By Allison Evans, assistant managing editor

For many years, dermatologists and their clinical staff have safely performed low-risk, low-volume in-office preparations for biopsies, skin cancer excisions, and other dermatologic procedures. Preparing medications in the clinical setting allows physicians to cater to the individual needs of patients. Since the New England fungal meningitis tragedy and the subsequent passage of the Drug Quality and Security Act (DQSA) in 2013, various federal and state policymakers and standard-setting organizations have increased oversight and regulation of medication preparation by not only pharmacists but also physicians. Congressional intent for the DQSA was presumably to regulate large-scale, high-risk compounding operations — but the unintended consequences of the regulations may jeopardize physicians’ ability to produce in-office preparations, and ultimately patient care.

What is the USP?

The United States Pharmacopeial Convention (USP) is an independent, scientific, non-governmental body that sets public standards for identity, strength, quality, and purity of medicines. USP wields much power over compounding practices with its Chapter 797: Pharmaceutical Compounding – Sterile Preparations, contained in the United States Pharmacopeia and National Formulary (USP–NF) and published in the USP Compounding Compendium. In 2004, Chapter 797 was published as a legally enforceable standard.

USP standards are not law. However, specific standards are recognized in various provisions of the federal Food, Drug and Cosmetic Act (FDCA) and by state pharmacy boards. More recently, the DQSA clarified the FDA’s authority over compounding and USP is revising its sterile and non-sterile compounding standards.

While the safety and effectiveness of drugs are generally regulated at the federal level, states have jurisdiction over the practices of medicine and pharmacy. Nearly all states have laws, regulations, or policies specific to compounding, enforced primarily through pharmacy and health boards. “USP chapters only apply when a policymaker, like a state pharmacy board, adopts the chapter,” said Natasha Pattanshetti, JD, MPH, AADA’s manager of regulatory policy. Even if USP adopts new or revised standards, it doesn’t necessarily become law; it only applies when a policymaker in your jurisdiction adopts it, she said. It depends on the state whether the state pharmacy board has jurisdiction over physicians preparing medications. (See the sidebar to learn more about state oversight of in-office preparations.)

What does all this regulation mean for dermatologists? “As dermatologists, our fear is that standards on how we see patients and patient safety are being set by a group [pharmacists] that doesn’t see patients or participate in clinical practice,” said Lawrence Green, MD, chair of the Academy’s State Policy Committee.

A seat at the table

Allison Vidimos, MD, RPh, chairman of the department of dermatology and program director of the micrographic surgery and dermatologic oncology fellowship at the Cleveland Clinic, was nominated by the American College of Mohs Surgery to serve as an Expert Consultant to the USP’s Compounding Expert Committee in 2018. While obtaining an appointment to this committee was no easy feat, now that she has a seat at the table, she has seen just how critical and helpful it is to have physician consultants on board. An anesthesiologist (also a pharmacist), allergist, pulmonologist, and Dr. Vidimos serve as non-voting Expert Consultants to this USP committee.

“Being in the room with the USP pharmacists and representatives from the FDA and CDC to educate them about daily dermatology practice and the safety and practicalities of in-office compounding has been a huge help. My experiences as a pharmacist have helped me better understand their practices and standards as well,” she said. “Addressing the pertinent issues with the 797 revisions has been a significant team effort by other Academy members and staff. I am very grateful dermatology has a voice at the table and a willingness on the part of the USP and FDA to work together toward a resolution.”

USP Chapter 797 revisions

Currently, USP is in the midst of revising Chapter 797, which was last updated in 2008, before the renewed regulatory focus on compounding. USP’s first draft proposal, published in 2015, received more than 8,000 public comments from 2,500 stakeholders; Academy members submitted nearly 900 letters to USP throughout the draft revision process. The overwhelming and energetic response to USP’s first revisions sent the Expert Committee back to the drawing table to work on a second round of revisions, which were published in 2018. The second round of revisions had minor improvements for the specialty, but would still impact most dermatology practices if further revisions are not made before the publication of the finalized chapter.

Becoming a pharmacy…almost

The 2018 proposed USP standards are extremely onerous to physicians who conduct in-office preparations, said Murad Alam, MD, MBA, chair of the AADA Congressional Policy Committee and vice chair of dermatology at Northwestern’s Feinberg School of Medicine. Under certain circumstances, practicing physicians would be required to function as a mini-pharmacy with a laminar airflow system, an ISO Class 5 cleanroom, and other burdensome standards — a virtual impossibility for physicians, he noted. “Dermatologists want what’s safe for patients more than anyone, but for us this isn’t a question about safety,” said Seemal R. Desai, MD, a member of the FDA Pharmacy Compounding Advisory Committee (PCAC), chair of the AADA’s Compounding Workgroup, and a member of the Academy Board of Directors. “This is a question about blanket rules and policies that are being made for procedures that don’t pose a risk to patients.”

Dermatologists prepare buffered lidocaine syringes at the beginning of the day to facilitate patient access. “If there are not significant revisions [to Chapter 797], we will not be able to continue to conduct practices that we have safely done for many years in ways that help our patients and are cost-effective and an integral part of our practices,” said Dr. Alam.

Urgent-use exemption

Among the Chapter 797 proposed revisions, the issue that will have the most impact on dermatologists is the urgent-use exemption, which would allow clinicians to avoid the burdensome Chapter 797 requirements. “The proposed revisions say that in order to remain exempt from Chapter 797 standards, the compound sterile product must be prepared and administered within one hour, otherwise it must be discarded,” Pattanshetti said.

Not being able to maintain compounded medications for longer than one hour would disrupt clinic flow and patient care, Dr. Alam said. “The proposed new rules are so onerous and impossible to implement that it would result in patients losing access to medications.”

Buffering lidocaine

Most per-patient dilutions will likely fall within the proposed one-hour timeframe, such as diluting Kenalog (triamcinolone acetonide), said Dr. Desai at the Academy’s 2019 Annual Meeting session, ‘The Future of Dermatology: What Changes are Coming and How Can We Prepare?’ The issue that is mission-critical for dermatologists, however, will be the ability to buffer lidocaine with sodium bicarbonate with or without epinephrine. The current 797 revision being considered by the USP Compounding Expert Committee would allow use of buffered lidocaine for up to four hours after compounding. USP intends to publish the revised chapter by June 1.

“Dermatologists need the ability to prepare and mix lidocaine and buffer it with sodium bicarbonate for hundreds of skin procedures done weekly in the office — and it’s what dermatologists have been doing very safely for decades. Ultimately, this leads to better patient outcomes and more patient comfort during the injection process. Without buffering, the injection becomes very painful and uncomfortable,” said Dr. Desai. “Here, we have a completely safe, tolerable, patient-friendly, and inexpensive way of mitigating pain,” added Dr. Alam. “I have operated on a lot of children — awake,” said Dr. Vidimos, “and one reason that I have been able to do that is because I use buffered lidocaine; it makes the injections hurt so much less. We’re fighting for this because we care about our patients. We want them to have timely access to safe and comfortable care.”

In addition to disrupting clinic flow, the issue of wastefulness is also of concern — particularly considering the ongoing shortages of lidocaine with and without epinephrine as well as sodium bicarbonate. For Dr. Green, who is a single private practice practitioner, he confirmed the wastefulness and inconvenience this proposal would cause. “I probably wouldn’t go through an entire bottle [of lidocaine] in one day — maybe half to three-quarters of a bottle of lidocaine for seeing a single doctor’s worth of patients. We cannot be mixing new bottles of lidocaine with sodium bicarbonate in such a short time frame. Think of how much lidocaine would be wasted,” he said.

Dr. Vidimos has presented evidence to the USP that buffered lidocaine may protect against infection in comment letters to USP. “There are a number of articles about the antibacterial properties of lidocaine in the medical, dental, and veterinary medicine literature. When you add sodium bicarbonate to lidocaine, it has been shown to increase the bacteriocidal properties of the lidocaine,” said Dr. Vidimos.

The AADA’s most recent comment letter to the USP

The AADA together with sister societies ACMS, ASDSA, and ASMS through the Compounding Workgroup, is pushing to lengthen the exemption to 12 hours for the final revision, said Pattanshetti. Dr. Desai noted that this would essentially allow most dermatologists to get through a regular working day, and even with a longer day, 12 hours would suffice. “We are still fighting the battle,” he said.

“We are also advocating for a specific exemption for buffered lidocaine, separate from the urgent-use exemption, so that physicians are able to prepare it at the beginning of the day and discard whatever remains at the end of the day,” said Pattanshetti. Dr. Alam believes the USP standards are well intentioned. However, he see it as, “overstepping into the practice of medicine and attempting to solve a problem — namely, the safety of mixed drugs in a physician’s office — that simply doesn’t exist.”

Federal regulation

Under the DQSA, no drugs may be compounded under insanitary conditions, Pattanshetti said. In 2016, the FDA issued a draft guidance on insanitary conditions, and then revised this draft guidance at the end of 2018. The FDA’s 2016 draft guidance proposed to require physicians’ offices to maintain a certified International Organization for Standardization (ISO) Class 5 area or cleanroom with a buffer area, HEPA filters, and conduct routine sampling of airborne particulates and surface areas, among other requirements.

The advocacy efforts of the AADA, along with others throughout the house of medicine, made significant gains in reaching the FDA. In January 2018, the FDA published its 2018 Compounding Policy Priorities Plan in which it recognized the hardships faced by dermatologists and others — a notable win for the specialty:

This [revised] guidance will address concerns raised by some providers who compound small quantities of drugs in their offices for patient use, and as part of their routine clinical practice. This came up in the setting of certain dermatological procedures, for example. The FDA plans to better define the circumstances under which we believe drugs are being mixed and applied in a manner that creates negligible patient risk, and therefore wouldn’t be subject to the same compliance policy.

In the September 2018, FDA guidance revision, Insanitary conditions at compounding facilities, a footnote further clarifies its intent: “FDA generally does not intend to take action under section 501(a)(2)(A) against a physician who is compounding or repackaging a drug product, or who is mixing, diluting, or repackaging a biological product, provided that such activities occur in the physician’s office where the products are administered or dispensed to his own patients.”

While the FDA has heard dermatology’s voice, the fate of in-office preparations lies largely with the USP’s final version of Chapter 797 and how states may adopt the new standard in a manner that could affect physicians.

What now?

In November 2018, a joint meeting was held among the AADA, other dermatology organizations, the American Medical Association, USP, the Centers for Disease Control and Prevention (CDC), and FDA. “We all met to try and talk through solutions to the 797 dilemma. It was surprisingly productive,” said Dr. Alam. “We’re really all focused on the same things — developing solutions that will keep our patients safe and provide them with the best care.”

From this meeting, Dr. Alam believes there is a hopeful path forward for dermatologists, although final decisions will not be revealed until the June publication. “The onus is on us in dermatology to do the parts that we can do,” he said — and that is exactly what the AADA and its members have been doing and will continue to do:

1. Antimicrobial testing

In response to concerns of microbial contamination, the USP has agreed to perform USP <51> antimicrobial testing on buffered lidocaine prepared in a clean segregated compounding area (non-ISO 5) to duplicate in-office preparation. This will be done in a compounding facility and certified testing lab. The study entails taking the mixed preserved lidocaine with epinephrine and sodium bicarbonate and systematically injecting different pathogens into it, and then seeing how rapidly the pathogens grow. “If the growth rate is very slow, then you can store it for longer, and if the rate of growth is faster, it can be stored for less time,” Dr. Alam said. If the initial antimicrobial testing is favorable to allow 12 hours of use, then stability testing will be conducted.

2. Draft a position statement

During the December meeting, it was made clear that regulatory authorities wanted “guidelines from our societies showing that we had a useful and customary way of mixing things in a sterile and safe manner,” said Dr. Alam. “We developed a position statement on how lidocaine should be buffered and prepared in-office. This statement will allow us to have more standardized methods of doing this and will demonstrate to USP and FDA what we’re doing,” Dr. Desai said. View the position statement on ‘Safe In-Office Preparation of Buffered Lidocaine as a Local Anesthetic’ at staging.aad.org/buffered-lidocaine-ps. “If the USP <51> antimicrobial testing and stability testing turn out favorably, all of the Academy’s efforts will likely lead to a USP monograph for buffered lidocaine,” said Dr. Vidimos. The monograph would not be timed with the publication of Chapter 797 revisions, but if published, it would supersede Chapter 797 standards, allowing dermatologists to treat their patients in a safe and effective way.

3. Join the USP

Historically, physicians have not taken part on USP Expert Committees as voting members. These committees set USP’s standards. “We have hardly any representation on these state pharmacy boards, which apparently now have the ability to reach into doctors’ offices and modify and restrict practices, noted Dr. Alam. The Academy and its sister organizations have recently gained approval to apply for membership in USP. “Once you’re on the inside, you’re perceived as one of them, not as an external agent who’s trying to modify what they’re trying to do,” he said.

Can you compound or prescribe it?

Answer a few questions to determine whether the type of compounding you are performing is in compliance with FDA regulations, and how to access a drug product if it cannot be compounded in-office at staging.aad.org/practicecenter/compounding.

A work in progress

“Part of what we are learning in this regulatory area is that sometimes there are clearly things you are forbidden to do, and there are some things you are clearly allowed to do. Then there’s a large gray area between them,” Dr. Alam said. “We have been trying to enlarge that gray area. We are forestalling the absolute prohibition that would make it impossible for us to do something. Within this gray area, now we have some wiggle room to try and come up with some long-term solutions.” These changes, however, occur slowly, and you can’t get them done exactly the way you want in exactly the time frame you want, he said.

Despite the difficulties and challenges in advocating to various regulatory authorities, Dr. Alam believes it’s been an important lesson for the specialty. “It’s been a really useful exercise for our whole profession in terms of increasing our interaction with various regulatory authorities. The AADA has spearheaded the effort, but other associations and organizations in medicine have participated intensely as well, and it’s helped unify our specialty,” he said. “In addition, we’ve learned a lot more about key stakeholder groups that we have been less knowledgeable about in the past, which will serve us well moving forward.”