Federal drug safety authorities report significant progress in efforts to protect the public from disasters such as the 2012 fungal meningitis outbreak linked to drugs from the New England Compounding Center in Framingham, Massachusetts. However, a new Congressional move to change the regulatory legislation is likely to mean that healthcare providers, clinics, and hospitals must remain cautious about where the drugs they prescribe or administer are produced.
Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), Silver Spring, Maryland, and Center for Drug Evaluation and Research Senior Science Advisor for Compounding Julie Dohm, JD, PhD, highlight actions taken after passage of the 2013 Drug Quality and Security Act in an article published in the December 28, 2017, issue of the New England Journal of Medicine.
“Much of the patient harm caused by compounded drugs is preventable, and the implementation of higher production standards (such as CGMP [current good manufacturing practice] standards for outsourcing facilities and revised U.S. Pharmacopeia standards, once finalized, for other compounding pharmacies) will be essential to reducing harm associated with pharmaceutical compounding,” they write.
Feds, States Trying to Keep up With Compounding Changes
The Drug Quality and Security Act was passed after the New England Compounding Center produced contaminated methylprednisolone acetate and other injectable drugs and distributed them throughout the United States, exposing an estimated 14,000 patients to fungal infections, causing 778 cases of fungal meningitis, and killing 76 people.
The new law was meant to upgrade drug safety regulations to reflect major changes in compounding pharmacies during the previous decade. It established two classifications: traditional compounding pharmacies (which require a prescription for each individual patient) and outsourcing facilities (which manufacture sterile drugs intended to remain sterile for injection, sold in larger amounts to hospitals, clinics, and physicians’ offices, and not requiring a prescription for each patient). Outsourcing facilities are asked to voluntarily register with the FDA, and 74 have done so. Unlike traditional compounding pharmacies, outsourcing facilities must abide by CGMP standards.
Not Your Grandad’s Pharmacy
Traditionally, a compounding pharmacy was a local pharmacy in which a licensed pharmacist compounded a medication for an individual patient to fill a prescription from that individual’s physician. Compounding pharmacies remain important in treating patients for whom FDA-approved drugs are unavailable, such as the patient who cannot swallow tablets and needs a drug in a liquid formulation not commercially available, or the patient who is allergic to an inactive ingredient (such as a dye or filler) in an FDA-approved drug and needs it prepared without that ingredient.
Compounding pharmacies had always operated outside the established FDA regulatory system because of the specialized niche they occupied, and that opened the door to major public health risks once some of these relatively unregulated companies began mass-producing large quantities of drugs and distributing them across many states.
Michael Carome, MD, director of the Public Citizen Health Research Group in Washington, DC, told Medscape Medical News, “Although compounded drugs serve an important need for patients whose medical needs cannot be met by an FDA-approved drug, it is imperative that healthcare providers and patients alike recognize that compounded drugs pose a higher risk to patients than FDA-approved products.
“Compounded drugs are exempt from requirements for FDA approval. FDA has not reviewed data showing that these drugs are safe and effective. Compounded drugs do not have the same labeling requirements as FDA-approved drugs, for which the label clearly indicates what the drug is approved (and safe and effective to use) for, and under what conditions the drug should be used to ensure safety. The labeling of FDA-approved drugs includes contraindications and situations in which you should never use the drug. The labeling also describes interactions with other drugs that could be dangerous. Compounded drugs do not provide this information,” he continued.
How Compounded Drugs Differ From FDA-Approved Drugs
Dr Carome, who also sits on the FDA Pharmacy Compounding Advisory Committee, said in terms of safety, key differences between drugs made by traditional compounding pharmacies and FDA-approved drugs are that the former do not have to go through the New Drug Approval review process, do not have FDA safety and efficacy review, are not required to meet CGMP standards (which can be expensive), are not required to test each batch of drug to determine that it contains the right amount of active ingredient and is not contaminated, do not undergo FDA premarket inspection of manufacturing facilities before the first dose is marketed, and are not required to report adverse events to the FDA.
According to Dr Carome, there are more compounding pharmacies than a decade ago, their products are being distributed more widely, and they are being used by more people. “The compounding pharmacy business has exploded since the early 1990s. There are also much larger companies, such as the [New England Compounding Center], that are basically mass-producing numerous drugs and selling them across the country. In my view, these are companies engaged in illegal drug manufacturing,” he said.
Who Keeps Track of Who Is Making the Drugs?
Traditional compounding pharmacies and outsourcing facilities are regulated primarily by individual state boards of pharmacy, and laws that govern production standards vary from state to state. The authors explain that many states have adopted US Pharmacopeia standards, but that revisions to Chapter 797 (on sterile compounding) begun in 2015 are still in draft form. To help fill the gap, the FDA published in 2016 a draft guidance “to assist compounding facilities in identifying and correcting insanitary conditions and to assist state regulatory agencies in assessing whether the conditions they observe during inspections would be considered insanitary,” they explain.
The agency “has received a steady stream of reports of serious adverse events related to compounded drugs since 2012,” the authors write. These included three cases in which infants received a compounded morphine sulfate preparation that was 25 times the concentration indicated on the label, two patients who developed severe hypersensitivity reactions after intravenous infusions of a curcumin product compounded with an industrial-grade excipient, and 43 cases of patients with diminished visual function after intraocular injections of a compounded drug containing a steroid and an anti-infective agent. Earlier, Maragakis et al had reported eight cases of Sphingomonas paucimobilis bloodstream infections in patients after receiving intravenous fentanyl prepared at a compounding pharmacy and distributed to four states.
Drugs prepared in insanitary conditions have been a persistent problem. “Since the 2012 meningitis outbreak, the agency has conducted more than 425 inspections of compounding pharmacies. We have observed problematic conditions during the vast majority of these inspections,” the authors write. Problems included “dead insects in compounding areas designated for sterile processing, visible mold on ceiling tiles in compounding rooms, and dog beds and dog hairs in close proximity to compounding areas.”
The category of “outsourcing facilities” established in the Drug Quality and Security Act legislation was intended to meet the needs of hospitals, freestanding outpatient surgery centers, clinics, and other healthcare facilities for customized drugs and for dosage forms that are not in high demand, the authors explain. On the assumption that these drugs would be more safely prepared in facilities subject to CGMP standards than in healthcare facilities, the FDA is drafting guidance tailored to the scale and scope of such facilities.
“Because outsourcing facilities are permitted to compound sterile drugs in large volumes and ship them anywhere in the United States without patient-specific prescriptions, the move toward CGMP adherence is critical,” they stress.
Proposed Legislation “Would Eviscerate” 2013 Law
Dr Carome estimated several thousand traditional compounding pharmacies currently exist in the United States. Requiring individual prescriptions for individual patients has limited the harm from manufacturing problems identified in the FDA inspections.
A new bill sponsored by Congressmen H. Morgan Griffith (R-VA) and Henry Cuellar (D-TX) would weaken that protection by permitting traditional compounding pharmacies to distribute compounded drugs within a state without requiring an individual prescription (only a “drug order”) and without being required to follow CGMP standards as outsourcing facilities are. The proposed bill is HR 2871, The Preserving Patient Access to Compounded Medications Act.
“If passed, this bill would eviscerate the 2013 law that created the outsourcing facilities pathway,” Dr Carome said.
“It would allow compounding pharmacies to do what outsourcing facilities can currently do without having to register, without having to report adverse events, without having to pay the user fees that go with registration as an outsourcing facility, and without having to follow CGMP, which if done right can be expensive. It would take us back to pre-2013 and undoubtedly result in outbreaks such as we saw with the [New England Compounding Center].”
HR 2871 is strongly backed by the International Academy of Compounding Pharmacists, a trade group that donated $9843 to Rep. Griffiths’ campaign in 2017 and $5000 to Rep. Cuellar’s campaign.
How to Decide Where to Get a Safe Drug
Dr Carome had some straightforward advice for clinicians: “The rule should always be that if the patient has a medical need that requires a drug, the first choice should be an FDA-approved product. If a sterile drug for injection is needed and there is not an FDA-approved drug available, the next choice should be a registered outsourcing facility. If hospitals, clinics, and doctor’s offices need sterile drugs for which there is no FDA-approved product available, for example, because of a drug shortage, they should rely on a registered outsourcing facility, particularly if they are going to order and store a large quantity of those products (for example, for patients who might be sent to the emergency department for emergency surgery). They should not be getting them from a traditional compounding pharmacy.”
The authors and Dr Carome have disclosed no relevant financial relationships.
N Engl J Med. 2017;377:2509-2512. Full text
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