The current outbreak of fungal meningitis, which has been linked to epidural injections of a contaminated steroid product from the New England Compounding Center, has brought a great deal of attention to pharmacy compounding. As of this writing, 137 cases have been confirmed in 10 states, 12 patients have died, and the company has voluntarily recalled a 71-page list of products. Several US legislators have called for the closure of regulatory loopholes that have allowed commercial compounding to flourish on such a large scale without federal oversight.
Compounding refers to the process of “combining, mixing or altering ingredients to prepare a customized medication for an individual patient upon receipt of a valid prescription“. This is how most medications were dispensed prior to the advent of modern pharmaceutical manufacturing. Today, just over 2% of prescriptions require compounding. As with custom medical devices, defined at 21 CFR 812.3(b), pharmaceutical compounding has traditionally implied small-scale use within the boundaries of clinical practice. Just as it does not regulate the practice of medicine or dentistry, FDA does not regulate compounding within the scope of pharmacy practice.
By contrast, the company at the center of the fungal meningitis outbreak appears to have been engaged in illegal manufacturing. A 2002 FDA guidance includes a list of business practices that may indicate a manufacturing operation in disguise. “Compounding of drugs in anticipation of receiving prescriptions” is the first item. Preparation of compounded drugs for resale or redistribution by third parties is also on the list.
Few compounded products have been systematically evaluated to determine their safety, efficacy, purity and potency. Quality may vary widely because pharmaceutical compounding is typically done without the advice and guidance (and sometimes, without the consent) of the drug manufacturer. Additionally, compounders are not required by FDA to follow good manufacturing practices and do not have to comply with FDA labeling standards addressing adulteration and misbranding. This doesn’t mean that compounds prepared for individual patients are unsafe. It’s a different story when unregulated production is scaled up for many thousands of patients.
Although compounded drug products are not subject to the normal FDA approval process, they may still be encountered in research settings. Additional safeguards for human participants in research that involves compounded drugs may include:
- Carefully evaluating the research protocol against 21 CFR 312.2 to determine if an IND is required
- Including an appropriately qualified pharmacist in the review process
- Requiring that all compounding be done by an accredited pharmacy that complies with USP standards and state pharmacy regulations
Consultation with FDA is recommended if the IND exemption criteria do not appear to be met, particularly item (iii):
The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
Care should be taken to ensure that participants understand the nature of the treatment they will receive, should they agree to take part in a trial involving a compounded drug product. The consent form should explain in lay terms that the compound is not FDA approved and its risks are not fully known.