By A.J. Day, PharmD, PCCA Vice President of Clinical Services

When I made a decision to become a pharmacist, it was because I wanted to help people. Pharmacy compounding fulfilled that desire because it serves as the perfect balance between medicine, the practical application of chemistry and service to our communities. Nowhere in that picture did I imagine directly interacting with policymakers, boards of pharmacy and the FDA. However, I quickly learned that my ability to be a compounding pharmacist was dependent on decisions made by people who do not have expertise in compounding, so I either needed to find somebody to listen to me whine about it, or I needed to get involved. Due to a lack of friends with sympathetic ears, and a wife who already had to listen to me whining about other things, my only option was to get involved. One of the ways I’ve done this is by participating in FDA Pharmacy Compounding Advisory Committee (PCAC) meetings.

How the PCAC Process Works

When Congress passed the Drug Quality and Security Act (DQSA) in 2013, the FDA went to work implementing the law. It defines the qualifying factors for a substance to be used as an active pharmaceutical ingredient (API) in a human compounded preparation. If a substance does not have an applicable USP-NF monograph and it is not an API in an FDA-approved drug product, there is still a pathway to make it eligible for use in compounding: The FDA has to convene a PCAC meeting, and one of that committee’s duties is to make recommendations to the FDA on whether or not chemicals can be used as APIs in human compounding. The final list that the FDA creates is sometimes called the “positive list.” Interested parties can submit nominations to the FDA, and if the nominations provide sufficient information for the administration to review, then they will be discussed and voted on at a PCAC meeting. Importantly, the committee votes are just an advisory recommendation, and the FDA is not obligated to heed that advice.

There have been 10 PCAC meetings since the passage of the DQSA, and I have attended all of them (I have presented at nearly all of them, too). The meetings follow a set format:

1. The FDA presents their perspective on the nominated substance (for or against adding it to the positive list, and all the assessments they performed to come to that decision)
2. The PCAC can ask them clarifying questions
3. The nominator presents why they feel the item should be added to the positive list
4. The PCAC can ask them clarifying questions
5. There is an opportunity for members of the public (who preregister) to speak about the substance
6. The PCAC will then discuss the substance further and vote

Then the process repeats for the next items on the agenda.

Methylcobalamin and the 2021 PCAC Meeting

It is quite rare for the PCAC to vote against the FDA’s recommendation — it has happened for only five of the 57 substances reviewed. The most recent of these was on June 9, 2021, regarding the use of methylcobalamin. Multiple organizations nominated methylcobalamin and for a variety of uses. PCCA’s nomination focused on its use for patients with autism spectrum disorder (ASD). When the FDA announced the meeting and contacted all nominators about presenting, the other groups all declined to defend their nominations. I think it is vital that compounders are seen as reputable and professional, and defending our nominations is important for the reputation of our industry.

Having said that, their withdrawal from the meeting meant that I had more time for my presentation to the PCAC and the FDA, and I could keep the conversation focused on patients with ASD. I had help from Dr. Richard Frye, a physician and researcher specializing in neurodevelopment and ASD. He has a private practice and is an attending physician at Phoenix Children’s Hospital in Arizona. Dr. James Neubrander, who has a private practice in New Jersey and credits himself with bringing methylcobalamin injections to the treatment toolbox for ASD in 2003, also shared his knowledge. I have been working with both of these physicians, and others, since 2017 to provide data to the FDA. For the PCAC meeting, Dr. Neubrander was selected as a speaker for the open public hearing session. Therefore, I decided to give some of my speaking time to Dr. Frye so that the PCAC would also hear his expert testimony.

There was lots of discussion about potential risks, dosing, clinical assessment and stability of the specific formulation we nominated. Heaps of credit are due to PCCA’s Research and Development and Formulation Development teams for the robust testing they performed to validate the formulation as well as its stability, and to the PCCA Science team for getting all of that published in a peer-reviewed journal. The published stability data was cited by the FDA, and it is due to this peer-reviewed article that the FDA felt confident that compounders could make the formulation within the parameters of USP Chapter 797. We were able to secure a 9–5 PCAC vote in favor of adding methylcobalamin to the positive list (the FDA had recommended to the PCAC that it not be included on the positive list). This tale is far from over, and much still needs to be done.

Key Takeaways and Next Steps

• The FDA still needs to make a final decision on methylcobalamin. The PCAC vote is just the vote of an advisory committee making a recommendation to the agency, and the FDA can decide not to include methylcobalamin on the final positive list.
• Methylcobalamin, as an API for compounding, still must comply with the other requirements for DQSA Section 503A. Notably, it must be produced by a manufacturer that registers it as a drug with the FDA. PCCA’s methylcobalamin meets these and the extra requirements of The PCCA Standard™.
• If you are compounding with methylcobalamin for patients with ASD, we need your help. We need to work with researchers and practitioners, like Dr. Frye and Dr. Neubrander, to publish more data to provide evidence of safety and efficacy. We need to work on this now and get it published in peer-reviewed journals soon so that the FDA may consider it before making a final decision on the fate of methylcobalamin. Please contact me to discuss how we can work on this!

We are grateful to all the PCCA members who provided assistance in the lead-up to the June 9 methylcobalamin discussion, and to Dr. Frye and Dr. Neubrander. Dr. Dan Rossignol was not on the agenda for the PCAC meeting, but his work was also vital to our success.

Our goal in this advocacy work is to protect patient access to customized therapy so that compounding pharmacies can help the people in their communities. My colleagues here at PCCA and I look forward to many more years of serving PCCA member pharmacies and their needs.

A.J. Day, PharmD, is the Vice President of Clinical Services at PCCA. His focus areas include pediatric compounding, veterinary compounding, pain management, regulatory compliance and compounding technique. A.J. has provided CE and non-CE presentations to thousands of physicians, veterinarians and pharmacists around the world. He has provided expert testimony to the FDA on behalf of the compounding profession on multiple occasions. A.J. is active with the Alliance for Pharmacy Compounding, currently serving on their Board of Directors; the National Community Pharmacists Association, currently serving on their Committee on Compounding; the Society of Veterinary Hospital Pharmacists; and several other pharmacy groups.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.