Opinion: The FDA is in a Hole With MOU on Compounding Medications—It Should Stop Digging

June 21, 2022Scott Brunner, CAE

Congress expected the FDA to draft a memorandum of understanding on interstate distributions of compounded medications that states would be willing to sign, but that’s not what the agency did.

When FDA lawyers conceded in Federal Court in February that the agency had not properly followed Congress’ instructions for creating a memorandum of understanding (MOU) with states regarding interstate distributions of compounded medications, they finally seemed to be heeding Will Rogers’ advice: “If you find yourself in a hole, stop digging.”

For the FDA, that hole is now 25 years deep. Its impetus was a directive from Congress in 1997—part of revisions made to the Food, Drug & Cosmetic Act—that the agency execute an MOU under which state boards of pharmacy would report to the FDA certain information about state-licensed compounding pharmacies that distributed a large percentage of their compounded preparations across state lines.

As Congress conceived it, the MOU would be voluntary, but the law would impose restrictions on pharmacies shipping compounded drugs from states that chose not to sign it. Congress intended it to be a consensus document, created via the formal rule-making process, with input and endorsement of the states. In other words, Congress expected the FDA to draft an MOU that states would be willing to sign.

But that’s not what the agency did. Instead, it started digging. After several proposed iterations spanning 24 years, the FDA in 2020 finalized an MOU that:

• Did not go through formal notice-and-comment rulemaking.

• Failed to properly assess the economic impact on pharmacies and state boards of pharmacy.

• Conflated 2 important pharmacy law definitions: “distribute” and “dispense.”

That resulted in a lawsuit against the agency by 7 compounding pharmacies, whose arguments resonated in part with a federal judge and led to the FDA conceding its failures in court last February. Granted, the agency didn’t entirely abandon its shovel in that court appearance. Instead, it laid out plans for starting work on a new hole: proposing yet another version of the MOU, this time via the prescribed rule-making process it previously failed to follow.

But abandoning that MOU is precisely what the FDA ought to seek permission to do, because the specific problem the MOU was conceived in 1997 to address no longer exists.

To understand why the MOU as envisioned by Congress is out of date, let’s first return to those definitions mentioned earlier. Across federal and state pharmacy law, the terms “distribute” and “dispense” have remarkably consistent definitions.

“Dispensing” is patient-specific; it refers to a drug prepared for an individual patient pursuant to a prescription from a physician or other prescriber. “Distributions,” on the other hand, are not patient-specific; the term applies to batches of compounded medications prepared for in-clinic or in-hospital administration by a physician to a patient, and a prescription is not required.

Back in 1997 when Congress authorized creating the MOU, it was to address compounding and distribution by traditional compounding pharmacies of non-patient-specific medications intended for in-clinic administration. It was a practice generally allowed under most states’ laws at the time but was subsequently prohibited by Congress when it passed the Drug Quality & Security Act (DQSA) in 2013.

Under the DQSA, traditional compounders were forbidden from compounding drugs for in-clinic use without a prescription. Not only that, but a new category of compounding operation, called outsourcing facilities, was created. Those facilities would be allowed to distribute compounded medications to hospitals and clinics if they adhered to current good manufacturing practices, much like the manufacturers of FDA-approved drugs do.

The DQSA eliminated the need for that 1997 MOU because traditional compounders could no longer do what the MOU was envisioned to illuminate. Still, the requirement for an MOU remained in the Food, Drug & Cosmetic Act, so the FDA decided to dig a little deeper.

The agency re-drafted an MOU that applied to both distributions and dispensing of compounded medications—even though Congress had only authorized the MOU to cover distributions, and not patient-specific dispensing, regulation of which has long been the purview of state boards of pharmacy. That overreach led to the aforementioned lawsuit against the agency by compounding pharmacies and that February court appearance where the FDA climbed out of one hole and announced it would start another.

Here’s the thing, pharmacy compounders are not opposed to some level of reporting on shipments of compounded medications across state lines—even shipping of patient-specific compounded drugs. Because it’s not unusual in compounding that the pharmacy that makes that customized drug for your partner, your child, or your Aunt Sadie is in a different state, it’s not unreasonable for state boards of pharmacy and the FDA to want to know which pharmacies are shipping majorities of their compounded preparations out of state.

So instead of digging a new hole, the FDA should join with the compounding profession to change the law. Eliminate that out-of-date MOU requirement—an MOU that several states have already said they can’t sign (because of state law) or won’t sign (because of the administrative burden).

In its place create a statutory regime for reporting shipping info to state boards of pharmacy, to be shared with FDA. Maybe also create a narrow but permanent pathway in the statute for compounding pharmacies to mitigate drug supply chain problems by preparing urgent-use drugs in small batches for hospitals and clinics when those drugs are in national or regional shortage.

Stop digging FDA, and let’s start building a new framework that provides the reporting you want and maintains patient access to safe, life-enhancing compounded medications.

About the Author

Scott Brunner, CAE, is chief executive officer of the Alliance for Pharmacy Compounding.

https://tcih.org/

This link leads to an international declaration about integrative and alternative medicine: www.tcih.org/read

At the June 14th meeting, the board voted to become a signatory to this declaration.

 

 

FDA will hold a drug compounding annual listening session, virtually, from 9-11 a.m. ET on June 17. This listening session is an opportunity for stakeholders to voice their views on compounding to the FDA. Dr. Mary Ann Block met with IMC members this week for guidance in using her 5 minute opportunity. Alan Dumoff also plans to testify.

Filed Electronically at Regulations.gov
May 24, 2022
Pharmacy Compounding Advisory Committee
Center for Drug Evaluation and Research
US Food and Drug Administration
5630 Fishers Lane
Rockville, MD 20852
Re: Comments on Docket FDA-2021-N-0357
Message to PCAC Members regarding Glutathione
Dear PCAC Committee Members:
I write on behalf of the American Association of Naturopathic Physicians (AANP), one of the
nominators of glutathione.1 While the FDA appears to have provided an in-depth analysis that supports
its rejection of this important therapy, the rubric applied is deeply faulty and sharply slanted to yield
recommendations against the inclusion of safe and effective therapies on the positive list. While many
of the details provided are subject to challenge, the less obvious but more critical point is that the
standards being applied to these reviews are contrary to statute and poor public health policy. I begin
by writing of my own experience as it perfectly encapsulates the profound flaws in the FDA’s
ingredient review process and its recommendation against the inclusion of glutathione in the positive
list.2 I highlight the salient points from my experience and then expand on each below.
1 AANP has been partnered in these efforts with the Integrative Medicine Consortium
(IMC), the American Academy of Environmental Medicine (AAEM), the American College for
Advancement in Medicine (ACAM), the International College of Integrative Medicine (ICIM) and the
Academy of Integrative Health and Medicine (AIHM). Together we filed a detailed Citizens Petition
raising this and numerous other defects in the review process which can be found
https://www.regulations.gov/document/FDA-2019-P-1351-0001,
2 I would have preferred to also present to the Committee live at the meeting, but the
federal register notice gave only 11 days to learn of it and file the request for a public speaker slot. We
and many other stakeholders have complained repeatedly about the lack of notice given at every step of
the process, which is a disservice to us and to the Committee who deserves to have the input of those
with actual clinical experience about nominated ingredients. The inadequate timing has been ongoing
and appears intentionally designed to reduce public opposition. See for e.g., my correspondence in the
June 6, 2022 Briefing Package at 105-6.
The American Association of Naturopathic Physicians
300 New Jersey Avenue, NW, Suite 900 – Washington, DC 20001
Toll Free: 202-237-8150 – Fax: 202-237-8152
www.naturopathic.orgAANP Comments on Docket FDA-2021-N-0357 Regarding Glutathione
Alan Dumoff, JD, MSW
May 24, 2022
Page 2
My Encounter with Glutathione
Due to several inhalation mishaps that damaged my lungs, I spoke with about seven of my
client functional medicine and naturopathic doctors3 who all recommended that I nebulize glutathione.
Every doctor I talked with occasionally nebulized glutathione themselves as well as recommended it
for their patients, reporting considerable success. I have been nebulizing glutathione off and for the past
several years and found it to be profoundly helpful. My experience contrasts with FDA’s requirements
in a number of critical ways:
Functional Therapies Not Allowed. Note that I am not being treated for a specific “disease,” I
am using it to heal these injuries and improve lung function. It was not suggested to me by consulting a
diagnostic decision tree with a pathway through FDA’s narrow disease lens but because of its known,
direct therapeutic effects. Glutathione has been used for decades by physicians with a functional
approach to care4 to obtain benefits as an antioxidant, anti-inflammatory and detoxification agent and
for other therapeutic functional purposes. It may not be obvious to members of the Committee that
FDA’s position is that even demonstrated therapeutic effects are insufficient to allow use, but have
imposed a disease requirement without statutory basis and which serves no public health purpose. It
does allow the Agency to require proof supporting a disease indication even where use is generally as a
functional therapy. While we believe the disease standard has been met, FDA is engaged in
misdirection by focusing on this artificially imposed threshold.
3 Naturopathic medical schools provide equivalent foundational coursework as MD and
DO schools, including pharmacology, cardiology, neurology, radiology, obstetrics, gynecology,
immunology, dermatology, and pediatrics. Degrees are awarded after extensive classroom study,
clinical training and an extensive postdoctoral exam. ND training includes the prescription of clinical
doses of vitamins and herbs and safe administration via oral, topical, IM and IV routes. Currently, 27
states and territories license NDs to practice. In 9 of those states, NDs function as primary care
physicians with prescribing rights. Naturopathic physicians have an excellent safety record with
licensing boards and a low incidence of malpractice.
4 To ensure it is clear, functional physicians are fully trained and licensed medical doctors
whose practice focus and training is in an approach that considers metabolic, immune, and other
functional vectors in an effort to seek underlying causes of disease that are often highly individualized.
Their differential decisions about use of compounded ingredients includes consideration of the
therapeutic use of nutritional ingredients for their functional effects and are well-developed. See for e.g.
Gaby A. Nutritional Medicine, Fritz Perlberg Publishing (2011) (1326 pages); Werbach M., Moss J.,
Textbook of Nutritional Medicine, Third Line (1999) (740 pages); Katz D. Nutrition in Clinical
Practice: A Comprehensive, Evidence-Based Manual for the Practitioner (2nd Ed.) LMW (2008) (592
pages); Kligler B, Lee RA, Integrative Medicine: Principles for Practice, McGraw-Hill (2004) (700
pages); Rakel, D. Integrative Medicine (4th Ed.) (2017) (1152 pages). Naturopathic medicine also has a
strong evidence base exhibited in text books for that field, including Pizzorno J. et al. The Clinician’s
Handbook of Natural Medicine, Churchill Livingstone (3rd Ed. 2015) (1008 pages).

26 May 2022   APC amicus brief addresses ambiguity in FDA insanitary conditions guidance      “Insanitary conditions” are whatever FDA says they are. This is neither legal nor fair.   That’s the gist of APC’s argument in a “friend of the court” brief filed in U.S. District Court in New Jersey on May 13.   Funded by member contributions to the APC’s Legal Action Fund, the amicus brief was authorized in response to an urgent request from Wedgewood Pharmacy that APC support its filing for a temporary restraining order against FDA.    Wedgewood filed its papers seeking a TRO on May 5, 2022, only after FDA demanded that Wedgewood immediately recall all nonsterile products within their expiry period, gave the pharmacy only 24 hours to respond, and failed to provide the pharmacy any information supporting the need for such an extraordinary, broad recall. Wedgewood told the court it suspected that, without the TRO, FDA would move quickly to publish a news release impugning Wedgewood based on FDA’s unsubstantiated findings of “insanitary conditions” at the pharmacy.     In the TRO filing, Wedgewood and its lawyers argued that FDA had inspected the pharmacy and issued eight observations in a Form 483 related to vague notions of insanitary conditions, which focused on areas well outside the pharmacy’s compounding areas. Wedgewood further stated that none of the observations listed on the Form 483 FDA violated applicable USP standards.   APC’s amicus brief, approved by the Executive Committee*, focused solely on the lack of standards in FDA’s Insanitary Conditions GFI and FDA’s failure to promulgate any enforceable rules concerning the same.   APC engaged in the matter because we were—and remain—concerned about the significant implications on other APC-member compounding pharmacies if FDA continues to impose what appears to be the vague, subjective disciplinary standard suffered by Wedgewood. In particular, FDA derives its enforcement authority from a non-binding guidance document that contains not any objective standards, but instead relies on what appears to be a bunch of examples and the nebulous statement that “other conditions not described in the guidance may also be considered unsanitary.” How is a compounder to know what is in fact violative conduct?   In that vein, we argue in the amicus that a pharmacy “would have no basis to know under the plain meaning of the term ‘insanitary conditions’ or under the explanation set forth in the Insanitary Conditions Guidance that ‘observed personnel who moved rapidly in a sterile compounding area’ or who ‘was noted to have their safety glasses down on their nose’ would meet the standard for insanitary conditions.” Both of those were among FDA’s Form 483 observations against Wedgewood.   Last week the District Court denied Wedgewood’s request for a TRO. The judge said she could not issue a restraining order on an action that had not yet occurred—in this case, FDA’s publishing of a damning press release. But during oral argument, she also made clear that she expected FDA to work with Wedgewood to settle their difference and seemed to suggest she wanted that to occur without FDA publishing a news release that could unnecessarily damage Wedgewood’s reputation based on unsubstantiated or exaggerated claims of “insanitary conditions.”   While APC strongly supports the maintenance of sanitary workspaces where compounded drugs are prepared—it’s simply essential for assuring patient safety—there must be standards for what constitute “insanitary conditions,” and those standards need to be rooted in science and the law. Our amicus brief in this matter is the clearest elucidation of the flaws in FDA’s Insanitary Condition Guidance I’ve seen. I do urge you to read it.   APC is proud of our involvement in this matter. Just another way we’re looking out for you.    Best,

 

The FDA is reconvening their Pharmacy Compounding Advisory Board Committee (PCAC).  On the agenda for this meeting is compounded glutathione.  The agenda can be seen on the hyperlink below.  Practitioners and patients can comment only until the end of May 24th.  The American Association of Naturopathic Physicians (AANP)  have created an action alert link making it easy to comment.  Practitioners and patients should share how important compounded glutathione is to their practice and to their personal health. 

Here is the AANP action alert that is out regarding compounded glutathione. The FDA/PCAC request for comment docket on compounded glutathione is open until tomorrow, May 24th, for comment.

https://compounding.com/flaws-in-the-fdas-research?hsLang=en

https://a4pc.org/files/CCH2021_Pontikes-Handout.pdf

Check this link for updated news about compounding and specifically the use of bioidentical hormones: https://cbhrtcoalition.org/legal-and-political/

4164-01-P
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-D-0490]
Policy Regarding N-acetyl-L-cysteine: Draft Guidance for Industry; Availability
AGENCY: Food and Drug Administration, Health and Human Services (HHS).
ACTION: Notice of availability.
SUMMARY: The Food and Drug Administration (FDA or we) is announcing the availability of
a draft guidance for industry entitled “Policy Regarding N-acetyl-L-cysteine: Draft Guidance for
Industry.” The draft guidance, when finalized, will explain our intent to exercise enforcement
discretion with respect to the sale and distribution of certain products that contain N-acetyl-L-
cysteine (NAC) and are labeled as dietary supplements. This enforcement discretion policy
would apply to products that would be lawfully marketed dietary supplements if NAC were not
excluded from the definition of “dietary supplement” and that are not otherwise in violation of
the Federal Food, Drug, and Cosmetic Act (FD&C Act).
DATES: Submit either electronic or written comments on the draft guidance by [INSERT
DATE 30 DAYS AFTER DATE OF PUBLICATION IN THE FEDERAL REGISTER] to ensure
that we consider your comment on the draft guidance before we begin work on the final version
of the guidance.
ADDRESSES: You may submit comments on any guidance at any time as follows:
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Submit electronic comments in the following way:
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You may submit comments on any guidance at any time (see 21 CFR 10.115(g)(5)).
Submit written requests for single copies of the draft guidance to the Office of Dietary
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INFORMATION section for electronic access to the draft guidance.
FOR FURTHER INFORMATION CONTACT: Gerie Voss, Center for Food Safety and
Applied Nutrition (HFS-810), Food and Drug Administration, 5001 Campus Dr., College Park,
MD 20740, 240-620-9744; or Lauren Ferguson Baham, Center for Food Safety and AppliedNutrition, Office of Regulations and Policy (HFS-024), Food and Drug Administration, 5001
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SUPPLEMENTARY INFORMATION:
I. Background
We are announcing the availability of a draft guidance for industry entitled “Policy
Regarding N-acetyl-L-cysteine: Draft Guidance for Industry.” We are issuing the draft guidance
consistent with our good guidance practices regulation (21 CFR 10.115). The draft guidance,
when finalized, will represent the current thinking of FDA on this topic. It does not establish any
rights for any person and is not binding on FDA or the public. You can use an alternate
approach if it satisfies the requirements of the applicable statutes and regulations.
FDA has determined that, under section 201(ff)(3)(B)(i) of the FD&C Act (21 U.S.C.
321(ff)(3)(B)(i)), NAC is excluded from the dietary supplement definition because NAC was
approved as a new drug before it was marketed as a dietary supplement or as a food. FDA
received two citizen petitions requesting that we conclude that NAC is not excluded from the
definition of dietary supplement under section 201(ff)(3)(B) of the FD&C Act. On March 31,
2022, we denied this request.
In addition, one of the citizen petitions asked FDA “to recommend and support to the
Secretary of HHS” that he issue a regulation that would determine NAC to be lawful under the
FD&C Act. As we stated in our response to the citizen petitions, we have not yet reached a final
decision on this request, but we are considering initiating rulemaking under section 201(ff)(3)(B)
of the FD&C Act to permit the use of NAC in or as a dietary supplement (i.e., to provide by
regulation that NAC is not excluded from the definition of dietary supplement), and, if, among
other considerations, FDA does not identify safety-related concerns as we continue our review of
the available data and information, we are likely to propose a rule providing that NAC is not
excluded from the definition of dietary supplement. While our full safety review of NAC
remains ongoing, our initial review has not revealed safety concerns with respect to the use ofthis ingredient in or as a dietary supplement. In addition, NAC-containing products represented
as dietary supplements have been sold in the United States for more than 30 years, and
consumers continue to seek access to such products.
Accordingly, the draft guidance, if finalized, would state our intent to exercise
enforcement discretion with respect to the sale and distribution of certain products that contain
NAC and are labeled as dietary supplements. The enforcement discretion policy would apply to
products that would be lawfully marketed dietary supplements if NAC were not excluded from
the definition of “dietary supplement” and that are not otherwise in violation of the FD&C Act.
Unless we identify safety-related concerns during our ongoing review, FDA would intend to
exercise enforcement discretion until either of the following occurs: we complete notice-and-
comment rulemaking to allow the use of NAC in or as a dietary supplement (if we move forward
with such proceedings), or we deny the citizen petition’s request for rulemaking. Should we
determine that this enforcement discretion policy is no longer appropriate, we will notify
stakeholders by withdrawing or revising this guidance in accordance with 21 CFR 10.115.
II. Paperwork Reduction Act of 1995
FDA tentatively concludes that this draft guidance contains no collection of information..
Therefore, clearance by the Office of Management and Budget under the Paperwork Reduction
Act of 1995 is not required.
III. Electronic Access
Persons with access to the internet may obtain the draft guidance at
https://www.fda.gov/FoodGuidances, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or https://www.regulations.gov. Use the FDA website listed in the
previous sentence to find the most current version of the guidance.
Dated: April 15, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.[FR Doc. 2022-08560 Filed: 4/21/2022 8:45 am; Publication Date: 4/22/2022]

Special recognition to Michael Levine and the AANP for their work on this issue!