NCI has several mechanisms through which cancer clinical trials are funded, each with its own review and approval process. Initial protocol reviews for approval and funding take place either through centralized NCI mechanisms (e.g., study sections to review investigator-initiated grant proposals) or through more decentralized mechanisms, using the infrastructure of the 58 major cancer centers that exist around the country, or the networks of research institutions linked in the Cooperative Oncology Groups. VA has its own (mainly centralized) mechanisms for reviewing protocols for funding through its Cooperative Studies Program or other centralized review for trials proposed by individual investigators.
Both NCI and VA use a two-stage process for deciding on which clinical trials to fund. In the first stage, proposals are separated into those that are sound scientifically and meet the requirements for respecting the rights and ensuring the safety of participants, and those that fall short of those standards. Those in the former group—all of which are of a high enough quality to fund—are ranked and go on to compete for the limited pool of funds. Regardless of the availability of money, those in the latter category are not eligible for funding under any circumstances.
Protocols for all trials of new anti-cancer agents, or trials that are using approved agents in novel ways, must be the subject of an Investigational New Drug (IND) application (or a similar application for biologies or devices) to the Food and Drug Administration (FDA). FDA reviews IND protocols for scientific merit and the protection of participants, and will not allow studies to proceed until these criteria are met. NCI and the pharmaceutical industry are the only important sponsors of clinical trials of new anti-cancer agents, so they are the main sponsors that file INDs. NCI-sponsored trials under INDs will also have undergone review for NCI funding.
All government funding mechanisms and the FDA require periodic reporting on the progress of clinical trials. Reporting on the numbers of patients accrued is usually annual. Reports of non-serious adverse effects also takes place according to a periodic schedule. Serious or life-threatening adverse effects, and all deaths possibly linked to the treatment, must be reported (to the sponsor in the case of non-IND studies and to FDA in the case of those under INDs) expeditiously. All sponsors and FDA have the authority to terminate trials for reasons of patient safety or for poor performance of various types.
Requirements for protecting the safety and rights of clinical trial participants in studies funded by the Department of Health and Human Services (DHHS) are set down in regulations. The Office for Protection from Research Risks at NIH is the focus for implementation of the regulations and the provision of guidance on ethical issues in biomedical or behavioral research.
Initial evaluations of clinical trial protocols include explicit review for the safety and rights of participants. In addition, institutional review boards (IRBs) at all institutions participating in the trials must give initial approval, and are generally responsible for assuring that the appropriate steps are followed to protect participants during the course of the trial. Informed consent is a major focus of IRBs, but they also have more general responsibilities for the conduct of trials.
Review and monitoring procedures among clinical trial sponsors vary, but the content of the reviews is remarkably similar. There are some obvious common elements related to the review and conduct of trials that could be a starting point for defining what constitutes a “good” trial: