CLINICAL TRIALS IN CANCER: A PATIENT PERSPECTIVE

According to data presented by Margaret Mooney, Chief, Clinical Investigations Branch, Cancer Therapy Evaluation Program within NCI, and Musa Mayer, breast cancer advocate of AdvancedBC.org, approximately 3 percent of adult cancer patients participate in clinical trials. An analysis of more than 500 NCI Cancer Therapy Evaluation Program (CTEP) trials by Steven Cheng revealed that 40 percent of trials failed to achieve minimum patient enrollment, and more than three of five phase III trials failed to do so. As discussed in Chapter 3, the failure of clinical trials to enroll enough patients moves health care further away from evidence-based practice and represents a tremendous amount of wasted effort.

THE NATIONAL CANCER INSTITUTE’S CLINICAL TRIALS COOPERATIVE GROUP PROGRAM

The federal government plays a large and important role in funding and organizing clinical research in oncology. NCI funds approximately half of all cancer trials in the United States. Mooney described the unique structure of NCI’s Clinical Trials Cooperative Group Program.

NCI coordinates a large number of clinical research networks through the Clinical Trials Cooperative Group Program. The program includes nine groups focused on cancers that affect adults and one that focuses on pediatric cancers. Some of the adult groups look at multiple diseases, while some, such as the Gynecologic Oncology Group, specialize by focusing on one area of cancer. Since the 1960s, the NCI cooperative groups have grown from primarily regional sites to large, nationwide networks that encompass a range of different sites and participants. The successes of the program have resulted in improved care and outcomes for cancer patients. Mooney explained that the program’s accomplishments over the past 50 years have been a result of the direct involvement of clinical investigators, patients, and their families in designing, conducting, and monitoring clinical trials. The early and ongoing involvement of patient advocacy communities in designing and conducting clinical trials has resulted in some of the most robust improvements in cancer treatment to date.

Because the NCI cooperative groups are not oriented to gaining regulatory approval for a new drug, as is the case in industry, they can take a broader, public focus and examine multiple types of research questions in one trial. This breadth of focus is significant with respect to the amount of useful research data that has been generated by going beyond the traditional primary endpoint of a trial. Mooney explained that the large amount of data collected in response to multiple research questions in NCI-sponsored trials can be extremely helpful in learning more about cancer and how to manage it effectively, but also makes some of the trials less pristine in terms of efficiency.

As the field of oncology has progressed over the last 50 years, the true diversity of the set of cancer diseases has been uncovered. Mooney explained that the new understanding of the molecular classification of cancer diseases has allowed a greater focus on particular treatments and patient populations. Thus, new sets of challenges in cancer clinical research have been created. Screening patients for particular molecular characteristics using tissue samples has introduced a new level of scientific and logistic complexity to clinical trials. Mooney explained that the search for rare patient subsets is one reason why clinical trials have become increasingly global—enough patients cannot be found in the United States.

Streamlining NCI’s Clinical Trials Process

Despite differences in research focus, the NCI system shares with industry and all medical disciplines the growing pressure to reduce research costs in the face of declining budgets. In response to this challenge, the NCI Clinical Trials Working Group was launched in 2004. This group is charged with developing recommendations and an implementation plan to optimize the NCI clinical trials system in five critical areas (Box 6-1).

BOX 6-1

Current Initiatives of NCI’s Clinical Trials Working Group to Optimize the Clinical Trials System. Coordination through information sharing and collaboration. In addition to increasing collaboration within cooperative groups, NCI is working to (more...)

INDUSTRY-SPONSORED CANCER CLINICAL TRIALS

Many issues and obstacles encountered in the clinical trial process are common across organizations that sponsor the research, whether government or industry. In terms of cost, Canetta noted six major drivers for industry-sponsored clinical trials in cancer:

• clinical research personnel—investigational staff and the infrastructure to support the clinical trial;
• clinical supplies made by industry—procuring of comparators (drugs used in the control arm of a clinical trial), which often involves relabeling and approval to use the comparator as an experimental agent;
• processing of trial-related specimens—acquiring and banking tumors and biological fluids;
• negotiating of research grants;
• adjudication committees’ fees—more of an issue outside of the United States (adjudication committees are necessary when endpoints of time-to-event are used, such as progression-free survival in cancer); and
• fees associated with IRBs and Data Monitoring Committees (DMCs).

At each phase of clinical research (phases I, II, and III), the cost increases. Canetta explained that the later the stage of development in which a compound fails, the higher the cost of that failure will be. In cancer, the rate of success for bringing a compound through the drug development process to patients is less than stellar. Thus, there is significant interest in reducing the cost of clinical research and thereby the cost of drug development failures.

Canetta mentioned three aspects of clinical research that have the potential for cost reduction:

• Data collection—Standardized case report forms (CRFs) would help investigators conduct a trial more efficiently. Also, reducing the number of data points that require monitoring for each patient in a clinical trial (i.e., selective monitoring) could make it possible to reduce cost while maintaining quality.
• Comparator and experimental drug charging—Acquiring and relabeling expensive comparator drugs for a clinical trial is a significant cost driver. Canetta suggested that comparator drugs being used in a clinical trial for an approved indication could be paid for by the insurance industry as a way to induce more patients to enroll.
• Time cost—As discussed throughout the workshop, activating clinical trials has become a lengthy process. Canetta identified four aspects of the clinical trial initiation process that could benefit from increased efficiency: (1) internal review by the sponsor, (2) contract negotiations with institutions and investigators, (3) local regulations (IRBs), and (4) special protocol assessments (from the FDA in the United States) or scientific advice (outside the United States).

Canetta reported that historically the internal review process at Bristol-Myers Squibb involves 34 review cycles for each individual trial protocol, totaling 8 months for the company to produce/activate a trial protocol. Efforts are currently under way to bring the company’s timeline for internal review down to 5 months by aligning review cycles with various internal functions.

The time to activate a clinical trial protocol varies across institutions and clinical trial sponsors. In the United States, for example, the Eastern Cooperative Oncology Group (ECOG) requires a median of 808 days to complete the steps necessary to activate a clinical trial protocol (Dilts et al., 2008). Canetta presented data from individual institutions revealing shorter times to activation. At the University of Arkansas, for example, the median is 70 days. Canetta suggested that this shorter time is due to the fact that the university is a small operation and thus can streamline internal processes more easily. Outside the United States, the time required for approval of clinical trial protocols are very similar to those in the United States—that is, lengthy.

Footnotes

1

As noted in Chapter 3, equipoise is the point at which a rational, informed person has no preference between two (or more) available treatments (Lilford and Jackson, 1995). In clinical research, the ethical concept of equipoise is satisfied when genuine uncertainty exists as to the comparative therapeutic benefits of the therapies in each arm of a clinical trial.