By John E. Voliva, RPh, IACP Executive Vice President
Last week, IACP sent out a member alert about the FDA’s notice of final rulemaking for the “list of drug products that may not be compounded under certain sections of the Food, Drug, and Cosmetic Act (FD&C Act).” This list has been commonly referred to in the pharmacy industry as the “negative list” or the “do not compound list”. Since we sent the member alert, we have received many questions about what the list means, why domperidone does not appear on the list (and if it is now allowed for compounding) and what the FDA’s next steps are for this list. This series of articles will serve as a reference point for all of the “lists” FDA has been charged with creating via the Federal law (specifically, Section 503A of the Food, Drug & Cosmetic Act) to provide clarification to the FDA’s actions and regulation on these “lists”.
First things first – why do the lists need to be created?
Section 503A directly charges the FDA to create three lists & the “positive list”, the “negative list” & the “demonstrably difficult list”. Because these lists are directly laid out in the law and the FDA is given the power of passing regulations on these lists, we now have this notice of final rulemaking for the “negative list” published in early October 2016.
Additionally, with these “lists”, the FDA must consult the Pharmacy Compounding Advisory Committee (PCAC) regarding additions or deletions from any of these lists, “unless the Secretary determines that the issuance of such regulations before consultation is necessary to protect the public health.” FDA has published that they believe passing regulations regarding the lists before consulting the PCAC will “rarely be necessary.”
Therefore, this recent action by the FDA regarding the “negative list” is not only required by Federal law, but FDA must follow certain steps to publish or change any of these lists.
The “negative list” – what does it mean?
It’s always good to look at the actual law as a starting point to fully understand what is going on when an agency passes regulations. For the “negative list”, Section 503A states (emphasis added):
“(1) Licensed pharmacist and licensed physician. A drug product may be compounded under subsection (a) if the licensed pharmacist or licensed physician –
… (C) does not compound a drug product that appears on a list published by the Secretary in the Federal Register of drug products that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective;”
This paragraph is what the industry terms as the “negative list” (it’s just easier to call it that than the “list of drug products that have been withdrawn or removed from the market because such drug products… have been found to be unsafe or not effective).”
It’s important to pay attention to the emphasized text above because it gives us clear direction on how the FDA puts this list together. To appear on the list, the drug must have been available on the market, meaning, at some point in the drug’s history, it was FDA approved. This is key to the reason why drugs like domperidone are NOT on this list – the drugs have never been FDA approved. Does this mean pharmacies can now start freely compounding domperidone? Unfortunately, no, and we will explain this issue in a bit because this particular drug is covered by the “positive” list.
So, the “negative” list deals with drugs which were FDA-approved and on the market at some point in time but had been removed from the market because of safety or efficacy. The vast majority, if not all, of the list are drugs that have been removed from the market because of safety issues. Examples include cisapride, diethylstilbesterol (DES), phenformin, phenylpropanolamine (PPA), terfenidine, and chorionic gonadotropin (NOTE: PPA is not on the current list, but it will appear on the list on November 7, 2016). It is important to point out two important facts about this list:
– The “negative” list ONLY applies to compounding drugs for human use. Thus, compounding items like cisapride, DES and PPA can still be compounded for veterinary patients.
– Many items on the list have additional limitations. For example,
o Diethylstilbestrol: All oral and parenteral drug products containing 25 milligrams or more of diethylstilbestrol per unit dose.
o Gonadotropin, chorionic: All drug products containing chorionic gonadotropins of animal origin.
o Nitrofurazone: All drug products containing nitrofurazone (except topical drug products formulated for dermatologic application).
This is not an entire list of these special exceptions and pharmacists should frequently check and download the list for reference (note: this list will be updated with the new list on or around November 7, 2016). From the examples provided, a pharmacy can compound DES for human use as long as the unit dose does not exceed 25 mg. We receive a lot of questions about hCG, but the important distinction for this example is that in only applies to hCG of animal original – human recombinant hCG is still OK to compound. And, nitrofuazone is allowed for topical use. There are many other examples of these exceptions throughout the list.
OK – so that is the “negative” list, what about the “positive” list?
So, this list is a bit more complicated than the negative list, believe it or not. Let’s start with what Section 503A says about this list:
“A) compounds the drug product using bulk drug substances, as defined in regulations of the Secretary published at section 207.3(a)(4) of title 21 of the Code of Federal Regulations –
(III) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on a list developed by the Secretary through regulations issued by the Secretary under subsection (d)”
Don’t worry about subsection d – this explains the fact that the FDA can put together these lists and must consult the PCAC.
To rewind a bit, Section 503A requires compounders to use bulk drug substances that comply with one of three “buckets” – the bulk drug substance must have a USP or NF monograph OR appear in an FDA approved drug OR appear on the “positive” list. The reason the industry calls this the “positive” list is because items appearing on the list would be allowed to be compounded with, the opposite of what appears on the “negative” list.
It’s important to note now that the FDA calls this list something different than the industry – the “bulks list”. Positive list or bulks list, we are talking about the same thing. FDA has approached the creation of this list by requesting for nominations of bulk drug substances from compounding stakeholders – the general public, pharmacies and healthcare associations. After a couple rounds of nominations, FDA has put together a master list of nominations, which can be found here. The agency has split this bulks list into three categories:
– Category 1 – Bulk Drug Substances Under Evaluation
– Category 2 – Bulk Drug Substances that Raise Significant Safety Risks
– Category 3 – Bulk Drug Substances Nominated Without Adequate Support
Category 1 represents the substances FDA is presenting to the PCAC for their consideration to either add or not add to the “positive” list. To date, the PCAC have considered over 30 different bulk drug substance for inclusion or exclusion from the positive list. We are working to put together a full chart of substances which have already been considered (and the PCAC voting results) along with other items which will be considered in future meetings.
It is important to know that the PCAC recommendation is not binding. The FDA will seriously take the Committee’s vote under consideration, but until final rulemaking is complete (much like what we recently have seen with the “negative” list), the final determination on these substances is still in a state of flux. Also, FDA has announced they will not take enforcement action on any substances appearing in Category 1 until final rulemaking is complete. Therefore, at this point, even if the Committee has voted to not add an item to the positive list, it can still be compounded until rulemaking is complete.
Items which appear in Category 2 should not be compounded and FDA will take enforcement action if a pharmacy is compounding with one of these three substances: domperidone, germanium sesquioxide and quinacrine for intrauterine use. If a pharmacy is found compounding one of these three drugs for a human patient, the FDA will issue the pharmacy a warning letter.
Category 3 is a list of items which the FDA has determined to not have enough supporting information to warrant their presentation to the PCAC. At this time, IACP is working to provide information to “clean up” this list – to remove items which clearly are not bulk drug substances and would never be used in that manner. FDA has announced they would not provide enforcement discretion for these items, however, to date, we have not seen any enforcement actions be taken in regards to these items.
With all of this, we come to a bit of quandary, especially in regards to Category 2. While these items are not on the “negative” list, the FDA still feels these items should not be compounded because of safety risks. Why, then, do these three drugs not appear on the negative list? The answer is pretty simple: they were never FDA approved and never appeared on the market as such. Remember, the “negative” list are items which have been withdrawn from the market for safety or efficacy reason. For them to be removed from the market, they must have first appeared on the market. Thus, the items in Category 2 will most likely never appear on the “negative” list, however, they still should not be compounded or the pharmacy runs the risk of enforcement actions by the FDA.
Great – so we have covered “negative” & “positive” lists – what’s this about demonstrably difficult?
Once again, Section 503A provide for the FDA to put together a list of categories of drugs they feel are too difficult for compounders to make. From the law:
“(3) Drug product.–A drug product may be compounded under subsection (a) only if–
(A) such drug product is not a drug product identified by the Secretary by regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product;”
Thus, again, the FDA will put together a list, via consultation with the PCAC and via final rulemaking, a list of drug products (or categories) which compounders should not try to make. So far, the PCAC has considered to categories of drugs to add to this list: Metered Dose Inhalers and Dry Powders for Inhalation. Both categories of drugs were voted to be placed on the list. Additionally, the Committee will consider transdermal delivery systems (TDS) at the November 2016 meeting – but don’t worry – the types of transdermal drugs which will be considered are those which utilize reservoir or matrix type delivery systems. They are NOT considering transdermals which are liquids or semisolids, like gels, creams, lotions, foams, ointments or sprays. IACP fully expects the committee to recommend to add TDS to the list of demonstrably difficult drugs.
Please continue to watch for further communications from IACP regarding these “lists” and the actions of the PCAC as we continue to monitor FDA’s enforcement of Section 503A.
IACP has submitted comments to the Food & Drug Administration (FDA) regarding the Draft Guidance:Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act
“IACP understands and supports the need to protect public health. However, when providing guidance, it is essential that FDA adheres to the plain language of statutes and Congressional intent to preserve patient and prescriber access to vital compounded medications. Providing clear direction as to the FDA’s thoughts regarding this important subject help not only guide Agency investigators during inspections but gives additional insight to the pharmacy industry as a whole on what the FDA expects from this practice of pharmacy.
IACP is concerned with several main points of the proposed guidance, which we outline below, and we look forward to starting a dialog with the Agency on proposed solutions to the issues raised by our Academy.”
Please click here to view IACP’s entire comments to FDA.
Email firstname.lastname@example.org with any questions.
International Academy of Compounding Pharmacists
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IACP has submitted comments to FDA regarding the Draft Guidance for Industry: Insanitary Conditions at Compounding Facilities.
“IACP understands and supports the need to protect public health. However, when providing guidance, it is essential that FDA adheres to the plain language of statutes and Congressional intent that preserve patient and prescriber access to vital compounded medications. Ensuring compounded medications are not prepared under insanitary conditions should be of the upmost importance, however, Guidance to the matter for state licensed pharmacies should ensure that proper adherence to State law and USP General Chapters <795> and <797> are not superseded.
The current draft guidance fails to follow Congressional intent, current State laws or regulations and USP General Chapters <795> and <797> as it pertains to pharmaceutical compounding. It also appears to attempt to exert current Good Manufacturing Practices (cGMP) on pharmacies which are clearly exempt from these requirements via Section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
IACP is concerned, both from the language contained in this guidance and from the agency’s recent announcement on inspections, effective August 1, 2016, that the FDA will attempt to use findings regarding insanitary conditions as a mechanism to find a pharmacy not compliance with Section 503A and hold the pharmacy as an unregistered Outsourcing Facility or Manufacturer.”
The Scientific American examines, “How the FDA Manipulates the Media.” “The U.S. Food and Drug Administration has been arm-twisting journalists into relinquishing their reportorial independence, our investigation reveals. Other institutions are following suit.”
Please click here to read the article.
Have you read the opinion piece by Henry I. Miller in Forbes? “Lax FDA Oversight Of ‘Compounded Drugs’ Is A Matter Of Life And Death.” Unfortunately what we have here is another example of uninformed and just plain inaccurate reporting. Mr. Miller states that pharmacy compounding is virtually unregulated, and “loopholes in the regulations that set the standards for a practice called ‘drug compounding’ have enabled dangerous products to injure and kill untold numbers of unsuspecting patients.” Mr. Miller seems to be woefully unaware of the regulatory role state boards of pharmacy have engaged in for years in pharmacy compounding as well as of U.S. Pharmacopeial (USP) rigorous standards that are in place. Mr. Miller also has completely discounted the existence of the Drug Quality & Security Act (DQSA) which regulates pharmacies, namely those engaging in inter-state commerce and making sterile medications which are often dispensed to physicians and hospitals.
IACP is setting the record straight with Mr. Miller. We urge our members to do the same. Leave Mr. Miller your take on his opinion piece in the article’s comments section. Let’s set the record straight about our profession! Read the entire article and leave your comments by clicking here.
IACP’s John Voliva, RPh, Executive Vice President is quoted in a July 15th Inside Health Policy article, “Reacting to Stakeholder Complaints…FDA to Cease Citing cGMP Violations for Traditional Pharmacists.”
Inspections Procedure Change
Today, FDA posted a notice announcing a change in its procedure for inspections of certain human drug compounders, which will take effect on August 1, 2016. FDA has stated it’s making this change in response to stakeholder input. Click here to view FDA’s notice.
One of IACP’s primary 2016 Compounders on Capitol Hill Asks (click here to view) challenged FDA’s inspections of 503A compounding pharmacies using Current Good Manufacturing Standards (cGMPs) instead of under U.S. Pharmacopeial (USP) or other standards established by state pharmacy laws and regulations.
Specifically IACP has questioned why: (1) records of inspections (483s) based on cGMPs were published to the FDA’s website publicly, for all to see, even when FDA later determined the pharmacy was in compliance with section 503A and handed the pharmacy investigation back to the State Board of Pharmacy, and (2) the FDA would not always give pharmacies copies of the 483 when they were leaving the inspection. Essentially, pharmacies had to guess whether one would be issued and what would be in it.
Now according to FDA’s newly released notice, the inspector will have to make a preliminary determination that the pharmacy is or is not a 503A and alert them to that within the 483.
Although IACP is certainly encouraged by today’s notice, we are working to obtain clarification on what FDA will use to determine what constitutes a 503A pharmacy. It should be noted – we rarely see a Federal agency publish this type of notification where they outline a course correction in their procedures without some sort of influence. It is through the work of IACP, our members, the DQSA Coalition and our Congressional allies that result in the type of notification we saw the FDA publish today.
Thank you AGAIN to our Members for all of your efforts in making our CCH 2016 Asks heard by your congressional representatives. We also thank all of our current members and all of those who donate to the OneFund campaign – without your support, our work would not be possible! IACP will keep you apprised of any updates on this matter.
FDA Releases Additional Guidance
FDA released two draft guidance documents on July 8th regarding compounded drug products which are “essentially copies” of commercially available drugs under Section 503A and 503B. The guidance documents can be found at the below links.
IACP is reviewing these guidance documents and will provide a summary to the IACP membership.
Please email IACP at email@example.com with any questions. Thanks for your support!
The International Academy of Compounding Pharmacists (IACP) has named John Voliva, RPh, as its new Executive Vice President. Voliva will assume IACP’s EVP role on Monday, April 4, 2016. The EVP search was managed by a six-person committee representing the interests of the IACP Board of Directors, the IACP Foundation Board, IACP members and industry suppliers.
“IACP’s Search Committee is extremely confident that we found the most qualified person to lead the organization forward. After a national search, John Voliva’s extensive experience made him the clear choice for the position,”said Gary McCrory, RPh, CCN, IACP President. “John brings a distinctive combination of compounding pharmacy ownership, legislative relations at both a federal and state level, and a strong pharmacist background. He is one of us; he truly understands the value compounding pharmacy brings to patients, and how compounding pharmacists are the best suited in providing customized medications.”
“I am looking forward to continuing my work with this important sector of the profession—the compounding pharmacist,” Voliva said. “The compounding pharmacist’s ability to individualize medications, ensuring the most appropriate dose and delivery system which improves compliance, adherence and overall patient health outcomes. The provision of personalized medication solutions is the epitome of a patient-centric approach to health care.”
After receiving his bachelor of science in pharmacy degree from the Purdue School of Pharmacy and Pharmaceutical Sciences in 1999, Voliva became the owner/pharmacist of Hook’s Apothecary, Indiana’s first compounding-only pharmacy. For the past several years, he has worked for PCCA, a licensed bulk pharmaceutical repackager, as part of PCCA’s Public Affairs team. He is a long-time member of the International Academy of Compounding Pharmacists, National Community Pharmacists Association, American Pharmacists Association and Indiana Pharmacists Association. For the past two years, he has served on the DQSA Coalition which IACP established to ensure that the Drug Quality & Security Act legislation enacted in 2013 is being implemented as Congress fully intended.
Save-the-Date: IACP Member Town Hall on April 20th
Meet your new EVP John Voliva! Please join us for an IACP Member Town Hall on Wednesday, April 20th at 3:00 pm ET – 2:00 pm CT – 1:00 pm MT – 12:00 pm PT.
Call-information has been sent to all members. Please email firstname.lastname@example.org if you did not receive.
DQSA Coalition Milestone Report!
This morning in a House Education & Workforce Committee, Full Committee Hearing, “Examining the Policies and Priorities of the U.S. Department of Health and Human Services,” Congressman Buddy Carter (R-GA) questioned the Secretary of the U.S. Department of Health and Services Sylvia Mathews Burwell regarding office-use compounding.
Congressman Carter expressed concern that office-use provisions in the Drug Quality & Security Act (DQSA) are not being interpreted per congressional intent by the U.S. Food & Drug Administration (FDA). Secretary Burwell replied that office-use should be allowed per her understanding, and that she was prepared to work with Congress on this issue.
See the webcast archive link and the transcript below. Thank you Congressman Carter for placing this vital issue on the record!
Please click here to view the Archived Webcast from this morning’s session. Congressman Carter appears at the 2.00 portion of the webcast.
Rep. Carter (R-GA-1): As a pharmacist I wanted to ask you about compounding for office-use. I am concerned about the FDA interpreting for legislative intent. The FDA continues to prevent medications to be compounded for office use. Many states have already allowed for this to take place. He pointed out that office use prevents patients from having to go to the doctor, get a prescription, then go to the pharmacists, and allows for doctors to dispense necessary medications to patients without the additional steps.
Sec. Burwell: We don’t have any guidance out preventing that, maybe my team can follow up with your staff. Right now compounding should be occurring and there should not be a problem with any rules.
Rep. Carter: The problem is that you are requiring each patient to have a prescription.
Sec. Burwell: It is my understanding that should be able to be allowed, so I look forward to working with you on that.
Rep. Carter pointed out that they are looking for a guidance on this topic, and the Secretary said they welcomed Congress’s input on any guidance.
IACP and the DQSA Coalition will continue to keep our Members apprised of updates as they are available. Please email questions to email@example.com
The International Academy of Compounding Pharmacists (IACP) has submitted formal comments to the United States Pharmacopeial Convention (USP) regarding General Chapter <797>. These comments are based upon IACP member input as well as the input of the IACP Legislative Committee and Board of Directors. Thank you to all members who provided feedback.
IACP General Chapter <797> Comments
IACP supports practices and quality standards for preparing compounded sterile human and animal drugs. However, IACP has strong concerns with several of the proposed revisions that would place an undue burden upon pharmacists and result in decreasing time spent with patients as well as patient access to vital compounded medications. At a time when patients are already facing decreased access to compounded medications due to skyrocketing drug shortages and new burdensome regulations, the Revised Chapter <797> will result in further decreasing patient access to these vital compounded medications. The burden that these revisions place on pharmacists will result in many pharmacists foregoing sterile compounding altogether resulting in further reducing patient access to medications. The sections within the Revised Chapter <797> that will burden pharmacists the most and have the greatest impact on decreasing patient access are the sections related to air quality monitoring, establishing beyond-use dates, and in-use times are of greatest concern.
IACP shares the concerns of many other organizations that the current revisions provide very few citations in support of the specific proposed requirements. As the burden that is being placed on pharmacists is so high by these revisions as to lead to drastically reducing patient access to medications, IACP strongly encourages that any revisions proposed be based on data, studies, and specific information.
Therefore, while IACP appreciates USP’s work on this issue, IACP has strong concerns as to the unintended consequences of the proposed revisions on patient access to medications. IACP urges USP to consider patient access to compounded medications and revise the proposed revisions as detailed in our comments.
PLEASE NOTE: USP Extended the Comment Period to TODAY, Monday, February 1, 2016
If you have any questions, please email firstname.lastname@example.org.