Cancer Clinical Trials Basics Release Date: May 2004
This printable version is designed for reference information only. In order to complete the course exercises and print a completion certificate, the course must be taken on-line.
Cancer Clinical Trials Basics Course
May 2004
Table of Contents MODULE 1: COURSE INTRODUCTION 1.
Introduction ..................................................................................... 1-1
2.
Why Do Participants and Professionals Choose to Take Part in Cancer Research? .......................................................................... 1-1
3.
A New Paradigm for Designing Clinical Trials............................. 1-2
4.
Emerging Advancements in Cancer Treatment From Recent Clinical Trials................................................................................... 1-2
5.
Opportunities to Accelerate the Pace of Progress in Cancer Care .......................................................................................................... 1-3
6.
Summary.......................................................................................... 1-4
7.
Exercise ........................................................................................... 1-5
MODULE 2: UNDERSTANDING CANCER CLINICAL TRIALS 1.
Introduction ..................................................................................... 2-1
2.
How Are Clinical Trials Conducted?............................................. 2-1 2.1. Phases of Clinical Trials...................................................................2-2 2.1.1. Phase 1..............................................................................................2-2 2.1.2. Phase 2..............................................................................................2-3 2.1.3. Phase 3..............................................................................................2-4 2.1.4. Phase 4..............................................................................................2-4
2.2. Types of Clinical Trials.....................................................................2-5 2.3. The Clinical Trials Research Protocol.............................................2-7 2.4. Participant Assignment....................................................................2-8 2.4.1. Randomization..................................................................................2-8 2.4.2. Stratification .....................................................................................2-9 2.4.3. Blinding .............................................................................................2-9
3.
How Are Participants Protected?.................................................. 2-9 3.1. The HIPAA Privacy Rule and Research ........................................2-10 3.2. Protections Before Trials Start ......................................................2-11 3.3. Institutional Review Board .............................................................2-11 3.4. Protections During Trials ...............................................................2-12
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Benefits, Drawbacks, and Costs to the Clinical Trial Participant............................................................................. 2-14 4.1. Benefits and Drawbacks ................................................................2-14 4.2. Costs of Participating in a Cancer Clinical Trial ..........................2-14 4.2.1. Insurance Coverage .......................................................................2-15 4.2.2. Medicare Coverage ........................................................................2-16
5.
Drug Development and Approval Process and Special Access Program ......................................................................................... 2-17 5.1. Investigational New Drug Applications (INDs) .............................2-17 5.2. Steps in the Drug Development Process ......................................2-18 5.3. NCI Special Access Treatment Programs.....................................2-18 5.4. Group C Drugs ................................................................................2-18 5.5. Expanded Access Protocols..........................................................2-18 5.6. Special or Compassionate Exception ...........................................2-19
6.
Summary........................................................................................ 2-19
7.
Exercise ......................................................................................... 2-21
MODULE 3: LOCATING CANCER CLINICAL TRIALS 1.
Introduction ..................................................................................... 3-1
2.
Sponsorship .................................................................................... 3-1 2.1. NCI Programs ....................................................................................3-1 2.1.1. Clinical Trials Cooperative Group Program...................................3-2 2.1.2. Cancer Trials Support Unit ..............................................................3-2 2.1.3. Community Clinical Oncology Program.........................................3-3 2.1.4. Minority-Based Community Clinical Oncology Program..............3-3 2.1.5. Cancer Centers Program .................................................................3-4 2.1.6. Specialized Programs of Research Excellence (SPOREs) ...........3-4
2.2. Industry Sponsorship.......................................................................3-4
3.
Locating Trials & Cancer Resources ............................................ 3-5 3.1. NCI Resources ..................................................................................3-5 3.2. Other Online Resources ...................................................................3-6
4.
Summary.......................................................................................... 3-9
5.
Exercises ....................................................................................... 3-11
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MODULE 4: THE CLINICIAN'S ROLE IN CANCER CLINICAL TRIALS 1.
Introduction ..................................................................................... 4-1
2.
Discussing Trials ............................................................................ 4-2 2.1. Preparing for Discussion .................................................................4-2 2.2. Talking Points to Consider ..............................................................4-3
3.
Working With the Research Team................................................. 4-6 3.1. Working Relationship .......................................................................4-6 3.2. Communication.................................................................................4-7 3.2.1. Before a Trial ....................................................................................4-7 3.2.2. During a Trial ....................................................................................4-8 3.2.3. After a Trial .......................................................................................4-8
4.
Summary.......................................................................................... 4-8 4.1. Discussing Clinical Trials With Patients -- Suggested Discussion Points .............................................................................................4-9 4.2. Partnering With the Trial Researcher..............................................4-9 4.3. Case Study - Prostate Cancer........................................................4-10
5.
Exercises ....................................................................................... 4-15
APPENDICES Appendix A:
Participating in a Trial – Questions to Ask Your Doctor
Appendix B:
Discussing Cancer Clinical Trials With Patients
Appendix C:
How to Obtain More Information on Cancer Clinical Trials
Appendix D:
Resources
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Module 1: Course Introduction
May 2004
Cancer Clinical Trials Basics
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1. Introduction This course provides a broad overview of how cancer clinical trials advance cancer care by improving the approaches to cancer prevention, diagnosis, and treatment. Upon completion of this module, you will be able to: • •
Describe the changing paradigm of cancer diagnosis, treatment, and prevention Describe the role of clinical trials in the advancement of cancer care and provide examples
Parts of the content in this module are compiled from works of the following authors: National Cancer Institute (2001). Cancer Clinical Trials: The In-Depth Program. Available: http://oesi.nci.nih.gov/series/cted/indepth.html. National Cancer Institute (2002). The Nation’s Investment in Cancer Research for Fiscal Year 2004: Plans and Priorities for Cancer Research. Available: http://plan.cancer.gov. Individual references are not made in the text. See the bibliography in the Resources section of this document for more information.
2. Why Do Participants and Professionals Choose to Take Part in Cancer Research? Cancer clinical trials are research studies conducted with participants to assess the safety and efficacy of new approaches to prevent, detect, diagnose, and treat cancer. For individuals, reasons to participate in clinical trials include: • • • •
Potential benefit from the experimental intervention More control in their own healthcare decisions Close monitoring by the healthcare team Wish to give back and create a legacy
For health professionals, some of the reasons cited for becoming a clinical researcher include: • • • • •
Participation in advancing cancer care Professional stimulation and development Keeping abreast of new developments Opportunity to collaborate with other experts in the field Altruistic feelings of giving back to the community and medicine at large
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3. A New Paradigm for Designing Clinical Trials As researchers have gained insight into the fact that cancer develops as a result of cellular mutations in genes that alter the normal structure of certain proteins, a new paradigm in cancer diagnosis, treatment, and prevention is now emerging. This shift in thinking has arisen from a clearer understanding of how changes at the molecular level of the cell lead to cancer. The alterations in normal cellular pathways from these gene mutations result in uncontrolled cellular growth and cancer. Subsequently new anti-cancer agents are being directed toward the specific molecular targets present within the cancer cell, thus leaving the normal cells unharmed. These agents specifically target abnormal proteins, genes, or gene products, which directly relate to the process of neoplasia, and cancer cell growth. This methodology allows for more efficient treatment of the tumor, with less healthy tissue destruction thus greatly decreasing toxic side effects. Some examples of clinical trials emerging from this paradigm include the treatment of chronic myeloid leukemia (CML) in adults and children with imatinib (Gleevec). Imatinib blocks the cancer-causing effects of a genetically altered protein commonly found in CML. Another concept emerging from this paradigm shift includes anti-angiogenic therapy. The concept behind anti-angiogenesis is that by targeting a tumor’s blood supply, you can impact its viability. A clinical example, which has recently validated this hypothesis, is the positive results of a large phase 3 trial for metastatic colorectal cancer using bevacizumab (Avastin) plus conventional chemotherapy to improve overall survival. While targeted and anti-angiogenesis therapies are clearly demonstrating promise, researchers are already looking ahead to targeting multiple cellular pathways simultaneously. Since cells are programmed to compensate when one pathway is shut down by opening another, they may require drug treatments, which use combinations of targeted drugs. This paradigm may also benefit the participants whose tumors show resistance to one type of drug, but not another.
4. Emerging Advancements in Cancer Treatment From Recent Clinical Trials The advancements made through the successful completion of clinical trials include increased survival and better quality of life for people with a variety of cancers. As researchers improve conventional methods of cancer treatment, morbidity has decreased. The use of targeted, molecular-based therapies, immunotherapies with biological agents, and more efficient, less morbid techniques in surgery and radiation are increasing efficiency, while decreasing toxicity. Recent clinical advances have been seen in colorectal and breast cancers as well as T-cell acute lymphoblastic leukemia and hairy cell leukemia (HCL). For more details on these advances, go to the Cancer.gov website (http://www.cancer.gov). Scientific research has shown that cancer is not usually caused by a single catastrophic event, but rather is the result of a process that may take decades to culminate in disease. Because of the slowness of this process, there is opportunity to intervene to stop or reverse the process. Clinical trials for cancer prevention seek to take advantage of this Module 1
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time by identifying at-risk people, define methods to prevent or reduce their risk, detect cancer in its earliest stages and actively prevent cancer invasion. Clinical progress in this area has been seen with the use of tamoxifen for breast cancer prevention; the use of the arthritis/anti-inflammatory drug celecoxcib to reduce the development of polyps in familial adenomatous polyposis (FAP); and the use of low-dose aspirin for colon cancer reduction in patients with a history of colon polyps. For more prevention information, go to the Cancer.gov website (http://www.cancer.gov ).
5. Opportunities to Accelerate the Pace of Progress in Cancer Care Once an intervention is proven safe and effective, it may become the new standard of care. Current cancer care is based on the results of past clinical trials. An often-cited example of this was the discovery, through clinical trials, that lumpectomy with axillary node dissection, plus radiation, was as effective as modified radical mastectomy for early-stage breast cancers. This trial resulted in a true change in clinical practice, which decreased morbidity, while increasing quality of life for many women. Successful clinical trials have resulted in: • • •
Increased survival rates for a multitude of cancers Decreased morbidity and increased efficiency in surgical and radiation techniques The development of new compounds and techniques which reduce the side effects of cancer therapies and improve overall efficiency of treatment
As with all clinical trials, rapid accrual and timely completion of the study are what allow for results to then alter the standard of clinical care. Increasing patient referrals, and initiating trials within the community setting will further accelerate the advancement of cancer care. Here is what some professionals and patients say about why they chose to participate in cancer research: James Atkins, MD "We are at a very exciting time in oncology, and so I wanted to be in the action. I wanted to be involved in the clinical research and what was going on nationwide, I didn't want to get left behind." Stephen Gorsch, MD "If we're going to do our patients a service, we need to know that what we do works. And the only way we really know is by participating in clinical trials."
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Jenelle Foote, MD "I choose to discuss clinical trials with my patients as a means to enable them to have access to treatment, diagnostic, and preventative modalities that are unavailable to most doctors in clinical practice." Courtland (cancer patient) "I'm very glad that I listened to my doctor. I feel fantastic. I feel that the only thing that I worry about sometimes is if I hadn't had done this, where would I be today." Evelyn (cancer patient) "We wanted the latest medication, the latest procedures, and the latest information that we could get." Debbie (cancer patient) "I happen to think that clinical trials are the cutting edge. That's where great advances are coming from. I mean, after all, this is where the research is being done."
6. Summary Researchers are now looking at a new paradigm of cancer initiation and development, which includes molecular, cellular, behavioral, psychological, environmental, and social influences. As these factors are more fully understood, more effective, less harmful approaches to cancer prevention, detection, diagnosis, and treatment will be possible.
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7. Exercise Which of the following statements about cancer clinical trials is NOT correct? Circle one. A. It was discovered that a drug called Gleevec targets abnormal proteins fundamental to chronic myelogenous leukemia (CML), and Gleevec is now a new treatment option for CML. B. Researchers found that breast cancer was more effectively treated with the drug Gleevec than with tamoxifen and radiation therapy. C. Researchers have found that both overall survival and time to disease recurrence were significantly longer in colon cancer patients who received adjuvant chemotherapy than in those patients treated with surgery alone. D. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) will determine whether these two dietary supplements can protect against prostate cancer. Which of the following is NOT mentioned in this course as a reason that healthcare professionals choose to participate in clinical trials? Circle one. A. Keeping abreast of new developments in cancer care B. Professional development and stimulation C. Opportunity to make more money with less effort D. Opportunity to collaborate with experts in the field
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Module 2: Understanding Cancer Clinical Trials
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1. Introduction Health providers base their practices on scientific research data and continue to improve the quality of cancer care. Clinical trials are an important source of valuable research data. Cancer clinical trials are designed and conducted to show how a particular anti-cancer strategy affects the people who receive it. Following a scientific process, research data are collected on the efficacy and side effects of a drug or a treatment, and are analyzed to determine whether the new intervention is both safe and effective in humans. This module explains how clinical trials are conducted via distinct phases of research. The benefits, risks, and costs of trial participation are reviewed. Special Access Treatment Programs and the Food and Drug Administration (FDA) drug development and approval process are briefly highlighted. Upon completion of this module, you will be able to: • • • • • •
Identify the different types and phases of clinical trials and give examples of each type and phase Describe the purpose of a clinical protocol Identify patient protection measures in place during the conduct of a clinical trial Describe the risks and benefits to patients participating in clinical trials Identify alternatives to clinical trials in obtaining investigational drugs Describe the role of the clinical research process in new drug development
Parts of the content in this module are compiled from works of the following authors: National Cancer Institute (2001). Cancer Clinical Trials: The In-Depth Program. Available: http://oesi.nci.nih.gov/series/cted/indepth.html. Zivin, J.A. (2000). Understanding Clinical Trials. Scientific American, 2000: 6975. Individual references are not made in the text. See the bibliography in the Resources section of this document for more information.
2. How Are Clinical Trials Conducted? Cancer clinical trials are conducted by reputable investigators in both the academic and community settings in strict compliance with research protocols, Food and Drug Administration (FDA) guidelines when applicable, and good clinical practices (GCPs) principles. Federally funded research participants are also safeguarded by the Office of Human Research Protections (OHRP). An Institutional Review Board (IRB) oversees the conduct of the research and the protection of human participants. A series of oversight measures, such as the informed consent process, scientific review, adverse event reporting, data safety monitoring, and drug accountability, are built into the research process to address the optimal protection of human participants. Clinical trials differ by phase and type, but they all strictly follow a trial protocol, involve rigorous scientific review, and have an established study endpoint.
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Phases of Clinical Trials
Clinical trials occur in four phases, each of which is designed to answer different research questions: •
Phase 1: What are the effects of the intervention on the human body? How should it be given? What dosage is safe?
•
Phase 2: Does the intervention have the intended effect for a particular cancer? How does the intervention affect the human body?
•
Phase 3: How does the new intervention (or new use of an intervention) compare to the standard practice?
•
Phase 4: What are the effects of long-term or novel uses of an approved intervention?
The phases of clinical trials are explained in the context of treatment trials. Treatment trials are designed to test the safety and effectiveness of new drugs, biological agents, techniques, or other interventions in people who have been diagnosed with cancer. These trials evaluate the potential clinical usefulness of a therapy or compare investigational treatment against standard treatment, if there is one. 2.1.1.
Phase 1
Purpose
• • •
Find what dosage is safe Decide how treatment should be given Observe how the treatment affects the human body
Conduct
•
15 to 30 people are treated with increasing doses of the new therapy or technique The highest dose with acceptable toxicity is determined to be appropriate for further testing Subsequent phase 1 trials often evaluate new schedules or combinations of drugs or radiation
• • Participant
• •
Patients with a cancer that lacks or does not respond to standard treatment People with many types of cancer can participate in the same phase 1 trial
This phase is the first step in transforming preclinical testing data into clinical care. Preclinical testing is a process in which scientists test promising new cancer treatments in the laboratory and in animal models. This is done to find out whether agents have an anticancer effect and are safely tolerated in animals. Once an agent proves promising in the lab, the sponsor applies for Food and Drug Administration approval to test it in clinical trials involving people. While the primary goal of a phase 1 trial is to determine the toxic effects, pharmacological behavior, and recommended dosage of a therapy or technique for future trials, the trials are conducted with therapeutic intent.
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Phase 1 trials are not limited to "first in human" studies. Subsequent phase 1 trials often evaluate new schedules or combinations of established drugs, agents, or radiation. Later phase 1 trials may also be conducted to evaluate toxicity, response, and pharmacokinetics in populations that might not have been included in prior trials, such as children or the elderly. Some phase 1 trials are pilot trials for larger trials designed to determine the interaction of a drug with another treatment or substance. Almost all phase 1 trials of new anticancer drugs involve participants with a cancer that lacks or does not respond to standard treatment. Most often, people with many types of cancer can participate in the same phase 1 trial. Participants are generally required to have organs capable of metabolizing and excreting the drug and a 1- to 2- month life expectancy, in order to evaluate the drug's effects and the body's response to it. 2.1.2.
Phase 2
Purpose
Conduct
Participant
•
Determine whether treatment does what it's supposed to do for a particular cancer
•
See how the treatment affects the human body
• •
Less than 100 participants On the basis of their findings in phase 1 trials, researchers often focus phase 2 trials on cancers for which no effective trial exists and/or that are most likely to show a response to therapy
•
Some phase 2 trials compare different schedules of the same drug
Patients with a cancer that lacks or does not respond to standard treatment
Phase 2 trials are designed to evaluate the efficacy of the drug in a somewhat larger group of participants (usually under 100), using the dosage determined to be safe in phase 1 trials. On the basis of their findings in phase 1 trials, researchers often focus phase 2 trials on cancer presentations most likely to show a response to therapy. In choosing which type of cancer to study, researchers may also take into account effective alternatives and choose a cancer that has none. Some anticancer compounds being developed target molecular pathways in specific cancers, a development that may affect the cancers chosen for phase 2 trials. In most phase 2 trials, all participants receive the same dose of the drug (or undergo the same intervention). The new treatment is assessed for effectiveness, and additional safety information is noted. Some phase 2 trials compare different schedules of the same drug. At the end of such trials, the most promising regimen is chosen to move into phase 3 trials. Participants in this type of phase 2 trial are assigned at random to either schedule of the intervention or investigational agents. Neither the participants nor their doctors choose which group individual participants will be in. Module 2
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Generally, people who take part in phase 2 trials have not found the current standard of care effective or have cancers for which there is no standard treatment. Participants are generally required to have adequate organ function, a 3-month life expectancy, and a limited number of prior treatments. 2.1.3.
Phase 3
Purpose
Compare the new treatment (or new use of a treatment) with the current standard
Conduct
• • •
Participant
Conducted at multiple institutions around the country, including community settings Focus on specific types of cancer Participants are assigned at random to an investigational group or a control group
Eligibility requirements vary with the disease stage or other factors being studied
Phase 3 trials are large trials (usually involving over 100 participants) designed to determine whether a new therapy, technique, or procedure is more effective or less debilitating than a standard treatment. These trials are conducted at multiple institutions around the country, including community settings. The results of phase 3 trials guide health care professionals and people with cancer in making treatment decisions. Phase 3 trials focus on specific types of cancer. Participants enrolling in a phase 3 trial are assigned at random to an investigational group, which is given the new intervention, or a control group, which receives the current standard treatment. Some trials can also include more than two study groups, depending on the research questions being asked. Eligibility requirements vary with the disease stage or other factors being studied. Phase 3 trials typically involve large numbers of participants in order to determine true effectiveness. 2.1.4.
Phase 4
Purpose
Further evaluate the long-term safety and effectiveness of a new treatment
Conduct
•
•
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Take place after the new treatment has been approved for standard use Less common than the other 3 phases
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Types of Clinical Trials
Each of the following types of clinical trial attempts to answer different research questions, serve different purposes and recruit different types of participants.
Questions
What kinds of interventions, such as lifestyle modifications, dietary supplements, or drugs, can prevent or reduce the risk of cancer from occurring or from recurring?
Purpose
• •
Participant
• • •
Question
Evaluate the safety and effectiveness of various risk reduction strategies Include action trials and agent (chemoprevention) trials Participants from various age groups and socioeconomic backgrounds People who have combinations of cancer risk factors Participants in prevention trials can be people at risk for cancer, or people who have had cancer and are at risk of recurrence
What tests can find cancer in people before they have cancer symptoms? Methods of screening tests can include: • • •
Imaging tests - tests that produce pictures of areas inside the body Laboratory tests - tests that check blood, urine, and other body fluids and issues Genetic tests - tests that look for inherited genetic markers linked to some types of cancer, and molecular profiling for targeted treatment and prevention
An important note: The same tool or technique can be used either for screening or for diagnosis, depending on the situation in which it is used. Screening involves checking for cancer (or for conditions that may lead to cancer) in a person who does not have any symptoms of the disease. Diagnosis is looking for cancer in a patient who usually has signs and/or symptoms of the disease.
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Purpose
• • • • •
Participant
• • •
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Assess the effectiveness of new means of detecting earliest stages of cancer Examine whether early treatment improves overall survival or disease-free survival Assess imaging techniques to improve cancer screening and diagnosis Improve laboratory tests for screening and detecting cancer, including genetic markers, for high-risk individuals Determine how genetic make-up can influence detection, diagnosis, prognosis, and treatment Participants are healthy and may be chosen to represent particular age groups for socioeconomic backgrounds Participants with a combination of cancer risk factors, such as belonging to a family that has a genetic predisposition to cancer Participants who have symptoms of cancer and are seeking diagnosis
Question
What new interventions (e.g., drugs, biologics, surgical procedures, radiation, or combination of treatments) can be used to improve treatment for people with cancer?
Purpose
Test the safety and effectiveness of new drugs, biological agents, radiation or surgical techniques, or other interventions in people who have been diagnosed with cancer.
Participant
See the previous "Phases" section for detailed information on treatment trials.
Adjuvant Treatment Trials Purpose
• •
Participant
Participants are people who have no clinical evidence of disease after primary treatment but who are at high risk of recurrence
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Additional therapy after standard treatment Prevent the recurrence of cancer in people who no longer show clinical evidence of disease
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Neoadjuvant Treatment Trials Purpose
Additional therapy before standard treatment. Evaluate treatments designed to reduce tumor size to a point where it can be definitively treated by therapies that are considered the best standard treatment.
Participant
Participants are people whose cancer, once reduced, could be effectively treated by therapies considered the best standard treatment
Question
What interventions can improve the quality of life for people who have cancer and for cancer survivors?
Purpose
• • •
Participant
• • •
2.3.
Improve comfort and quality of life for people with cancer with better therapies or psychosocial interventions Help their families and caregivers cope Help survivors cope Participants are people who are interested in relief from the effects of cancer or its treatment Family members or others who want support in caregiving or meeting their own needs Cancer survivors
The Clinical Trials Research Protocol
Every trial has a written, detailed, scientific action plan, called a protocol. The protocol provides the background, specifies the objectives, and describes the design and organization of the trial. Use of a protocol ensures consistency of research procedures across the various sites where the study is conducted, promotes scientific validity of results, and protects patients. Every clinical trial site uses the same protocol for a particular study. In the table below, the questions answered by a protocol are listed in the left column, and the FDA-required protocol elements are listed in the right column. Such elements help investigators answer the questions in the left column and assist participants and healthcare professionals in understanding the goals of a clinical trial.
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Questions • • • •
• • • • • •
What is the scientific rationale or basis for conducting the trial? What are the objectives? How many participants will be in the trial? Who is eligible to participate? (This is determined on the basis of factors such as age and disease status.) What is the intervention, and what is its duration or schedule? What medical tests or follow-up visits will participants have? How often? What information will be gathered about participants? What side effects might there be? What are the endpoints of the trial?
FDA-Required Elements • • • • • • • • • • • • • • • •
General information Background information (with relevant references from the scientific literature) Trial objectives and purpose Trial design Participant selection and withdrawal Participant treatment Efficacy assessment Safety assessment Statistics Direct access to source data and documents Quality control and quality assurance Ethics Data handling and record keeping Financing and insurance Publication policy Supplements
Endpoints of a trial are what researchers measure to evaluate the results of a new treatment being tested in a clinical trial. Research teams establish the endpoints of a trial before it begins. Examples of endpoints include toxicity, tumor response, survival time, and quality of life. 2.4. 2.4.1.
Participant Assignment Randomization
In phase 3 trials (and some phase 2 trials), participants are assigned to either the investigational or control groups by chance, via a computer program or table of random numbers. This process, called randomization, gives each person the same chance of being assigned to either group. Randomization ensures that known or unknown factors do not influence the trial results so that the treatments being compared receive a fair test. If physicians or participants themselves chose which therapy participants would receive, assignments might be biased. Physicians, for instance, might unconsciously assign younger participants with a more hopeful prognosis to the experimental group, thus making the new therapy seem more effective than it really is. Conversely, participants with a less hopeful prognosis might pick the experimental treatment, leading it to look less effective than it really is. Randomization tends to produce comparable groups in terms of factors affecting prognosis and other participant characteristics. In this way, randomization minimizes threats to statistical validity.
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Stratification
Stratification is used in randomized trials when factors that can influence the intervention's success are known. For instance, participants in cancer prevention trials are separated or stratified by risk factors such as age since cancer risk increases with older age. Assignment of interventions within the two groups is then randomized. Stratification enables researchers to look in separate subgroups to see whether differences exist, and it ensures that the two groups are balanced for the known risk factors. 2.4.3.
Blinding
Trials designed so that participants do not know which intervention they are receiving are known as single-blinded trials. Those in which neither researchers nor participants know who is in the investigational or control group are called double-blinded trials. Double-blinded trials ensure that people assessing the outcome will not be influenced by knowing which intervention a participant is receiving. Blinding is more commonly used in cancer prevention trials than in treatment trials. For example, the SELECT (Phase 3 Randomized Study of Selenium and Vitamin E for the Prevention of Prostate Cancer) trial uses the double-blind method.
3. How Are Participants Protected? The strong international and federal safeguards in place today to protect research participants evolved to avoid medical abuses of human rights that have occurred in the past. Safeguards of human particpants include federal regulations (including the Health Insurance Portability and Accountability Act of 1996 [HIPAA]), Institutional Review Boards (IRBs), the Office of Human Research Protections (OHRP), scientific review, informed consent, adverse event reporting, and audits. For a more detailed account of human rights abuses and the scientific community's response, see the course "Human Participant Protections Education for Research Teams." This course is required for those involved in federally funded research. In 1974, the President established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1979, the commission issued the Belmont Report, which delineated the ethical principles upon which today's regulations regarding research participants in the United States are based: • • •
Respect for persons - recognition of the personal dignity and autonomy of individuals, as well as special protections for people with diminished autonomy Beneficence - the obligation to protect people from harm by maximizing unanticipated benefits and minimizing possible risk of harm Justice - fairness in the distribution of research benefits and burdens
In addition, the commission concluded that "a permanent board with the authority to regulate at least all federally supported research involving human subjects" should be formed.
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In response, Congress also passed the National Research Act, which mandated the establishment of Institutional Review Boards (IRBs) to review all U.S. Department of Health & Human Services (HHS)-funded research. The procedures established for IRBs were further delineated and revised in 1981. The Office for Human Research Protections (OHRP) under the HHS is one of the federal agencies that oversees the protection of clinical trial participants. It safeguards participants in federally funded research and provides unity and leadership for numerous federal departments and agencies that carry out research involving human participants. OHRP enforces the Common Rule regulation. 3.1.
The HIPAA Privacy Rule and Research
The HHS issued the Standards for Privacy of Individually Identifiable Health Information (the Privacy Rule) under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) to provide the first comprehensive federal protection for the privacy of personal health information. Many of those who must comply with the Privacy Rule must have done so by April 14, 2003. While certain provisions of the Rule specifically concern research and may affect research activities, the Privacy Rule recognizes that the research community has legitimate needs to use, access, and disclose Protected Health Information (PHI) to carry out a wide range of health research protocols and projects. The Privacy Rule protects the privacy of such information while providing ways in which researchers can access and use PHI when necessary to conduct research. The Web site http://privacyruleandresearch.nih.gov has been developed to provide the research community with information about the HIPAA Privacy Rule and how it might affect research. Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule, a booklet discussing how provisions of the Privacy Rule may affect research, is now available. HHS has developed sample language that covered entities may wish to consider when developing an authorization for use and disclosure of protected health information for research. Additional companion pieces to the booklet that will address the possible affects of the Privacy Rule on specific types of research activities are under development and will be available soon through this web site. HHS Office for Civil Rights (OCR) has also developed tools to help entities determine whether they are covered entities and subject to the Rule. Access these tools at: http://www.cms.hhs.gov/hipaa/hipaa2/support/tools/decisionsupport/default.php.
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To view the:
Go to this website:
HIPAA Resources Web site for OCR
http://www.hhs.gov/ocr/hipaa/
Complete final Privacy Rule
http://www.hhs.gov/ocr/hipaa/finalreg.html
HHS PowerPoint Presentation on the Privacy Rule and Research
http://www.hhs.gov/ocr/hipaa/conference/research.pdf
3.2.
Protections Before Trials Start
Participant safeguards begin well before a participant is enrolled into a trial. Measures range from scientific review of the research proposal before a trial starts to informed consent obtained from participants. Scientific Review: It assesses the scientific and technical merit of research proposals. Institutional Review Board Approval: An IRB determines whether the risks involved in a clinical trial are reasonable with respect to the potential benefits, and it must approve any clinical trial before it begins. The IRB also monitors the ongoing progress of the research. 3.3.
Institutional Review Board
The primary function of the Institutional Review Board (IRB) is to ensure the safety of the patients participating in clinical trials. It serves as both a review group and a monitor of the trials, and determines whether the risks to the patient participating in a trial are reasonable with respect to the potential benefits. The IRB reviews and approves, or disapproves, the clinical research protocol, informed consent forms, study advertisements, and patient brochures. It monitors the ongoing progress throughout the research study, and conducts continuing reviews of approved protocols not less than once per year. Federal regulations require that an IRB include at least five people from diverse occupations and backgrounds. In addition, one member must be outside the sponsoring institution - that is, not connected to it by employment or relatives. To meet these requirements, IRBs are usually made up of a mix of medical specialists, nurses, other healthcare professionals, ethicists, and lay members from the community. Most institutions that carry out clinical trials have their own review boards (there are roughly 3,000 IRBs in the United States). In some cases, a small institution might arrange for its research to be reviewed by another IRB rather than set up its own. All trials that are federally funded or evaluate a new drug or medical device regulated by the FDA must be submitted to an IRB for review and approval. However, many institutions require that all clinical trials conducted in their facilities, regardless of funding source, be IRB-approved.
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Before a trial can begin, the principal investigator submits an application to an IRB. The board reviews it on the basis of the following criteria: • • • • • • • •
Risks to participants are minimized as much as possible through sound research design Risks to participants are reasonable in relation to the anticipated benefits, and the knowledge that may result Participant selection is equitable Informed consent is sought in accordance with 45 CFR Part 46.116 Informed consent is documented in accordance with 45 CFR Part 46.116 Provisions are made for monitoring the data collected to ensure the safety of participants Provisions are made to protect the privacy of participants and the confidentiality of data collected during the trial Additional safeguards are in place if any participants are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, people with mental disabilities, or people with low income or education levels)
The IRB decides whether to approve the clinical trial and notifies the researcher and the institution in writing. The IRB may specify changes the researcher must make in order to gain approval. After approving a trial, the IRB must decide how frequently to monitor it usually on the basis of the risk involved. At the very least, the trial's progress must be reviewed yearly. For more in-depth information on IRBs, visit the NCI-sponsored Web-based course "Human Participant Protections Education for Research Teams" (choose the course from the curriculum menu). Informed Consent: As a legal, regulatory, and ethical concept, informed consent is an integral part of research. In clinical trials, informed consent is the process of providing relevant information about the trial's purpose, risks, benefits, alternatives, and procedures to a potential participant, who then, consistent with his or her own interests and circumstances, makes an informed decision about whether or not to participate. 3.4.
Protections During Trials
The protections of human research participants in clinical trials do not end with initial approval of the study or a signed informed consent document. In clinical research, the commitment to participants is to safeguard their interests throughout the study. Informed Consent Process: The informed consent process provides clinical trial participants with ongoing explanations that will help them make educated decisions about whether to begin or to continue participation in a clinical trial Institutional Review Board (IRB): Monitoring occurs at least yearly but sometimes more frequently. During these review sessions, the IRB examines a progress report provided by the clinical researcher in charge of the project. Data and Safety Monitoring Board (DSMB): The National Institutes of Health (NIH) requires all phase 3 and some phase 1 and 2 clinical trials to undergo monitoring by a
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data and safety monitoring board (DSMB). The objectives of data and safety monitoring plans are to: • • •
Ensure that risks associated with participation are minimized to the extent practical and possible Ensure the research results are reviewed appropriately while maintaining confidentiality of study data Stop a trial early if unacceptable safety concerns arise or if its objectives are met
Quality Assurance Monitoring: The National Cancer Institute (NCI) has several ways of ensuring the quality of data collected during clinical trials. Many trials, for example, have committees that review major elements of the study for accuracy, such as pathology, radiotherapy, surgery, and administration of investigational drugs. In addition, data management and statistical centers use quality control measures to help identify and correct or clarify inconsistencies and inaccuracies in submitted data. Another part of NCI's quality assurance program is onsite monitoring, or audits, of trial procedures, documents, and data. Adverse Event Reporting: For all federally funded trials, investigators need to report adverse events (AEs) to the organization leading the trial (e.g., a Group), their IRB (requirements for reporting may differ by toxicity grade or expected vs. unexpected), the trial investigational new drug (IND) holder if different than the organization leading the trial (i.e., CTEP in some cases for the Groups), and the FDA (for devices or investigational drugs). Ending Trials Early: There can be compelling reasons for halting a trial early. If participants experience severe side effects, or if there is clear evidence that risks outweigh benefits, the IRB and DSMB will recommend that the trial be stopped early. A trial might also be stopped if there is clear evidence that the new intervention is effective - in order to make it widely available. For more in-depth information on human participant protections, visit the NCI-sponsored Web-based course "Human Participant Protections Education for Research Teams" (choose the course from the curriculum menu).
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4. Benefits, Drawbacks, and Costs to the Clinical Trial Participant There are potential benefits from participating in a clinical trial, as well as drawbacks and costs. The patient's decision whether to participate in a trial or not involves consideration of these issues. 4.1.
Benefits and Drawbacks
Possible Benefits of Clinical Trial Participation: • • • • •
If a participant is taking the new intervention and it is shown to work, he or she may be among the first to benefit Study participants get regular and careful medical attention and are closely monitored by a research team, and may feel that they received more attentive care than if they had not participated in the clinical trial Participants can take part in a clinical trial and still maintain the relationship with their primary care physician Some participants feel good about helping advance medical knowledge that will improve cancer care and help others Even when they don't lead to new therapies, clinical trials answer important questions and help move research forward
Possible Drawbacks of Clinical Trial Participation: • • • • • • •
4.2.
New treatments or interventions may be inferior to standard care New interventions may have unexpected side effects that are worse than those of standard methods Although a new intervention is beneficial, it may not work for every participant. Even standard approaches do not help everyone If a participant in a randomized study receives standard care instead of the new intervention being tested, it may not be as effective as the new approach Participation in a clinical trial may require increased patient responsibilities such as more testing, more appointments, and self-monitoring for side effects. It may also mean less flexibility in treatment schedule Participants may have to incur the costs of travel, childcare, lost work hours, hotels, and meals Participants may have additional patient care costs that are not covered by the study sponsor or by their health insurance plan. What insurers and health plans cover varies by plan and by clinical trial Costs of Participating in a Cancer Clinical Trial
The costs associated with clinical trials can be a barrier for many professionals and the public. Healthcare providers are often concerned about reimbursement related to the expenses of either caring for people enrolled in trials or offering trials within their practice. Potential trial participants often fear that their insurance company will not cover
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participation. Those who are uninsured will need to know how their participation in a trial will be covered. 4.2.1.
Insurance Coverage
There are two types of costs associated with a trial: patient care costs and research costs. Patient care costs fall into two categories: •
Usual care costs include costs for doctor visits, hospital stays, clinical laboratory tests, x-rays, etc., which occur whether the patient is participating in a trial or receiving standard treatment. These costs have usually been covered by a thirdparty health plan, such as Medicare or private insurance.
•
Extra care costs are associated with clinical trial participation, such as additional tests required to evaluate the study interventions. These may or may not be fully covered by the clinical trial sponsor and/or research institution. The sponsor and the participant's health plan need to resolve coverage of these costs for particular trials.
Research costs are those associated with conducting the trial, such as data collection and management, research physician and nurse time, analysis of results, and tests purely performed for research purposes. Such costs are usually covered by the sponsoring organization, such as the NCI or a pharmaceutical company. Health insurance companies and managed care companies decide which healthcare services they will pay for by developing coverage policy regarding the specific services. In general, the most important factor determining whether something is covered is a health plan's judgment as to whether the service is established or investigational. Health plans usually designate a service as established if there is a certain amount of scientific data to show that it is safe and effective. If the health plan does not think that such data exist in sufficient quantity, the plan may label the service as investigational. For some health plans, clinical trial participation may result in a denial of coverage. However, some health insurance plans make case-by-case decisions about clinical trials, and some health insurers, such as Medicare, now cover the usual patient-care costs in clinical trials. A health insurance plan may define specific criteria that a trial must meet before extending coverage, such as: •
Sponsorship: Some plans may only cover costs of trials sponsored by organizations whose review and oversight of the trial is careful and scientifically rigorous, according to standards set by the health plan.
•
Trial phase and type: Some plans may cover patient care costs only for the clinical trials they judge to be "medically necessary" on a case-by-case basis. Trial phase may also affect coverage; for example, while a plan may be willing to cover costs associated with phase 3 trials, which include treatments that have already been successful with a certain number of people, the plan may require some documentation of effectiveness before covering a phase 1 or 2 trial.
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While health plans are interested in efforts to improve prevention and screening, they currently seem less likely to have a review process in place for these trials. Therefore, it may be more difficult to get coverage for the care costs associated with them. Some plans, especially smaller ones, will not cover any costs associated with a clinical trial. Policies vary widely, but in most cases the best bet is for the investigator's office to initiate discussions with the health plan. •
Cost "neutrality": Some health plans may limit coverage to trials they consider cost-neutral (i.e., not significantly more expensive than the treatments considered standard).
•
Lack of standard therapy: Some plans limit coverage of trials to situations in which no standard therapy is available.
•
Facility and personnel qualifications: A health plan may require that the facility and medical staff meet specific qualifications to conduct a trial involving unique services, especially intensive therapy such as a bone marrow transplant (high-dose chemotherapy with bone marrow/stem cell rescue).
4.2.2.
Medicare Coverage
For evolving information about Medicare coverage of clinical trials, go to the Web site for the Centers for Medicaid & Medicare Services (formerly the Health Care Financing Administration). The following are some frequently asked questions (FAQS) about Medicare and clinical trials. What will Medicare pay for a participant of a clinical trial?
Anything normally covered is still covered when it is part of a clinical trial. This includes test, procedures, and doctor visits that are ordinarily covered Anything normally covered even if it is a service or item associated with the investigational treatment. For example, Medicare will pay for the intravenous administration of a new chemotherapy drug being tested in a trial, including any therapy to prevent side effects from the new drug Anything normally covered even if it resulted from the participant's being in the clinical trial. For example, a test or hospitalization resulting from a side effect of the new treatment that Medicare would ordinarily cover
What costs are not covered?
Investigational items or services being tested in a trial. Sponsors of clinical trials often provide the new drug free, but make sure you ask your doctor before you begin Items or services used solely for the data collection needs of the trial Anything being provided free by the sponsor of the trial
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What kinds of clinical trials are covered?
May 2004
NCI's Cancer Information Service has provided a fact sheet for Medicare beneficiaries. In general, cancer treatment and diagnosis trials are covered if: •
• •
They are funded by the National Cancer Institute (NCI), NCIdesignated Cancer Centers, NCI-Sponsored Clinical Trials Cooperative Groups and all other federal agencies that fund cancer research. Other trials may be eligible for coverage and the investigator can ask Medicare to pay the patients' costs They are designed to treat or diagnose the participant's cancer The purpose or subject of the trial is within a Medicare benefit category. For example, cancer diagnosis and treatment are Medicare benefits, so these trials are covered. Cancer prevention trials are not currently covered
See www.cancer.gov for strategies and initiatives related to reimbursement.
5. Drug Development and Approval Process and Special Access Program Cancer clinical trials are designed to answer specific research questions about the effects of a therapy or technique designed to improve the diagnosis, treatment, or prevention of cancer. They are a key part of the drug development and approval process. Before a new drug or biologic agent that shows promising results in the lab can be tested on people, its sponsor must submit an Investigational New Drug (IND) application to the FDA. 5.1.
Investigational New Drug Applications (INDs)
Any organization seeking to sponsor clinical trials with experimental agents must first submit an Investigational New Drug (IND) application to the FDA. The initial application describes initial laboratory and animal data and presents the rationale for human testing. No experimental agents may be administered legally to patients for research in the United States without an IND. The most common way a person obtains access to an experimental agent is by participating in a clinical trial sponsored under an IND. Once the application is approved, the sponsor can begin testing the agent in clinical trials with human participants. If these trials demonstrate that the experimental agent is safe and effective, the sponsor can file a New Drug Application (NDA) or Biologics License Application (BLA) with the FDA. Only after the FDA approves the agent can it be marketed. After an agent becomes commercially available, the FDA continues to conduct postmarketing surveillance that tracks manufacturer compliance with phase 4
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commitments, monitors advertising for the agent, and handles feedback from professionals and consumers. 5.2.
Steps in the Drug Development Process
For an overview of the drug approval process from start to finish, see the FDA's From Test Tube to Patient. This book tells the story of new drug development in the United States and highlights the consumer protection role of the FDA. The PDF file is available on the FDA Web site, or call 1-888-INFO-FDA.
For more information on the development and approval process of device development, clinical imaging techniques, and prevention trials, visit the Web sites of the FDA and the Cancer Therapy Evaluation Program (CTEP). 5.3.
NCI Special Access Treatment Programs
For patients who may not be eligible to receive treatment on a clinical trial, NCIsponsored investigational agents may be made available for use outside the clinical trial. Working with the FDA, the NCI has established special conditions under which a person with cancer can receive experimental agents that have shown clinical benefit. Physicians with patients who are refractory to standard measures, who are not eligible for an ongoing research protocol, and who have a cancer diagnosis for which an investigational agent has demonstrated activity should contact CTEP to determine if the investigational agent is available under the special access program. 5.4.
Group C Drugs
Investigational agents that have been given Group C designation by the FDA have reproducible efficacy in one or more specific tumor types. Such an agent has altered or is likely to alter the pattern of treatment of the disease and can be safely administered by properly trained physicians without specialized supportive care facilities. A physician should request agents under Group C if he or she wishes to treat a patient with an indication specifically authorized for the requested agents. Information on how to obtain a Group C agent and the associated responsibilities when using the agent are contained in the Cancer Therapy Evaluation Program (CTEP) Web site. 5.5.
Expanded Access Protocols
Expanded access protocols are available for a limited number of well-studied investigational drugs awaiting final FDA approval. Expanded access allows a wider Module 2
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group of people to be treated with a drug. The purpose is to make investigational drugs that have significant activity against specific cancers available before the FDA approval process has been completed. The IND sponsor must apply to the FDA to make the drug available through an expanded access program. There must be enough evidence from studies already completed to show that the drug may be effective to treat a specific type of cancer and that it does not have unreasonable risks. The FDA generally approves expanded access only if there are no other satisfactory treatments available for the disease. 5.6.
Special or Compassionate Exception
The purpose of the Special Exception mechanism is to make unapproved investigational agents that have a significant activity against specific malignancies available to cancer patients and investigators who otherwise cannot participate in a clinical trial. The physician contacts the trial sponsor and provides the person's medical information and treatment history; requests are evaluated on a patient-by-patient basis, based on the following considerations: • • • • •
Is there a research protocol for which the patient is eligible? Have standard therapies been exhausted? Is there objective evidence that the investigational agent is active in the disease for which the request is being made? Is the agent likely to benefit this patient? Even if the agent has been reported to be active in the disease, the specific circumstances of the patient must be weighed by both his or her physicians and CTEP physicians.
Visit the Web site of the Cancer Therapy Evaluation Program (CTEP) for more information on non-research (compassionate) use of investigational agents. Other trial sponsors may have their own special access programs.
6. Summary Please answer the following questions: 1. Basic laboratory research and tests on animals are enough to determine the true effectiveness of an intervention. TRUE
FALSE
2. Clinical trials are conducted in a series of phases with distinct purposes. TRUE
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3. Clinical trials are for only those people who are being treated for cancer. TRUE
FALSE
4. Clinical trials are experiments, and therefore they are not as good as standard care. TRUE
FALSE
5. Patients in the control group of a trial are not treated and are given placebos. TRUE
FALSE
6. Participant accrual rates in clinical trials and professional referral and participation are two of the key factors in the successful implementation of clinical trials. TRUE
FALSE
It takes 14 years, on average, for an experimental drug to travel from the laboratory to U.S. consumers. Often the longest part of the process is finding people to participate in each trial phase. Approximately three quarters of children under 15 years of age with cancer participate in clinical trials, yet fewer than 3 % of adults with cancer do. To answer the most pressing questions about cancer - and to do so quickly - many more adults must participate in clinical trials. Professional participation and professional referrals, especially referrals from the community, increase participant accrual rates and ensure the quality of research data by improving ethnic and gender diversity in cancer clinical research.
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7. Exercise Which of the following is a correct statement about the main purpose of clinical trials? Circle one. A. Phase 1 trials compare a new treatment with a current standard B. Phase 3 trials decide how a treatment should be given C. Phase 2 trials determine if the treatment does what it is supposed to for a particular cancer D. Phase 2 find out what dosage is safe Which of the following is a correct statement about cancer treatment clinical trials? Circle one. A. All treatment trials are phase 3 trials B. Treatment trials study what kinds of interventions can better diagnose people with cancer C. Treatment trials are always randomized D. Treatment trials study which new interventions can help people who have cancer Of the following, which is the main purpose of a clinical trial protocol? Circle one. A. To allow physicians to individualize each patient's care B. To ensure high-quality patient care C. To explain how the study will be carried out D. None of the above Which of the following is NOT a patient protection mechanism in clinical trials? Circle one. A. Institutional Review Board (IRB) B. Data and safety monitoring board (DSMB) C. Randomized study design D. Informed consent form Which of the following is NOT one of the principles upon which today’s regulations regarding research participants in the United States are based? Circle one. A. Respect for persons B. Ability to pay C. Justice D. Beneficence
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What is the primary function of the IRB? Circle one. A. To design all clinical studies that use human patients B. To develop federal regulations for clinical trials that use human patients C. To ensure the safety of patients participating in clinical trials D. To organize a group of reviewers to review the research protocol How is the clinical trial participant protected during the study? Circle all that apply. A. Adverse events are monitored and reported. B. The study receives on-going scientific review by the clinical trial sponsor. C. Patients are given on-going explanation about the trial. D. If one arm of the study is found to be significantly better than the other, the trial will be halted and patients be offered to be put on the better arm. Which of the following is a possible benefit for a patient with cancer if the patient participates in a clinical trial? Circle one. A. If a new agent under investigation has an effect on the cancer, participants may be among the first to benefit B. By examining the benefits and drawbacks of clinical trials and other treatment choices, participants are taking an active role in a decision that affects their health care and life. C. Participants are taking a direct role in advancing cancer care through their participation in clinical trials D. All of the above Which of the following statements is correct about costs associated with clinical trial participation? Circle one. A. Medicare does not reimburse for routine participant care costs for its beneficiaries participating in clinical trials. B. In general, health plans do not cover treatments that they consider to be investigational. C. Research costs are usually covered by participants' health plans. D. Extra care costs are those costs not directly associated with the clinical trial, like transportation to the doctor’s office, or parking fees.
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The following conditions are necessary before a patient's clinician may request treatment through the Special Access treatment program: Circle one. A. The patient is refractory to standard measures B. The patient is not eligible for an existing trial C. The patient has a life expectancy of under 3 months D. The patient has a diagnosis for which the agent has shown clinical activity E. A, B, and D Which of the following is NOT a required part of the FDA’s drug approval process? Circle one. A. Phase 4 clinical trial B. Investigational New Drug application C. Preclinical testing D. Phase 2 clinical trial Which of the following is NOT a purpose of clinical trials? Circle one. A. To answer scientific questions B. To evaluate new prevention and treatment approaches C. To study the incidence and prevalence of cancer D. To improve cancer care to patients Which of the following is a common myth about clinical trials? Circle one. A. Only a small percentage of adults with cancer enroll in clinical trials B. Cancer treatment clinical trials are the treatment of last resort C. Prevention trials typically involve healthy people who are at high risk for developing cancer. D. Standard treatment options may or may not be better than the new experimental treatment
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Module 3: Locating Cancer Clinical Trials
Cancer Clinical Trials Basics
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1. Introduction Whether health providers are interested in referring people to a cancer clinical trial or in becoming clinical trial investigators themselves, they will need to locate clinical trials and various resources. This module explains the different sponsorships of cancer clinical trials, introduces the tools to use in locating trials and resources, and provides guided practice in locating trials. Upon completion of this module, you will be able to: • • •
Describe how cancer clinical trials are sponsored Describe six programs supported by the National Cancer Institute that conduct cancer clinical trials Locate clinical trials appropriate to the patient population
Parts of the content in this module are compiled from works of the following authors: National Cancer Institute (2001). Cancer Clinical Trials: The In-Depth Program. Available: http://oesi.nci.nih.gov/series/cted/indepth.html. Individual references are not made in the text. See the bibliography in the Resources section of this document for more information.
2. Sponsorship In order to find a cancer clinical trial, it is helpful to understand how clinical trials are sponsored. The National Cancer Institute (NCI) or a pharmaceutical company may sponsor a given trial. (Trials that pharmaceutical companies fund are referred to as industry-sponsored trials.) Cooperative Groups, cancer centers, individual institutions, and local physician practices all conduct clinical trials via funding from clinical trial sponsors. They take place all over the United States, in locations as diverse as a rural community clinic or a cancer center in a large urban area. There are also other entities that sponsor cancer clinical trials. These include other National Institutes of Health (NIH) Institutes, parts of the government such as the Department of Defense and Veterans Affairs, and foundations and non-profit organizations. 2.1.
NCI Programs
The National Cancer Institute sponsors clinical trials around the country through numerous programs: • • • • • •
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Clinical Trials Cooperative Group Program Cancer Trials Support Unit Community Clinical Oncology Program Minority-Based Community Clinical Oncology Program Cancer Centers Program Specialized Programs of Research Excellence
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2.1.1.
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Clinical Trials Cooperative Group Program
The Clinical Trials Cooperative Group Program supports a large consortium of organizations, including affiliates of small academic centers and community hospitals that continually generate and conduct new clinical trials consistent with national priorities in cancer treatment research. Member organizations carry out large randomized phase 3 trials, as well as the developmental efforts that lead up to them (including some phase 2 and even some phase 1 trials). Members conduct clinical trials in locations nationwide, while administration and data are handled at a central location. Members of the consortium include: • • •
Academic institutions Cancer centers Physicians in the Community Clinical Oncology Program and the MinorityBased Community Clinical Oncology Program Affiliates (smaller academic centers and community hospitals). Formerly known as CGOPs (Community Group Outreach Programs).
•
Each year, the consortium enrolls nearly 30,000 new people in treatment trials alone. The consortium also conducts prevention and imaging trials, evaluates some 12,000 new participants in ancillary studies, and follows the progress of many times that many participants in ongoing trials. Thousands of individual investigators participate in protocols. The Cooperative Groups have been instrumental in developing both new standards of care for people with cancer and sophisticated clinical investigation techniques. NCI's Clinical Trials Cooperative Group Program sponsors these 10 groups: • • • • • • • • • • 2.1.2.
American College of Radiology Imaging Network (ACRIN) American College of Surgeons Oncology Group (ACSOG) Cancer and Acute Leukemia Group B (CALGB) Children's Oncology Group (COG) Eastern Cooperative Oncology Group (ECOG) Gynecologic Oncology Group (GOG) National Surgical Adjuvant Breast and Bowel Project (NSABP) North Central Cancer Treatment Group (NCCTG) Radiation Therapy Oncology Group (RTOG) Southwest Oncology Group (SWOG) Cancer Trials Support Unit
The NCI and the Clinical Trials Cooperative Group Program are collaborating in a pilot project - the Cancer Trials Support Unit (CTSU) - to reduce administrative burdens and increase physicians' participation in clinical trials. CTSU is designed to streamline and centralize many regulatory, financial, and data collection tasks. CTSU provides participating healthcare providers with a single access point to nearly all of NCI's phase 3 treatment trial system, facilitating access to protocols, training, and educational information.
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Highlights of the fully developed CTSU system include: •
Cross-group registration enabling healthcare providers to register people on adult Cooperative Group trials in leukemia and lung, genitourinary, colorectal, and breast cancers, even if they are not members of the group conducting the trial Online registration, eligibility assessment, and reporting of data that will use a common format and state-of-the-art data management systems A coordinated auditing system that will avoid multiple quality assurance audits for research personnel participating in more than one Cooperative Group via the CTSU Centralization of administrative tasks, including credentialing and verification of Institutional Review Board (IRB) approval for all investigators participating in Cooperative Groups and CTSU
• • •
CTSU opened in July 2000 for Cooperative Group members. As of May 2002, CTSU has opened its protocol menu to qualified health care providers who are not affiliated with an NCI-sponsored adult Cooperative Group. For more information about CTSU, visit its Web site at www.ctsu.org. 2.1.3.
Community Clinical Oncology Program
The Community Clinical Oncology Program (CCOP), sponsored by the Division of Cancer Prevention (DCP), enables community healthcare providers to work with investigators conducting NCI-supported clinical trials. The program increases the number of participants and physicians who can take part in clinical trials operated simultaneously in major research centers and in the community. It benefits investigators by giving them an opportunity to conduct large-scale cancer prevention and control studies at the community level. Facilities participating in the program must be affiliated with an NCI-supported clinical Cooperative Group or cancer center and use research protocols developed by these groups. 2.1.4.
Minority-Based Community Clinical Oncology Program
The Minority-Based Community Clinical Oncology Program (MBCCOP), sponsored by the Division of Cancer Prevention (DCP), was initiated in 1990 to provide people with cancer who belong to minority groups access to state-of-the-art treatment, prevention, and control technology. The minority-based program was begun in response to the fact that 40 % of the people with cancer referred to CCOP physicians each year are from a minority group. Each MBCCOP pledges to accrue more participants from minority groups than other CCOPs do. Since funding began, participant enrollment in the minority-based program has grown to account for approximately 10 % of all ethnic minorities enrolled in NCI-approved clinical trials.
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2.1.5.
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Cancer Centers Program
The Cancer Centers Program consists of more than 50 NCI-supported research centers. Each cancer center also belongs to at least one Cooperative Group. The NCI supports three types of centers: •
Comprehensive cancer centers, which conduct basic, clinical, and preventive research programs, as well as community outreach and education programs Clinical cancer centers, which conduct primarily clinical research programs but may have programs in other research areas as well Generic cancer centers (formerly called Basic Science Cancer Centers), which conduct basic or preventive research programs and do not have clinical programs
• •
All clinical and comprehensive cancer centers also provide clinical care and service for cancer patients. In addition, comprehensive cancer centers have extensive ancillary cancer-related activities such as outreach, education, and information dissemination, as do some clinical centers to a more limited extent. A comprehensive list of cancer centers is available on the NCI Web site. 2.1.6.
Specialized Programs of Research Excellence (SPOREs)
The Specialized Programs of Research Excellence (SPOREs) were established in 1992 by the NCI to promote interdisciplinary research and to speed the bi-directional exchange between basic and clinical science to move basic research finding from the laboratory to applied settings involving patients and populations. The goal of the SPORE program is to bring to clinical care settings novel ideas that have the potential to reduce cancer incidence and mortality, improve survival, and to improve the quality of life. Laboratory and clinical scientists work collaboratively to plan, design, and implement research programs that have an impact on cancer prevention, detection, diagnosis, treatment, and control. To facilitate this research, each SPORE develops and maintains specialized resources that benefit all scientists working on the specific cancer site, as well as SPORE scientists. In 2002, the NCI funded SPOREs on breast, prostate, lung, gastrointestinal, ovarian, genitourinary, brain, skin, head, and neck cancers, and lymphoma. In the upcoming years, the NCI will increase the use of the SPORE mechanism to include funding for other major cancer sites such as GYN, leukemia, myeloma, and pancreas. 2.2.
Industry Sponsorship
Pharmaceutical and biotech companies also conduct clinical trials, both locally and nationally. They may conduct these trials in collaboration with universities, hospitals, the NCI, and local physicians. The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country's leading research-based pharmaceutical and biotechnology companies, which are devoted to inventing medicines that allow patients to live longer, healthier, and more
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productive lives. The PhRMA Web site publishes a list of new cancer drugs in development.
3. Locating Trials & Cancer Resources The National Institutes of Health (NIH), as well as many other organizations and companies also have a variety of online clinical trial information sources. A selected number of these services are summarized in this section. If internet access is unavailable, a call to the local oncologist to inquire about clinical trial participation is always possible. 3.1.
NCI Resources
The NCI Web site – www.cancer.gov -- provides comprehensive, research-based information on all types of cancer, clinical trials, cancer statistics, research programs, funding opportunities, and the Institute itself. Cancer.gov also contains the world's most comprehensive cancer clinical trials database, with approximately 1,800 abstracts of trials that are active and approved for patient accrual, and 12,000 abstracts of closed clinical trials that have been completed or are no longer accepting patients. Types of trials include treatment, genetics, diagnosis, supportive care, screening, and prevention. PDQ® (Physician Data Query) is an NCI database that contains the latest information about cancer treatment, screening, prevention, genetics, and supportive care, plus clinical trials. It contains information for both on-going trials and trials that are no longer accepting participants. It may be accessed at http://www.cancer.gov/cancertopics/pdq. Cancer Information Service (CIS) is a national information and education network for the public and health professionals. From 14 regional offices covering the entire United States, Puerto Rico, and the U.S. Virgin Islands, trained staff provide the latest cancer information through a toll-free telephone service. Staff can respond to calls in either English or Spanish. CIS now also offers a service called "Live Help" which allows chatting with a trained Cancer Information Specialist via instant messaging. To contact CIS, go to http://cis.nci.nih.gov/ or call: • •
Toll-free number: 1-800-4-CANCER (1-800-422-6237). Callers with TTY equipment: 1-800-332-8615.
Hours of operation are Monday through Friday, 9:00 a.m. to 4:30 p.m., Eastern Time. Callers have the option of listening to recorded information about cancer 24 hours a day, 7 days a week.
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Other Online Resources National Library of Medicine Database produced by NIH
What is it?
Registry now lists 5,200 primarily NIH-supported clinical studies on many conditions, and more will be added All trials on PDQ® are listed in this database What does it provide?
Summaries about clinical trials for a wide range of conditions
How may I access it?
http://clinicaltrials.gov
Food and Drug Administration's Cancer Clinical Trials Directory A list of sources prepared by FDA's Office of Special Health Issues
What is it?
Guides user to other Web locations for institutions that conduct or list cancer clinical trials What does it provide?
Web addresses and telephone numbers Information listed on the Web sites in this directory varies widely
How may I access it?
http://www.fda.gov/oashi/cancer/trials.html Local Cancer Centers' Hospital Web Sites
What is it?
Locally produced Web sites that include listings for trials sponsored by NCI and some pharmaceutical companies Good supplementary resources for locating clinical trials
How may I access it?
Different sites can be found through: ® • PDQ • National Library of Medicine (http://www.nlm.nih.gov) • Local institutions Information on trials taking place at NCI's Clinical Center in Bethesda, Maryland, is searchable at http://clinicalstudies.info.nih.gov Some centers may also have telephone information center
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PhRMA What is it?
Organization that represents the country’s leading pharmaceutical research and biotechnology companies
What does it provide?
Publishes a list of new cancer drugs in development by state, provides description, sites, telephone numbers, and investigator names
How may I access it?
www.phrma.org/ Click on "New Medicines in Development" and search by disease. The drugs are listed by tumor type American Cancer Society A nationwide, community-based voluntary health organization
What is it?
Has state divisions and more than 3,400 local offices What does it provide?
Research and research grants information National Cancer Information Center Online bookstore with patient education brochures and pamphlets, books, and professional journals Search engine for community programs and services
How may I access it?
http://www.cancer.org 1-800-ACS-2345
CancerWatch Clinical Trials Listing Service What is it?
An information services Web site used by patients, pharmaceutical, biotechnology and medical device companies, CROs, and research centers involved in clinical research around the world
What does it provide?
An extensive list of IRB-approved clinical trials being conducted internationally A list of promising therapies newly approved by the FDA Reports that patients and advocates can purchase. These reports focus on specific illnesses and offer in-depth information on clinical trials and new medical therapies
How may I access it?
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American Society of Clinical Oncology (ASCO) What is it?
Leading professional organization representing physicians who treat people with cancer. With over 20,000 members, ASCO is dedicated to improving cancer care and prevention via clinical research and education
What does it provide?
A network of resources for oncology professionals and local oncologist references
How may I access it?
http://www.asco.org (703) 299-8044 TrialCheckSM
What is it?
Provides doctors, nurses, patient advocates, and other healthcare professionals a "real-time" search tool that quickly queries and screens hundreds of cancer clinical trials
What does it provide?
Nationwide locations where trials are open and enrolling patients. It's easy, customizable through the coordinator function, and will soon be portable in PDA format. Helps physicians screen trials for their patients. Enables advocates to be more effective in providing specific trial information to people who call their organizations
How may I access it?
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4. Summary Depending on your personal preference or availability of communication tools, you can access clinical trial information and resources via the Internet or telephone. There are many sources of information sponsored by the government, industry, and other non-profit organizations. You and your patients may wish to look at information from many sites and consider the source of the information before making important healthrelated decisions. Problem Solving Scenario 1 Dr. Smith is a gynecologist and practices in Cincinnati, Ohio. One of her patients is at high risk for breast cancer. Dr. Smith is considering referring this patient to a breast cancer prevention trial. She would like to find out what such trials are conducted in nearby locations. Your Task
Help Dr. Smith locate such trials on Cancer.gov's clinical trials search.
• Complete the task by yourself by going to http://www.cancer.gov/. or
• Go to http://www.cancer.gov/ and follow these suggested steps to locate a breast cancer clinical trial in locations near Cincinnati, Ohio:
1. Select the "Clinical Trials" tab 2. Choose the "Finding Clinical Trials" link 3. Follow the instructions to search for breast clinical trials
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Problem Solving Scenario 2 Upon completing this course, primary care physician Dr. Lee decides to start referring patients to cancer clinical trials if there is a match. The first thing he wants to do is get an idea of the trials that are available in his area, San Jose, California. He remembers from the course that local cancer centers conduct both NCI- and industry-sponsored trials, and that Web sites for such centers are informative and current. He decides to check out the Web sites for nearby cancer centers. Your Task
Help Dr. Lee find out about available trials in his nearby area.
• Complete the task by yourself by going to the list of NCI-designated Cancer Centers found at http://cancercenters.cancer.gov/. or
• Go to http://cancercenters.cancer.gov/ and follow these suggested steps to browse available cancer clinical trials in the nearby area of San Jose, California: 1. Click "CA" in the state list or scroll down the screen to "California" 2. Find a cancer center that is located conveniently for patents in San Jose. The UCSF Cancer Center & Cancer Research Institute in San Francisco is the most convenient location among all the eight cancer centers in California 3. Click on the link to this center 4. Click the "Clinical Trials" button on the left of the screen to browse all the available cancer trials at this site
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5. Exercises Which of the following is NOT one of the NCI-sponsored cancer clinical trial programs? Circle one. A. Cancer Trial Support Unit (CTSU) B. Biotech company programs C. Clinical Trials Cooperative Group Program D. Cancer Centers Program Which of the following statements is NOT correct? Circle one. A. The Clinical Trials Cooperative Group Program supports a large consortium of organizations that continually generate and conduct new clinical trials. B. Health care providers need to be affiliated with an NCI-sponsored adult Cooperative Group to participate in clinical trials through the Cancer Trial Support Unit (CTSU). C. The Community Clinical Oncology Program (CCOP) enables community health care providers to work with investigators conducting NCI-supported clinical trials. D. The Minority-Based Community Clinical Oncology Program (MBCCOP) provides people with cancer who belong to minority groups access to state-ofthe-art treatment, prevention, and control technology. Which of the following statements is incorrect about NCI’s PDQ? Circle one. A. PDQ is a comprehensive, computerized cancer information database. B. PDQ contains cancer information summaries about cancer treatment, screening, prevention, genetics, and supportive care. C. PDQ contains information about both open, active protocols and closed clinical trials from around the world. D. PDQ is an e-mail service that provides information on cancer clinical trial. Choose the correct statement regarding locating clinical trials and resources: Circle one. A. NCI’s PDQ does not provide information for Phase 1 or 2 trials. B. Physicians can access information on the Internet, via cancer.gov, or can contact the CIS at 1-800-4-CANCER. C. PhRMA is a good source for clinical trials sponsored by NIH. D. All of the above
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Module 4: The Referring Clinicians' Role in Cancer Clinical Trials
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1. Introduction All healthcare professionals have a role to play in advancing cancer care, whether they are physicians, nurse practitioners, or nurses. Some offer cancer clinical trials within their practice, generating scientific data that are translated into clinical care. Others refer people to appropriate clinical trials. Referring people to clinical trials involves discussing clinical trials as an option with potential participants and working closely with clinical trial investigators on the shared care of trial participants. • • • • •
Upon completion of this section, you will be able to: Discuss the importance of professional referral to clinical trials and the advancement of cancer care Outline points to consider in preparing to discuss a clinical trial with the patient Identify possible talking points when discussing clinical trials with the patient Identify key patterns of responsibilities in an effective referring clinician-research team working relationship
Parts of the content in this module are compiled from works of the following authors: Braddock, C.H., Fihn, S.D., Levinson, W., Jonsen A.R., & Pearlman, R.A. (1997). How Doctors and Patients Discuss Routine Clinical Decisions: Informed Decision Making in the Outpatient Setting. Journal of General Internal Medicine, 12(6): 339-345 Grunfeld, E. (1994). Family Physicians Caring for Cancer Patinets. Can Fam Physician; 40:874. Kaluzny, A.D., Lacey, L.M., Warnecke R., Morrissey, J.P., Sondic, E.J., & Ford, L. (1994). Accrual of Patients to Ramdomized Clinical Trials: Factors Affecting Cancer Prevention and Control Research. International Journal of Technology Assessment in Health Care, 10(3):506-516. National Cancer Institute (2001). Cancer Clinical Trials: The In-Depth Program. Available: http://oesi.nci.nih.gov/series/cted/indepth.html. Williams, P.T. & Peet, G. (1994). Differences in the Value of Clinical Information: Referring Physicians versus Consulting Specialists. J Am Board Fam Pract; 7:292-302 Individual references are not made in the text. See the bibliography in the Resources section of this document for more information.
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2. Discussing Trials 2.1.
Preparing for Discussion
Before beginning a discussion with the patient about clinical trials participation, the clinician needs to prepare. Points to be aware of include: • • • • •
Understanding the study objectives and eligibility requirements and determining whether the patient meets the criteria Knowing the therapeutic options in general for this patient, and specifically what clinical trial is relevant. Awareness of the benefits, risks, and uncertainties of participation Does the trial involve potential randomized assignment of participants, and how will that be clearly explained to maximize patient understanding? Are you personally comfortable with the trial design and clinical integrity, and feasibility? Would you personally be willing to participate in a study of this nature if you were the patient?
Here is an example of how one urologist, Dr. Jenelle Foote, prepares to discuss clinical trial options with her patients: "I feel that referring physician should have the basic information to share with the patient because I feel that the patient may make a decision to go or not to go based up on such information." Do Research - What "When I discuss clinical trial options with my patients, I'll have always done my research, already done my homework, you might say. When discussing clinical trials with my patients, I'd like to have had the time to review the literature and to know whether this patient may or may not benefit from the clinical trial, so I can be as specific as possible with the patient. I find that to gain the patient's confidence, I need to present to the patient as much information as I possibly can. And I'd rather not present the information if I don't have as much information as possible. "The location of a clinical trial can be important for a patient. Some patients will travel to obtain treatment, some patient will not. The mode of therapy that the clinical trial involves may be important for the patient, for example, some patients may consent to surgery, some patients would not. Clearly if the treatment trial involves radiation or chemotherapy or any other variety of treatment modalities, knowledge of what exactly is the part of the patients is important to enable the patient to have an informed consent in regards to whether or not they'd like to be involved in such a study.
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"In addition for me as a physician the academic reputation of the chief investigator is of importance to me. I'm also wanting to know what else has been published in the literature in regards to these treatment modalities or diagnostic modalities for that matter that are part of that clinical trial." Do Research - How "One of the nice things that are available is the PDQ Web site. That PDQ web site is a very easy way that just about anyone can access information about a variety of clinical trials. Once I've read about the trial on the PDQ Web site, I can use the information on that Web site to access additional information which includes information about the researchers that are involved in the clinical trial as well as references to read other information about the treatment modalities, prevention modalities, or diagnostic modalities that are discussed for that particular clinical trial." Note to readers: Clinical trials can now be accessed via the cancer.gov website by selecting the site's clinical trials tab. Review Patient's Charts "I take some time to re-familiarize myself with the patient's clinical chart so that I can be conversant with the specific aspect of the patient's case. I feel that being able to talk specifically to the patient's specific case to demonstrate how the clinical trial may be of specific benefit to this patient will enable this paint to have the confidence in me as the treating physician also to get excited about potential clinical trial, because ultimately patients are interested in how the clinical trials affect them in their particular situation." Prepare Written Material "Having some type of written material to send the patient home with can be helpful because it can reinforce the discussion that you had with the patient at the time of the face-to-face meeting." 2.2.
Talking Points to Consider
When addressing why a clinical trial is an option for your patient in general, and specifically why a particular trial is relevant, you may want to consider the following talking points: • • • •
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Begin with the conceptual framework: This is how we treat this/your malignancy today (the standard of care) Discuss how treatment has changed over time, the history, or evolution of the standard of care. The message is that treatment has changed and improved because of previous clinical trials Discuss how science is evolving to lead us toward even better treatments Explain how patient participation is needed to realize the promise of improved cancer treatment
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Explain the details of the study, as outlined in the Preparing for Discussion section previously Explore the patient's preference
Emotions and concerns are very often expressed by patients in discussions about therapeutic options. Dr. Jenelle Foote has found that many patients, particularly AfricanAmerican patients, have strong concerns about participating in research. She explains why it is important to dissolve such concerns and how to do so: "I've found that many patients, particularly African-American patients, have very strong concerns about being involved in research that are usually negative. There have been experiences of African-American and poor people in this country with research that has been negative. And patients many times will point to the experience of others, for example, the Tuskegee syphilis experiments, as a reason not to want to be involved in clinical research. I think it's important whether or not this fear or anxiety is voiced or not voiced. As a referring physician, I'm sensitive to the concerns of the patient and let them know that there are safeguards in place by law to protect them as subjects of clinical trial. The safeguards include the clinical review board. The discussion of what a clinical review board is and how it evaluates the appropriateness of the activities of a clinical trial is something that I think will engender some comfort on the part of the patient. It is important for them to understand that important review process and to appreciate that prior to them signing any piece of paper that would give their permission to be involved in the clinical trial that is encumbered upon the researcher or the proxy of the research that the clinical trial is explained in depth, and in terminology, both verbally and in written form, that is understandable, that is clear. The patient also needs to appreciate that in time the patient can stop their participation in the clinical trial, and they do have rights that are specified very clearly."
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Dr. Stephen Gorsch is a cancer trial investigator who is experienced in discussing clinical trials as one of the options with his patients: "One of the concerns that patients have is whether they're in fact a guinea pig when they're being offered the study. And I tell them that there's several reasons why they might want to be on a clinical trial. The first reason is that it's a way of getting a national second opinion. It's not what Dr. Gorsch thought of, it's what the best colon cancer doctors in the country or the best breast cancer doctors in the country, sat down, they hammered this out they said how are we going to advance the treatment? This is the national second opinion they say this is the best we have. Another reason is it's quality assurance. I can tell patients that if you're on this clinical trial, everything I do is reviewed. Your x-rays, your blood work, the doses of chemotherapy. You know that what I'm doing is being done the right way, and that's something that is, I think reassuring to patients. And then ultimately, of course there's the altruistic motivation of providing information that will be useful for future patients." Nurse practitioner Kathleen Haden is also a cancer trial investigator with experience in discussing clinical trials as one option with her patients. She has developed a routine for such discussions: "We always give the patient options. I try to explain it as best I can. There are some patients I know that are just not going to understand it. They don't understand the disease, you try to get them through step by step, and sometimes the first meeting is very overwhelming. You know it takes two or three meetings before a patient may understand the prognosis of a terminal illness if that's the case, or just the emotions of developing cancer.
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We talked about dispelling the myths about the guinea pig. I tell people, you're getting the best treatment, and try to explain what it is and step by step in terms of the follow-up and what we do. And there's been plenty of studies that people on clinical trials rate that their quality of care is much higher than the ones that aren't on clinical trials because you have to dot every 'i' and cross every 't' and you have to follow this protocol, and you're following them a little closer maybe so they think that the quality is much better. And we work as a team. We have a clinical research associate that tries to keep us on track, that helps with the data monitoring and that we're doing everything that we have to do...and I tell the patients that, too. You know not that we wouldn't give you good care anyway, but that it may be superior or better. And especially when you're allowing the patient to get a drug that isn't even commercially available. And I tell them that you're not only going to help yourself but you're going to help millions of other people in the world by going on this study. And of course, the most important point - they understand and that they know that they can stop at any time, you know that they're not married to the protocol."
3. Working With the Research Team Referring clinicians not only work with the patient to make the decision to participate in a clinical trial, they also partner with the research team of the trial in the shared care of the patient. 3.1.
Working Relationship
As the referring clinician works closely with a research team, a pattern of responsibilities emerges: • • •
• •
Determine eligibility and feasibility of this patient enrolling into a clinical trial Discuss the trial with the patient Establish initial contact with the clinical research team (this is preferable to direct communication by the potential participant as he or she may not have sufficient information on their medical conditions and prior treatment to determine eligibility) Determine preliminary eligibility over the phone or via the Internet Schedule appointment and share appropriate clinical data with the research team
If the person is accepted into a trial, the referring clinician: • • • •
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Continues to provide clinical care of their patient Communicates with the research team regularly regarding patient's condition and any significant changes Provides emotional support to their patient Helps answer questions
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Referring clinicians play several important roles throughout the clinical trial process: • • •
Supply information to the clinical trial team enabling it to care for the trial participant Provide shared care for the participant while the patient is on the study and upon patient's completion or removal from the clinical trial Facilitate participant retention in the clinical trial by providing participants with continuity of care, emotional support and answers to their questions
The referring clinician, research team, and participant should develop a clear understanding of responsibilities for optimizing the participant's care. 3.2.
Communication
There is a direct relation between patient satisfaction and quality of communication between involved health professionals. Because the quality of such communication depends on the amount and quality of information provided to the clinical research team by the referring clinician, this section discusses the information that should be communicated to the research team. 3.2.1.
Before a Trial
The following categories of information should be provided by the referring physician to the researcher when a patient is referred to a trial: • • • • • • • •
Diagnosis and stage of disease Chief symptoms, if any, and for cancer treatment trials, the natural history milestones (stages or specific steps in the disease progression that the patient has experienced) Relevant history (especially that the patient is unlikely to supply) and for prevention or screening trials, any family history of cancer or known risk factors Patient's current medication Drug details, including sensitivities Referring physician findings Treatment that might mask symptoms Health beliefs and attitudes of patients
Besides clinical data, information about the concerns that the potential participant has is also helpful to the research team. Many people's decision on whether to participate in a clinical trial depends largely on whether their concerns are addressed to their satisfaction. However, research team members are not always aware of those concerns because many people may feel less comfortable discussing concerns and questions with them than with their referring clinician.
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During a Trial
When the participant is receiving the protocol intervention, the referring clinician may be providing care if any side effects result from the intervention and/or be involved in the primary care of the participant. It is important that the referring clinician communicates the following information to the researcher after each encounter with the participant: • • 3.2.3.
New problems if they arise Any changes in care that might have been initiated by the referring clinician After a Trial
After a patient completes a trial or is no longer a trial participant, document and report the following information: • • • • •
Change in health status Toxicity related to the trial Disease progression Change of address Date and cause of death
4. Summary Referring clinicians are a valued part of the research team. They have come to provide many levels of input, from trial design to data-collection tools, relevant follow-up issues, and improving informed consent processes. Referring clinicians help identify and establish the standard of care upon which future trials are built. Their contribution is paramount, and some would argue, an obligation, in advancing cancer care. Two tools are now provided to help assist you in your preparation before sharing information about a clinical trial with a patient. They are (1) suggested discussion points for discussing clinical trials with patients and (2) ideas for building an effective working relationship when partnering with the trial researchers. In the case study, read the clinical case of a male patient with prostate cancer. With the help of the tools, consider how you would discuss a clinical trial with this patient and how you would refer him to the clinical trial investigator. Suggested responses to some of the common patient questions are demonstrated by health professionals experienced in trial referral.
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Discussing Clinical Trials With Patients -- Suggested Discussion Points
Before discussion, consider providing a question prompt sheet to the patient to encourage them to ask questions during the session. Encourage patients to ask the research team the questions for which you don't have specific information. A sample question prompt sheet is provided in Appendix A. About clinical trials in general: • • • • •
Three phases of clinical trials Four types of clinical trials Advantages and disadvantages of participation in clinical trials (See Appendix B) Clinical trial costs Participant protections
To print out patient education materials to share with the patient, visit http://www.cancer.gov/clinical_trials/understanding/. About the particular trial you'd like to discuss: Objective Eligibility criteria What, if any, long-term follow-up is required Time commitment by participants of this trial Abbreviated discussion of findings of clinical trials conducted previously To print out patient version of the study abstract, locate the trial on the NCI Web site (http://www.cancer.gov/). If the patient would like to learn more about clinical trials, provide them with a list of resources on cancer clinical trials (see Appendix C). 4.2.
Partnering With the Trial Researcher
Making a Referral: (Information, documents, and/or written reports to provide to the research team) • • • • • • • • •
Referring physician diagnosis Relevant history (especially that the patient is unlikely to supply) Chief symptoms and natural history milestones (stages or specific steps in the disease progression that the patient has experienced) Patient's current medication Referring physician findings Relevant diagnostic tests and results Treatment that might mask symptoms Drug details, including sensitivities Health beliefs and attitudes of patients
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Documenting the Clinical Trial: (Information, documents, and/or written reports provided by the research team) • • • • •
Treatment schema (schedule of cycles and interventions based on day of cycle) Medication given Possible side effects Possible toxic reactions Diagnostic test schedule
Documenting Medical Care of Patient: (Medical care you have provided to the patient in the course of the trial. To be provided to the research team) • • • • •
Date Problems and symptoms Diagnosis and findings Medications Follow-up
Documenting and Reporting Certain Information After the Trial: • • • • • 4.3.
Change in health status Disease progression Death Toxicity related to the trial Change of address Case Study - Prostate Cancer
The following case study is an example of how the process of treatment and referral can proceed. It is not a recommendation for prostate cancer treatment. The Clinical Case Mr. John Webber, a 59-year-old black male, presents to his primary care physician, Dr. Sam Jenson, in rural Wisconsin, with an abnormal rectal exam and an elevated prostatespecific antigen (PSA). Mr. Webber's mass is a prostatic tumor. After radical prostatectomy surgery in his community hospital, a 1.5 cm tumor with a high risk for eventual tumor spread is found. At 3-month follow-up, his PSA is 0.2 (undetectable). The nearest comprehensive cancer center is 100 miles away, and Mr. Webber currently wishes to receive his care from Dr. Jenson. He verbalizes wanting to stay close to home and his family, and does not wish to be cared for by "those big city doctors." Dr. Jenson follows Mr. Webber. Mr. Webber's PSA slowly rises to 11 over 3 years; his bone scan and CT scans remain negative. Dr. Jenson explains to Mr. Webber that there are many clinical trials for men with prostate cancer at all stages. He explains that these trials are being conducted to try to find the best methods for cancer prevention, early detection and treatment. At this point in his disease, Mr. Webber does not wish to
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explore a clinical trial, and so he continues to receive standard care with hormone therapy injections monthly. The patient's PSA drops to less than 0.2 again. Two year later the PSA is 15 with a positive bone scan. Mr. Webber is started on an antiandrogen drug and his PSA drops to 10 at 3-month follow-up. One year later his PSA has risen to 40, and he now verbalizes mild rib pain. Dr. Jenson explains to Mr. Webber that he now needs to consult with an oncologist from the Cancer Center, Dr. Kyla Beacon. Mr. Webber somewhat reluctantly agrees to see Dr. Beacon, who also recommends exploring available clinical trials. She feels this is reasonable as Mr. Webber is still young, is in good health with mild symptoms, and has a tumor that now appears to be progressing. Finding a Clinical Trial Dr. Beacon decides to access the NCI's clinical trial system, as her center has no active trials for prostate cancer. The system will allow her to see current active clinical trials and evaluate what, if any, trials Mr. Webber is eligible for. Your Task Search NCI's clinical trials database and find out what, if any, clinical trials are available for prostate cancer patients. . Follow these steps to find clinical trials for prostate cancer: 1. Go to http://www.cancer.gov/ 2. Select the "Clinical Trials" tab 3. Click on the link "Finding Clinical Trials" 4. Follow the instructions to search for the appropriate clinical trial If you did not have Internet access, how else could you find a trial? If a physician does not have Internet access, clinical trial information is always available through the NCI's Cancer Information Service (CIS) at 1-800-4-CANCER (1-800-422-6237). After reviewing available trials, Dr. Beacon selects a phase 2 trial entitled "A phase 2 Randomized Study of High Dose Ketoconazole With or Without Alendronate Sodium in Patients With Androgen Independent Metastatic Adenocarcinoma of the Prostate" to discuss with Dr. Jenson and Mr. Webber. Discussing the Clinical Trial Dr. Beacon finds that Mr. Webber is clinically eligible for the study. She encourages Mr. Webber to bring his wife and sons along to the appointment to discuss the trial. Dr. Beacon first explains the treatment scheme to Mr. Webber. "This is a phase 2 cancer clinical trial. You would be randomized to one of two arms: In arm one you will take a single oral dose of ketoconazole on day 1, and then three times daily oral dose beginning on day 8. In arm two you will take a single oral dose of alendronate sodium on day 1 and a single oral dose of ketoconazole on day 3 and then daily alendronate sodium and three times daily ketoconazole beginning on day 8. Patients who experience a clinically complete remission receive treatment for an additional 60 days beyond complete remission. Module 4
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You would have to be willing to have follow-up visits at NIH in Bethesda, MD every two months and be seen in the Cancer Center every two weeks for evaluation of toxicity and drug tolerance." The following are common questions that come up during discussions about participating in clinical trials. How would you answer these questions? We encourage you to think through your answers before referring to the suggested responses. What is a randomized trial? Can my doctor choose the treatment I will get? "It is important that patients understand that there is an objective group of professionals monitoring clinical trials called a Data Monitoring Safety Board. Their job is to evaluate the data from the study to interpret if the therapy or technique being studied appears to be clearly better (more beneficial), or worse (more harmful), than standard therapy. A trial can be halted early to allow all participants access to clearly more beneficial intervention, or to protect participants from harm. There are three phases for trials and that randomization is generally seen in most phase 3 studies where researchers are unsure whether a new intervention is better than the currently accepted standard therapy for a certain cancer. When patients enter a phase 3 trial, and as in this case some phase 2 trials, they are randomly assigned to groups (called randomization) - and that neither the patients nor their doctors choose which therapy or technique they will receive. This is done because if physicians themselves determined which therapy participants would receive, there could be an unconscious bias in their assignments. They could tend to assign patients with a more hopeful prognosis to the investigational therapy group and make the new therapy seem more effective than it really is. Similarly, if patients were allowed to choose which therapy they would receive, the results could also be influenced. Patients with a less hopeful prognosis could tend to pick the investigational treatment, for example, which may lead that treatment to look less effective than it really is." How do I know I am really safe if I enter this trial? You and I both know there are bad feelings in our community about research. “Tragedies have occurred in the past related to clinical trials. The African American community most notably remembers the infamous Tuskegee syphilis study, which followed, but did not treat, black men with syphilis. There are now strong safeguards in place to protect research participants from the notorious human rights abuses of the past. These safeguard measures include • • •
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Government oversight and regulations, An Institutional Review Board that review and approve a clinical trial before it begins and annually while it is in progress, A process of informed consent which gives a potential participant the information they need to make a decision about participation, including foreseeable risks and benefits, and
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The Data Safety and Monitoring Boards which ensure minimization of risks, integrity of trial data, and oversight to end a trial early if clear benefit or harm arises from the intervention being studied."
Aren't these clinical trials only for dying cancer patients? "Clinical trials are not just for patients with the most advanced disease - in fact, many cancer patients get their first treatment in a clinical trial. If only the sickest patients participated in treatment trials, researchers would not know how to treat patients with earlier stages of cancer. Phase 3 treatment includes all stages of cancer, from the most advanced to the most localized. These trials enroll hundreds or thousands of patients. Phase 1 and 2 trials, which enroll fewer than 100 patients, seek people with few treatment options or people who have exhausted all the current treatment options, like in your case." Aren't people who join clinical trials just "guinea pigs" for research? "People who decide to take part in a clinical trial are called participants, and strict guidelines are in place to ensure that these volunteers are treated as participants: A participant has the right to withdraw from a trial at any time. The participant's decision does not jeopardize their future treatment and he/she may discuss further treatment options with the study physician or be referred back to their primary care provider for standard care. Although people fear that trial participants are treated like guinea pigs, reports from actual trial participants disagree. According to the Harris Poll conducted in 2000, the vast majority of trial participants said their overall experience was positive. Ninety-seven percent said they were treated with dignity and respect and that the quality of care they received was "excellent" or "good". More than 80 percent said they did not receive more tests than they felt were necessary and 86 percent said their treatment was covered by insurance." Mr. Webber's wife is very concerned that cancer patients who join clinical treatment trials get a sugar pill (placebo) instead of really being treated. Will my husband really get treatment? "In Phase 3 cancer treatment trials, participants with cancer get either a new treatment or the best standard treatment. In Phase 2 trials, like the one Mr. Webber is considering, different schedules and combinations of two drugs are being evaluated for their effectiveness. It is unethical to deprive any person with a serious illness or condition of the best available treatment. There would be no placebo involved in your husband's treatment."
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His oldest son is wondering if only people who have cancer can participate in a clinical trial. Aren't my brother and I at higher risk now? "While treatment and diagnostic trials are concerned with people who already have cancer, genetics, prevention, and screening trials are designed for persons at risk of developing cancer, who may be interested in trials that attempt to reduce the risk. This is relevant for you because you now do have an increased risk for prostate cancer. I'd suggest that you make an appointment to discuss a cancer prevention clinical trial with your private physician. You can also research what's out there via the NCI web site at www.cancer.gov." Mr. Webber is wondering if he agrees to participate in this cancer clinical trial, will it cost him any more than having standard treatment? Will insurance cover the costs? "The costs of new treatments for different cancers vary. Some treatments under study cost no more than standard therapies. Others, such as bone marrow transplants, are very expensive. There are hundreds of insurance companies and managed care organizations in the United States, and each has a different policy about covering clinical trial costs. In general, most companies have contract language that prohibits coverage for "experimental therapies." However, decisions are often made on a case-by-case basis, and costs for patient care in clinical trials are often covered. The best way to evaluate each situation is to ask questions such as: • • • • • • •
What will the total patient care costs of the treatment be? What parts of the treatment, if any, does the study provide free of charge. What parts of treatment must be paid for by the participant or the participant's insurer? What is the situation for people who have no health insurance? Will total patient charges be higher for a clinical trial than for standard care? How often have insurers reimbursed all costs of the new therapy? Are there other resources or organizations that might help cover the fees or provide services such as free transportation?"
Another option is to discuss reimbursement issues with the insurance company ahead of time. The company is unlikely to promise coverage before the fact, but it will give information about general policies and trends. Some patients choose not to take this step, however, for fear of raising a red flag that could hurt their eventual chances of reimbursement. In considering costs of out-of-town treatment or follow-up, you need to remember to include travel-related costs. It is important to ask about such costs when you meet with the research team. They will know how many times participants will need to visit, for how long, and whether housing or stipends will be provided, and whether participants will be hospitalized during their stay."
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5. Exercises Why are low accrual rates into treatment trials a problem? Circle one. A. Low accrual delays the completion of clinical trials B. They increase a trial's costs C. They are slowing the process towards better treatment options D. All of the above Before beginning a discussion with a patient about clinical trials participation, the referring clinician should be aware of: Circle all that apply. A. Study objectives and eligibility requirements of the trial B. Benefits, risks, and uncertainties of clinical trial participation C. Therapeutic options for the patient, including relevant clinical trial(s) D. How to explain randomized participant assignment if randomization is involved E. Personal comfort level with the trial design and its clinical integrity Which of the following points can be discussed with the patient regarding a clinical trial? Circle all that apply. A. The standard of care for the patient's condition B. How the standard of care was improved because of results from clinical trials C. The importance of patient participation on the continued improvement of cancer care D. Details of the study, including the objectives, benefits and risks, etc. E. Enrollment of the patient into the study Which of the following fall(s) under the responsibility of the referring clinician before and while a patient is enrolled in a clinical trial? Circle all that apply. A. Discussing the clinical trial with the patient B. Establishing initial contact with the research team C. Determining patient's preliminary eligibility over the phone or via the internet D. Providing the research team with the patient's information such as the chief symptoms, current medication, and the refereeing clinician's diagnosis E. Providing emotional support to the patient, but only resuming clinical care of the patient after the patient's clinical trial enrollment has ended
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Appendices
Cancer Clinical Trials Basics
May 2004
Appendix A: Participating in a Trial -- Questions to Ask Your Doctor The Study
• • • • • • •
What is the purpose of the study? Why do researchers think the approach may be effective? Who will sponsor the study? Who has reviewed and approved the study? How are study results and safety of participants being checked? How long will the study last? What will my responsibilities be if I participate?
Possible Risks and Benefits
• • • • •
What are my possible short-term benefits? What are my possible long-term benefits? What are my short-term risks, such as side effects? What are my possible long-term risks? What other options do people with my risk of cancer or type of cancer have? How do the possible risks and benefits of this trial compare with those options?
• Participation and Care
•
• •
What kinds of therapies, procedures, and /or tests will I have during the trial? Will they hurt, and if so, for how long? How do the tests in the study compare with those I would have outside of the trial? Will I be able to take my regular medications while in the clinical trial? Where will I have my medical care? Who will be in charge of my care?
• •
How could being in this study affect my daily life? Can I talk to other people in the study?
• • •
Personal Issues
Appendix A
Cancer Clinical Trials Basics
Cost Issues
• • • • • • • • •
Tips for Asking Your Doctor About Trials
May 2004
What will the total patient care costs of the treatment be? Will I have to pay for any part of the trial such as tests or the study drug? If so, what will the charges likely be? What is my health insurance likely to cover? Who can help answer any questions from my insurance company or health plan? What is the situation for people who have no health insurance? Will total patient charges be higher for a clinical trial than for standard care? Are there other resources or organizations that might help cover the fees or provide services such as free transportation? Will there be any travel or child care costs that I need to consider while I am in the trial?
•
When you talk with your doctor or members of the research team:
•
Consider taking a family member or friend along, for support and for help in asking questions or recording answers. Plan ahead what to ask—but don't hesitate to ask any new questions you think of while you're there. Write down your questions in advance, to make sure you remember to ask them all. Write down the answers, so that you can review them whenever you want. Consider bringing a tape recorder to make a taped record of what's said (even if you write down answers).
• • • •
Appendix A
Cancer Clinical Trials Basics
May 2004
Appendix B: Discussing Cancer Clinical Trials With Patients Possible Benefits of Clinical Trial Participation:
Possible Drawbacks of Clinical Trial Participation:
Participants will receive either the best standard treatment or intervention or the new method. The standard approach may be as good as or better than the new approach
New treatments or interventions are not always better than standard care
If a participant is taking the new intervention and it is shown to work, he or she may be among the first to benefit
New interventions may have unexpected side effects that are worse than those of standard methods
By examining the benefits and drawbacks of clinical trials and other healthcare choices, participants are taking an active role in a decision that affects their life
Although a new intervention is beneficial, it may not work for every participant. Even standard approaches do not help everyone
Participants may feel that they received more If a participant receives standard care instead attentive care than if they had not participated of the new intervention being tested, it may in the clinical trial not be as effective as the new approach Because study participants get regular and careful medical attention, some health problems may be found earlier than they would otherwise have
Participants may have to incur the costs of travel, child care, lost work hours, hotels, and meals
Participants can take part in a clinical trial and still maintain the relationship with their primary care physician
Participants may have additional patient care costs that are not covered by the study sponsor or by their health insurance or managed care plan. What insurers and health plans cover varies by plan and by clinical trial, but the most important factor determining whether a treatment or service is covered is the payer's judgment as to whether the service is "established" or "investigational."
Some participants feel good about helping advance medical knowledge that will improve cancer care and help others
Even when they don't lead to new therapies, clinical trials answer important questions and help move research forward
Participation in a clinical trial may require increased patient responsibility (more testing, more appointments, self-monitoring for side effects, etc.)
Appendix B
Cancer Clinical Trials Basics
May 2004
Appendix C: How to Obtain More Information on Cancer Clinical Trials To receive answers to specific questions about cancer: •
Call the National Cancer Institute's Cancer Information Service (CIS) at 1-800-4CANCER (1-800-422-6237); Deaf and hard of hearing callers with TTY equipment may call 1-800-332-8615.
•
Visit the National Cancer Institute's Web site (http://www.cancer.gov/) – information available on this site includes peer-reviewed summaries on cancer treatment, screening, prevention, and supportive care; a registry of clinical trials; and a range of additional resources for patients, health professionals, and researchers.
•
Visit the Cancer Information Service Web site (http://cis.nci.nih.gov/), which provides information about the CIS, cancer news, cancer resources, and frequently asked questions about cancer.
Appendix C
Cancer Clinical Trials Basics
May 2004
Appendix D: Resources Bibliography Breslin, S. (2000). History and Background. In Klimaszewski, A.D., Aikin, J.L., Bacon, M.A., DiStasio, S.A., Ehrenberger, H.E., & Ford, B.A. (Eds.), Manual for Clinical Trials Nursing (pp. 3-6). Oncology Nursing Press, Inc. Pittsburgh, PA. Jenkins, J. & Hubbard S. (1991, November). History of Clinical Trials. Seminars in Oncology Nursing, 7(4):228-234. National Cancer Institute (2001). Cancer Clinical Trials: The In-Depth Program. Available: http://oesi.nci.nih.gov/series/cted/indepth.html. Zivin, J.A. (2000). Understanding Clinical Trials. Scientific American, 2000:69-75. Braddock, C.H., Fihn, S.D., Levinson, W., Jonsen A.R., & Pearlman, R.A. (1997). How Doctors and Patients Discuss Routine Clinical Decisions: Informed Decision Making in the Outpatient Setting. Journal of General Internal Medicine, 12(6): 339-345 Grunfeld, E. (1994). Family Physicians Caring for Cancer Patinets. Can Fam Physician; 40:874. Kaluzny, A.D., Lacey, L.M., Warnecke R., Morrissey, J.P., Sondic, E.J., & Ford, L. (1994). Accrual of Patients to Ramdomized Clinical Trials: Factors Affecting Cancer Prevention and Control Research. International Journal of Technology Assessment in Health Care, 10(3):506-516. Williams, P.T. & Peet, G. (1994). Differences in the Value of Clinical Information: Referring Physicians versus Consulting Specialists. J Am Board Fam Pract; 7:292-302.
Appendix D
Cancer Clinical Trials Basics
May 2004
Online Resources Module 1: Course Introduction Resource Name
URL
Recent developments in cancer research
http://www.cancer.gov/clinical_trials/devel opments/
High-dose interferon prolongs time to recurrence in melanoma
http://cancer.gov/clinicaltrials/results/highdose-interferon1001
Biological therapies
http://cis.nci.nih.gov/fact/7_2.htm
Selenium and Vitamin E Cancer Prevention Trial (SELECT)
http://www.crab.org/select/
Digital Mammographic Imaging Screening Trial (DMIST)
http://cancer.gov/dmist/
Module 2: Understanding Cancer Clinical Trials Resource Name
URL
Insurance coverage strategies for participants and professionals
http://www.cancer.gov/clinicaltrials/unders tanding/insurance-coverage
Legislation and congressional activities
http://www3.cancer.gov/legis/index.html
Non-research (compassionate) use of investigational agents
http://ctep.cancer.gov/requisition/compassi on.html#NRC
From Test Tube to Patient
http://www.fda.gov/cder/about/whatwedo/t esttube.pdf
Appendix D
Cancer Clinical Trials Basics
May 2004
Module 3: Locating Cancer Clinical Trials Resource Name
URL
NCI's Clinical Trials Cooperative Group Program
http://cis.nci.nih.gov/fact/1_4.htm
Cancer Trial Support Unit
http://www.ctsu.org
Comprehensive list of Cancer Centers
http://www3.cancer.gov/cancercenters/cent erslist.html
Pharmaceutical Research and Manufacturers of America (PhRMA)
http://www.PhRMA.org
Physician Data Query (PDQ速)
http://www.cancer.gov/search/clinical_trial s/
Cancer Information Service
http://cis.nci.nih.gov
ClinicalTrials.gov
http://www.clinicaltrials.gov
TrialCheck
http://www.trialcheck.org/services
National Library of Medicine
http://www.nlm.nih.gov
Food and Drug Administration's Cancer Clinical Trials Directory
http://www.fda.gov/oashi/cancer/trials.htm l
Search The Studies
http://clinicalstudies.info.nih.gov/
CenterWatch
http://www.centerwatch.com
Module 4: The Referring Clinician's Role in Cancer Clinical Trials Resource Name
URL
Understanding Cancer Clinical Trials patient education materials
http://www.cancer.gov/clinical_trials/under standing/
Appendix D