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Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington (DC): National Academies Press (US); 2010.

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Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary.

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6Clinical Trials in Cancer

Cancer rates increase as the population ages. Diagnoses of cancer are increasing worldwide, including in developing countries. Renzo Canetta, Vice President, Oncology Global Clinical Research, Bristol-Myers Squibb Company, noted that for the most part, cancer is an equal opportunity disease—throughout the world there are no dramatic differences in its biology and paths of treatment. Despite significant progress in cancer prevention, early diagnosis, and treatment, there is a large unmet medical need for treatments for major cancers (e.g., lung, prostate, breast, colon).

Canetta cited three main factors that are currently affecting the clinical trial enterprise in oncology: cost, time, and motivation. He contended that the cost of conducting clinical trials in cancer, the length of time required, and the commitment of investigators and patients to participating are interconnected. According to PhRMA, there are currently more than 800 new anticancer drugs in the development pipeline. At the same time, the participation rate in trials among adult cancer patients is extremely low. Questions arise, then, as to who will study all of these drugs, who will prioritize their study, and how enough patients will be identified to study them, especially given limitations in the infrastructure necessary to conduct clinical trials, including investigators and patients, discussed in Chapter 3.

This chapter begins with presenting a patient’s perspective on clinical trials in cancer. Next, the National Institutes of Health’s (NIH’s) National Cancer Institute (NCI) Clinical Trials Cooperative Group Program is discussed as one of the major sponsors of clinical research in cancer. The chapter ends with a discussion of industry-sponsored clinical trials in cancer.

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.

Patient Perceptions of Clinical Trials

In an analysis of 23 oncology studies and 6,000 patients, some of the barriers to participating in clinical trials cited most frequently by patients were (1) fear of a reduced quality of life, (2) concern about receiving a placebo, (3) potential side effects, and (4) concern that the experimental drug might not be the best option (Mills et al., 2006). In addition, patients also cited barriers such as inconvenience of participation, dislike of randomization, wanting one’s own doctor to make decisions, feeling coerced, and loss of control over treatment decisions. The single most influential factor in enrolling patients in clinical trials is physician influence.

As discussed in Chapter 3, however, a number of barriers affect a physician’s willingness to refer patients to clinical trials. As a breast cancer advocate and a 20-year cancer survivor, Mayer has focused her work on metastatic breast cancer, the most advanced form of the disease. Over the last 10 years she has participated in an online community (BCMets.org) of women with metastatic breast cancer and their families. Mayer described the 1,100-person community as relatively typical Internet users seeking health care information; they tend to be younger, better educated, less diverse, and more affluent (i.e., of higher socioeconomic status) than the general population. As metastatic breast cancer patients, they are keenly aware that their treatment options are limited and thus are profoundly vested in the search for the next drug to treat their disease. Mayer noted that because of these factors, women with metastatic breast cancer should be good candidates for clinical trials of new drugs.

Mayer conducted an informal, qualitative survey of 49 women from the BCMets.org community to explore the level of physician and patient involvement in clinical trials, attitudes about participating in trials, eligibility criteria issues, motivation for participation or nonparticipation, and the overall clinical trial experience. The survey results revealed the following barriers to patient participation in clinical trials:

  • Lack of encouragement (or active discouragement) from treating physicians to participate. More than half of the women surveyed said their oncologists never mentioned clinical trials to them or actively discouraged them from participating. Oncologists who did recommend trials to patients were usually investigators themselves or recommending a trial at their own institution.
  • Inconvenience of trial participation (travel, cost, missing work and/or time with family).
  • Misinformation in that women fear getting “no treatment” (placebo), even though providing the best standard of care is the ethical requirement in cancer trials. Equipoise1 is poorly understood by patients; some believe that the control arm of the trial will offer them no treatment and that the experimental arm is inherently better.
  • The misconception that clinical trials are a last-ditch effort, and one should participate only after failing to respond to approved, conventional treatments.
  • Difficulty with eligibility criteria. Some women reported that in trying to enter a clinical trial, they were disqualified because of:

    past treatment regimens (i.e., “extensively pretreated” or too much chemotherapy);

    stage of disease (i.e., not recently diagnosed) or the presence of brain metastases; or

    the presence of advanced disease when many drug trials test first-, second-, or third-line treatments.

Advanced-disease patients and those who have had extensive pretreatment are the most motivated to participate in clinical trials, according to Mayer, but, as indicated by the survey results, are frequently disqualified because of a trial’s eligibility criteria. Conversely, recently diagnosed patients who are frequently sought for clinical trials are attempting to cope with the news of their diagnosis and tend to follow the standard treatment protocols prescribed by their doctor rather than participating in clinical trials. On the other hand, as noted in Chapter 3, patients who participate in trials generally report having an overwhelmingly positive experience. Access to emerging therapies and a desire to help other women through advances in research were two of the reasons reported by the women in Mayer’s survey for participating in a clinical trial.

Public Education on Clinical Trials

Well-designed clinical trials play a key role in medical advances and the development of evidence-based health care. However, Mayer noted that public education on the true value of clinical research and the reality of participating in a clinical trial is seriously lacking. As described above, a large number of myths and misconceptions about the experience of participating in a trial exist. Therefore, public education on the link between improvements in health care and clinical research—specifically, clinical trials—is needed. Mayer suggested that involving trained patient advocates at each step of the clinical research process, even in preclinical phases, could provide significant benefit in helping to design informative trials, as well as recruit patients to participate.

Melvyn Greberman, President of Public Health Resources, LLC, referred to the collaboration of the Cancer Biomedical Informatics Grid (caBIG), the Dr. Susan Love Research Foundation, and the Avon Foundation for Women in creating the Army of Women—an initiative designed to enhance consumer participation in clinical research. According to Greberman, the Army of Women has reached 400,000 of the 1 million women it has committed to signing up as potential participants in cancer research studies. The Army of Women collaboration is interested in working with industry and provides a good format for addressing patient and public education issues.

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 Icon

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.

Copyright © 2010, National Academy of Sciences.
Bookshelf ID: NBK50895

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