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Substances Doubtful for Bulk Drug Substances List Could Be INDs

[April 15, 2016, AJHP News]

Cheryl A. Thompson

BETHESDA, MD 24 Mar 2016—Pharmacists, physicians, and advocacy groups that want patients to use substances unlikely to be on the upcoming "bulk drug substances list" for compounders should consider submitting "treatment" investigational new drug (IND) applications, FDA personnel recently suggested.

FDA-cleared treatment IND applications, they explained, offer a legal workaround that can benefit many patients.

"An interested party, whether it be an advocacy group, a treatment center, or a compounding pharmacy, could submit a treatment IND, which once that was in place could be expanded to treat a large number of patients," said Jonathan Jarow, from the Center for Drug Evaluation and Research (CDER) Office of the Center Director.

The suggestion arose during the discussion of quinacrine hydrochloride at the March 8–9 meeting of the Pharmacy Compounding Advisory Committee in Silver Spring, Maryland.

It was the fourth time that FDA had convened a meeting of the committee to discuss possible entries on the bulk drug substances list.

Substances on that list can be used by pharmacy compounders to prepare patient-specific products despite not being the subject of a United States Pharmacopeia or National Formulary monograph or a component of an FDA-approved drug product.

Quinacrine hydrochloride is among the 61 substances that FDA announced in October 2015 may continue to be a component of compounded products while FDA works on the regulation concerning the bulk drug substances list.

Commercial products containing quinacrine hydrochloride left the U.S. market more than a decade ago for undetermined reasons, Jane Axelrad, head of FDA's compounding oversight activities, told the committee.

Yet physicians still prescribe the drug.

Some 15,500 prescriptions for quinacrine hydrochloride products were compounded and dispensed by community and mail-service pharmacies from 2010 through 2015, said Grace Chai, with the Office of Pharmacovigilance & Epidemiology.

Rheumatology, dermatology, and general practitioners accounted for the "vast majority" of quinacrine hydrochloride prescribers during that time, Chai said, noting that 0.5% were obstetrics–gynecology specialists.

Axelrad said FDA, even though it had approved the marketing of quinacrine hydrochloride products decades ago, still had to seek the committee's advice on the substance.

"It would have to be on the bulk list in order to be compounded because it is not a compound in a currently FDA-approved drug," she said.

Three divisions in the CDER Office of New Drugs (OND) reviewed the safety and effectiveness of quinacrine hydrochloride.

No use other than treatment of lupus received a favorable review, according to the briefing documents for the meeting.

CDER's Division of Pulmonary, Allergy, and Rheumatology Products saw merit in keeping quinacrine hydrochloride available as an oral treatment of cutaneous lupus erythematosus and as an add-on oral therapy for patients whose lupus is resistant to hydroxychloroquine monotherapy.

Reviewers at FDA expressed concern about quinacrine hydrochloride's safety profile. Aplastic anemia and hepatitis are among the known adverse effects.

But in the setting of pharmacy compounding, reviewers stated, whatever labeling is provided may not mention adverse effects.

"There is a population of patients with lupus who likely benefit from the treatment with oral quinacrine," said OND's Susan Johnson in summing up FDA's presentations to the committee.

"OND is committed to helping the clinical community maintain the availability of quinacrine for use in well-informed and -managed therapeutic situations," she said. "We recommend that quinacrine access be maintained under an IND."

With a standing treatment IND, Jarow said, individual healthcare providers would not have to pursue the approval of an institutional review board before having a patient use the drug substance.

"They would just have to be aware of the existence of that IND," he said, and then abide by it, including use of the approved informed-consent form.

Another advantage is that any number of healthcare providers could prescribe the drug under an expanded-access treatment IND, Jarow said.

CDER receives about 1000 expanded-access IND applications per year, Jarow said.

Those that have clear explanations of a treatment's risks, benefits, and alternatives and an adequate informed-consent form, he said, are allowed to proceed.

ASHP, in a letter to FDA, supported patients' continued access to quinacrine hydrochloride as an option for treatment of lupus.

But the letter also stated ASHP's concern that placement of quinacrine hydrochloride on the bulk drug substances list does not limit the substance's use to lupus treatment (the only OND-supported indication).

ASHP recommended that if FDA does not add quinacrine hydrochloride to the list, the agency should "establish a regulatory pathway" that would facilitate future access to the substance for patients with lupus.

Further, ASHP stated, absent "significant" revision, FDA's current expanded-access IND application process will not facilitate access to any drug available only from compounders.

Jarow, in speaking to the committee, acknowledged that submission of an IND application has seemed difficult to many individual healthcare providers seeking a drug for a single patient.

"There's now a special form in development that has not been finalized—it's available in draft form—that caters to that specific type of IND rather than the general form that's used for all types of INDs, which looks very complicated," he said.

Form FDA 3926, also known as "Individual Patient Expanded Access Investigational New Drug Application (IND)," went on display in February 2015 as part of a draft guidance (PDF) for the pharmaceutical industry.

 

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