FDA’s Publishes (Yet Another) Interim Policy on Compounding with Bulk Substances for Both Section 503A and Section 503B Compounders
Posted: 17 Jan 2017 08:10 PM PST
By Karla L. Palmer –
On Friday, January 13, 2017, FDA issued two revised interim policies on compounding with bulk substances for Section 503A compounders and Section 503B outsourcing facilities. As you likely recall, FDA’s guidance on use of bulk substances in compounding has had a slow start, in part because of “over nominations” in early 2014 and general confusion in the nomination process (see our previous posts here and here). And, once FDA created its original “bulks” lists of substances that may be used in compounding, those lists caused significant additional consternation because they included substances that plainly should not have been included. .
FDA’s latest iterations of its two sets of bulks lists include updates based on public comment and meetings of the Agency’s Pharmacy Compounding Advisory Committee, which has held several (quarterly) meetings to review whether bulk substances should be placed on one of FDA’s three bulks lists for Sections 503A and 503B (however, PCAC input is not statutorily required for Section 503B’s bulks lists). The lists are divided into the same three categories as previous lists (i.e., Category 1 (may be used in compounding based on sufficient support in a nomination, and no apparent safety risk); Category 2 (may not be used in compounding based on significant safety risk); and, Category 3 (substances nominated without adequate support, thus may not be used in compounding)). As an aside, FDA continues to assert in these guidances that USP/NF substances referenced in 503A and 503B only include substances that are the subject of a USP/NF “drug” monograph, and not a dietary substance monograph. Presumably, to the extent a compounder seeks to compound with a dietary substance as the active bulk ingredient in a compounded formulation (that is not a component of an approved drug product or otherwise on FDA’s list 1); it would need to nominate that substance per FDA’s interim policy.
Ultimately, FDA must promulgate final lists through notice and comment rulemaking pursuant to the applicable statutes. Because so many substances are at issue, FDA has adopted its interim policy approach, where it reviews and then nominates for comment the proposed substances at a pace of about ten at a time. On December 16, 2016, FDA published its first notice proposing six substances to the Section 503A bulks list, four to not be included on the bulks list, and setting forth criteria for evaluation of substances. [Here, comments due by March 16, 2017]
New Policy Concerning Re-Nominations, Mistaken Nominations, Withdrawal of Nominations
FDA’s latest iterations make one significant change - benefiting those who failed to nominate a particular substance, or who mistakenly nominated a substance which was inadvertently included on, for example, List 3 (substances nominated with insufficient support; thus may not be used in compounding).
Specifically, FDA had repeated several times that once FDA received nominations for the bulks lists (for the nomination period that ended back in 2014), interested parties could nominate additional substances (in a docket opened in October of 2015); but FDA would review those substances only after completion of the review process for the original nominated substances. Thus, any substances inadvertently omitted, or new substances necessary in compounding would, in effect, go to the bottom of the nominations stack. Given the number of already nominated substances, and pace of FDA’s review, any chance of review of new or overlooked substances at any point in the next several years seemed dim at best.
FDA now states that after a substance is nominated to the nominations docket for bulk substances (now deemed the “October docket”), FDA will determine whether the nomination is supported with sufficient information to allow FDA to evaluate it. After FDA makes that determination, the nominated substance will be placed in one of the three bulks categories and published on FDA’s website. FDA states it “generally expects to categorize bulk drug substances nominated to the October docket and to publish updated categories on its website on the first business day of each month.” FDA notes that until substances nominated for the “October docket” have been categorized, FDA’s interim policy does not apply to those substances.
In addition, FDA has created a solution for those substances that may not appear on an appropriate list. Those comments may be submitted to docket number FDA-2015-N-3534. Further, if a commenter has new information on a previously nominated substance that was placed in Category 3, the substance can be re-nominated with the additional information. A nominator may request withdrawal of any of its nominations. If the party nominating the substance was the sole nominator, FDA will update the categories described in this guidance to reflect the withdrawn nomination, and will provide notice to the public before removing any nominated substances from Category 1 or Category 2. However, FDA may continue to evaluate a substance at its discretion even if the nominator submits a comment requesting withdrawal of the nomination.
Shortage Medications: Section 503B
As a final note, for medications in shortage, FDA states that does not intend to take action against an outsourcing facility for compounding a drug product using a bulk drug substance that is not on the 503B bulks list if the drug compounded from the bulk drug substance: (i) appeared on FDA’s drug shortage list within 60 days of distribution and dispensing, and (ii) was to fill an order that the outsourcing facility received for the drug while it was on FDA’s drug shortage list. FDA’s Section 503A interim policy does to contain a similar provision for Section n503A facilities that may compound shortage medications.
Posted: 17 Jan 2017 01:05 PM PST
By Sara W. Koblitz & Kurt R. Karst –
After months of promises and postponements, FDA has finally published its long-awaited draft guidance on biological product interchangeability, Considerations in Demonstrating Interchangeability With a Reference Product, under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). While FDA had originally promised the guidance in 2016, FDA’s biosimilar user fee reauthorization commitment letter pushed its goal to December 31, 2017. Imagine our delight when we saw that FDA released the guidance so early in 2017! (And just days after the U.S. Supreme Court granted certiorari in a case concerning two important provisions of the BPCIA – see our previous post here.)
FDA's draft interchangeability guidance is incredibly important for biosimilar and reference product manufacturers alike. As of now, only four biosimilar products have been approved, and none of them are considered interchangeable. While these products are “highly similar” to their respective reference product counterparts, as shown by a “B” rating in the Purple Book, only interchangeable products (shown in the Purple Book with an “I” rating) can be substituted for the reference product by a pharmacist without the intervention of a health care provider. “Interchangeable” is obviously a coveted status for biosimilar manufacturers and a source of anxiety for reference product manufacturers. As such, the entire biologics industry has anxiously awaited this guidance.
As explained in the draft guidance, FDA requires interchangeable biologics to be biosimilar to the reference product in addition to other criteria. An interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, if the product is administered more than once to an individual, the sponsor must demonstrate that the safety and efficacy risks of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using only the reference product. FDA expects clinical data to demonstrate this in all of the reference product’s licensed conditions of use.
As with generic versions of small molecule drugs, the data and information to support an interchangeable biosimilar application will vary based on the nature of the proposed product. To that end, FDA reiterates the Agency's “totality of the evidence” and “reduction of residual uncertainty” approaches first expressed by the Agency in the biosimilars world in the context of demonstrating biosimilarity (see our previous post here). The potential interchangeable product will first need to provide all of the information necessary to demonstrate biosimilarity (i.e., analyses of critical quality attributes and mechanisms of action for each condition of use for which the reference product is licensed; PK and biodistribution of the product in different patient patients; and differences in toxicities in each condition of use and patient population). These data likely will also suffice to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in any given patient. However, other elements of interchangeability will require additional testing.
FDA anticipates that interchangeable applications will include data from a switching study or studies in one or more appropriate conditions of use. The guidance outlines considerations for the design of these studies and stipulates that only the U.S. version of the reference product should be used in these studies. If the product is not designed to be administered more than once, a sponsor should provide justification for the omission of a switching study in the interchangeable application.
Importantly, the guidance notes that postmarketing data collected from products first licensed and marketed as a biosimilar, without corresponding data from an appropriate switching study, is not sufficient to demonstrate interchangeability. While postmarketing data may be helpful to determine what data is necessary to support interchangeability, the data itself are not enough. This means that even already-approved biosimilar products may be able to obtain interchangeable status if sponsors provide switching study data. In addition, the draft guidance notes that while a non-U.S.-licensed comparator may be used for purposes of demonstrating biosimilarity, for switching studies intended to demonstrate interchangeability “using a non-U.S.-licensed comparator product generally would not be appropriate” for various reasons.
Finally, the draft guidance emphasizes that the presentation and design attributes of the proposed interchangeable product should be the same as the reference product in an effort to simplify substitution. This reasoning applies to container closure systems and delivery devices, as well.
The guidance rates to be a handy tool for sponsors, but FDA encourages sponsors to consult FDA early and often rather than relying on the guidance alone. And remember, this is just FDA’s first attempt at outlining interchangeability requirements, so there is likely room for other approaches.
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