“What’s past is prologue.”
—William Shakespeare
Today, a cancer drug under study in a clinical trial is commonly provided for a finite period of time after the study closes to accrual. If that drug were not yet U.S. Food and Drug Administration (FDA)-approved when the study began, the complimentary drug supply to patients would end following FDA approval. In order to continue therapy with the drug, it would become the patient’s responsibility to purchase it. But this was not always the case.
The following commentary is not meant to be a critique of any individual or group but rather a rallying cry, urging us to join together to make changes in health-care delivery that respect the primacy of patients who choose to enroll in a clinical trial.
SWOG S0033
In the fall of 2000, the National Cancer Institute (NCI) invited several clinical investigators to plan a clinical trial for patients with gastrointestinal stromal tumor (GIST) and strong evidence of metastasis. Before imatinib, the median survival of this patient population was a few short months, and the response rate for the best cytotoxic chemotherapy was less than 5%.
Phase II studies both in the United States and in Europe had shown remarkable and unprecedented clinical benefit from imatinib. It was clear from the phase II studies that the drug was beneficial; we just didn’t realize how beneficial. Novartis agreed to provide the drug and was a major initiator of this meeting. At the end of the day, the investigators agreed to a study proposed by George Demetri, MD, of Dana-Farber Cancer Institute, that asked the simple question of dosage: Is 800 mg/d better than 400 mg/d? (This study preceded the identification of kit mutational analysis as a predictive biomarker.)
The investigators also agreed that the clinical trial should be coordinated by SWOG. The S0033 trial accrued more than 690 patients in 8 months. As Charles Coltman, MD, who was SWOG Chair at the time, would say, “This trial set a new indoor record for accrual.” At the next year’s ASCO Annual Meeting, I joked that we had accrued 150% of all known cases of metastatic GIST.
‘Third D’ of Clinical Research
In 2012, I recognized that we had a cadre of more than 100 patients who had survived 10 years since starting imatinib. We studied these long-term surviving patients in order to learn what characteristics had permitted this extraordinary response and survival. I drafted a manuscript with the help of the SWOG Statistical Center’s Cathryn Rankin, MS, and John Crowley, PhD.
Six of the 13 coauthors strongly objected to a paragraph I had written in the discussion section stating that the patients had to pay for their drug to “teach their doctors” that they could survive for a decade or longer with widespread metastatic cancer. Those six authors were firm that in their “opinion [this] did not belong in the discussion of a scientific manuscript”—or at least that opinion did not belong.
Before the study was initiated, SWOG failed to insist that the drug be provided by its manufacturer to those patients who had volunteered for the clinical trial. In addition, the NCI failed to insist that Novartis agree to continue to provide its drug to those patients enrolled in the trial who were still benefitting. When Novartis volunteered to provide the drug to NCI/SWOG for the clinical trial, it already knew that the FDA had agreed to approve the investigational new drug for this GIST indication and thus would allow the drug to be sold for this new indication. This meant that once it became approved, each patient had to pay for his own drug.
Our patients and their oncologists are of course grateful for the discovery and development of imatinib, but there are three D’s in clinical research: discovery, development, and delivery. Bill Gates and the Gates Foundation were the first to remind us about the third D: delivery. This essay, in part, is intended to address our delivery of potentially lifesaving drugs. Too often, academic oncologists don’t pay enough attention to the issue of drug delivery.
Queries for Pharma and NCI
I invite my colleagues in the pharmaceutical companies to respond to these challenging queries: For 30 years or more, drugs were provided to all patients enrolled in National Institutes of Health clinical trials at no cost, even after the trial ended. Why the change in practice? All pharmaceutical companies proclaim that their efforts are first and foremost to benefit patients. Is the change in practice consistent with these noble mission statements?
When pharmaceutical companies justify drug pricing, they include discussion of the high cost of “discovery and development.” For example, a very conservative estimate suggests that if 100 patients took imatinib as in our trial for the past 10 years, the total cost for the drug would be $80 million paid to Novartis. Does the estimate of the discovery and development costs deduct the estimated income derived from selling the drug to study participants (ie, $80 million)?
I also challenge my colleagues at the NCI: Why did you allow and accept this change in the delivery of drugs to patients who have volunteered for a clinical trial?
Queries for Oncologists
I raise the following question to oncologists who value clinical trials, particularly those supported by the NCI and its National Clinical Trials Network: What would happen if we were to refuse to open a study that did not provide continued use of the drug for enrolled patients who are benefitting from the study drug once the trial has ended?
And I pose this question to my oncology colleagues who manage these patients’ ongoing care: Is there anything we can do about this unjust practice? Oncologists at Memorial Sloan Kettering elected not to include the drug ziv-aflibercept (Zaltrap) in their formulary, in large part because of the price. In response, Sanofi dramatically lowered the price. So there has been success in voicing disapproval and, in turn, convincing pharmaceutical companies to lower their prices.
Everyone is aware of the challenges patients face on a daily basis. No doubt there are bigger challenges than being forced to pay for drugs after volunteering for a clinical trial. But to continue this practice just seems wrong! ■
Disclosure: Dr. Baker has received grant support from the National Institutes of Health and the Gates Foundation. Hyatt Corporation provides a suite, but no grant support. He is President of the Board of the Hope Foundation and on the data safety monitoring board for CytRx and Morphotek. He has also served on advisory boards for Merck and Millenium.
Dr. Baker is Professor of Internal Medicine and Pharmacology, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.
