Neil Singla, MD- Public Comments on FDA's February 2022 Draft Guidance for Industry

The draft guidance document can be found here. April 8, 2022 RE: Development of Non-Opioid Analgesics for Acute Pain: Guidance for Industry; Draft Date February 7, 2022 Docket ID: FDA-2021-N-0556 Dear Reviewer, Below please find my comments on FDA’s draft document: Development of Non-Opioid Analgesics for Acute Pain: Guidance for Industry, dated February 7, 2022. I am a board-certified anesthesiologist and Chief Scientific Officer of Lotus Clinical Research, LLC, a contract research organization, regulatory consulting firm and research site network specializing in analgesic clinical trials. The final version of this guidance document will be an important resource for my organization and our clients. My recommendations are as follows:

Create separate sections for systemic and local drugs in acute pain

Section 1, General Considerations, gives an overview of the requirements for an approval for acute postoperative pain. Historically, to approve a systemically-administered drug for acute pain, FDA has generally required positive studies in one soft tissue and one hard tissue model (assuming a drug’s mechanism of action is well understood and other key data has been provided). I believe this is still FDA’s position on systemic drugs, but as the document mentions in lines 87-91, this paradigm may not apply to “topical analgesics”. Infiltration analgesics, local anesthetics, nerve blocks, etc. (hereafter “infiltration analgesics”) have historically been held to different requirements than systemically-administered drugs (with good reason), and often obtain more indication-specific labeling related to specific surgery types or anatomical areas. The document would benefit from making a distinction between the two categories (systemic vs. infiltration) and discussing each in a separate section. A revised guidance could first outline the general requirements for systemic drugs, then explain how and why infiltration analgesics are different and have different requirements, and outline those requirements. Looking at recent infiltration analgesic programs like those for Zynrelef or Exparel, there has been confusion and controversy around their clinical trial requirements and labeling. Infiltration analgesics are an important non-opioid tool for the control of acute pain, and a significant amount (perhaps 30% or more) of acute pain drug development is currently occurring in this space. The research community and patients would both benefit from clear, specific guidance on the approval pathways for these drugs. If a separate section on infiltration analgesics were to be added, I would recommend structuring it as follows:

• Outline any requirements that carry over from the section on systemic drugs, e.g. the paradigm of demonstrating efficacy in both hard tissue and soft tissue if appropriate
• Discuss the need to obtain pharmacokinetic data on the drug when administered into diverse areas/ tissue types in the body, in order to support a broad label
• Discuss the need to obtain safety data on the drug when administered into diverse areas/ tissue types in the body, in order to support a broad label
• Specify any additional pivotal program requirements to obtain a broad indication for an infiltration analgesic

Reconsider pain relief primary endpoints

The draft guidance states the following on page 5: We discourage using a primary endpoint that is based on pain relief (i.e., decrease in pain) rather than pain intensity (i.e., how bad the pain is), as pain relief scales require subjects to report current pain relative to their prior pain experience and may be influenced by other factors such as concurrent adverse reactions, and may be limited by patients’ ability to recall their prior experience of pain. This language is in line with FDA’s position in the 2014 Draft Guidance. In 2015, working with the ACTTION group, I performed a rigorous analysis on the assay sensitivity of the TOTPAR (Total Pain Relief) assessment vs. SPID (Summed Pain Intensity Difference). Our finding was that the TOTPAR pain relief measure is in fact more sensitive than the SPID pain intensity measure. As such I would suggest revisiting this concept and potentially deleting the language. The relevant manuscript can be found here: https://lotuscr.com/wp-content/uploads/2017/05/Singla-et-al.-201521.pdf ¹

Expand on discussion of 2-stopwatch method/ time to onset data

The current discussion of the 2-Stopwatch method is valuable as written, but could be expanded to include some other important key points. I might add the following:

• Include a definition of Time to Confirmed Perceptible Pain Relief (i.e. Time to Perceptible Pain Relief data reported only from subjects who went on to report meaningful pain relief. If a subject never achieves meaningful pain relief, their perceptible pain relief data is not considered).
• Further emphasize that Time to Meaningful Pain Relief is the preferred endpoint of interest among time to onset endpoints, with the greatest relevance for labeling
• Briefly outline the statistical techniques that should be used to analyze 2-stopwatch data. Specifically, in light of the issue regarding Baudax Bio’s stopwatch data raised by Avenue Therapeutics in their 2022 advisory committee meeting, clearly outline that stopwatch data must be right-censored if/ when patients use rescue before achieving the relevant pain relief milestone.

Other comments

Page 4: “All pain intensity measurements, including at baseline, should be obtained before rescue drug administration.” It would be more clear to say: “Every protocol should outline both its scheduled pain intensity measurements and the circumstances in which unscheduled pain intensity measurements are required. For example, unscheduled measurements should occur prior to each use of rescue.” Page 4: “The primary efficacy analysis should compare the SPID between treatments at a prespecified time point” This should read “SPID between treatments over a prespecified time period.” Page 5: “Time to second use of rescue medication may be informative when considering dosing interval for the investigational drug and supplement knowledge of the drug’s pharmacokinetic properties.” Time to second use of rescue is informative regarding the kinetics of the rescue medication, but less informative regarding when a second dose of investigational drug should be given. I would suggest deleting this language. Page 5: “These secondary outcome measures include measurement of time to onset of pain relief and time to rescue or request for next dose of the study drug.” Most acute pain studies use fixed-interval dosing (although some do use variable-interval dosing). I would suggest removing “request for next dose of the study drug” from the sentence above. Best, Neil Singla, MD Lotus Clinical Research^®, LLC Chief Scientific Officer www.LotusCR.com References:

1. Singla N, Hunsinger M, Chang PD, et al. Assay sensitivity of pain intensity versus pain relief in acute pain clinical trials: ACTTION systematic review and meta-analysis. J Pain. 2015;16(8):683-691. doi:10.1016/j.jpain.2015.03.015