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Applied Clinical Trials
Life can change in an instant, but there is one thing that always abides: hope.
Life can change in an instant, but there is one thing that always abides: hope. Understanding the reality that comes when one is faced with a life-threatening disease and understanding how hope, the unfailing feeling and expectation that tomorrow will be better, challenges autonomous decision-making and explains why, only 3% to 5% of cancer patients participate in clinical trials. Although oncology projects account for almost 31% of global projects,1 they remain the most difficult therapeutic area in which to conduct clinical trials. As an industry we must learn to put the patient at the center of the clinical trial enterprise and see clinical trials through their eyes.
The definition of hope, a feeling of expectation and desire for a certain thing to happen, seems simple but managing that hope isn't. Managing hope became a reality as I began my journey that day in April when I heard the neurosurgeon say: "Your husband has glioblastoma multiforme (GBM), an extremely aggressive, highly vascularized, and incurable brain cancer." Through this journey I learned, from both a personal and professional perspective, that although hope remains a constant, hope changes form. When our neurosurgeon said, "someone is on the right side of the curve," it made perfect sense to me as a clinical research professional. In the beginning we hoped for a cure. With time and disease progression hope changed. A balance must be found between the hope that standard of care will work, the hope that the investigational agent in a randomized clinical trial will work, and the hope that there will be dignity in death. Hope changes and how it changes is based on actual alternatives available to the patient at any given time.
Plans for a dinner party hit a snag when 58-year-old Randy, my husband of 35 years, with noticeable concern in his voice, remarked that he just "didn't seem right." I called the doctor, who advised a trip to the emergency room. "Everything seemed so normal until I took him into the emergency department. All of a sudden someone was asking my husband to count backwards by 10 and he couldn't do it."2 Rather than enjoying a pleasant dinner with friends, we embarked on our new reality.
A glioblastoma tumor is like an octopus. It's difficult to surgically remove all the tendrils without jeopardizing the brain. Consequently, even when the primary tumor is removed, microscopic ones remain. Doctors recommended a three-phase treatment plan. A balloon implanted during surgery would be injected with radioactive iodine and removed after six days. Randy would later receive local radiation five days a week as well as low-dose chemotherapy daily for five weeks. In mid-summer he would receive high-dose chemotherapy five times over the course of a month.
Even with a plan in place, I began exploring options. It's hard to imagine anyone better suited to navigating the clinical trial process than I was. I have a doctorate in neurophysiology and I am the Executive Director and Head of Clinical Operations at a biotechnology company where I have been conducting oncology research for years and currently manage a Phase III melanoma trial. I suddenly found myself completely responsible for Randy's care and these were life and death decisions.
For the first time I came face to face with the reality of just how difficult it is for patients to navigate their way through the clinical trial process. Much as I liked, respected, and trusted our medical oncologist, he was primarily familiar with the trials at the academic cancer center where he practiced. My professional experience with the website www.clinicaltrials.gov, led me to believe even more strongly that this site meets researchers' and sponsors' needs more than would-be participants'. I reached out to colleagues and friends for opinions and recommendations, but could not help wondering how people who did not have access to such a network coped.
As chair of a hospice IRB (research ethics committee) for 15 years I understood the concept of morality, the protection of human subjects, and the ethical principles that guide clinical research. Therefore, I understood why our oncologist would not try to influence me when it came to exploring potential clinical trial participation. He would not and should not say, "I think this is the best choice." Avoiding the "therapeutic misconception" is something that we train our investigators to do. In order to protect human subjects participating in clinical research one must avoid any form of coercion in order to maintain the individual's autonomy. However, the reality is that as ethical and proper that neutrality may be it puts an enormous burden on the patient and the family who are trying desperately to discern the best care path. There is no one there to help you navigate between standard of care (SOC) and research choices. "In the end, you make the best decisions you, and you alone, can make, because there is no one else to make the decision for you."2
Hope may be one of the greatest obstacles to clinical research participation. Periodic cancer scans become a part of life. And periodically you would have a good scan which would provide a little glimmer of hope. Randy would go to work every day, void of symptoms, and life would seem somewhat normal. I would think: "This is working. There is hope." And because of hope, patients and their families often choose the path of SOC because it is known and understood by their physicians and healthcare providers. I understand why only 3% to 5% of cancer patients participate in clinical trials; it is because of hope.
However, I knew the odds were against him. SOC treatment works for only about 2% of patients. Still, given my research experience I knew the odds of success with a Phase I or Phase II trial were even lower, or at best, unknown. In order to manage hope one must consider the success rate for SOC, predicated on the data submitted for approval, and the assumed success rate for a clinical trial, based on scientific assumptions. The choice may be 2% of patients respond to an approved treatment, and 10% may respond to an investigational agent. Which one would you choose? These statistics may be meaningful to the physician but are often meaningless to the patient and family. Now on the "other side of the table," I wasn't interested in generalizable results. I wanted to keep Randy alive so I held on to the hope that the outcome with SOC would be favorable.
When do you reach the point of deciding to participate in a clinical trial? For many patients and families facing life-threatening diseases, you wait until it is clear that traditional SOC treatments are no longer working. Yet by the time it was clear that SOC was not working, Randy no longer qualified for the Phase II trial we had been considering; he had had too many treatments. With no further choices available, what we hoped for changed. Our two sons moved home, hospice was called in, and we held on to the hope that there would be continued quality of life and dignity in death. Just before midnight on April 16, 2010, Randy died at home, surrounded by his family.
Clinical research professionals must understand the enormity of the decisions they are asking would-be participants to make. Sponsors should be challenged to consider the ethical issues facing patients and families with life-threatening diseases when designing protocols and preparing to recruit research subjects. Innovation in medical care will come from designer drugs, targeted therapies, gene therapies, new technologies, and most likely, a longer life. Although there are many changes that the drug development industry could consider, I believe that clinical research professionals can and must pragmatically alter their practices to better meet the needs of study volunteers, and do so now. We must redefine how we look at oncology clinical trials and look at these trials from the patient's perspective. This includes understanding the impact of autonomy and obtaining informed consent, developing appropriate clinical trial design, and improving access to clinical trial information while paying special attention to those volunteers facing life-threatening diseases.
Managing autonomy and the informed consent process. A little glimmer of hope has a significant impact on both the patient and the individuals (surrogates) who make decisions for people facing life-threatening diseases. Although the patient may maintain their ability to make an autonomous decision, their decision may be influenced by hope.
Hope is an ethical domain of the patient-provider relationship. On one hand, the experience of hope is a central and a necessary element of the experience of sickness, healing, and wellness. On the other hand, the hopes of the patient, surrogate, and healthcare providers may generate subtle and ethically murky effects on the autonomy of patients who are facing life-threatening diseases and are therefore especially vulnerable. Healthcare providers have a specific knowledge and authority that influences the on-going evaluation of a patient's health and hope. This is further complicated by the unspoken interaction between the patient's hope and that of the healthcare provider. Ardalan and Mohrmann (2005) stated that: "The line at the end of one's hopes and the beginning of another's autonomy is among the central contestable issues at stake in the patient-provider relationship." The authors recognized the impact of hope and strongly suggested that, at the very least, the encouragement of false hopes should be avoided as false hope may constitute a violation of individual autonomy.3
With the current culture of "encouraging disclosure," the question of how much information and what type of information should be provided to patients or subject volunteers has come into question. The informed consent process has to manage the jargon-filled document-the Informed Consent Form (ICF)-interpretation of inclusion and exclusion criteria, and understanding of incomplete and uncertain safety information. This is even more complicated when that potential subject is facing a life-threatening disease. The amount of information that should be provided depends on the patient's abilities, desires, and the intervention or healthcare that is being provided.4 When a patient is facing a life-threatening disease, the potential for the patient to exaggerate a benefit or minimize a risk is greater. From the subject's perspective, there is the reasonable expectation that the study would not be conducted unless there was some degree of therapeutic benefit; some level of hopefulness.
When facing life-threatening diseases, surrogates are often in the position to make life and death choices. In a study by Zier et. al.5 surrogates were able to accurately interpret statements expressing a high probability of a good outcome (such as "90% chance of surviving") but not those expressing a high risk for death (such as "5% chance of surviving" or "50% chance of surviving"). They found that doctor's messages regarding a prognosis were often viewed optimistically and that this optimistic bias, rather than a simple misunderstanding, resulted in inaccurate interpretation. Helping surrogates attain realistic expectations about the patients' likely outcomes is more complex than just giving clear information. With life or death choices, assessing therapeutic merits can be challenging. Oncology research participants may interpret the clinical trial information including ICF, exclusion/inclusion criteria, risks/benefits, and safety, as hopeful and optimistic while not acknowledging that there may be no direct benefit.
The ethics of clinical research also requires equipoise, a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a clinical trial. However, the question of whether clinical equipoise exists in a clinical trial in oncology is not clear. Often, approved therapies have response rates of less than 20%, while the drugs or biologics being studied are of unknown effectiveness but may have much lower toxicity. With the promise of improved efficacy, some would argue that putting half of the potential subjects into a control arm (SOC such as chemotherapy) as well as delaying access of the investigation product cause needless suffering. However, defenders of controlled and randomized clinical trials say that they are crucial in determining whether an investigational product really does extend life more than other approved treatments. Without hard proof that clinical trials can provide, doctors are left to prescribe "unsubstantiated hope;" the hope that you or your loved one is among the 20% or less that respond to SOC or among the unknown percent that responds to an investigational product. The history of cancer research is littered with drugs that appeared efficacious in early clinical trials and then failed when subjected to more rigorous testing. History has demonstrated that clinical research equipoise in the setting of life-threatening disease is not without biases. In one highly publicized melanoma trial, in which two cousins participated in a Phase II clinical trial with one randomized to the investigational product and the other to SOC, chemotherapy,6 the outcome was unfortunate. The cousin on the investigational product is alive while the cousin that received the chemotherapy has died. The data from the Phase I trial with PLX4032 had excellent results which may have been enough to claim that there was not clinical equipoise between PLX4032 and chemotherapy. Zelboraf (PLX4032) was approved in August 2011; however its long-term future remains unknown.
Clinical trial design. In clinical trials for oncology or any life-threatening disease, there is always the need to balance wanting the cleanest possible results (generalizable knowledge) with doing the best for each individual patient. Both physician/investigators and subject/patients want the investigational product to work, yet determining whether it does is a balance between the ethics of the physician/investigator and the hope and altruism of patients who choose to become human subjects participating in clinical trials. Our goal is to find out as quickly as possible, in as few patients as possible, whether an investigational product is efficacious and safe. Yet in doing so, sponsors often compromise strong statistical validity and protocol design in favor of a lower number of enrolled patients and more restrictive clinical trial design.
Rising protocol complexity and burden has resulted in information that is not usable by the lay public; patient or family/caregiver. In a survey conducted by Getz et al., it was found that 69% of all protocols were amended; 46% before or during the conduct of the study and 37% of them were considered to be avoidable.7 The increase in the number of unique procedures and total procedures per protocol resulted in an increase in the total work burden at the investigational site of 47.5%.8 Analysis of six studies by the Tufts Center for Drug Development found that approximately 30% of procedures performed supported non-essential endpoints, 30% to 60% supported secondary endpoints, and between 10% and 40% of the study procedures performed supported the primary endpoint. It is clear from the analysis by the Tufts Center for the Study of Drug Development that protocols are not becoming more concise and clear; but rather just the opposite.
Sponsors must be challenged to improve protocol designs in such a way as to address issues, such as inclusion and exclusion criteria, that are consistent with the patients' SOC. Protocols that allow for SOC in combination with an investigational product and include treatment schedules that follow conventional patient care would facilitate participation by making it more convenient for the patient and the family. The SOC for GBM is surgery, radiation, and chemotherapy; sometimes in sequence and often in combination. In addition, multiple brain surgeries, multiple radiation treatments, and multiple cycles of chemotherapy are not uncommon during the course of the disease. Protocols that exclude any one of these treatments or the number of treatments makes participation extremely difficult.
As we enter an era of "personalized" medicine, clinical trial design will, out of necessity, focus on a more homogenous population. The number of new oncologic targeted therapies has increased significantly over the past few years. In metastatic melanoma, the approval of the Roche's Zelboraf, a targeted therapy for patients with the BRAF mutation, signals this change. Approximately 50% of metastatic melanoma patients are positive for the BRAF mutation. In the clinical trials, the response rate among these patients was approximately 50% rather than less the 20% seen in most oncology clinical trials in the past.9 As personalized medicine emerges into both clinical research and medical practice, it is possible that the adaption of new and novel protocol designs will allow for inclusion and exclusion criteria to be consistent with SOC while not increasing the number of patients required to meet statistical significance in a clinical trial.
Improved access to clinical trial information and improved recruitment. For the past few decades clinical research professionals have recognized that less than 5% of cancer patients participate in clinical trials. The Los Angeles Times10 wrote: "Enrolling patients in clinical trials is one of the biggest barriers in cancer research. Only 3% to 5% of adult cancer patients enroll in clinical trials. And despite efforts to improve the experience for patients, the number of participants hasn't grown over the last decade. Some studies never enroll enough participants to complete the project. Patients cite the complex requirements of some studies, lack of insurance coverage, or just lack of awareness for not enrolling in trials." In a study of over 700 women screened for breast cancer in Sydney, Australia it was found that the decision to enter a clinical trial was an active one and correlated with a woman's knowledge, understanding of clinical trials, and desire to play an active role in treatment decision making.11
Patients and caregivers/surrogates should receive a continuum of "clinical trial education" that makes information regarding clinical trial options available to patients and their families continuously, from the time of diagnosis until death or remission. Patients and their families make "life and death" decisions at each and every point in their care so without current, timely, and accurate research information it is not possible to weigh participation in a clinical trial against continuation of SOC. Providing on-going information and education would help to balance the discrete units of hope that may come at each appointment or each MRI result. Education about clinical trials that is provided in a continuum may prevent disqualification at a later time.
Additionally, there should be easy access to information that is "usable and understandable" to the public, patient, and family. The most well-known website for clinical trial information is www.clinicaltrials.gov. It is the first to appear when searching on the web, followed by the National Cancer Institute, CenterWatch, disease-specific advocacy groups, and a variety of hospital systems. Information posted on these websites is not usable or understandable to the majority of individuals for which it may be important-patients and caregivers/surrogates. The inclusion and exclusion criteria are listed directly from a protocol and often meaningless to the patient. The best use of this information by the patient and family is to print it out and take it with them to their next doctor's visit. Organizations such as CISCRP and patient advocacy groups often serve as resources to help patients and their families to interpret and navigate through this information. Explanations pertaining to potential benefits and potential risks must be available. In addition, potential benefits and risks of clinical research participation must be weighed against the likelihood of a response (risks and benefits) from continuing on SOC.
Making an effort to design protocols that maintain the trial's validity while enabling seriously ill participants to receive both SOC and investigational products will help to improve patient participation in clinical trials. There exists an obvious paradox in clinical trial participation especially among cancer patients and those facing life-threatening diseases. Although less than 5% of cancer patients enter clinical trials, 42% of those patients surveyed said that they would agree to participate in a clinical trial and 48% of those surveyed were simply uncertain. Uncertainty stemmed from mixed feelings about new treatments, unknown side effects, randomization, and the perception that clinical trials were frightening. Slevin et al.12 suggested that it is time for the clinical research enterprise to review and revise both how clinical trials are described to potential subjects and the ways in which patients with cancer are invited to participate in clinical trials. Understanding the concept of hope and managing that hope through the duration of treatment, from diagnosis to death, may improve participation in clinical trials.
The three principles of the Belmont Report are autonomy, beneficence, and justice. Protection of human subjects participating in clinical trials requires us to ensure the individual's autonomy by avoiding coercion, undue influence, and affording additional protections for vulnerable individuals. Autonomy is the capacity of an individual to make an informed, un-coerced decision. In research, respect for the autonomy of patients is an important goal, though it often conflicts with the competing ethical principle, namely beneficence. In addition, the "therapeutic misconception," a distortion of the subjects' understanding of the risk/benefit relationship of the research, challenges the clinical investigator's ability to communicate information about a trial to a potential participant. The conflict between hope and autonomy challenges the fundamental ethical tenets of clinical research. "The line at the end of one's hopes and the beginning of another's autonomy is among the central contestable issues at stake in the patient-provider relationship."3
Patient participation may also be improved by providing patients with trial information soon after diagnosis so that they can make decisions about their care that will not preclude trial participation in the future. Such changes will help ensure autonomous decision making and improve participation in clinical trials. For Randy, when the appearance of a new, small, easily accessible lesion outside the original tumor bed was found the best approach determined was to forgo a biopsy and simply treat with a round of "targeted" radiation. That single decision, an additional round of radiation, resulted in his being excluded from possible participation in a Phase II trial at a later date.
Given the emotional need to hope for the best outcome weighed against the uncertainty of clinical research and whether the investigational product will work for you, the choice of whether or not to participate in a clinical trial is a difficult and very personal one. This is especially true when facing a life-threatening disease. Hope springs eternal and no matter how slim the potential for cure or recovery is, people will choose life over death. How do you manage that hope?
"If a patient goes into a clinical research trial with the attitude that, 'this is my only hope,' are they truly capable of making an autonomous decision? We have to somehow balance the needs of the patient and the needs of the companies that are trying to introduce new therapies to prolong the life of the patients while maintaining quality of life. In the end researchers need to take a moment and put themselves in the position of the patient and the family. They need to understand the elements of time and hope because if they do, then they will learn to create protocols that better meet the needs of these patients, their families, and their physicians."2
Linda Strause, PhD, is Executive Director and Head, Clinical Operations, Vical Inc. Research Scientist & Founder, Institute of Palliative Medicine & San Diego Hospice IRB, e-mail: .
Linda Strause, PhD, will speak about patient perspectives during a pre-conference workshop at CBI’s Clinical Patient Engagement Summit, which takes place October 24-25, 2013, in Philadelphia. Click here to see the full conference agenda.
1. EvaluatePharma, "2010: A Strong Year, Further Growth Targeted in 2011," (2010), http://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=236961
2. L. Strause, "Patient Perspective: Dwindling Time and Lingering Hope," Interview, DIA Global Forum, 4 (2) 124-126 (2012).
3. K. Ardalan and M. E. Mohrmann, "Hope and Autonomy in the Context of Heart Transplantation," Penn Bioethics Journal, 1 (1) 1-3 (2005).
4. P. Schwartz, "Questioning the Quantitative Imperative," Hastings Center Report, 42 (2) 30-39 (2011).
5. L. S. Zier, P. D. Sottile, S. Y. Hong, L. A. Weissfield, and D.B. White, "Surrogate Decision Makers' Interpretation of Prognostic Information. A Mixed-Methods Study," Annals of Internal Medicine, 156 (5) 360-366 (2012).
6. A. Harmon, "New Drugs Stir Debate on Basic Rules of Clinical Trials," New York Times, September 18, 2010, http://www.nytimes.com/2010/09/19/health/research/19trial.html?_r=2 .
7. K. Getz and D. Zuckerman et al., "Measuring the Incidence, Causes and Repercussions of Protocol Amendments," Drug Information Journal, 45 (3) 265 – 275 (2011).
8. K. Getz et al., "Variability in Protocol Design Complexity by Phase and Therapeutic Area," Drug information Journal, 45 (4) 413-420 (2011).
9. Roche, "FDA Approves Zelboraf (vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer," (2011), http://www.roche.com/media/media_releases/med-cor-2011-08-17.htm
10. S. Roan, "Clinical Cancer Trials May Become More Enticing to Patients," Los Angeles Times, March 23, 2011, http://articles.latimes.com/2011/mar/23/news/la-heb-clinical-trials-20110323
11. P. M. Elis et. al, "Randomized Clinical Trials in Oncology: Understanding and Attitudes Predict Willingness to Participate," J. Clin. Onc, 19 (15) 3554-3561 (2001).
12. M. Slevin et. al., "Volunteers or Victims: Patients' Views of Randomized Cancer Clinical Trials," British Journal of Cancer, 71 (6) 1270-1274 (1995).