Cancer incidence rises as the population ages. Cancer diagnoses are growing globally, particularly in poor nations. Renzo Canetta, Vice President, Oncology Global Clinical Research, Bristol-Myers Squibb Company, said that, for the most part, cancer is an equal opportunity illness, with no significant disparities in its biology and treatment pathways throughout the globe. Despite substantial advances in cancer drug trial, early detection, and treatment, there is still a huge unmet medical need for therapies for major malignancies (e.g., lung, prostate, breast, colon).
Canetta identified three major elements influencing the cancer drug trial industry in oncology: cost, time, and motivation. He maintained that the expense of conducting cancer clinical trials, the amount of time necessary, and the willingness of investigators and patients to participate are all linked. According to the PhRMA, there are now over 800 novel anticancer medicines under research. At the same time, the rate of trial participation among adult cancer patients is exceedingly low. The question of who will study all of these drugs, who will prioritize their study, and how many patients will be identified to study them arises, especially given the limitations in the infrastructure required to conduct clinical trials, including investigators and patients, discussed in Chapter 3.
This chapter opens by offering a patient’s viewpoint on cancer drug trial. Following that, as one of the largest funders of clinical research in cancer, the National Institutes of Health (NIH) National Cancer Institute (NCI) Clinical Trials Cooperative Group Program is described. The chapter concludes with a review of industry-sponsored cancer clinical trials.
Cancer Drug Trial: A Patient’s view
According to Margaret Mooney, Chief, Clinical Investigations Branch, Cancer Therapy Evaluation Program at NCI, and Musa Mayer, breast cancer advocate at AdvancedBC.org, roughly 3% of adult cancer patients enroll in clinical trials. Steven Cheng discovered that 40% of NCI Cancer Therapy Evaluation Program (CTEP) studies failed to meet minimum patient enrolment, and more than three out of five phase III trials failed to do so. As noted in Chapter 3, the failure of clinical trials to recruit a sufficient number of patients takes health care away from evidence-based treatment and constitutes a massive waste of effort.
Patient Attitudes Toward Clinical Trials
Some of the most common barriers to participating in clinical trials cited by patients in an analysis of 23 oncology studies and 6,000 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). Patients also mentioned inconvenience, distaste of randomization, preferring one’s own doctor to make choices, feeling forced, and loss of autonomy over treatment decisions as obstacles to participation. Physician influence is the single most significant element in enrolling people in clinical trials.
However, as stated in Chapter 3, a variety of factors influence a physician’s inclination to send patients to clinical trials. Mayer, a breast cancer advocate and 20-year cancer survivor, has concentrated her efforts on metastatic breast cancer, the disease’s most advanced stage. She has spent the past ten years as a member of an online community (BCMets.org) for women with metastatic breast cancer and their families. Mayer defined the 1,100-member group as “typical” Internet users looking for health care information; they are younger, more educated, less diverse, and more wealthy (i.e., of higher socioeconomic position) than the broader population. As patients with metastatic breast cancer, they are acutely aware that their treatment choices are limited and are so deeply invested in the quest for the next medicine to treat their condition. Women with metastatic breast cancer, according to Mayer, should be ideal candidates for clinical trials of novel treatments because of these criteria.
Mayer conducted an informal, qualitative survey of 49 women from the BCMets.org community to investigate physician and patient involvement in clinical trials, attitudes toward trial participation, eligibility criteria issues, motivation for participation or nonparticipation, and overall clinical trial experience. According to the study findings, the following hurdles to patient involvement in clinical trials exist:
- Treatment doctors are not encouraged (or actively discouraged) from participating. More than half of the women polled said that their oncologists either never suggested clinical trials to them or actively discouraged them from participating. Oncologists who did propose trials to patients were typically themselves investigators or advocating a study at their own institution.
- Inconvenience of trial participation (travel, expense, time away from job and/or family).
- Misinformation exists in that women are afraid of receiving “no treatment” (placebo), despite the fact that giving the highest level of care is an ethical imperative in cancer studies. Patients have a poor understanding of Equipoise1; some assume that the control arm of the study will provide no therapy and that the experimental arm is intrinsically superior.
- The notion that clinical trials are a last-ditch attempt in which one should only enroll after authorized, conventional therapies have failed.
- Eligibility conditions are difficult to meet. Some women reported being excluded from participating in a research study because of:
- Treatment doctors are not encouraged (or actively discouraged) from participating. More than half of the women polled said that their oncologists either never suggested clinical trials to them or actively discouraged them from participating. Oncologists who did propose trials to patients were typically themselves investigators or advocating a study at their own institution.
- Inconvenience of trial participation (travel, expense, time away from job and/or family).
- Misinformation exists in that women are afraid of receiving “no treatment” (placebo), despite the fact that giving the highest level of care is an ethical imperative in cancer studies. Patients have a poor understanding of Equipoise1; some assume that the control arm of the study will provide no therapy and that the experimental arm is intrinsically superior.
- The notion that clinical trials are a last-ditch attempt in which one should only enroll after authorized, conventional therapies have failed.
- Eligibility conditions are difficult to meet. Some women reported being excluded from participating in a research study because of:
- previous treatment regimens (for example, “extensively pretreated” or excessive chemotherapy);
- stage of illness (i.e., newly diagnosed) or existence of brain metastases; or
- Many medication studies examine first-, second-, or third-line therapy in the context of advanced illness.
According to Mayer, advanced-disease patients and those who have had substantial pretreatment are the most eager to engage in clinical trials, yet as the survey findings show, they are commonly denied due to a trial’s eligibility requirements. Recently diagnosed individuals, on the other hand, are struggling to deal with the news of their illness and prefer to stick to the normal treatment procedures advised by their doctor rather than engaging in clinical trials. Patients who engage in studies, on the other hand, have overwhelmingly good experiences, as indicated in Chapter 3. Access to developing medications and a desire to assist other women via improvements in research were two of the reasons given by Mayer’s survey participants for enrolling in a clinical study.
Public Awareness of Clinical Trials
Clinical trials that are well-designed serve an important role in medical advancement and the creation of evidence-based health care. Mayer, on the other hand, said that public education on the genuine benefit of clinical research and the realities of participating in a clinical trial is severely inadequate. As previously said, there are several myths and misunderstandings concerning the experience of participating in a trial. As a result, public education on the relationship between health-care advancements and clinical research—specifically, clinical trials—is required. Mayer proposed that enlisting qualified patient advocates at every stage of the clinical research process, including preclinical stages, might bring major benefits in terms of designing informative trials and recruiting patients to participate.
Melvyn Greberman, President of Public Health Resources, LLC, mentioned the Army of Women, an initiative created by the Cancer Biomedical Informatics Grid (caBIG), the Dr. Susan Love Research Foundation, and the Avon Foundation for Women to increase consumer participation in clinical research. According to Greberman, the Army of Women has reached 400,000 of the one million women who have committed to participating in cancer research trials. The Army of Women partnership is eager to collaborate with business and offers a suitable structure for tackling patient and public education challenges.
The Clinical Trials Cooperative Group Program Of The National Cancer Institute
The federal government is heavily involved in supporting and directing clinical research in cancer. Approximately half of all cancer trials in the United States are funded by the NCI. Mooney outlined the unusual structure of the National Cancer Institute’s Clinical Trials Cooperative Group Program.
Through the Clinical Trials Cooperative Group Program, the NCI oversees a wide number of clinical research networks. The program contains nine groups dedicated to adult malignancies and one dedicated to children tumors. Some adult organizations look at various illnesses, while others, like the Gynecologic Oncology Group, concentrate in one kind of cancer. Since the 1960s, NCI cooperative organizations have expanded from largely regional venues to big, countrywide networks with a diverse spectrum of places and members. The program’s results have resulted in better treatment and outcomes for cancer patients. Mooney noted that the program’s success over the last 50 years has been due to the direct engagement of clinical investigators, patients, and their families in the design, conduct, and monitoring of clinical trials. The early and continuous engagement of patient advocacy networks in clinical trial design and execution has led in some of the most significant advances in cancer therapy to date.
Because the NCI cooperative groups are not focused on obtaining regulatory clearance for a new treatment, as is the case in industry, they may adopt a wider, public perspective and investigate various sorts of research issues in a single experiment. This breadth of emphasis is crucial in terms of the quantity of usable research data obtained by extending beyond a trial’s usual main objective. Mooney noted that although the vast quantity of data generated in answer to various research questions in NCI-sponsored studies may be highly beneficial in understanding more about cancer and how to treat it effectively, it can also make some of the trials less efficient.
The full variety of the set of cancer disorders has been revealed as the study of oncology has evolved over the previous 50 years. Mooney noted that the increased knowledge of cancer illness molecular categorization has allowed for a stronger emphasis on specific therapies and patient categories. As a result, new obstacles in cancer clinical research have emerged. The use of tissue samples to screen patients for specific molecular traits has added a new degree of scientific and logistical complexity to clinical studies. Mooney noted that one reason clinical trials have grown more global is the quest for uncommon patient subsets—enough people cannot be located in the United States.
Streamlining the Clinical Trials Process at the NCI
Despite variances in research concentration, the NCI system shares the rising demand on business and other medical disciplines to minimize research expenditures in the face of shrinking funds. The NCI Clinical Trials Working Group was formed in 2004 in response to this difficulty. This group is tasked with providing suggestions and a strategy for implementing them in five essential areas of the NCI clinical trials system (Box 6-1).
Cancer Clinical Trials Sponsored By The Industry
Many challenges and roadblocks faced throughout the clinical trial process are shared by all institutions that fund the study, whether government or private. Canetta identified six significant cost factors for industry-sponsored clinical trials in cancer:
- Clinical research people—investigatory employees as well as the infrastructure required to support the clinical study;
- Clinical supplies manufactured by industry—acquisition of comparators (drugs used in the control arm of a clinical trial), which often requires relabeling and permission to use the comparator as an experimental agent.
- collecting and storing tumors and bodily fluids for trial-related specimens
- research grant negotiations
- Fees for adjudication committees—more of a concern outside of the United States (adjudication committees are required for time-to-event endpoints, such as progression-free survival in cancer), and
- Fees for IRBs and Data Monitoring Committees (DMCs).
The cost of clinical research rises with each step (phases I, II, and III). Canetta emphasized that the longer a compound fails in its development, the larger the expense of that failure. The success rate for delivering a chemical through the medication development process to patients is less than spectacular in cancer. As a result, there is considerable interest in lowering the cost of clinical research and, as a result, the cost of drug development failures.
Canetta identified three components of clinical research that have the potential to reduce costs:
- Standardized case report forms (CRFs) would aid investigators in conducting a trial more effectively. Furthermore, decreasing the amount of data points that must be monitored for each patient in a clinical study (i.e., selective monitoring) may allow for cost savings while preserving quality.
- Acquiring and relabeling costly comparator medications for a clinical study is a key cost driver. Canetta proposed that the insurance sector pay for comparative medications used in a clinical study for an authorized indication in order to encourage more patients to join.
- Time investment—As mentioned during the program, launching clinical trials has become a time-consuming procedure. Canetta identified four aspects of the clinical trial initiation process that could be more efficient: (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 US) or scientific advice (from outside the US).
Canetta said that traditionally, the internal review procedure at Bristol-Myers Squibb includes 34 review cycles for each individual trial protocol, with the business producing/activating a trial protocol taking 8 months. Efforts are now being made to reduce the company’s internal review schedule to 5 months by aligning review cycles with different internal roles.
The time it takes to activate a clinical trial protocol varies depending on the institution and clinical trial sponsor. The Eastern Cooperative Oncology Group (ECOG) in the United States, for example, needs a median of 808 days to complete the processes required to activate a clinical trial protocol (Dilts et al., 2008). Canetta provided data from individual universities that revealed reduced activation times. The median at the University of Arkansas, for example, is 70 days. Canetta argued that the quicker time is due to the university’s modest size, which allows it to optimize internal operations. Outside of the United States, the time necessary for clinical trial protocol approval is quite comparable to that required in the United States—that is, long.
