THE NATIONAL BREAST CANCER COALITION:
SETTING THE STANDARD FOR ADVOCATE COLLABORATION IN CLINICAL TRIALS
Fran Visco
National Breast Cancer Coalition, Washington, DC, USA
1. INTRODUCTION
The National Breast Cancer Coalition Fund (NBCCF) has had a profound influence on breast cancer clinical trials. By educating advocates and ensuring their involvement in all aspects of the clinical trial process, NBCCF is recognized in the scientific, industry, medical and advocacy communities as a leader in progressing breast cancer clinical trials. Founded in 1991, NBCCF has grown to a network of hundreds of organizations and tens of thousands of individuals across the country. The Coalition has one mission: to eradicate breast cancer through action and advocacy. To achieve this mission, NBCCF focuses on three main goals:
Research: Increasing appropriations for high-quality, peer-reviewed research, and ensuring that the funding is well spent. NBCCF works with the scientific community to focus research efforts on well- designed clinical studies that have a meaningful impact on breast cancer prevention and care.
Access: Increasing access for all women to high quality treatment and care, and to breast cancer clinical trials.
Influence: Increasing the influence of women living with breast cancer and other breast cancer activists in the decision making that affects all issues surrounding the disease.
This chapter explores the ways in which NBCCF pursues these goals through its Clinical Trials Initiative.
2. THE COLLABORATIVE ROLE OF ADVOCATES IN CLINICAL TRIALS: A VITAL PERSPECTIVE
From the beginning, NBCCF recognized that advocates offer something few scientists can bring to the table: the unique and personal perspective of being diagnosed with breast cancer, the experience of treatment and its aftermath and a point of view outside of the scientific and health care system. NBCCF's grassroots network represents the diversity of breast cancer in every way, including geography, race, socio-economics, age, sexual orientation and perspective, among others. Equally as important, NBCCF's network incorporates the perspective of those with the disease.
NBCCF educates and trains this network and then brings that educated power to the research and health care communities. In fact, the Coalition trains advocates who have been affected by breast cancer-in most cases those who have had the disease-in order to represent a genuine patient- centered approach in clinical trial design, oversight and implementation.
Due to NBCCF's work, advocates now contribute to aspects of clinical trials that were once the sole province of scientific and health care professionals. They sit on trial steering committees, attend investigator meetings, participate in Data Safety Monitoring Boards and Institutional Review Boards, assist with protocol and informed consent design, and coordinate the outreach to and accrual of participants. They analyze trials and report to the public and policy makers from an informed patient perspective. They address the public policy issues that surround scientific and health care decisions, from barriers to access to care to the design and reporting of trials.
Many advocates have had breast cancer or have been affected by the disease in some way, which enables them to raise questions or evaluate data with the perspective of "having been there." This is invaluable to creating an authentic patient-centered approach.
2.1 A Groundbreaking Initiative
Recognizing the complexity of the clinical trial system and process, NBCCF approaches its clinical trials work with an integrated strategy, combining education and training, legislation and public policy change, and collaborations on specific clinical trials. All components of the strategy are required to advance the search for meaningful solutions to breast cancer.
2.2 Why Clinical Trials?
The grassroots advocates who make up NBCCF recognize that clinical trials provide the most effective venue to determine how to prevent, treat, and cure breast cancer. We often hear the statistic that less than three percent of adult cancer patients in the United States currently participate in clinical trials. Many trials either take too long, or are not long enough.
Some never accrue a sufficient number of patients to adequately inform - or even begin - the trial. NBCCF asked the question: What percentage of patient participation should we achieve? What are the clinical trials we should be interested in? How many trials warrant patient participation?
Which should get financial support? NBCCF refused to support the notion that any and all breast cancer clinical trials should move forward. NBCCF developed its Clinical Trials Initiative to help change the system and address these and other issues within the clinical trial process.
2.3 NBCCF's Clinical Trials Initiative
NBCCF's Clinical Trials Initiative incorporates the belief that advocate involvement is imperative to changing clinical trials. Therefore, the Initiative's strategies are based on the rich potential of connecting the power and perspective of trained advocacy with the expertise of science and health care.
To put the Initiative into action, the Coalition developed programs to equip advocates with the information needed to participate fully in all aspects of the clinical trial process. Advocates now provide important insights into the research and design of trials, and also work to heighten awareness about the trials within the breast cancer community.
The Clinical Trials Initiative is defined by three approaches:
1. Education: Educating advocates about the science, processes and policies behind clinical trials;
2. Public Policy: Designing and supporting legislative and public policy approaches to support appropriate clinical trials; and
3. Scientific Collaboration: Collaborating with researchers and industry to design, oversee and implement meaningful clinical trials.
EDUCATION
NBCCF's integrated strategy includes educational programs that inform advocates about all aspects of clinical trials. These programs help advocates understand all phases of the clinical trial process and enable them to prioritize and decide which clinical trials warrant their participation andlor support. Educational materials also teach advocates how trials are designed and how to critically analyze trial data. NBCCF's clinical trial education programs address a comprehensive range of topics and are accessible to all advocates - from beginner to advanced.
Advocates need specific skills and knowledge to participate constructively in the wide range of forums that often influence decisions on breast cancer research. To provide advocates with these tools, the Coalition developed Project LEAD@ - an acronym for Leadership, Education, Advocacy and Development - which is an extensive four-day program now recognized for innovation and excellence by the medical, science, research and advocacy communities.
The Coalition recruits motivated applicants for the LEAD training, as the coursework is demanding. NBCCF also seeks out students to participate in LEAD who will provide a diverse perspective to the clinical trial process.
Applicants must demonstrate experience in activism and interest in medical research to be selected. NBCCF also accepts a large number of applications from advocates abroad. As of the spring of 2005, more than one thousand advocates - including 50 international students - have participated in the program.
The LEAD program is offered multiple times a year around the United States, and has been offered internationally. The program's curriculum is drawn from open communication among scientists, researchers, policymakers, and consumers nationwide. Faculty members include renowned scientists from academic and research institutions such as Brown University, Harvard University, University of California at Los Angeles and the National Institutes of Health, and provide expertise in such topics as:
Basic science, such as the biology of cancer, basic genetics, the roles of DNA, RNA and proteins and development of cancer at the molecular level;
Basic epidemiology such as biostatistics, descriptive studies, analytic studies, clinical trials, causality and screening; and
Leadership and advocacy development skills.
Project LEAD@ also includes a special session devoted specifically to clinical trials and their purpose, design and limitations, and includes information on systematic review and meta-analysis.
Advocates leave Project LEAD@ armed with the expertise and insights needed to make a meaningful contribution to the clinical trials research process. They are well prepared to influence the work of trial investigators at pharmaceutical and biotechnology companies, as well as at the National Cancer Institute (NCI) and other research institutions around the country.
B. Pro-iect LEAD@: Clinical Trials
To provide intensive training for advocates in all the important aspects of clinical trial design, implementation and oversight, NBCCF designed its Clinical Trials Project LEAD@ course. Developed as an advanced training program for Project LEAD@ graduates, this course covers the scientific, ethical and practical aspects of the clinical trials process. Graduates of this course are expected to participate in NBCCF's Clinical Trials Initiative and representative NBCCF in partnerships with clinical researchers. Clinical Trials Project LEAD@ graduates participate in peer review programs, present at scientific meetings and function as members of scientific committees.
The Clinical Trials Project LEAD@ curriculum includes courses such as:
-Role of Clinical Trials in Breast Cancer and the Research Protocol -Key components of Clinical Trials: Phases 1-4
-Overview of the Drug Development, Approval, and Regulatory Processes -Measurement of Quality of Life Issues
-Endpoints, Interim Results and other Methodological Issues -Clinical Trials Issues in the Metastatic and Adjuvant Settings -Ethical Issues in Clinical Trials
C. Annual Advocacy Training Conference
In addition to the LEAD educational seminars, NBCCF also hosts an annual advocacy training conference. The event draws more than 700 breast cancer advocates, caregivers, researchers and industry representatives to participate in plenary sessions and workshops on the latest information in breast cancer research, legislation and quality care issues.
Conference faculty members are experts in the fields of medicine, science and advocacy. A sample of research-related sessions illustrates the range of topics explored:
Breast Cancer Care: Who Decides and How Safe Are We?
New Trends in Breast Cancer Research Clinical Trials and Advocate Involvement Advanced Topics in Epidemiology
Race, Ethnicity and the Science of Breast Cancer Science and the Controversy of Biomarkers
Breast Cancer Treatment: New and Emerging Therapies Clinical Trials and Informed Consent
Clinical Trials and Public Policy
Evidence-based Medicine and its Implications
D. Fact Sheets, Position Papers and Analyses
To continually educate advocates, and the general public, about the latest in ongoing and upcoming clinical trials and to help them analyze trials, NBCCF publishes Fact Sheets, Position Papers and Analyses on its web site (www.sto~breastcancer.org).
Some examples of these materials include:
Fact Sheets:
- Outcomes in Breast Cancer Clinical Trials
o This fact sheet provides some basic background information about the endpoints or outcomes that are selected for measurement in breast cancer clinical trials. It explains sample size and selection of outcome measures and describes the concept of interim results.
- Early Stopping of Clinical Trials
o This fact sheet explains the benefits and detriments of stopping of breast cancer clinical trials early. It describes the problem of
"cross over" and the lost opportunity to gather information about long-term side effects and the fact that small but statistically
significant increases in the time to recurrence may or may not be associated with longer or healthier life.
Position Papers
-
Access to Investigational Interventions Outside of Clinical Trialso This position paper explains NBCCF's belief that access to investigational interventions undermines the clinical trials system and the principle of evidence-based medicine and that such access should only be allowed in very limited circumstances.
- Mammography Screening
o This paper lays out the scientific, thorough reasoning behind NBCCF's position that there is insufficient evidence to recommend for or against screening mammography in any age group of women.
Analvses
-
Clinical Trial Comparing Breast Cancer Screening Optionso NBCCF's analysis examines the first breast cancer screening trial that compared mammography plus physical examination to physical examination alone in 50-59 year-old women.
- Aspirin Use and Breast Cancer Risk
o NBCCF analyzed a study that examined the association between aspirin use and breast cancer risk. This was the first study to explore whether the protective effect of nonsteroidal anti- inflammatory drugs (NSAIDs) varied by estrogen or progesterone receptor status.
PUBLIC POLICY
Another way in which advocates influence clinical trials is by impacting legislation that plays a role in breast cancer research. In order to conduct these lobbying efforts, NBCCF - which is classified as a 501(c)(3) educational non-profit - relies on its sister organization, the National Breast Cancer Coalition (NBCC) - which is classified as a 501(c)(4) - its lobbying arm.
The work of advocates under the umbrella of NBCC focuses on legislative priorities that will increase funding for breast cancer research, including clinical trials, provide access to high quality health care and clinical trials, and expand the influence of advocacy in all aspects of the breast cancer decision-making process. The accomplishments of these efforts to date are impressive: NBCC advocates have created an increase in annual federal funding for breast cancer research by more than 800 percent, from less than $200 million before 1991 to more than $14 billion in 2005, including a cumulative appropriation of $1.75 billion for the Department of Defense Peer Reviewed Breast Cancer Research Program.
One of NBCC's most sweeping legislative achievements is the development of the Department of Defense Breast Cancer Research Program (DOD BCRP). The project was created as a result of NBCC's 1993 "$300 Million More" campaign. NBCC launched this campaign after holding a series of research hearings at which fifteen of the nation's most prominent scientists working in the field of breast cancer testified. As a result of the hearings, the Coalition told Congress that an additional $300 million would be needed in 1993 for breast cancer research, for a total of $430 million.
This total appropriation comprised the first significant increase in federal breast cancer research funding.
The DOD BCRP forged the way for new and innovative directions in breast cancer research. The program is renowned for its efficient use of resources - more than 90% of the funds go directly to research grants - and a unique part of the program has been the participation of advocates at every level. Since 1992, more than 600 breast cancer survivors have served on the BCRP review panels that determine which research proposals receive funding based on scientific merit.
The DOD BCRP has supported several mechanisms to advance meaningful breast cancer clinical trials including, for example, support for Clinical Translational Research, Centers of Excellence and Clinical Bridge Awards. The Clinical Translational Research Awards are designed to sponsor innovative research that will result in substantial improvements over current approaches to breast cancer chemoprevention and therapy by accelerating the progression of recent, highly promising findings in
preclinical breast cancer research from the laboratory to the clinic. The Centers of Excellence Awards are intended to support the establishment of multi-institutional collaborations among highly accomplished scientists from diverse backgrounds to focus on a major scientific problem in breast cancer.
And the Clinical Bridge Awards support critical pre-clinical or post-clinical trial research with high potential for imminent clinical application.
Recognizing that support for researchers designing and implementing clinical trials is not the only answer, NBCC developed strategies to help patients interested in trials.
If the public, including patients, doctors and researchers, do not have access to information about trials, then treatment decisions and research are impeded, health care costs are affected and lives are lost. NBCC recognized the need to focus on ensuring that individuals have access to critical information on ongoing clinical trials and to the results from those trials. In 2005, NBCC set the Fair Access to Clinical Trials Act (FACT) as one of its legislative priorities. FACT would create two publicly available sets of information provided in the national data bank of trials: a registry of clinical trials and a results database. The registry would include information on all trials for drugs, biologics or devices to treat serious andlor life-threatening diseases. The results database would require that all trials (except Phase I) testing the safety or effectiveness of any drug, biologic or device, report specific information including a summary of results regardless of whether the results were published in a journal.
Financial burdens for patients and access to information can also create barriers to clinical trials; NBCC pursued various public policy approaches to alleviate these problems. On a federal level, in 1999, one of NBCC's priorities was the Medicare Cancer Clinical Trials Coverage Act that would provide Medicare coverage of routine patient care costs associated with clinical trials. While that bill did not become law, NBCC was instrumental in the Clinton Administration's resolution of this issue through an executive memorandum in June 2000. In large part due to NBCC's advocacy, routine care costs such as tests, procedures and doctors visits that are normally covered will also be covered for Medicare recipients participating in clinical trials. On a state basis, NBCC published model state legislation and helped its grassroots network work within their home states to get meaningful laws enacted that would require insurance companies to cover these patient costs incurred in clinical trials.
SCIENTIFIC COLLABORATION
The third component of NBCCF's clinical trials initiative involves collaborating with researchers and industry on specific trials - but not all trials. In fact NBCCF's Board of Directors, made up of 25 organizations from across the country that reflect the diversity that is breast cancer, developed criteria for NBCCF participation.
Once a trial meets NBCCF criteria, advocates work alongside scientific and medical professionals in every step of the trial process.
5.1 High Standards for Clinical Trials
When NBCCF chooses to participate in a clinical trial, they bring the power and the trust of a nationwide grassroots advocacy network.
Therefore, before engaging in a collaboration, NBCCF evaluates every clinical trial according to rigorous principles. To enter into a partnership with NBCCF, the study must:
Be designed to answer an important, novel question relevant to breast cancer;
Be a well-designed clinical trial that is scientifically rigorous, employing appropriate and meaningful outcomes;
Be conducted in an ethical manner, with data to support efficacy and safety standards sufficient for reasonable people to believe the trial should proceed;
Provide participants with sufficient information to provide meaningful informed consent; and
Receive approval from the Institutional Review Board.
The trial must also employ mechanisms to provide adequate protection for participants' privacy and confidentiality. And, there must be a system in place-such as a Safety Monitoring Committee-for evaluating the protocol and patient safety as the trial proceeds.
In addition, the research agreements between the trial sponsor and any academic or independent investigators must adhere to all of the guidelines for sponsorship, authorship and accountability outlined by the 2004 International Committee of Medical Journal Editors' "Uniform Requirements for Manuscripts Submitted to Biomedical ~ournals."' he academic or independent research institutions participating in the study must be involved in the design, recruitment and data interpretation for the trial.
A mechanism must also be in place to adequately address NBCCF's concerns about the payment of costs for the trial participants' patient care.
The trial must adequately address NBCCF's concerns about the inclusion of diverse populations and inappropriate exclusion of specific populations, as well, and must meet NBCCF's expectations regarding partnerships.
NBCCF also expects the trial sponsor to provide the Coalition with the following:
Opportunities for meaningful input into study design and implementation;
Opportunities for meaningful review of and input regarding safety data;
Information about every breast cancer clinical trial it is conducting; and, Updates, to the extent feasible, on the trial's progress, status and results-even if the trial is cancelled or ends early.
In addition, NBCCF expects the primary results of the study to be published in full form in a respected peer-reviewed journal. The findings are to be disseminated regardless of final FDA approval, the strength or direction of the results, or findings of significant adverse events.
Because of these high standards, the Coalition's participation has become an indication of a clinical trial's excellence within advocacy communities.
The clinical trial that paved the way for the role of breast cancer advocates in this process took place between NBCCF and the biotechnology firm, Genentech. In 1996, Genentech was poised to bring ~ e r c e ~ t i n ~ to trial. The drug was developed to improve the survival and disease progression rates in women with metastatic breast cancer who overexpress HER2. The company had already invested in the early stages of a trial design, but they were unable to recruit breast cancer patients to participate.
Based on NBCCF's strong reputation for coordinating outreach at the grassroots level, officials from Genentech contacted the Coalition. NBCCF responded by initiating a groundbreaking collaboration between advocates and industry.
Before recruiting patients to participate, NBCCF wanted to ensure the quality and potential of the trial. NBCCF representatives sat on the trial's Data and Safety Monitoring Committee and its Steering Committee. They sent advocates to all major principal investigator meetings and NBCCF's advocates reviewed and helped revise the trial protocol. Once they were satisfied with each step of the trial, the Coalition mobilized their grassroots network to recruit cancer patients to participate. NBCCF's role led to the
U.S. Food and Drug Administration's (FDA) rapid approval of the first monoclonal antibody treatment for metastatic breast cancer.
This experience established a standard of excellence for other medical industries seeking to collaborate with advocacy organizations. In today's research circles, the high criteria and stringent requirements that NBCCF requires of clinical trials have made their participation highly sought-after.
5.2 Ongoing
Trials
NBCCF has partnered on a number of clinical trials since initiating the collaborative model in 1996. In each case, they ensure that the most strategic and necessary questions are asked, and that trials include enough participants - with an equitable representation of the diverse patient population - to explore these questions effectively. And, to maintain a strident level of objectivity, NBCCF does not accept compensation from industry for any of its work on clinical trials. These trials include the following:
A partnership with BCIRG (The Breast Cancer International Research Group, a not-for-profit academic, global, cooperative group of oncology researchers) on a phase I11 clinical trial. The trial was fully enrolled as of spring 2004, and as of 2005 was in the data collection phase. NBCCF was involved in many aspects of the design and implementation of this adjuvant trial. Representatives of NBCCF served on the Steering Committee, attended and participated in the investigator meetings and served on the Data and Safety Monitoring Committee. Outreach on the part of NBCCF allowed the trial to achieve its enrollment goal of 3,150 women more quickly than expected.
NBCCF is partnering with a biopharmaceutical company on its investigational drug being tested in breast cancer patients with brain metastases to improve the effectiveness of radiotherapy and to increase survival. The drug showed promise for patients with breast cancer during a Phase I1 trial of several types of cancer. As of spring 2005, the company was conducting a confirmatory Phase I11 breast cancer trial.
Protocol and consent materials have been reviewed and amended, and outreach efforts are in the initial phase in 15 cities. NBCCF representatives sit on the Data Safety Monitoring Board and participate at investigator's meetings. In addition, the Coalition has engaged its network to help with trial outreach.
A continuing collaboration with one company has led to a Phase I11 clinical trial of an anti-angiogenic therapy. This therapy is being studied in a variety of tumor types including breast, colorectal and lung cancers.
The clinical trial offers standard treatment while also helping the cancer community evaluate the safety and efficacy of a potential new treatment.
The trial enrolled approximately 400 patients across the United States. It was an open-label, active-controlled trial that evaluated the safety, efficacy and pharmacokinetics of one drug in combination with another in patients with previously treated metastatic breast cancer. NBCCF was involved in all aspects of the trial, from targeting specific sites for accrual to serving on review boards and the Data Safety Monitoring Committee.
NBCCF partnered with a company on a pivotal Phase I11 trial of a vaccine for women with metastatic breast cancer. The potential of the drug was promising, but the clinical trial revealed obstacles that indicated the drug was not ready for general use. This case demonstrates that, while clinical trials are intended to test unproven treatments, positive treatment results are never a certainty. Despite the outcome, however, there was valuable knowledge gained about the drug through the trial process.
6. CONCLUSION
The National Breast Cancer Coalition Fund revolutionized the model of educated advocates and clinical trials. Through the Clinical Trials Initiative and ongoing efforts, the Coalition educates, empowers and enables advocates to make a meaningful contribution to the clinical trials research process, and sets the standard for excellence in those trials through their stringent evaluation process.
Despite the impressive accomplishments of the Coalition, neither the best treatments nor the cure for breast cancer is known. Breast cancer remains the most commonly diagnosed cancer among women in the United States and worldwide (excluding skin cancer). In 2005, it is estimated that 269,730 new cases of breast cancer will be diagnosed among women in the United States. Breast cancer is also the second leading cause of cancer death for women in the U.S (after lung cancer); approximately 40,410 women in the U.S. will die from the disease in 2005.
These numbers will only decrease when prevention and a cure for the disease are found. Until then, the National Breast Cancer Coalition Fund will continue to bring the power of advocacy to influence science and industry in the pursuit of ending breast cancer.
REFERENCE
1. International Committee of Medical Journal Editors (ICMJE), Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. ICMJE, 2005. www.1CMJE.org
