private pharmaceutical companies most commonly sponsor such research in cancer. The designation obviously implies a substantial commitment of resources.
In addition, the Public Health Service Act mandates a number of safeguards for the rights and welfare of individuals who are involved as subjects of the research. Regulations of the Department of Health and Human Services (DHHS) administered by the Office for Human Research Protections (OHRP), DHHS, specify the requirements to ensure adequate protections for human subjects. Clinical investigators and institutions taking part in the clinical trials network are responsible for meeting the requirements of the HHS regulations.
As sponsor of an investigational agent, DCTD, and specifically CTEP, is responsible for seeing that clinical trials proceed safely and rationally from the initial dose-finding studies through to a definitive evaluation of the role of the new agent in the treatment of one or more specific cancer(s). Fulfillment of this goal obviously requires the active participation of CTEP staff throughout the entire process.
A full discussion of the means by which NCI funds research is beyond the scope of this handbook. Whether support comes from investigator-initiated grant, contract, or cooperative agreement, however, the process of peer review is central. Government officials can provide monies to investigators only in the context of mechanisms involving peer review; this process requires formal application by the investigator and (usually) multiple levels of evaluation. Once an application is approved, the NCI cannot provide more funding than is stipulated by the judgement of peer review and the Board of Scientific Advisors. Additional awards can, of course, be made after review and formal approval of a supplemental application. The provision of investigational agents for clinical studies is a separate issue and does not imply that NCI will provide funding for these same studies. However, for funded research proposals CTEP will make a good faith attempt to supply investigational agents required for that research.
2.2 Preclinical Drug Development
The DCTD could not effectively accomplish its overall aims in new agent development without a very extensive preclinical effort. The DCTD Developmental Therapeutics Program (DTP, http://dtp.nci.nih.gov) is heavily committed to the discovery and development of new anticancer agents. Readers are referred to a summary of the objectives, methods, and status of DCTD's preclinical agent discovery and development program in Boyd, MR: Status of the NCI Preclinical Antitumor Drug Discovery Screen, Principles and Practice of Oncology Updates, Vol. 3(10): 1-12 (1989), Appendix XVI.
2.3 Collaboration Between Sponsors: DCTD and the Pharmaceutical Companies
At present, most of the anticancer agents in clinical development by CTEP are also being developed by a pharmaceutical company. Although involvement of the pharmaceutical companies in research on antineoplastics is not new, the maturing of medical oncology as a specialty and the advent of agents for the successful treatment of many cancers have stimulated interest by industry in cancer treatment to an unprecedented degree.
Collaboration between DCTD and the pharmaceutical industry may occur at any step along the new agent development process. Private companies often submit compounds to DCTD for testing and joint development. Compounds may be submitted for antitumor screening, for preclinical toxicology, or for clinical testing. Conversely, if a compound is discovered by DCTD, the involvement of a collaborator is sought as early in development as possible, because DCTD does not market new agents. The early involvement of a pharmaceutical company permits substantial cost-sharing between public and private sectors, and can hasten by several years the availability of effective agents for all cancer patients.
Development plans for new agents, therefore, are usually a collaborative effort between DCTD and a pharmaceutical company. These plans are heavily influenced by the findings and opinions of the clinical investigators working with the agent. In this joint effort, DCTD and the private sector share the common goal of defining the contribution of a new agent to cancer treatment as precisely and expeditiously as possible. The timely approval of a New Drug Application (NDA) or Biologic License Application (BLA) by the FDA is in the public's interest. However, there may well be differences between these partners in sponsoring certain kinds of trials. The three-way relationship among clinical investigators, the DCTD, and private industry involves complex issues in coordination, in establishing priorities, and in the allocation of limited resources. To facilitate the necessary interactions, CTEP has developed a policy on the nature of the relationship between the participants. The policy, which formally recognizes the involvement of the private sector in the support of clinical trials, is articulated in a document entitled "Policy Statement: NCI-Cooperative Group-Industry Relationship Guidelines" (See Appendix I), http://ctep.cancer.gov/industry/industry.html.
2.4 Private Support of Trials Sponsored and Funded by NCI)
As private support for clinical trials in cancer becomes more widespread, investigators holding grants, contracts, or cooperative agreements from NCI should carefully consider the allowable allocation of resources provided by a private sponsor for a trial already having NCI support. Investigators must make certain that Federal funds are not used to cover those costs of research that are also supported by private resources. Grants management personnel at NIH and auditors from DHHS are required to scrutinize such arrangements closely and may take steps to recover Federal funds if they have been used inappropriately.
In the specific case of the clinical Cooperative Groups, the Terms of Award of NCI's agreements with the groups permit them to accept industrial support, provided that industry funds are used for the support of additional costs generated as a direct result of the interest of a pharmaceutical company in a particular clinical trial. Such costs might include additional laboratory tests or special requirements for data collection.
In the case of trials funded under Phase 1 and Phase 2/3 cooperative agreements or contracts, the provision of resources for tasks not supported by Federal funds may or may not be appropriate; all such agreements should be submitted to the grant or contracting officer for prior approval.
2.5 Private Support of Trials Sponsored but Not Funded by NCI
Private support of a trial sponsored under an IND held by DCTD is appropriate under certain circumstances. However, there should be a written agreement between the protocol chair and the private firm; this agreement should also be sent to the Chief, Regulatory Affairs Branch (RAB), CTEP. In general, CTEP will favor the provision of data from trials of this kind to a pharmaceutical company. These arrangements may not be exclusive (i.e., may not serve to prohibit the supply of data to another party), however, unless CTEP has previously agreed with the pharmaceutical company that exclusivity is appropriate. In any case, the obligations of the investigator to DCTD as the sponsor, as detailed throughout this handbook, remain unchanged.
2.6 The Investigational New Drug Application (IND)
Any organization seeking to sponsor clinical trials with experimental agents must first submit an IND to the FDA (Note 1). The IND is the legal mechanism under which experimental agent research is performed in the United States (Note 2). No experimental agents may be administered to patients for research in the U.S. without an IND.
All IND sponsors have obligations which are specified in the regulations of the FDA. The DCTD, as a component of an agency in the DHHS, is just as accountable as a pharmaceutical company for meeting the IND regulations of the FDA.
The initial IND submission by the sponsor to FDA is a lengthy document that sets forth the experimental rationale for human testing, including results of animal toxicology studies, manufacturing data, purity and stability information, and an initial plan of clinical investigation.
The IND is the official record at the FDA of the sponsor's clinical research with the agent. Under FDA regulation, CTEP must maintain the IND as an accurate, timely repository of all information concerning clinical use of the agent, including all protocols, adverse events, and an annual report of the results of all clinical trials, plus any new relevant preclinical (particularly toxicologic) data. Obviously this means that there can be no use of the experimental agent without the knowledge and prior approval of the sponsor.
After a sponsor has submitted an IND, FDA has 30 days to complete its review. If FDA has safety concerns, it may place a hold on the initiation of any or all clinical trials with the agent. In certain circumstances, the sponsor may request a waiver of the 30-day waiting period. Please note that these are matters between the sponsor and the FDA. No investigator may initiate patient treatment on a protocol using DCTD agents until he or she has received written notice of approval from CTEP.
Note 1:
The use of the term sponsor is generally reserved for organizations assuming broad responsibilities for the development of a new agent. It is also possible for an individual investigator to hold an IND.
Note 2:
An IND must be submitted to perform clinical studies under the following conditions:
Although situations arise in which an agent is manufactured and tested within a state, technically, if any component of that clinical product (from the diluent to the vials and labels) is obtained from another state or country, the FDA could require an IND to be submitted and all the requirements to be adhered to.
After clinical trials have shown that the new agent is safe and effective, there is reason to make the agent generally available to patients and physicians. The formal process in the U.S. by which this occurs is the approval by FDA of a marketing application (New Drug Application for cytotoxic/cytostatic agents or a Biologic License Application for biological agents) submitted by a private firm; as noted previously, NCI does not submit NDAs or BLAs since it does not market products. The applicant seeks approval from FDA for one or more specific indication(s). Review and approval of an NDA or BLA are based on the demonstration of safety and efficacy assessed from detailed reports of the clinical trials; particularly randomized controlled studies. The contribution of a new agent in the treatment of a disease is demonstrated unambiguously if the agent is the only variable between the treatments.
The specific endpoints that constitute satisfactory evidence of efficacy (e.g., response rate, quality of life, survival) have been addressed in a published paper prepared by FDA and NCI entitled "Commentary Concerning Demonstration of Safety and Efficacy of Investigational Anticancer Agents in Clinical Trials." This paper was prepared with input and advice from the Oncologic Drugs Advisory Committee of FDA (a panel of outside experts in clinical oncology) and the Board of Scientific Counselors of the DCTD (a panel of outside experts in both preclinical and clinical oncology). A copy of this paper is included as Appendix II.
The approval of the NDA or BLA is a critical milestone not only for the pharmaceutical company but also for the clinical investigator, the practicing oncologist, NCI, and the general public. An affirmative decision by the FDA permits the pharmaceutical company to market and promote the agent for the approved indication(s). Once an agent is marketed, no Federal regulation prevents any licensed physician from prescribing it for any indication he or she deems appropriate.
For the practicing oncologist, NDA or BLA approval means that the agent is readily available for routine treatment of patients. The practitioner no longer has to devise acceptable protocols with research intent, simply for the purpose of obtaining the agent for patient care. No longer must he or she use the cumbersome procedures for obtaining compassionate INDs from the FDA to treat individual patients.
For the clinical investigator, NDA or BLA approval means that it may be more difficult to recruit patients for further clinical trials with the agent, since use of the agent is no longer restricted to patients on research protocols.
For the NCI, NDA or BLA approval marks a step forward in the development of effective cancer therapies. Although the role of DCTD as a sponsor of clinical trials focusing on the approved agent usually decreases dramatically at that point, the NCI continues to sponsor further research with commercially available agents through its general support of clinical trials.
For the general public, NDA or BLA approval means that a new effective agent is now available on the widest possible basis. It is admittedly also true that an agent that was formerly available without cost for research purposes is no longer free to the patient after NDA or BLA approval. For financial reasons, the DCTD has found it necessary to discontinue the distribution of virtually all marketed agents, except for certain clinical trials of particularly high priority when the company continues to supply the agent to DCTD at no charge.
| Table of Contents |
Part A 1 2 3 |
Part B 4 5 6 |
Part C 7 8 9 10 11 |
Part D 12 13 14 15 16 |
Part E 17 18 19 |
Appendices |
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