The US FDA Acts To Bolster Adverse Event Reporting For Compounded Drugs
Executive Summary
After discovering one firm suppressed over 4,000 compounded-hormone adverse event reports, agency leans on compounders and outsourcers to improve reporting.
The US Food and Drug Administration is taking steps to improve the reporting of adverse events with compounded drugs, and aims to finalize a memorandum of understanding with states agreeable to reporting such events to the FDA when they occur at state-regulated compounding pharmacies.
This action was prompted by a recent case involving BioTE Medical, which suppressed 4,202 adverse events over a five-year period involving compounded hormones it was marketing; the firm chose not to share these reports with the outsourcing facilities that compounded them nor with the agency. The firm is located in Irving, TX, and markets bioidential hormone replacement therapy (BHRT) to help solve hormone imbalances in men and women.
Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, on 9 September announced plans to bolster such reporting through a campaign to increase public awareness about drug safety issues with compounded medications.
She said that “while adverse event reports have some limitations, this information is one of the best safety tools we have at our disposal. The FDA is dedicated to increasing public awareness about drug safety issues and we’re continuing our efforts to improve reporting for all types of drugs, including compounded medicines.”
She added that outsourcing facilities are required to report adverse events to the agency and encouraged all companies, health care professionals and patients to report adverse events “as soon as they know about them.”
Besides BioTE Medical, there have been other cases where adverse event reports were not submitted for compounded drugs. In 2016, Pacifico National, doing business as AmEx Pharmacy, documented 28 adverse events yet did not report these to the FDA after patients experienced floaters after receiving intravitreal injections of repackaged sterile Avastin. (Also see "FDA Warns Consumers Not To Use Sterile Drugs Made By Pacifico National After Firm Refuses Recall Requests " - Pink Sheet, 30 Aug, 2019.)
The FDA Takes Action
Woodcock said that FDA inspectors found 4,202 adverse event reports during a routine inspection of BioTE in 2018. These reports were kept internally in a company data file and not sent out during the five-year period they were collected, from 2013 and 2018.
Woodcock said that “the adverse event information our investigators found suggested compounded hormone pellets were possibly associated with endometrial cancer, prostate cancer, strokes, heart attacks, deep vein thrombosis, cellulitis and pellet extrusion.”
BioTE contracted with Carie Boyd’s Prescription Shop and AnazaoHealth Corp., which are 503B outsourcing facilities, to compound them. Some of the drugs they made included compounded progesterone and testosterone.
BioTE Did Not Investigate Complaints
Woodcock wrote in a Journal of the American Medical Association article posted online 9 September that not only did the firm not submit reports, it also did not investigate complaints. "For most of the adverse events submitted to its website, BioTE did not investigate the products or the processes used to compound the products, not did it conduct a follow-up with those who reported the events.”
Woodcock co-wrote the article, “Improving Adverse Event Reporting for Compounded Drugs,” with Julie Dohm, a former director of the FDA’s compounding office. Dohm left the agency in March and is now with the law firm of Covington and Burling. (Also see "Compounding Chief Departing US FDA After Leading Office Through 'Tumultuous Times'" - Pink Sheet, 21 Mar, 2019.)
The co-authors wrote that “despite the poor quality of information collected through the BioTE website, the FDA was able to identify adverse events attributed to the use of compounded hormone pellets containing testosterone. Pellet extrusion and cellulitis were common among the reported adverse events.”
FDA Plans To Finalize MOU With States This Year
They wrote that “in view of the lower regulatory standard for compounded products and increased risk that such unapproved products present,” the FDA plans to take concerted steps to improve adverse event reporting and analyses for compounded medications.
These include plans to finalize a memorandum of understanding with the states. Under this agreement, states would investigate complaints of adverse events associated with certain compounded drugs from 503A pharmacies and report serious adverse events and serious product quality issues to the FDA. A revised version of the MOU was published for comment in September 2018. (Also see "FDA Proposal On 'Inordinate' Interstate Compounding Sparks State Oversight Debate" - Pink Sheet, 22 May, 2019.)
After the BioTE incident, the FDA made it a priority to follow through on a statutory obligation to negotiate the MOU.
States that sign the MOU must also agree to notify the FDA with this information within three business days after receiving any complaint relating to a drug product compounded by a pharmacist and distributed outside the state involving a serious adverse drug experience or serious product quality issues.
The FDA has also contracted with the National Academy of Sciences, Engineering and Medicine (NASEM) to conduct a study on the risks associated with compounded hormone products. The study report, expected in 2020, is expected to “inform FDA’s decision-making including its review of labeling and marketing materials.” The release of the study is also expected to “increase public awareness” about safety risks that clinicians and patients should consider before using compounded medicines.
The agency also plans to work with 503B outsourcing facilities to improve mechanisms for obtaining adverse event reports and for submitting them to the agency.
The authors also point out that compounded products are riskier for patients than FDA-approved products, as the compounded drugs have not gone through the requisite safety, effectiveness and quality checks.