“But no perfection is so absolute,
That some impurity doth not pollute.”
– William Shakespeare
While lounging in the ivory tower of academia, we frequently find ourselves condemning the peasantry who fail to grasp limitations of clinical trials. We deride the ignorant masses who insist on flaunting the inclusion criteria of the latest study and extrapolate the results to the ineligible patient sitting in front of them. The disrespect heaped on the “referring doctor” for treating their patients in the absence of evidence from prospective, randomized, multi-institutional trials is routine in conference rooms across the National Cancer Institute’s designated cancer centers.
There is a danger lurking in these not-so-private denigrations of clinicians doing their best to do the right thing. To understand the danger, we have to consider the current state of health care economics and our complicity in its continued evolution.
The introduction of third-party insurers decades ago warped the economics of health care to the point that modern patients generally expect to pay little or nothing for pretty much any medical intervention. As a result, physicians tend to prescribe treatments without regard to cost. Predictably, this results in a steady increase in costs, which have now become unsustainable for our nation. Those rising costs have resulted in many proposals for control, including the Affordable Care Act and the efforts to reverse it. Many see a single payer, government administered system as the only viable way forward.
No matter the final system our society settles on, it will have to account for the almost miraculous results from modern therapeutics, which seem to be announced more and more frequently.
As I write this column, the annual meeting of the American Society of Hematology is being held in Atlanta. The presentations recount studies of new agents alone, or in combination, that report unprecedented response and survival rates. In particular, cellular immunotherapy with chimeric antigen receptor T cells (CAR T cells) has captured the attention of physicians, patients, and investors. Simultaneously – and recognizing this revolution in oncologic therapeutics – the New England Journal of Medicine prepublished two papers presenting the results of CAR T-cell therapy for diffuse large B-cell lymphoma (DLBCL). The results are impressive, and earlier this year, the Food and Drug Administration approved axicabtagene ciloleucel for the treatment of relapsed or refractory DLBCL based on these data. An approval for tisagenlecleucel exists for the treatment of B-cell acute lymphoblastic leukemia, but approval for DLBCL is likely forthcoming, too.
These are wonderful developments. Patients with incurable lymphoma may now be offered potentially curative treatment. Hematology News has covered the development of these treatments closely.
Yet, there is a glaring problem that has also attracted attention: CAR T-cell therapy is incredibly expensive. The potentially mitigating effect of competing products on cost will be canceled by the demand, as well as by geographic scarcity, because only certain large centers will provide this treatment. Remember that the price of imatinib went up over time even though competitors entered the market.
Entering CAR T-cell treatments into the nation’s formulary for some patients will lead to rising premiums for all patients. Disturbingly, CAR T cells are just a treatment for hematology patients at present. What about the equally impressive new – and expensive – technologies in cardiology, neurology, surgery, and every other medical subspecialty? Our system is already struggling to accommodate rapidly rising costs as our population ages and demands more and more medical care.
Many believe that our society will ultimately require strict controls on access to these expensive treatments. While the idea of rationing care is abhorrent to clinicians, “evidence-based” restrictions to access appear not to be. For example, rituximab is effective for immune thrombocytopenic purpura (ITP), but is not FDA approved for it. Despite the restriction, rituximab is frequently used for ITP and generally reimbursed. Venetoclax is a useful agent for patients in relapse of chronic lymphocytic leukemia, but the FDA only approved it for those harboring a deletion of 17p. While insurers seem willing to reimburse the use of rituximab for ITP, they balk at covering venetoclax for off-label indications. More recently, and more ominously for the implications, the FDA approval for tisagenlecleucel in the treatment of B-cell acute lymphoblastic leukemia only extends to those up to age 25. That could mean a 26-year-old in relapse after an allogeneic transplant would be denied coverage for potentially curative CAR T-cell therapy.
The federal government is not the only bureaucracy with a financial interest in limiting access to expensive treatments. Commercial insurers have a fiduciary duty to their shareholders, not to the patients who consume their services. They employ thousands, among them physicians, tasked with reviewing our treatment recommendations to determine whether treatments will be paid for, often citing FDA approvals. Preauthorization for coverage results in innumerable treatment delays and added administrative costs that frustrate us and anger our patients. The insurers defend this incessant obstructionism by claiming they are protecting patients from unnecessary or unhelpful care. Like the FDA, they invoke our own penchant for evidence-based medicine or declare that some care pathway is the ultimate arbiter of truth in coverage determination. Therein lies the danger.
Where do you suppose the evidence and care pathways the FDA and insurers rely on come from? They come from academics like many of this publication’s readers. We gladly provide them with the data needed to restrict care. Through published studies in “major” journals, consensus guidelines promulgated through national organizations, and care pathways generated by our own institutions, we provide the fodder that feeds the regulatory apparatus that decides whose care is approved and paid for. As Walt Kelly’s Pogo stated in 1970, “We have met the enemy and he is us.”
In the interest of science and in the interest of safety – but mostly in the interest of ensuring regulatory approval – clinical trials of new agents often restrict eligibility. Our group recently found that randomized trials routinely exclude patients for rather arbitrary organ dysfunction ( Leukemia. 2017 Aug;31[8]:1808-15 ).
Another recent study concluded, “Current oncology clinical trials stipulate many inclusion and exclusion criteria that specifically define the patient population under study. Although eligibility criteria are needed to define the study population and improve safety, overly restrictive eligibility criteria limit participation in clinical trials, cause the study population to be unrepresentative of the general population of patients with cancer, and limit patient access to new treatments.” ( J Clin Oncol. 2017 Nov 20;35[33]:3745-52 ).
By setting narrow limits on eligibility, we court rationing through regulatory restriction. Federal and private agencies will necessarily become stricter in their interpretations of studies and policies in order to control costs. They will happily cite the data we produce in order to do so. For the vast majority of patients who do not meet stringent inclusion criteria, access to new treatments may well be denied. To ensure that patients are provided with the best and most economical care, I am an advocate for evidence-based medicine and care pathways to standardize practice. However, I am progressively more wary of their potential to restrict the availability of innovative remedies to our patients who are not fortunate enough to meet exacting inclusion criteria. Faced with complex patients for whom no study applies, our colleagues in the fields who feed us need flexibility to provide the best care for their patients. Those of us in the ivory tower who determine such inclusion criteria should not let perfect be the enemy of good and must do everything we can to help them and our patients.
Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at kalaycm@ccf.org .
