In June 2021, the FDA’s Office of Prescription Drug Promotion (OPDP) announced that it was planning two studies to complement its previous work on patient understanding of accelerated approvals. Nine months later, the office has reaffirmed its intentions in an announcement that addresses industry concerns point-by-point.
Regulatory background: Accelerated approvals and consumer disclosures
- Accelerated approval is a regulatory pathway through which the FDA may approve drugs for serious or life-threatening illnesses based on intermediate or surrogate endpoints that are reasonably likely to predict the clinical benefit of the drug for a specific group of patients. Because the data used to support approval are preliminary, companies that obtain accelerated approval for a product must then conduct confirmatory testing. If that testing fails to confirm the benefit of the drug, the FDA may initiate proceedings to withdraw the drug from the market.
- To the average consumer, it is difficult to distinguish a drug that was approved under accelerated approval and one approved under standard approval. In fact, there is no legal or regulatory requirement for companies to label drugs with a special disclaimer that the product was approved using accelerated approval. Instead, FDA’s labeling regulations require only that the “indications and usage” section of the drug label must include a “succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits.” As the FDA notes, that section “generally should also acknowledge that the drug was approved based upon accelerated approval and that continued approval for the drug (or indication) may be contingent upon verification and description of clinical benefit in a confirmatory trial or trials.” These recommendations are contained within a 2019 final guidance document on labeling of drugs approved under the Accelerated Approval regulatory pathway.
- However, the way in which accelerated approval and surrogate endpoints are described in product labels is far from obvious, especially to lay people. If a person is not already familiar with the concept of accelerated approval, they might not understand the limitations of the approval or the collected data. For example, the label doesn’t contain any explanation of accelerated approval, the surrogate endpoint’s limitations, the ongoing confirmatory studies or when data are expected to be obtained from those studies.
- These issues often extend to materials used to promote products. According to an FDA study, 27 percent of direct-to-consumer websites for accelerated approval products “did not include any disclosure that the products attained approval through this pathway.” In addition, the same analysis cited by the FDA found that “84 percent of accelerated approval disclosures on DTC websites mentioned the approval basis, 68 percent mentioned unknown outcomes, and 47 percent mentioned confirmatory trials.”
- OPDP has previously expressed concern about accelerated approval, and in 2018 it devised an “experimental study of an accelerated approval disclosure,” to look at the wording and prominence of a disclosure about a drug’s accelerated approval that would appear in direct-to-consumer (DTC) promotional materials, which include consumer-facing websites.
- That study’s proposed consumer-friendly disclosure: “In a clinical trial, [Drug X] returned blood counts to normal. However, we currently do not know if [Drug X] helps people live longer or feel better. We continue to study [Drug X] in clinical trials to learn more about [Drug X]’s benefits.”
- According to the FDA, preliminary results from the study suggested that “consumer-friendly disclosure[s] helped study participants understand information related to the drug’s accelerated approval, but that participants’ understanding was low overall.”
- The FDA proposed another pair of studies on this topic in June 2021, focusing on cancer patients and their caregivers and testing additional consumer-friendly disclosures. The agency’s rationale for the patient population is that most – 84% — accelerated approvals have gone to oncology indications.
- The first study would compare patient perceptions and understanding of DTC websites with high- and low-prominence accelerated approval disclosures, with consumer-friendly and physician labeling of each, and a fifth version with no disclosure at all.
- The FDA also wants to study four versions of its new “consumer friendly” disclosure, in which it will disclose (1) the basis of approval, (2) the basis of approval and unknown outcomes, (3) approval basis and confirmatory trials, or (4) approval basis and unknown outcomes and confirmatory trials.
- The study: According to the FDA, the design of the study will involve participants viewing a website for a fictitious oncology prescription drug. “After viewing the website, participants will complete a questionnaire that assesses whether participants noticed the disclosure and their understanding of it, as well as perceptions of the drug’s risks and benefits.”
The FDA has just re-announced the study after fielding comments from PhRMA
- The new Federal Register announcement duplicates the text of the June 2021posting regarding the background behind and plans for the upcoming studies. However, the announcement also addresses in detail comments made by the one organization that filed a response when the plan was initially open for 60 days of public consultation last year.
- PhRMA, the industry trade association, sent the FDA a letter that “applauded” the general intent to study consumer understanding of accelerated approvals, but also voiced numerous concerns about the specifics of the agency’s intended course of action. Broadly, PhRMA suggested that the FDA should focus more on health care professional (HCP) communications with patients and less on promotional materials, and drilled down to identify specific points of concern.
- In the latest Federal Register notice, the FDA takes PhRMA’s comments and addresses them, point by point. “For brevity, some public comments are paraphrased and therefore may not reflect the exact language used by the commenter. We assure the commenter that the entirety of their comments was considered even if not fully captured by our paraphrasing in this document,” the agency took care to point out.
- First, PhRMA expressed concerns that the proposed research would duplicate previous FDA work and thus lack utility. PhRMA requests that the FDA publish in full the result of the prior study before proceeding to the next proposed studies. The FDA responded: “Contrary to the comment’s suggestion, we do not plan to duplicate the prior research, although there often is value in that undertaking. Rather, the present research seeks to replicate the previous study in a new patient population and extend the previous study by testing additional versions of the disclosure.” The FDA highlighted that value that might be drawn from zooming in on what cancer patients and their caregivers absorb from various presentations of consumer information about accelerated approvals.
- Next, the association posited that the risks associated with overemphasizing accelerated approval and “new required disclosures” might be a deterrent to patients seeking treatment. “This notice proposes a data collection for research purposes and does not establish a mandate or propose a new rule,” noted the FDA in response. The agency specifically noted that the second study addresses previous public comment on just this point; two of the four disclosures to be tested will not include wording that the “we” (the FDA) “currently do not know if [Drug X] helps people live longer or feel better.”
- PhRMA suggested that the FDA modify its study plan to focus on prescriber-patient communication, rather than marketplace promotions, noting that shared decision-making with HCPs is an important component of the therapeutic process. The FDA, while agreeing that “the prescriber-patient interaction is important,” held firm on its stance that DTC messaging can inform these interactions, and so merits study.
- A qualitative study design, or a blended approach, combined with more time for participants to digest the materials they are presented, would have merit as a research approach, according to another PhRMA comment. In response, the FDA pointed out that a series of nine 1-hour interviews “will allow for in-depth discussions with participants,” and maintained that the proposed study protocol will allow time for the patient to see the disclosure being tested, and then to see it again at a later point, as suggested in this comment by PhRMA.
- Study participants should be “screened” for patients with acute lymphoblastic leukemia (ALL) who have received accelerated approval products, suggested PhRMA. The FDA’s response points out that patients are not likely to know whether their therapy fall into this category. However, the agency will explore allocating quotas for “a broad range of cancers” in its recruitment, to include blood cancers. They may also restrict enrollment to patients who have receive systemic therapies, and their caregivers.
- PhRMA also questioned the rationale behind including caregivers in the study. Previous public comments on this question have encouraged the FDA to do so, said the agency in its response; further, “surrogate seekers” of information about treatments are likely to be caregivers. And some DTC prescription drug websites directly target caregivers, as evidenced by having “patient or caregiver” as an option when choosing a role for viewing the site.
- Study participants should, before viewing the disclosures being tested, be told that the drug in question has received acceleratedapproval and be told the regulatory basis for this type of approval, so they can understand the disclosures, suggested PhRMA. The FDA’s response: “Consumers encountering DTC websites for accelerated approval products would not have this background information, so giving this information to participants would defeat the purpose of testing what perceptions these consumers form from the website disclosures.”
- In the remainder of its comments on the proposed studies, PhRMA primarily suggests wording changes or requests that some questions to participants be deleted. The FDA addresses each of these comments individually and frequently points to the pretest process as an opportunity for refining how questions are asked, though it agrees to delete a couple of questions as well. In a sign of internal consistency, the agency agreed to delete a question that would have asked whether participants had taken any accelerated approval products, agreeing that “participants are unlikely to know whether the product they used was an accelerated approval product.”
- However, the FDA took issue with PhRMA’s characterization of how and when consumers form opinions about the benefits and risks of taking a drug. PhRMA asked that two questions asking patients about risk-benefit tradeoff after viewing DTC materials be adjusted to include an option to include a prescriber in decision-making on this topic. “We disagree that consumers do not form their own perceptions about risk-benefit tradeoffs after seeing DTC promotional materials and prior to any discussion with a HCP. Thus, we plan to ask participants about their perceptions of the risk-benefit tradeoff,” replied the agency.
- The FDA has signaled that it plans to proceed with the studies, taking an in-depth look at how DTC content should address the question of accelerated approvals. The highly technical language of the label is appropriate for HCPs. However, OPDP’s other work, and evidence from the broader study of health literacy, suggests that patients and their caregivers are not likely to absorb the nuances of this regulatory classification, and its implications, from the HCP label wording.
- The agency took the time to compose responses to PhRMA and publish them in the Federal Register. The industry association made the point in several different ways that the FDA was missing an important part of the picture by not focusing more on prescriber-patient interactions and communication. But the agency held firm, pointing out repeatedly that DTC messaging, including communication found on consumer-facing drug websites, is an important source of information for patients and caregivers. Therefore, argues the FDA, OPDP needs to understand how best to inform patients who visit these sites about the benefits and risks of receiving drugs whose clinical benefit has yet to be directly confirmed.
- This OPDP effort is but one lens the agency is applying to the question of accelerated approvals. Although oncology drugs have received the most accelerated approvals, arguably the most high-profile of these has gone to Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease. If FDA has concerns about consumer understanding about accelerated approval for more narrow indications like specific advanced oncology indications, than those concerns could be magnified by a drug with a broader indication of use.
- The path from research to potential policy is a long one, however. It generally takes months or years between the initiation of FDA research and the publication of study results. Because of this, even if FDA was motivated to create new standards or guidance it may take until 2024 or beyond for such policies to be announced.