April 11, 2022
National Center for Health Research’s Comments on the Food and Drug Administration’s Draft Guidance on the Development of Non-Opioid Analgesics for Acute Pain
We are writing to express our views on the Food and Drug Administration’s (FDA) draft guidance on the development of non-opioid analgesics for acute pain.
The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
In light of the ongoing opioid epidemic, we commend FDA’s goal of fostering the development of non-addictive alternatives to opioids for managing acute pain, and thereby decreasing exposure to opioids and preventing new addiction. We agree with many of the recommendations FDA provides in this guidance. For example, we concur with FDA that, where appropriate, labelling should describe non-opioid analgesia as comparable or better than the comparator opioid. This description should also include a strong focus on the direct benefit patients can expect from using non-opioids, for example earlier functional recovery and a reduction of adverse events associated with opioids. We also concur with FDA’s decision to highlight the importance of obtaining the specific reasons of participants for withdrawing from trials, and for sponsors to not rely on terms such as “other”, “subject request” or “investigator decision”. This will ensure that the reason for patient discontinuation is captured accurately. Similarly, we agree with FDA that sponsors need to carefully evaluate the use of rescue medication, such as sooner-than expected first use.
While FDA raises many important points in their recommendations for trial design, such as the importance of data demonstrating superiority to a comparator or using well-defined, reliable patient-reported outcome measures, we also have concerns about this draft guidance that we strongly urge FDA to address.
- FDA should clarify that superiority can be based on reducing the risk of addiction and other safety issues, not only superiority of pain relief. We also urge FDA to also include language encouraging sponsors to increase diversity in their clinical trials, with sufficient numbers of major demographic groups to enable the sponsor to provide data on safety and efficacy for different subgroups, so that it is possible to determine if benefits outweigh the risks for those subgroups. While FDA highlights that composite scales which measure not only pain, but also function and sleep, can be problematic for non-opioid analgesic trials, we encourage FDA to include guidance for sponsors to help them ensure that clinical trials measure those outcomes in ways that are most meaningful to patients.
- We are very concerned about FDA’s statement that non-opioid analgesics may be eligible for one or more of FDA’s expedited review programs, particularly accelerated approval. We agree that these drugs are greatly needed and should “go to the head of the line”, and we support the idea that the FDA should meet regularly with the sponsors to help ensure appropriate study design, data collection, and analyses. However, we would not support shorter and smaller clinical trials, since those often result in insufficient evidence regarding safety and efficacy. Moreover, smaller studies inevitably result in inadequate diversity, with too few patients in key demographic groups. That makes it impossible to conduct meaningful subgroup analyses to determine if the benefits outweigh the risks for specific demographic subgroups. Given that the ongoing opioid epidemic was in part exacerbated by insufficient oversight and regulatory control as well as inadequate risk mitigation, expediting reviews of drugs whose mechanism of action may not be fully understood could also be harmful to patients, particularly for demographic subgroups (age, race, gender, ethnicity) that may not be adequately studied prior to approval.
The bottom line is that the FDA needs to ensure that approval of any new non-analgesic drugs is based on clear, solid scientific evidence that they are more beneficial to patients than other non-opioid analgesics that are already on the market, in terms of the balance of safety and efficacy.
The National Center for Health Research can be reached at firstname.lastname@example.org or at (202) 223-4000.