What did government officials know, when did they first know it, and what did they do in response?
It's a classic question faced by nearly every agency in the US government, including the US Food and Drug Administration (FDA), which has in recent months been under pressure from legislators regarding its oversight of the pharmaceutical compounding industry. In light of a massive outbreak of fungal meningitis that has since been linked to products manufactured at a Massachusetts pharmaceutical compounder's facility-a facility that had been on FDA's radar for years due to previous inspections finding deficient practices-legislators claimed the agency should have done more to stop the company's products from reaching the market until changes were made.
Now the public watchdog group Public Citizen is leveling similar claims against the agency, alleging that it acted too slowly to crack down on another compounding pharmacy whose products were recalled earlier this week after more than a dozen patients were found to have come down with infections after being administered products manufactured by the company.
FDA regulates pharmaceutical compounders differently than traditional manufacturers, both because of statutory limitations and their traditional roles within the healthcare system. Compounders have traditionally existed within hospitals, and make customized compounds for use by patients who may have particular restrictions or need a product at a dose or strength not available directly from the manufacturer. Unlike traditional manufacturers, these compounders do not need to seek approval from FDA for each compounded drug so long as they create the drug in response to a valid prescription.
The last two decades have seen a resurgence in the popularity of compounders, which many analysts attribute to two factors: the ease with which products can now be ordered through the Internet, and increasing drug shortages, which have made compounders an increasingly attractive option for physicians who may not be able to order their products from their preferred channels.
That resurgence, however, has resulted in some large-scale problems, such as the outbreak of fungal meningitis that affected hundreds of patients in 2012 and ultimately killed dozens of people. In the wake of that outbreak, FDA markedly stepped up its enforcement of compounding pharmacies, and has since pressured several into launching recalls of all products and issued dozens of reports outlining deficiencies (known as FDA Form 483s) to other companies.
A Prophetic 483
One of the most recent compounding pharmacies to fall under the suspicions of FDA has been Specialty Compounding Pharmacy, a Cedar Park, TX-based facility that received a Form 483 on 22 March 2013.
That report noted a variety of alleged deficiencies, including:
- numerous instances of contamination in which there is no record of corrective action
- Procedures intended to prevent microbiological contamination did not include a validation component.
- Routine sterility and endotoxin testing was not conducted for all injectable drug products.
- deficient practices for monitoring environmental conditions meant to ensure aseptic processing of compounded products
- improper clothing worn by employees, which left areas around the eyes exposed
- behavior practiced by employees that could have exposed multiple products to contamination
- deficient surface sampling and glove sampling practices to test for contamination
One of those observations would come to be problematic. As FDA notes in "Observation 4" of the 483 letter, the company manufactures vials of calcium gluconate, an injectable product that must be produced under sterile conditions.
However, FDA said that "media fills performed by [Specialty Compounding]… do not closely simulate actual production conditions or cover worst case or most challenging conditions." In other words, the sterilization process used by the compounding facility hadn't been adequately validated for use under the conditions to which it was regularly exposed.
Public Citizen: FDA Could Have Prevented Outbreak
By August 2013, the company said it had become aware of serious issues affecting the product, with at least 15 patients coming down with infections after being injected with calcium gluconate.
The company then moved to recall all products it had compounded and distributed, noting that there was a "potential association between the infections and the medication" it had manufactured.
A statement released by FDA noted that the contamination appeared to be of Rhondoccus equi, a gram-positive bacteria often found in soil and most often known to infect animals or immunocompromised people.
Regulatory Focus noted at the time that the recall could place more pressure on FDA, in particular to do more to protect consumers, and now that prediction seems to have been realized, with Public Citizen issuing a press release blasting the agency for not doing more to stop Specialty Compounding from manufacturing products in March 2013 when it first found problems.
"The FDA knew there was a serious problem here but didn't use its existing legal authority to take prompt, aggressive enforcement action against the company. That exposed patients to unnecessary risk and might have contributed to 15 people being infected," said Michael Carome, director of Public Citizen's Health Research Group. "What's the purpose of inspecting a facility if you're not going to take appropriate action when you find conditions that pose a safety threat to patients?"
"Since the fall of 2012, the FDA has identified significant objectionable conditions at 50 compounding pharmacy facilities, but only 16 of those have initiated a product recall or have been the subject of an FDA enforcement action beyond issuance of an inspection report," the group added in its statement.
Public Citizen said FDA should review its existing 483s and subject any of those facilities that were found to have "significant objectionable conditions" to "further action."
"The FDA could potentially have prevented the current outbreak linked to Specialty Compounding products by taking swift action against the company after the FDA inspected its facility in March 2013," the letter adds. "It can prevent future injuries by exercising its authority more aggressively when it identifies problems during an inspection."
In addition, the letter requests the US Department of Health and Human Services (DHHS) request that its Inspector General conduct an investigation into why FDA did not initiate a public safety alert, recall or seek an injunction against the compounder after the March 2013 inspection.
Focus has reached out to FDA for comment and will update this piece if we receive any.
Public Citizen Statement
Letter to DHHS
483 to Specialty Compounding