The recent key decision by the FDA for Exparel® stresses the importance of reevaluating 505(b)(2) strategy throughout a product development lifecycle. A solid, data-driven development strategy is important from the beginning; however, new data, including related regulatory actions, must be considered and incorporated to realign the program throughout development to achieve success in the end.

We note many sponsors set up 505(b)(2) strategy at the beginning of a program only to abandon reevaluation of the strategy once the program is in motion. Whether those decisions are made to conserve cash or result from losing focus on the big picture during development, advancing a program at the expense of reevaluating strategy throughout 505(b)(2) development can be catastrophic.

The Case of Exparel® and its Impact for Heron Therapeutics

Recently, we received a market update on a Heron Therapeutics product in development that attempted to interpret the impact of a convoluted regulatory action for a related product, Exparel® (liposomal bupivacaine), on the potential outcome for Heron’s product. The publicly available information for the Exparel® story started with an FDA Advisory Committee meeting held on 14-15 February, 2018, in which the FDA asked the Committee members to discuss the merits of a proposed new indication for Exparel®. The FDA then approved a modified indication statement, which was not the language the NDA holder, Pacira Pharmaceuticals, Inc., requested. In part, this language modification appears to result from the Advisory Committee and the FDA agreement that the data provided by the Sponsor did not support the specific language proposed by the Sponsor. The Agency did, however, approve a narrower version of the proposed indication statement that was presumably supported by the data.

The FDA is under extreme pressure to work with Sponsors to develop therapies that decrease the need for, or addictive properties of, opioid analgesics, which therapies like Exparel® may be able to do. A reviewer of a Heron business update suggested that the approved indication, despite a no-vote from the Advisory Committee, shows the FDA’s interest in opioid-sparing therapies despite the lack of supporting data to support such an indication. This would suggest that the FDA loosened its requirements to allow this labeling modification; however, at Premier Consulting, we would take a different view of this result. In fact, we would suggest that the Agency followed the data to provide an update to the indication that did not over-reach their pre-stated guidelines and have taken the next step in the expansion of an approved indication based on the totality of available evidence supporting such a change.

Details

Specifically, Pacira Pharmaceuticals was attempting to broaden the indication for Exparel® to include regional nerve block for post-surgical analgesia in addition to local post-surgical analgesia. The FDA and its Advisory Committee did not agree that the data supported the broader regional nerve block indication, recommending that the FDA not approve the language.

Interestingly, Exparel® was originally approved in 2011 with the following indication language:

“administration into the surgical site to produce postsurgical analgesia.” (2011 Labeling)

The Sponsor followed with a supplemental NDA submission with data from two new clinical trials, including a specific interscalene brachial plexus administration study, and requested that the indication statement be revised to the following based on those data:

“single-dose infiltration to produce local analgesia and as a nerve block to produce regional analgesia” (FDA AdCom Briefing Package.

What the Agency has approved based on the data provided by the Sponsor for Exparel® is the following indication statement:

“single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia.

Safety and efficacy has not been established in other nerve blocks.” (current labeling)

Alternative Interpretation of Impact

While it is possible that the FDA was more willing to work with the sponsor of Exparel® due to its potential societal impacts of an expanded indication, Premier Consulting interprets these results in a different light based on our experience with finding the best, data-driven path to approval for our sponsors. In fact, the FDA even said in its Advisory Committee briefing documents that it does not dispute the local efficacy of the drug based on historical data and on the new data submitted by the sponsor. However, what was in question was the approval of an expanded indication for which the clinical data were unconvincing.

Based upon our evaluation, it would appear that the Agency’s decision was consistent with the Advisory Committee’s recommendation. Further review of the regulatory history of Exparel® suggests that the decision appears to be consistent with the Agency’s approach to analgesic indication expansion in which different methods of administration can be evaluated to expand the indication in a stepwise manner followed by subsequent stepwise expansion of the indication language until the totality of evidence supports a more general indication (analgesic indication guidance).

We agree that it is important to be aware of new developments with market competition and would add that it is equally and/ or more important to evaluate the totality of data associated with a product under development at regular milestones. Interpretation of the available information at each milestone relative to current and previous regulatory actions requires consistent exposure to, and deep knowledge of, the Agency’s decision-making process and factors that may influence that process. Unfortunately, misinterpretation of the information may lead a Sponsor down a costly path, for example, the misconception that the Agency is willing to loosen the requirements for approval to succumb to political pressure. One thing we know is that the Agency is willing to be reasonable provided a sound scientific justification is given for a specific action; however, we also know that the Agency is not going to allow unjustified risks to public health.

It would be ill-advised for the Heron team to read the FDA’s action on Exparel® as a sign that the Agency is going to be lenient with their product as it approaches regulatory approval. Rather, the Sponsor should ensure that they work with the agency to leverage all available information to support their product development program and understand that the Agency is going to scrutinize all available data both supporting and refuting the approval of their product. The Agency will follow the data to guide their final decision; therefore, Sponsors should follow the data to guide their development programs.

Conclusion

This case emphasizes the importance of a product’s development strategy and the impact new information should have on an ongoing program. It is critical to let the available data drive the decision-making process, especially prior to NDA submission, when the stakes are highest for a Sponsor.

Premier Consulting utilizes a long-standing relationship with the FDA and in-house multi-disciplinary teams to assess data and align each program for success. To learn more about ways Premier Consulting can help your 505(b)(2) project account for new data and stay on track, contact us.