Drugmakers, compounders at odds over FDA’s difficult-to-compound rule

Drugmakers laud the US Food and Drug Administration’s (FDA) proposed rule on drugs that are difficult to compound by pharmacies and outsourcing facilities. Compounders, on the other hand, argue that the agency failed to follow rulemaking requirements and that the rule will negatively impact smaller outsourcing facilities.

FDA’s recently proposed a rule to implement sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which contain a list of requirements for drug products to be exempt from certain current good manufacturing practice (cGMP) requirements, adequate directions for use in drug labeling, and drug approval for new drug applications or abbreviated new drug applications when compounded. The rule would create two lists for drugs with demonstrable difficulties for compounding (DDC lists) and, therefore, cannot be exempted from full regulatory oversight. (RELATED: FDA proposes rule for difficult-to-compound drugs, drug categories, Regulatory Focus 20 March 2024)

Novo Nordisk wrote to FDA and asked it to focus on evaluating frequently compounded drugs as it develops its DDC lists. The company said that so far, the agency seems to be prioritizing drugs that regulators don't think are being compounded. It said the agency should include coated oral solid modified-release drugs, liposome drug products (LDP), and those made with hot melt extrusion (HME) to the lists.

While the FDA said it is not aware of compounded versions of such drugs being marketed, Novo Nordisk said it has evidence to the contrary and asked the agency to finalize the rule immediately to stop the practice. The company said prioritizing evaluating drugs and categories of drugs that are currently being compounded immediately will prevent further harm from drugs that are difficult to compound.

"Indeed, [Novo Nordisk] is aware of a significant number of adverse event reports relating to compounded 'semaglutide' products currently on the market," said the company. "Data from FDA’s Adverse Event Reporting System (FAERS) database includes 442 cases of adverse events associated with compounded 'semaglutide' since 2018, many of which were classified as 'serious.'"

"Thus, going forward, we urge FDA to prioritize evaluating drug products or categories of drug products for inclusion on the DDC Lists that are actually being compounded frequently and currently pose patient safety risks," it added. "Doing so would fulfill the core purpose of the section 503A and 503B provisions relating to drugs that present demonstrable difficulties for compounding—to protect the public from compounded drug products with complexities that are reasonably likely to adversely affect their safety or effectiveness."

Novo Nordisk emphasized that LDPs should be added to the DDC lists not only because they are highly complex, including having complex formulations, complex drug delivery mechanisms, and complex dosage forms, but also because they are currently already being compounded for human use. The company said it has become aware of compounded LDPs that are already being sold to patients.

"The liposomal delivery mechanism is marketed for use with a variety of high-molecular weight drugs; however, it seems most frequently marketed for use in compounded sublingual 'semaglutide' products," said Novo Nordisk. "A growing list of compounding pharmacies are compounding sublingual 'semaglutide' drug products by combining 'semaglutide' with the delivery mechanism that, allegedly, allows for the encapsulation of the semaglutide within a liposome, thus creating an LDP."

"The distributor of the drug delivery system and certain compounding pharmacies marketing the compounded sublingual semaglutide products claim that the mechanism is self-emulsifying and permeates the mucosal tissues beneath the tongue, ensuring rapid and efficient absorption and bypassing the gastrointestinal track," the company added. "The safety and efficacy of this delivery system have not been demonstrated, and given the significant complexities with compounding LDPs that the Agency has identified, NNI believes such products pose a significant risk to patients."

Novo Nordisk agreed with the FDA's decision to weigh the risk-benefit to patients when determining what drugs to add to the lists but also asked it to consider evidence of improper compounding as part of its calculus. It also asked the agency to be transparent and timely when considering drugs to be included in its DDC lists, with consultation from the Pharmacy Compounding Advisory Committee (PCAC).

The Association for Accessible Medicines (AAM) called on FDA to move faster on the issue, noting that even though more than 70 drugs or categories of drugs have been nominated for the difficult-to-compound list over the past decade, the agency has moved very slowly to consult with PCAC and conduct rulemaking,

“Indeed, although FDA has consulted the PCAC about six categories of drug products, only three are being proposed for inclusion on the lists in this rulemaking,” said AAM. “Furthermore, FDA acknowledges that it is not aware of any marketing of compounded drugs in the three proposed categories.”

“While AAM appreciates that FDA needed to establish the criteria for placing drug products and categories of drug products on the lists and evaluate how the criteria would work in practice by applying them to some of the nominated categories of drugs, it is imperative that FDA move more swiftly to address drugs that are currently being compounded and should not be because they are demonstrably difficult to compound,” the group added. “The public health importance of identifying these drugs and taking appropriate steps to prevent them from being compounded cannot be overstated.”

In the proposed rule, FDA lists six criteria it will consider when determining whether to include a drug on the DDC lists. Novo Nordisk wants the agency to explicitly state that not all six criteria must be met before regulators consider adding a drug to the lists.

"In order to protect the public health from the safety and effectiveness risks associated with improperly compounded drug products, FDA should clarify in the Final Rule that, if the evidence in favor of inclusion on the DDC Lists for one or more of the criteria is particularly compelling, it is not necessary to show that the drug product or category of drug products also satisfies the remaining criteria," said the company.

AAM also addressed the six categories FDA proposed to use to evaluate drugs for its DDC lists and asked the agency to add an additional category to evaluate a drug based on its demonstrable difficulty for compounding. The group said it thinks the proposed categories are adequate for the most part, but hopes the added category will help address unforeseen factors as technology evolves.

“AAM’s members believe the proposed criteria, as explained more thoroughly in the preamble to the Proposed Rule, adequately capture the principal factors that should be considered in determining whether a drug or category of drug product should be placed on the DDC list, but we recommend that FDA add another criterion that would allow it to consider other factors that at this time might not be foreseeable but that might come into play as it considers other drug products or categories of drug products in the future, such as products that rely heavily on artificial intelligence for correct dosing,” said AAM.

Outsourcing facilities disagreed with FDA’s proposed rule for several reasons. The Outsourcing Facilities Association (OFA) wrote to FDA and argued the proposed rule does not follow the rulemaking process because it doesn't include the necessary information needed to create a rule. It also argues that rulemaking process itself was flawed, and doesn't provide a real reason on what standard to use when putting drugs or drug categories on the DDC lists.

OFA said FDA's proposed rule omits three types of information required by Section 503B of the FD&C Act, including evidence demonstrating the compounding difficulties that justify why each drug or drug category should be included in the lists, does not identify any compounding conditions that are necessary to prevent the drug or category of drugs from presenting demonstrable difficulties, and evidence that the compounding conditions would mitigate potential adverse effects.

"The Proposed Rule is further flawed because it was not developed in consultation with an advisory committee comprised of pharmacists and physicians with expertise in 503B compounding capabilities and operations," said OFA. "Although 503B facilities are not expressly identified in Section 503B(c)(2), expertise in their capabilities and operations is clearly required for promulgating a new rule affecting the regulated class. Yet not a single current or former advisory committee member has any experience or expertise in 503B compounding capabilities and operations. As such, the Proposed Rule is procedurally deficient."

OFA also argued that the six criteria used by FDA to determine whether a drug or drug category should be on one of the DDC lists fail to provide an objective standard on whether they present a significant compounding difficulty and more broadly the rule is not supported by evidence demonstrating compounding difficulties.

"The Proposed Rule cannot be finalized at this time," said OFA. "It was proposed with deliberate disregard of applicable rulemaking procedures."

OFA said FDA's PCAC should include members with experience in Section 503B compounding or cGMP requirements relating to Section 503B compounding, its DDC listing criteria should include objective standards to determine how drugs get on the lists, identify compounding conditions that could negate the DDC List criteria, and conduct a regulatory flexibility analysis because the rule will have a significant economic impact on small er facilities.

The law firm Baker & Hostetler, which represents compounders, agreed with much of what OFA had to say. It echoed that the proposed rule doesn’t include evidence to support why certain drugs or drug categories should be included on the DDC lists, and it also fails to propose conditions that would allow outsourcing facilities to continue to produce compounded drugs that are on the lists.

More broadly, the law firm argues that FDA's proposed rule is arbitrary and capricious because it fails to provide evidence showing there are compounding difficulties that warrant putting certain drugs and drug categories on the DDC lists.

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Drugmakers, compounders at odds over FDA’s difficult-to-compound rule

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