BY Mikkael A. Sekeres, MD, MS
The costs to conduct clinical trials of new drugs in cancer have skyrocketed. And I’m not sure I know how to fix them.
Consider the processes that need to happen just to initiate a study.
The ideal, of course, involves an independent, academic laboratory designing or identifying a compound that perfectly inhibits the biologic abnormality responsible for cancer cell growth. That compound is tested in vitro and then in animals, and next comes to humans. The pre-clinical research might be funded by an RO1 or similar NIH grant, and the clinical studies through an R21 or equivalent NIH mechanism. This is referred to as “bench-to-bedside” research. Cancer centers with any support from the National Cancer Institute espouse this approach as their model for conducting clinical research.
But let’s be honest. It rarely happens.
More commonly, a pharmaceutical company already owns a collection of drugs, and screens them in various cell lines that mimic how cancer behaves in the body. Drugs with promise are then tested in animals with representative cancers, and again, promising ones are given the green light to move to patients.
Here’s where the fun begins.
Lead investigators, those with expertise in a given cancer and a proven track record in conducting similar trials, are approached to gauge their interest in offering a trial to their patients. Timing here is critical -- if studies competing for the same patient populations are already underway, the investigators may pass due to limited resources. This runs the risk of engaging less experienced investigators who may not be as familiar with disease and trial nuances, which may in turn result in undertreatment with an active drug, overtreatment with an inactive drug, or failure to recognize adverse events or to record responses accurately.
While some of these errors could potentially be fixed using central review, a patient who is prematurely removed from a study due to the erroneous conclusion that she was not responding to a new drug, when in fact she was, cannot be re-enrolled on the study. In addition to the potential harm this introduces to patients, these errors can waste millions of dollars in study costs for faulty data, and significant delays in bringing a drug to market.
An investigator who agrees to participate in a study then must obtain buy-in from a disease group, submit the trial through a scientific review committee, and then through an Institutional Review Board. These are all good things, intended to engage other disease specialists, maintain scientific integrity, and ensure protection of human subjects. Involving multiple investigators helps guarantee that a checks and balances system is in place that a study is sound and targets the appropriate patient population, and that a center sees enough patients with a particular disease to justify the resources to open the study.
Depending on how much back-and-forth is involved between committees and an investigator, though, this part of the process may take a few months. Time is money, as the saying goes, and while large pharmaceutical companies can weather these delays, smaller companies, dependent on funding that often requires meeting milestone, may not be able to.
Is that a big deal? A very wise man once told me that I shouldn’t weep when a small pharmaceutical company goes out of business, because those companies that have highly active drugs always find a way to secure investors, while those companies that fail due to limited resources likely didn’t have a great drug to start with.
That’s probably true, but can we afford to let even one miracle cancer drug slip through the cracks?
Speaking of resources, a budget also needs to be developed to pay for the study. This often occurs simultaneously with the other processes listed above. One of the major steps here involves defining what aspects of a trial are considered standard of care, and which are specific to the research being conducted.
The most common question I receive from patients considering clinical trial participation is, “Will this be covered by insurance?” For patients on Medicare (and most private insurers follow Medicare’s lead), the answer is pretty clear. On June 7, 2000, the President issued an executive memorandum directing the Secretary of Health and Human Services to "explicitly authorize [Medicare] payment for routine patient care costs and costs due to medical complications associated with participation in clinical trials."
This makes perfect sense -- if I would ordinarily treat a lung cancer patient with chemotherapy every three weeks, and obtain CT scans for a baseline assessment and twice thereafter, then treating a similar patient with an every-three-week experimental drug and obtaining identical radiographic scans should also be billable to insurance, with the exception of the experimental drug itself.
Why are trials so expensive, then? It takes a lot of people to make sure good research happens. Research coordinators, regulatory staff, clinical research associates, research nurses, and sometimes the doctors conducting the research all time track to trials. The more indolent the cancer, the longer the survival and follow-up, the more time that each of these people may track to a trial.
Non-standard-of-care tests are expensive, too. In the example above, a lung cancer trial may require the same patient to undergo five CT scans, two PET scans, and a repeat biopsy. In addition, it has increasingly been recognized that many novel drugs affect cardiac electrical conduction, and electrocardiograms are being required, in triplicate, before and after drug dosing. Additional labs may be required for the off-chance of unexpected adverse events, and additional doctor and nurse visits for the same purpose.
Add it all up, and some budgets run to more than $50,000 per patient.
So, is there a way to fix these costs?
Well yes, but not overnight, and everyone would need to feel some pain. Those involved in clinical research need to be good stewards of tests, procedures, and follow-up, to reduce these to standard of care as much as possible.
Cancer centers have to agree not to pad budgets with escalated cost estimates, pharmaceutical companies need to agree to pay for the real price of research, and regulatory groups should not demand across-the-board testing for rare side effects without a solid clinical basis. We should probably limit clinical research to a few centers with demonstrated expertise, and these should be supported in part through a national mandate.
And yes, I’d like to ask for world peace and an end to hunger, while I’m at it. But those seem like easier fixes.
Dr. Sekeres, OT’S Clinical Advisory Editor for Hematology/Oncology and Chair of the FDA's Oncologic Drugs Advisory Committee, is Director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Institute and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee.
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