[vc_row full_width=”stretch_row” gap=”35″][vc_column][vc_column_text]The first half of 2022 saw several encouraging developments in the pharmaceutical sector. In June alone, we learned that all of the rectal cancer patients in clinical study of dostarlimab were in remission after 12 months and saw the results of a study of the use of trastuzumab deruxtecan (Enhertu) for HER2-low metastatic breast cancer described as “unheard of” in a New York Times story.
It is, unquestionably, an exciting time in medicine, with biologics and gene therapies affording treatments with survival rates undreamed of just a few decades ago.
But each scientific advancement carries with it the weight of patient hope and expectations and, all too frequently, misunderstanding.
Confusing terminology
One of the greatest sources of confusion for the general public may be the term “breakthrough” which the media alternately uses in both its colloquial and regulatory sense, sometimes in the same news story.
The “breakthrough therapy designation” (BTD) was established by the U.S. Food and Drug Administration Safety and Innovation Act of 2012 as a means of facilitating the rapid review of treatments for serious conditions. For a drug to qualify under BTD, there must be preliminary clinical evidence that it “demonstrate(s) substantial improvement over existing therapies on one or more clinically significant endpoints.”
However, for those not versed in Food and Drug Administration (FDA) terminology, “breakthrough” remains synonymous with “enhanced,” “improved,” or “advanced.” Unsurprisingly, the word’s use in news stories about emerging treatments can lead to critical misinterpretations.
In a randomized trial assessing the impact of language on perceived drug efficacy, researchers found that the use of the word “breakthrough” led non-clinical participants to rate a drug as “very” or “completely effective” despite the fact that the designation refers to the expedited track for its approval and not to how well it works or to how well it ultimately works in comparison to other treatments for the same condition. Subsequent research identified the same cognitive phenomena among physicians—including oncologists— who, like their non-clinical peers tended to associate the “breakthrough” designation with greater efficacy of a theoretical pharmaceutical.
In fact, a 2018 review of cancer medicines published in the Journal of Clinical Oncology found no statistically significant evidence that drugs approved under the BTD process performed better than those approved through the regular steps.
Timelines
Patients expect immediate access to the best therapies and treatments, and it is reasonable to assume that many patients with rectal cancer asked their providers about dostarlimab last month. But personal urgency is often thwarted by regulatory timelines. Even under a BTD designation, or the FDA’s Fast Track Designation, Accelerated Approval Pathway, or Priority Review Designation, it can take the agency up to six months to act on an application. And frequently the studies that make headlines and bring a potential treatment to a patient’s attention involve small sample sizes or have design flaws that necessitate the overlooked caveat that “further testing is needed to confirm.”
The cautionary tale of Aduhelm approval
While delays in drug approval can frustrate patients, expedited decisions can be confounding.
For the families of the approximately 6.5 million Americans living with Alzheimer’s disease, there may be no better example of this than the expedited approval of aducanumab (Aduhelm).
A recombinant human monoclonal antibody developed by Biogen for the treatment of Alzheimer’s disease, Aduhelm first came to public attention after its phase 1 trial results were published in the September 2016 issue of Nature. Biogen reported that aducanumab infusions were associated with a reduction in the amyloid-β (Aβ) plaques in the brain which characterize Alzheimer’s.
In its discussion, the Cleveland Clinic referred to the study as demonstrating “perhaps even some cognitive effect.” But the popular media was less measured. A CNBC story with the headline “New Biogen drug stops memory loss in Alzheimer’s patients” quoted scientists as describing the Aduhelm study as the “best news they’ve seen for treating (Alzheimer’s) in 25 years.” The Australian Broadcasting Corporation even suggested that the Biogen study “vindicated” Colin Masters, the Australian researcher who had proposed that amyloid plaques were not only a symptom of Alzheimer’s, but its cause.
Confusion followed as Biogen subsequently halted large-scale Phase 2 studies of the drug and withdrew its application for Aduhelm’s approval in the spring of 2019, only to submit a new application based on a “new analysis of a larger dataset” later that year.
The FDA granted Aduhelm accelerated approval in June of 2021, against the recommendations of its own advisory committee, but with the enthusiastic support of patient advocacy groups, which had argued that patients and their families favored approval and were entitled to some measure of hope after decades without new treatment options.
Two members of the FDA advisory committee panel resigned in protest, one telling the Washington Post that he would not take part in a “sham process.” The American Academy of Neurology issued a position statement in which it described the approval of Aduhelm as indicative of “a lowering of the standards of scientific evidence used for drug approvals.”
In light of Biogen’s announcement that Aduhelm would cost $56,000 annually—not inclusive of infusion costs or monitoring services—the Centers for Medicare & Medicaid Services (CMS) ultimately made the decision restrict coverage for the drug to those participating in clinical trials. Private payers similarly declined to include Aduhelm on their formularies, expressing concerns about both its cost and efficacy.
Once optimistic at the prospect of a new treatment, patients and their families were ultimately left with limited access to a drug of questionable efficacy and conflicting opinions expressed as widely differing policies on the part of key government agencies.
Treatments for rare diseases
Among patients with rare diseases—defined by the FDA as occurring in less than 200,000 individuals in the U.S.—hope is often placed in the Orphan Drug Act (ODA), which was adopted in 1983. Under ODA, a manufacturer may apply for orphan-drug designation from the FDA and qualify for “tax credits for qualified clinical trials, exemption from user fees (and a) potential seven years of market exclusivity after approval.”
ODA policies have led to treatments for such rare conditions as Alagille syndrome and Glioma. But, despite any waiflike imagery evoked by the term orphan, pharmaceutical companies holding ODA authorizations have been found to be in sounder financial standing than their counterparts. While originally approved as a non-orphan drug, Adalimumab (Humira), one of the world’s top selling drugs, received subsequent orphan drug designation for the treatment of certain forms of uveitis in 2014.
When drugs are delayed in development or approval, desperate patients may seek experimental treatment under “compassionate use” or “expanded access” policies. Under the FDA’s Expanded Access program, a patient with an immediately life-threatening disease or condition (defined as “disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment”) can seek treatment with an investigative drug without being enrolled in a clinical trial.
This access to unapproved treatments is echoed in the Right to Try Act, which was signed into law in 2018, but which, unlike the Expanded Access, does not require oversight by an institutional review board. In choosing options under either Expanded Access or Right to Try, patients and families under extreme emotional stress may be inclined to believe assertions that “promising” or “proven” treatments have been withheld.
Costs
While discussions of drug pricing can have uncomfortable political undercurrents, the fact remains that drug development is expensive.
A 2021 study by the Congressional Budget Office concluded that the cost of developing a drug can range from less than $1 billion to over $2 billion. Adjusted for inflation, pharmaceutical companies are spending 10 times more for research and development (R&D) today than they did four decades ago. And according to the Government Accountability Office, pharmaceutical companies spend more on R&D as a percentage of total sales than such obviously R&D intensive sectors as semiconductor and other electronic components.
Americans are spending nearly $500 billion annually on prescription drugs with an increasingly large percentage of this spending going toward what are called “specialty drugs” developed specifically for chronic, complex, or rare conditions such as cancer, hepatitis C, and multiple sclerosis.
The American Association of Retired Persons (AARP) found that the average annual cost of specialty drug therapy per drug was $84,442 in 2020. And in May of this year, Forbes reported that health plans and prescription benefit managers were “bracing” for specialty drugs to “(eclipse) 50% of prescription spending” even though they might still represent 2% or less of claims.
The cost of drug development plays a key role in drug pricing, which ultimately factors into formulary decisions by payors. That a treatment option exists does not guarantee its availability to a given patient.
Pressure on physicians
Americans continue to place special trust in their medical providers. But doctors aren’t always available, while the internet, social media, and disease-specific online forums are just a click away. A patient sleepless with anxiety over a chronic or newly diagnosed life-threatening condition can find comfort and an online cohort in wandering the internet in the wee hours of the morning. And we can assume that countless individuals shared hopeful “Did you see this?” links to the Enhertu story with loved ones with breast cancer.
While online research can be a means of empowerment for patients, it can also be a source of misinformation, with even factual data frequently provided without appropriate context. Doctors can play an important role in helping their patients sort fact from fiction, interpret scientific literature, and to appreciate the nuances of regulatory processes.
But managing patient expectations about the promise of new drugs may come at some cost to clinicians. In position paper published in 2021, the American Academy of Neurology recognized the issues attendant to the management of high-cost drugs as adding to the administrative burdens that contribute to physician burnout. Further, mismatched understandings of available treatments options can complicate the doctor-patient relationship.
There are many adages equating hope with medicine, and the powers of both the placebo effect and faith have been demonstrated by research. However, medicine, while inexact, is ultimately an evidence-based science and clinicians make decisions based on data, not on hope.
Physicians can play an important role in helping patients and their families interpret the data, understand the broader regulatory context of drug approval, and cut through the noise of “breakthrough” headlines. Yet, in a culture of greater scientific literacy, regulatory consistency, and measured journalism they might not need to do so quite as often.[/vc_column_text][/vc_column][/vc_row]
