Clearing up confusion over which sclerosants are FDA-approved, which aren’t, and the significant differences between the brand name and compounded versions.

Roundtable moderated by Dr. Nick Morrison. Panelists: David Horowitz, Esq; Margaret Mann, MD; Gilly Munavalli, MD

ON JULY 31, 2020, the FDA proposed taking polidocanol off the list of active pharmaceutical ingredients that 503B compounding pharmacies can use for compounding. The FDA found that the approved polidocanol product (Asclera in the US) is medically suitable and compounding using polidocanol bulk drug substance is, therefore, not clinically necessary.

Here, Dr. Nick Morrison dives deeply into this topic, leading an esteemed panel of experts in a detailed discussion about the ins and outs of compounded sclerosants. The panel discusses what the data shows in terms of safety, the new rules proposed by the FDA, and the intricacies of compounding pharmacies, to name a few of the topics covered. Read on to stay up to date on this critical topic affecting all vein specialists.

Notable vein specialists have been expressing concerns over the efficacy and safety of compounded sclerosants in journal papers and presentations at educational meetings for at least a decade. Many point to false or misleading information promoted by compounding pharmacies as the cause of confusion that many physicians experience.

WATCH 2 MINUTE TOPIC: COMPOUNDED SCLEROSANTS: BUYERS BEWARE

Nick Morrison: Thanks, everybody, for taking the time to do this. I want to lay a little groundwork to start this discussion. David, what is meant by an FDA-approved sclerosant?

David Horowitz: An FDA drug product has been specifically approved by the US Food and Drug Administration as safe and effective after conducting a comprehensive review of a new drug application or a biological licensing application. An application for FDA approval has to contain extensive information and scientific data, including rigorous clinical trials to prove safety and effectiveness as well as detailed information and data on the chemistry and manufacturing controls. The FDA will generally conduct a comprehensive on-site inspection of the manufacturing facilities for both the drug product and the active ingredient used to make the product to evaluate compliance with FDA's Current Good Manufacturing Practice (CGMP) regulations.

Nick: Concerning compounded sclerosants, what compounded sclerosants are FDA-approved?

David: Though the FDA has approved sclerosants containing polidocanol and sodium tetradecyl sulfate, there are no FDA-approved compounded sclerosants because compounded drugs are not FDA-approved. They could, however, be exempt from FDA-approval requirements if they meet all the statutory conditions for such an exemption. Still, the FDA does not review data on the safety or effectiveness of a compounded formulation nor require a passing FDA inspection before a compounded drug can be marketed, as it does for an FDA-approved drug.

Margaret Mann: I think this is an important distinction. We have some physicians who say, “Hey, I’m using sodium tetradecyl sulfate (STS) on you, and it’s FDA-ap- proved,” but they’re using compounded drugs. So technically, they can’t say that because that compounded drug is not FDA-approved. It’s not STS that’s FDA-approved, it’s the actual brand name Sotradecol, or Asclera, that’s FDA-approved. That distinction is important because the FDA is approving a drug by a specific company.

David: The FDA doesn’t approve drugs that anyone can make; the FDA approves applications that allow the applicant to market the specific drug that was in their application and that the FDA approved.

Nick: To your point, Margaret, unfortunately, there are compounding pharmacies that will swear to the person who is inquiring that they have FDA-approved, compounded STS or polidocanol when that can’t be true.

David: Another misleading thing I’ve seen is compounders who say they use FDA-approved ingredients. The FDA does not approve ingredients; the FDA approves drug products.

Margaret: Absolutely. That’s something we need physicians to understand because it’s so misleading, and it’s false; it’s false advertising.

Nick: What is a compounding pharmacy? And what’s the difference between it and an outsourcing facility?

David: State pharmacy boards generally regulate a compounding pharmacy, but there also are some federal requirements that apply. These are under section 503A of the Food, Drug, and Cosmetic Act. The restrictions for a compounding pharmacy include the requirement for individualized prescriptions and the prohibition on copying commercially available drugs. Compounding pharmacies are subject to minimal FDA oversight and do not follow those CGMP regulations that I mentioned earlier, even if they’re making sterile drug products. In contrast, there’s another type of entity that compounds sclerosants, known as an outsourcing facility, and that is regulated by the FDA under section 503B. These outsourcing facilities do not need to obtain individualized prescriptions, and they must comply with the CGMP requirements for manufacturing quality. But they are also prohibited from copying commercially available drugs.

There are limits on the use of the active ingredient or the bulk drug substance that outsourcing facilities can use for this kind of compounding. In particular, the active ingredient must appear on FDA’s list for 503B compounding. Although STS and polidocanol are currently on FDA’s interim list of bulk ingredients that can be used for 503B compounding, in July 2020, FDA proposed to remove both substances from this list, based on FDA’s findings regarding the absence of a clinical need to compound these drugs. If the FDA finalizes these proposals, compounding these two sclerosants will be prohibited under federal law for outsourcing facilities.

Just a little more detail on those two FDA proposals: On July 31, 2020, FDA published this proposal to take polidocanol off the 503B list. They found no basis to conclude that an attribute of the approved polidocanol products is unsuitable such that a compounded product is clinically necessary. The FDA said that although compounded polidocanol in concentrations higher than the approved products may be out there, these higher doses, if used in the same volume, potentially pose greater risks to patients.

Likewise, in September 2019, the FDA did a similar thing for STS—they proposed to take it off the list because they found no basis to conclude that STS must be compounded using a bulk drug substance.

If it needed to be compounded, the FDA said that you could use the approved drug product instead.

Nick: The FDA proposed to take the STS off the list about a year ago. How long does this take until it becomes a regulation?

David: Now you’ve asked me a question that I can’t answer. FDA does not have a deadline, and they’re pretty busy with COVID and other things. They’re moving very slowly, so I don’t know how long it will be before the FDA finalizes these proposals.

Nick: Like manufactured FDA-approved sclerosants, are compounding pharmacies required to report adverse events to their sclerosants?

David: There is no adverse event reporting for compounding pharmacies under 503A, but outsourcing facilities under 503B are supposed to report adverse events to FDA just like approved products.

Nick: I wonder how active that is; I know it’s fairly active for devices, but I don’t know about for drugs.

David: I can say drug manufacturers take that responsibility very seriously. There’s a very active program for manufactured products. In some cases, the compounder may not be aware of the adverse event if the physician doesn’t report it to them. I don’t know the level of compliance with this requirement more generally for outsourcing facilities.

Gilly Munavalli: The other point is that companies such as Merz have a medical director or liaisons who are available at any time. And so if you do have a complication with one of these medications, you can get them on the phone and discuss it, physician-to-physician, with someone who has an intimate knowledge of the product and has used it. That often is not the case with compounding pharmacies at all.

Nick: Gilly, that’s interesting because for a while, and I’ve forgotten which company, I served as that liaison and would routinely get calls from physicians with adverse events related to the drug, and they always wanted to talk to me. I was pretty independent about doing that. Even though the company was paying me, I wasn’t very good about being a company man; I was straightforward with the people when they would call.

Gilly: Right, I was too. And you had all levels of either physician or mid-level provider, and I could tell you some of the stories of people who called in for things you would not imagine. In those cases, the callers were desperate or very upset and needed advice.

Nick: Who is it that’s responsible for the testing of the safety and efficacy of a compounded sclerosant?

David: A compounded sclerosant is not tested for safety or effectiveness. For example, a compounded product might be made in a concentration that the FDA would not approve as safe or effective for the general population. It might also contain impurities that are different from the approved product and under CGMP requirements. Outsourcing facilities conduct some limited testing of quality attributes, but not for safety or effectiveness.

Nick: In essence, it’s the provider who is going to be responsible for the safety and efficacy of the use of that drug if it comes to a legal situation.

Let’s talk more specifically about compounded sclerosing agents. As many of you know, about a decade ago, several articles concerning inconsistent potency of contaminants in compounded sclerosants were published in peer-reviewed journals.^{1, 2} After that, compounding pharmacies were directed by the FDA essentially to clean up their act. What has happened since then? Have compounded sclerosants been shown to have appropriate potency as shown on the label and to be free of contaminants?

Margaret: It’s been about ten years, and sadly, compounding pharmacies have not cleaned up their act. Nick, yourself, Gilly, and I wrote a paper looking at commercially available polidocanol to see whether they contained impurities and whether there were variations in concentration.³ We published our article in 2019, and there are still variabilities and impurities. Unfortunately, companies are still advertising essential copies of FDA-approved sclerosant that are commercially available. They’re still out there, and lots of physicians are purchasing it and many times doing it because it’s less expensive; it’s a profit margin issue.

Nick: That’s a good point. There’s not much else in terms of a reason they use a compounded polidocanol or STS other than to save money. That can be a real, significant problem. Margaret, what are the three FDA-approved, most commonly used detergent sclerosants?

Margaret: There’s polidocanol, which is FDA-approved as Asclera by Merz. And those of you who are in Europe know this by Aethoxysklerol, which is by Kreussler. And there are two sodium tetradecyl sulfate products that the FDA approved. They’re also both known as Sotradecol by Mylan and Leucadia Pharmacy.

Nick: David, back to you. I understand that compounders can use pharmacy-grade or pharma-grade ingredients, and they can also use an industrial grade. What’s the difference between the two?

David: A bulk drug substance or active pharmaceutical ingredient, used in compounding is required to adhere to the quality standards in the United States Pharmacopeia if there is an applicable monograph. But there have been instances of compounding pharmacies using industrial-grade versions of these chemicals that may not meet USP standards. They may not have the same purity or potency. Bulk drug substances for compounding do not undergo pre-marketing review by the FDA, and they might contain potentially harmful impurities as a result.

Nick: I’m reminded of a situation that we had, probably fifteen years ago, when polidocanol wasn’t approved yet. We were using a compounding pharmacy and noticed that we started having more and more ulcer problems. I called the pharmacy and told them about the ulcers and asked what they were using, what their ingredients were, whether they were pharma grade or industrial. They told me that it was pharma grade, but when I asked for that in writing, several times, I could not get an answer. So that was my answer to why I was having so many problems with it.

Gilly: The paper Margaret referenced speaks precisely to that. When you look at the study in detail, you'll see that seven different samples were analyzed, and they showed the differences between USP and industrial-grade ingredients. Number one is from the standpoint of potency because the samples in the study were either sub potent or superpotent. Both can have their hazards—one in the sense that what you’re injecting is not effective, the other in the sense that you get an exaggerated skin response or potentially even more serious injury when you’re using something more potent than you’re anticipating. Number two, in terms of the impurities, there were some found in the compounded products.

Several were not identifiable, but one of which has been identified in the past in previous studies.3 Frankly, we don’t know the impact of impurities, and these industrial-grade products are much more likely to have them.

Nick: Let’s talk a little bit more about the side effects of sclerosants that are not concentrated the way they are labeled and that may have impurities.

Margaret: The concentration of a sclerosant has a direct impact on efficacy and side effects. So if it’s too strong or too weak, that makes a huge difference. When treating small spider veins, the difference between 0.1% versus 0.2% can influence whether you get hyperpigmentation, matting—maybe less so with ulceration. Anytime I teach new physicians or providers about sclerosant, I always talk about minimum effective concentration. What’s

the lowest concentration you need to get the vein closed without causing side effects? And that concentration is super important. So if you can’t rely on what percentage that solution is with compounded sclerosants, you can’t count on good results. That’s the bottom line.

Nick: Agreed. So let me ask David about the shelf life of FDA-approved products in compounded sclerosants. Tell me about shelf life.

David: An FDA-approved sclerosant will often have a longer shelf life that has been established by rigorous stability studies the manufacturer conducts to show that the quality attributes will be retained during the expiry period. Although a 503B compounded product may also have an expiration date based on a stability study, FDA guidance allows these outsourcing facilities to use a shorter beyond-use date by default, as long as their production volume is below certain thresholds. So if an outsourcer doesn’t add a preservative or complete sterility testing before release, FDA allows a default BUD (beyond-use date) as short as six days. So that’s much less than the approved product. Now, if a 503A pharmacy compounds the sclerosant, there would be no expiration date, no stability studies, and there could be a BUD of 12 hours or less, depending on the relevant USP chapter for sterile compounding. It’s much more limited, and exceeding that beyond-use date is potentially very risky.

Nick: I’d like to now add to this discussion about the potential risks of using compounded sclerosants for the sclerotherapist. In my mind, these risks include claims of insurance fraud—if you use a compounded drug on a patient covered by an insurance contract you sign or Medicare rules that prohibit the use of a drug on a patient under those contracts. In the event of an adverse outcome, if a patient brings a malpractice action against the provider and it’s shown the provider used a non-FDA-approved drug, which was responsible for the adverse event, the provider is liable. Period. There’s no discussion after that, according to medical liability attorneys, and we’ve had several attorneys speak at some of the educational meetings.

I myself have been asked to review a case for a physician. He had used a compounded drug because the compounding pharmacy told him it was FDA-approved. He used the drug and got an adverse event, and I said, “I’m sorry, but I can’t defend that.” Furthermore, if it can be shown that the provider used the compound drug to save money, which is, again, the primary reason you would use it, damages triple. So it’s a very, very significant effect.

In some of the lectures we’ve heard by malpractice attorneys for the plaintiffs, there are eight key questions that they ask a provider in a malpractice action (See “Eight Questions Providers have to Answer in a Malpractice Suit” below). Comments from any of the panelists?

Margaret: As dermatologists, Gilly, and I are super passionate about the idea of compounding medications. We use it a lot in our office. I sell compounded topical agents. I do it because we tailor the specific medication to the patient. For example, we combine ingredients to improve compliance because sometimes putting three things on is much more difficult than putting one product on. Sometimes, we use higher concentration that’s not available commercially because it’s more efficacious, but we very much tailor these to each patient. It’s also products that are not available commercially, and they’re topical. In this case, we’re talking about medications that are injected and their use over multiple patients. The standard of care needs to be higher. If you can’t be assured of the potency of the drug and ensure there are no impurities—if there’s something commercially available—we should use what’s commercially available.

Gilly: I agree. I also was involved in reviewing a lawsuit many years ago using a compound polidocanol product. It was a case out of Florida that resulted in a pretty significant ulcer in the medial malleolar area. It was the same issue that Nick discussed, in that a compounded product that was used. There wasn’t much you could do. Unfortunately, this treatment resulted in a serious ulcerative and necrotic injury at the injection site. Now whether it was technique dependent or whether it was the actual product itself, whether the impurities contributed to that, we may not know. Still, there’s a reason we have guidelines to follow, and it’s important that we do that.

Nick: I want to thank all of my panel members. What an outstanding group; I think we have provided some meaningful information for providers. I hope readers take it to heart, and I thank you very much for your opinions. V

Key Questions Physicians have to Answer in a Malpractice Suit

In the lectures we’ve heard by malpractice attorneys for the plaintiffs, there are eight key questions that a provider in a malpractice action will be asked.

• Why did you utilize a non-FDA-approved product when one is available commercially?
• Where and when was the agent compounded?
• They want to know the exact date and person, not the pharmacy, who did the compounding. What steps did the provider take to ensure that the compounded agent used was manufactured in an FDA-registered facility?
• Do you purchase the agent in bulk? If so, how is it stored? What steps do you take to encourage dosage consistency?
• How did you test the compounded agent to ensure it was safe? Do you test each batch?
• Have you ever visited the compounding pharmacy to look for yourself? Where does that compounding pharmacy acquire its raw materials?
• Are they pharma grade or industrial grade?
• Do you use compounded agents to increase profits?

WATCH: 2 MINUTE TOPIC - COMPOUNDED SCLEROSANTS: BUYERS BEWARE

REFERENCES:

1. 1 Weiss, A., et al. (June 2011). Absence of Concentration Congruity in Six Compounded Polidocanol Samples Obtained for Leg Sclerotherapy. Dermatological Surgery, 37(6), 812–5.

2. Goldman, M. (2019). Commentary: Safety Profile of Sclerosing Agents. Dermatological Surgery, 45 (12), 1529–1530.

3. Mann, M. Munavalli, Amatangelo, L., and Morrison, N. (November 2019). Improper Potency & Impurities in Compounded Polidocanol. Journal of Drugs in Dermatology, 18(11), 1124–1127.