The popular narrative surrounding cancer drugs or other therapies for rare diseases is that patients are willing to assume more risk and uncertainty to gain rapid access to investigational agents. This is, in part, the impetus behind the frequent use of surrogate endpoints by the US Food and Drug Administration (FDA)1 and European Medicines Agency,2 as well as the right-to-try legislation.3 This US law permits patients with terminally ill conditions to receive experimental therapies without the approval of the FDA.
The narrative that cancer drug regulations impose an obstacle on patients was echoed by President Trump, who said, “Our slow and burdensome approval process at the FDA keeps too many advances … from reaching those in need.”4 Here, from the perspective of a medical resident (DLT), a long-time caregiver for family members with cancer (SS), and a practicing hematologist-oncologist (VP), we wish to argue that the current narrative is incomplete. Too often, patients are portrayed as seeking access to untested drugs while regulators insist on careful clinical trials. Instead, we believe the true narrative is that some patients are tolerant of risk and desire fewer regulatory standards, but other patients actually desire increased knowledge regarding their care. In the current system, patients seeking more data to inform their choices are routinely deprived because incentives to generate more data after approval are essentially absent. We begin with the experiences of SS. Over the years, SS has cared for several family members with medical conditions, several with cancer. This is the story of her brother, in SS’s words:
At age 40, my brother was diagnosed with stage IV peripheral T-cell lymphoma, a relatively rare disease. He’d been ill for a year and I’d already turned into a research fiend. PubMed was my new best friend. I read and printed out what became hundreds of pages. The kind oncologist we traveled to see reflexively prescribed 4 rounds of CHOP, a standard chemo that he called a “gold standard.” Treatment was discontinued after round 3 owing to progression. The next combination therapy went similarly. The third showed some regression.
Trying to evaluate the then-new lymphoma treatments such as gemcitabine, pentostatin, and Bexxar seemed like throwing darts at a dartboard in the dark. Where were the randomized data and trials? Where were they for CHOP? Have things improved? Considering recent drug approvals in peripheral T-cell lymphoma, including romidepsin, pralatrexate, and belinostat, it wouldn’t seem so. All are approved based on uncontrolled data. One thing that has improved from that time to this is a better appreciation and articulation of adverse effects.
Fourteen months after his original diagnosis, my brother underwent allogeneic donor bone marrow transplantation, a dangerous treatment whose results nonetheless seemed to hold a better survival prospect than available drug regimens. No one wants this treatment if they have any better option. Partially and poorly tested treatments were not a preferable option. For my brother and me, we wanted more information not just more choices.
In VP’s clinic, conversations often center on whether a patient with cancer wishes to attempt a therapy that has only been proven to improve progression-free survival, and overall survival or quality-of-life effects are unknown. In VP’s words:
I often explain at length that progression means the time until new tumors grow or existing tumors increase in measurement more than 20% their smallest size. If a tumor increases 19%, that isn’t progression, but 21% is. So, it is arbitrary. Feeling bad from cancer and the 20% cut-off don’t always go hand in hand. After I explain the evidence base, risks, benefits, and alternatives, patients sometimes throw up their hands: “Why can’t you just tell me if this drug will make me live longer or feel better?”
As a resident, DT has seen how frequently prescribing a new medication can be accompanied by optimistic discussions focused on improvement. In DT’s words:
When faced with an ill patient, the treatment team wants to focus on the promising aspects of the novel treatment. It requires great discipline to balance that optimism with consideration for the gamut of possible adverse reactions. During my first intensive care unit experience, it was eye opening to realize the severity and frequency of serious treatment complications and how life-threatening additional side-effects can be for these critically ill patients. The risk of trying an unproven drug cannot be taken lightly.
The current regulatory system fosters uncertainty regarding already available compounds in several ways. First, estimates of FDA drug approvals show that two-thirds of cancer drugs are approved with surrogate endpoints,5such as progression-free survival or response rate—in other words, data that are often easier to obtain but not reflective of patient survival or quality of life. The situation with the European Medicines Agency is similar.2
To read this article in its entirety please visit our website.
-Derrick Tao, MDa, Sally Schott, BAb, Vinay Prasad, MD, MPHc
-This article originally appeared in the March issue of The American Journal of Medicine.
