In FDA Effort to Strengthen Regulation of Compounded Drugs, Protections and Profits Intersect

Posted 04 September 2014 By Alexander Gaffney, RAC


A new law meant to protect consumers from unsafe pharmaceutical compounding practices is drawing interest from pharmaceutical companies, who are petitioning the US Food and Drug Administration (FDA) to add some of their products to a new list of restricted drugs that could protect patients from deficient drugs—and likely companies from compounded competition as well.


The Drug Quality and Security Act (DQSA) of 2013 was passed into law in the wake of a massive and deadly outbreak of fungal meningitis caused by deficient compounding practices at a Massachusetts-based company.

Historically, compounding pharmacies were regulated by state boards of pharmacynot FDA. But in the aftermath of the meningitis scandal, legislators sought to update the standards by which pharmaceutical compounding is regulated, including at the federal level.

The DQSA accomplished this by instituting several reform measures. The legislation creates a voluntary registration system by which compounding facilities can sign up to be inspected by FDA (known as "outsourcing facilities"). The hope of legislators is that facilities will have a greater incentive to purchase supplies from federally inspected facilities, which will in turn incent companies to become registered with FDA in the first place.

The legislation also bans compounders from making "essentially a copy of a marketed and approved drug," and gives FDA new authority to inspect compounding facilities in accordance with a "risk-based schedule." Companies, in turn, will be required to report adverse events to FDA.

Importantly, the legislation also calls for FDA to establish a list of drugs which are "difficult-to-compound"—those drugs found to be "reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug of category of drugs," according to the legislation. (Section 503(B)(a)(6))

These restrictions would apply not only to federally regulated outsourcing facilities, but also to non-outsourcing facilities primarily overseen by state boards of pharmacy.

What's Difficult to Compound?

In general, difficult-to-compound drugs are characterized as such by virtue of their manufacturing processes' effects on their potency, purity, quality, consistency and bioavailability. FDA has also highlighted the complexity of the manufacturing process itself, saying that the more steps a product requires to be made, the more opportunities there are for something to go wrong.

But while the DQSA established a need for a difficult-to-compound list, it did not establish what specific drugs should be included on that list.

And now dozens of companies have a message for FDA: Our drugs—many of them, in fact—are difficult to compound.

Petitions Come Pouring In

In Citizen Petitions and comments on an FDA docketestablished in December 2013, companies are trying to make the case that their drugs—sometimes dozens of their drugs—meet the letter and the spirit of the difficult-to-compound provisions of the law.

But whether those concerns are the result of concerns about patient safety or the profits earned by those drugs may well start a broader debate.

Take, for example, UK drug maker GlaxoSmithKline's submission to FDA. GSK calls for FDA to ban compounded copies of 34 drugs, which together represent billions of dollars in yearly revenues for the company, according to GSK sales data.

The company is also advancing something of a novel argument. While the DQSA permits FDA to require compounded versions of drugs with Risk Evaluation and Mitigation Strategies (REMS)—essentially plans to ensure the safe use of potentially dangerous drugs—to also have REMS, GSK is arguing that the "sophisticated facilities and equipment" needed to produce many of those same drugs should cause them to be added to FDA's "difficult-to-compound" list.

Other companies with top-selling drugs are also seeking protections. In comments to FDA, drug maker AbbVie recommended that all drugs manufactured by extrusion or nanotechnology, delivered using transdermal delivery systems, modified release drugs, light- or temperature-sensitive drugs or products susceptible to oxidation be added, categorically, to FDA's difficult-to-compound list. The limit on transdermal delivery systems would notably protect AbbVie's Androgel, a testosterone product which is administered through the skin and has already earned AbbVie more than $400 million in revenues so far in 2014.

Another company, Biogen Idec, nominated its new blockbuster multiple sclerosis drug Tecfidera (dimethyl fumarate) for inclusion on the list, citing the potential for a sub-potent product due to the product API's subjection to sublimation.

Smaller Companies, too.

Other companies, including ones with much smaller product portfolios, are also weighing in, hoping to add their products to FDA's list.

Kythera Biopharmaceuticals' comments express its wish to add deoxycholic acid (DCA) to the list, citing adverse events associated with compounded versions of its experimental drug, ATX-101. The drug has not yet been approved by FDA.

Acorda Therapeutics, meanwhile, has called on FDA to add dalfampridine (Ampyra) to the list, citing the narrow therapeutic range in which the drug is most effective. The drug earned more than $84 million for the company during the first quarter of 2014.

Other companies have opted to submit Citizen Petitions to FDA for inclusion on the list. A Citizen Petition filed this week by the law firm Arnall Golden Gregory LLP requests the inclusion of ophthalmic mitomycin-c on the difficult-to-compound list. The branded version of that drug, Mitosol, is manufactured by Mobius Therapeutics. The petition notes the drug is, among other things, highly unstable in liquid form and is difficult to manufacture to current good manufacturing practice (cGMP) standards.

Final List Still Under Development

Of course, while companies can petition FDA to be included on the difficult-to-compound list, there's no guarantee they will actually find their products on the final list once it's published.

But the potential for the list to become a line of defense against compounded competition is surely on the minds of regulators, and has the potential to be a source of friction between regulators, companies, compounders, patients and payors, all of whom have a stake in which products are, and which products aren't, allowed to be compounded under federal law.

And with the stakes so high for some specialty drug makers—consider the case of KV Pharmaceutical for a case study in the power of compounded competition—this could be one area that sees its fair share of criticism and litigation.

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Categories: Drugs, Manufacturing, Regulatory strategy, News, US, CDER

Tags: 503A 503B, Pharmaceutical Compounding, Compounding, DQSA, Drug Quality and Security Act, Difficult-to-Compound List

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