June 18, 2009 — Patients with life-threatening illnesses have the right to refuse treatment, but do they also have the right to treatment with experimental drugs if no approved treatments exist?
These questions were addressed during a session here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.
"We know that there is strong demand for experimental therapy from patients," said Jeffrey Peppercorn, MD, MPH, assistant professor of medicine at Duke University in Durham, North Carolina. Oncologists need to understand the arguments for and against wider access to these agents, he added.
Investigational cancer therapies being tested in clinical trials can be available outside of trials or "off-protocol," and the extent to which patients should have access to these agents is a hotly contested issue. The demand for and the availability of off-protocol therapies, combined with differences in practice and attitudes among oncologists, demonstrates a need for wider awareness and discussion of this issue in the oncology community, Dr. Peppercorn explained.
Under most circumstances, treatment with an unproven agent outside the auspices of a clinical trial cannot be justified on clinical or ethical grounds. However, the challenges and ethics of off-protocol therapy have to be addressed, according to Dr. Peppercorn.
One of the concerns is that increased access to off-protocol treatment will lead to slower accrual in clinical trials, which are urgently needed in many oncology settings to improve outcomes. "While patients participate in trials through altruism and to help us improve care for future patients, we know from many studies and common sense that many patients come to us seeking clinical trials for their own needs," said Dr. Peppercorn. He pointed out that the same factors that drive the need for cancer research also drive patients to seek out promising experimental therapies.
Off-protocol therapy also raises issues regarding access to novel interventions by patients of different socioeconomic backgrounds, patient safety, and diversion of focus and resources.
Patient-Advocate Perspective
Ellen L. Stovall, acting president and CEO of the National Coalition for Cancer Survivorship, noted that many patient advocates are ardent supporters of clinical trials. "We have a long history of clinical-trials advocacy, and that has been a very high priority for our organization and many others in the advocacy community," she told the meeting.
"We feel that clinical trials are really the way to go in order to find out what works and what doesn't work in cancer care before exposing thousands of patients to these drugs. But we also know that very few patients are enrolled in clinical trials, which creates a terrible dilemma for us and for the investigators," she said.
This creates a conundrum, she contended. "How do we support both clinical trials as a standard of care and ready access to unapproved drugs outside clinical trials without hopeless inconsistency and lack of credibility for advocacy?"
Patient demand for access to experimental therapies drew media attention when the advocacy group Abigail Alliance filed a lawsuit against the US Food and Drug Administration (FDA), asserting that cancer patients with no other treatment options who were ineligible for clinical trials had a "constitutional right" to experimental therapies that had completed phase 1 trials. Although the court ruled in favor of the Abigail Alliance in 2006, an appeals court reversed that decision the following year. The US Supreme Court declined to hear the case, which effectively ended the appeals process, leaving the existing FDA regulations intact.
But there is currently very little middle ground for patients between viewing a single-use investigational new drug as a constitutional right and randomized clinical trials. "Some advocates have agreed to individual access outside of trials under certain circumstances, such as when all standard treatment options have been exhausted and patients do not meet the criteria for a clinical trial," said Ms. Stovall.
Ideally, any expanded access should be part of an overall clinical development plan, and patients participating in expanded-access plans should primarily be those ineligible for clinical trials. "Expanded-access plans should provide a framework for data collection and reporting that requires compliance for collection and reporting by sponsors," she added.
Variation in Practice Among Oncologists
A pressing issue for the oncologist is what to do when a patient requests an experimental drug outside of a clinical trial. Another issue to ponder, Dr. Peppercorn pointed out, is whether there is "a clear rationale for withholding an experimental therapy outside of a trial, when we are prepared to use it to treat a patient within a trial."
Dr. Peppercorn and colleagues conducted a survey to evaluate the practices and attitudes among American oncologists and to gain a better understanding of how oncologists deal with requests for experimental therapies (J Clin Oncol. 2008;26:5994-6000). Of 500 oncologists randomly selected from the ASCO database, 31% responded. "That's a good response rate for doctors," he noted, "but it does introduce some bias into our results."
The vast majority of respondents (93%) reported discussing experimental therapies with patients, and 81% stated they had prescribed them. Within this group, 66% reported prescribing investigational treatments at least once a year, and 12% said they prescribed an off-protocol therapy once a month or more frequently.
"We found that this is happening in the real world and most often in the academic environment," said Dr. Peppercorn. "I should add that most of the physicians felt that patients should be discouraged from doing experimental therapy outside of clinical trials."
However, the most interesting part of the survey was the responses from oncologists when specifically asked about case scenarios that were drawn from then-ongoing clinical trials. There was lack of consensus, Dr. Peppercorn noted. An example was the use of adjuvant trastuzumab, which 41% stated they would provide to patients outside of the ongoing trial and 59% stated they would not.
"We found a split among oncologists," he said, "and it didn't really vary by practice setting, but I think this was significant."
Implications of Off-Protocol Use
Dr. Peppercorn pointed out that the majority of recent oncology trials involve experimental regimens that are available outside of a clinical-trial setting. In a study presented during an Education Session at the ASCO meeting, Dr. Peppercorn and colleagues evaluated the availability of off-protocol therapies outside of clinical trials, and the potential impact on trial accrual, patient safety, and access to care.
They identified 172 phase 3 randomized controlled studies over a 2-year period ending April 17, 2008. The majority of trials (108; 63%) evaluated drugs that were available off-protocol at the beginning of the trial, and an additional 19 (11%) evaluated drugs that became available during the study period. More than half of these (64; 55%) were available because they had FDA approval for the same cancer in a different setting, 40 (35%) had approval for a different cancer, and 12 (10%) had approval for a noncancer indication.
The studies conducted with experimental therapies that were available outside the confines of the trial had a slower time to completion than trials with drugs that were unavailable (48 vs 26 months; P = .04). There was also a trend toward slower accrual (14.0 vs 40.7 patients/month; P = .06).
"We found that for the majority of these studies, the experimental arm had at least 1 new grade 3 or 4 toxicity, which highlights the importance of testing these drugs in trials," he said. "There were several studies where the experimental arm was worse than standard care."
These findings show that there is a need for discussion and guidelines within the oncology community, Dr. Peppercorn said. "I know as much as we are all fans of clinical trials and evidence-based medicine, as doctors, we are going to come up against this," he said.
The Abigail Alliance case did not end the legal battles for access, Dr. Peppercorn pointed out. "There are still pending legislative efforts to move this forward, so this is not the last that we'll hear of it."
"I think the Abigail Alliance is part of the beginning of the discussion and not the end, and I hope we continue to think through and work on these issues together," he added.
Access to Medical Devices
At the same, ASCO session moderator Joel Tepper, MD, a Hector MacLean Distinguished Professor of Radiation Oncology at the University of North Carolina/Lineberger Comprehensive Cancer Center in Chapel Hill, addressed a related issue — that of medical devices. There are ethical and practical issues involved with the use and approval of medical devices, he explained, but they are not well addressed by regulatory bodies.
"They really are, in many ways, inherently different than pharmaceuticals," said Dr. Tepper. "Medical devices all provide a critical function in medical care, but does an improved scalpel need a phase 3 randomized trial?"
The regulatory hurdle for devices is different than for pharmaceuticals; they basically have to perform the function for which they were designed and be able to do it safely. "But there is no real definition of efficacy," he noted. "And relatively few devices are really different from what came before. The critical issue is that the biology remains the same."
In some cases, the technology is very different from what is conventionally used. This includes robotic surgery, laparoscopic surgery, the harmonic scalpel, and proton radiation therapy. Even though the technology is dramatically different, the biology is the same, Dr. Tepper said.
One example is when improvements are made to x-ray delivery systems. Although new technology enhances the accuracy of the system, it still produces the same type of radiation beam, so it doesn't change the basics. The same is true for Port-a-Caths and infusion pumps — they deliver the same drug, but in a different way, Dr. Tepper said.
"In my opinion, randomized trials are ethically necessary when the new modality is, in some sense, inherently different," he said. "New biological therapy is, in virtually all situations, experimental."
But the dividing lines are very murky to say the least, Dr. Tepper added.
New technologies can be considered experimental if it is unclear whether the new approach does the same thing as the older technology and it is reasonable to assume that there can be alterations in outcomes. Dr. Tepper cited the example of laparoscopic vs open surgery: Do the surgeons perform the same operation?
The primary question, he said, is whether randomized trials need to be performed in the absence of any change in biology. He pointed out that randomized trials comparing laparoscopic and conventional techniques in colorectal cancer surgery have been conducted, but wondered what the end point should be.
"The primary reason for randomized controlled trials is to protect patients, and if the risk is low, I believe that you don't need them because you are not protecting anyone," he said.
As with new pharmaceutical agents, it is unclear whether new devices should be available to the patient outside of clinical trials, he noted.
Dr. Peppercorn reports serving in a consultancy/advisory role for AstraZeneca and Genentech; receiving honoraria from AstraZeneca, Eli Lilly, Genentech, and Pfizer; and receiving research funding from Genentech and Merck. Dr. Tepper and Ms. Stovall have disclosed no relevant financial relationships..
American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Education Session, presented May 30, 2009; Abstract 6539, presented June 1, 2009.
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