Francis Godwin, Director of the Office of Manufacturing Quality of the Office of Compliance at FDA’s Center for Drug Evaluation and Research provided useful information (presentation attached here) Tuesday at the GMP by the Sea Conference.  He talked about regulatory discretion being exercised for drug manufacturing facilities with serious compliance problems, about how firms should respond to FDA inspectional observations, and about an upcoming guidance that will be of interest to generic drug manufacturing firms that have received Warning Letters.

First, Mr. Godwin provided updated information on the presentation made the day before by another CDER official, Jennifer Maguire, the Director of the Office of Quality Surveillance within the Office of Pharmaceutical Quality at CDER,.  We summarized in a blog post yesterday  her comments about facilities with FDA inspections that had been classified as Official Action Indicated, the most serious classification for FDA inspections relating to current Good Manufacturing Practice compliance.  Mr. Godwin’s presentation made the same point, although with more data to back it up: so far this fiscal year (since October 1, 2022), the number of OAI inspections resulting in the exercise of regulatory discretion is unusually high.  Regulatory discretion, in this context, means basically that FDA has decided not to issue a Warning Letter, request a Regulatory Meeting, impose an Import Alert, or to take a more serious enforcement action.  There were 286 FDA GMP-related inspections of drug manufacturing facilities in this period with OAI classifications.  Of that number, 80 of the facilities were graced with FDA’s regulatory discretion (28%), 75 resulted in imposition of an import alert (26%), 66 resulted in Warning Letters (23%), and 62 prompted Regulatory Meetings (22%).

Mr. Godwin confirmed that the percentage of OAI facilities receiving regulatory discretion was unusually high, and stated that he believes (as we posited in the blogpost yesterday) that the higher percentage was due to COVID-related causes: there were more facilities making critically needed drugs, and the drug supply chain has not recovered from COVID shutdowns and delays, making shortages of important drugs much more likely.  FDA would not want to curtail supplies of vitally needed drugs by, for example, imposing an Import Alert.

Second, Mr. Godwin said he reads numerous responses to FDA Forms 483, the report that FDA issues at the end of a GMP inspection, and that it is critically important that the responses include a narrative summary of the major remedial actions that a company has made or intends to make, and discuss if a company contests a finding.  “Document dumps,” he said, are not helpful without the assistance of a narrative placing the documents in context.

Third, Mr. Godwin said that he expects FDA to issue soon a Guidance document that will address how generic drug manufacturers should request, and what they should present, at meetings with his office that will be held after the company receives a Warning Letter.  After his remarks, Mr. Godwin stated that the Guidance, and the necessity of FDA providing such a meeting is one of the commitments in the GDUFA III  Commitment Letter.

At the GMP by the Sea Conference ongoing in Cambridge, Maryland, a presentation was made by a representative of FDA’s Center for Drug Evaluation and Research that shows some interesting trends in enforcement.

Jennifer Maguire, the Director of the Office of Quality Surveillance within the Office of Pharmaceutical Quality at CDER, told attendees that there were 163 FDA inspections from the beginning of October 2022 to the end of March 2023 conducted at drug manufacturing facilities (excluding drug compounding facilities) that were classified as Official Action Indicated (OAI).  OAI is FDA’s classification for facilities it deems to be in an unacceptable state of compliance.

Of those, only about a quarter (26%) resulted in Warning Letters, less than a quarter (19%) resulted in imposition of import alerts (restricting or prohibiting imports into the United States of drugs from a specified facility), slightly more (24%) resulted in regulatory meetings with the agency, and the plurality (29%) resulted in FDA exercising “regulatory discretion,” which means a decision not to take enforcement action.  One inspection resulted in FDA’s securing a consent decree to restrict or shut down operations, and two resulted in an “untitled letter,” which is not available to the public on FDA’s website.

The large percentage of OAI inspections resulting in the exercise of regulatory discretion is unusually high.  Lest we grow too optimistic, though, industry should be aware that this-larger-than-historical number of what is a favorable disposition may not be a trend that will continue.  It is believed that many of the inspections conducted during this period were of facilities producing essential medicines, such as COVID-related medications, for which FDA did not want to create or exacerbate product shortages.

Other interesting datapoints from her presentation:

For the period from FY2000 to May of 2023, the percentages of drug manufacturing inspections with OAI classifications was lower in China (about 5% of inspections) than in the United States (8%).  Again, this is a trend that may not continue: not many FDA inspections were conducted in China during this period due to COVID travel restrictions, whereas U.S. facility inspections are approaching traditional levels.

FDA has created a list of essential medicines, and provided calculations of how many of the drugs were totally or partially manufactured in countries other than the United States.  FDA also looked at how may of the Active Pharmaceutical Ingredients for those drugs were manufactured overseas.

• Remarkably, only 11% of the finished drug products were totally manufactured overseas, although 92% of the API for those drugs was either totally or partially manufactured in foreign countries.
• Of those facilities manufacturing essential medicines deemed to be the product of complex manufacturing processes, 68% were located in the U.S., the European Union, or the United Kingdom. For those facilities manufacturing essential medicines deemed to be non-complex, 60% were located in these countries.

These figures confirm that, although the vast percentage of active ingredients of important pharmaceuticals comes from overseas, the actual manufacturing of finished dosage form drugs occurs in the United States or Europe (broadly defined to include the UK).

The GMP by the Sea conference, an annual conference sponsored by PharmaConference.com, is an annual event in Cambridge, Maryland, linked here.

On August 7, 2023, a little less than five months before the registration and listing of cosmetic product facilities and products becomes mandatory, FDA announced the availability of a draft guidance regarding the new facility registration and product listing requirements under the Modernization of Cosmetic Regulations Act of 2022 (MOCRA).  The information is presented in a Q&A format.

As reported previously, MOCRA includes a requirement for facility registration and listing of cosmetic products.  Specifically, with some exceptions, parties that own or operate a facility engaged in the manufacturing or processing of a cosmetic product for distribution in the United States must list their facilities.  In the case of contract manufacturers, either the contract manufacturer or the person whose name appears on the label (i.e., the “responsible person”) must register (only one single registration per facility is required, even if the same facility contract manufactures products for more than one responsible person).   As discussed in the draft guidance, before registration, a facility must have a facility registration number which will be the facility establishment identifier (FEI).  Companies that do not have a FEI can request one.

MOCRA also requires that the responsible person for each cosmetic product submit a product listing. A single listing submission may include multiple cosmetics with identical formulations or formulations that differ only in respect to colors, fragrances or flavors, or quantity of contents.   The cosmetic product listing information must include the facility registration number of each facility where the cosmetic product is manufactured or processed.  For facilities that are small businesses that may not have a facility registration number, the facility name/address may be submitted.  In addition to the mandatory information to be submitted (i.e., the facility registration number of each facility where the product is manufactured or processed, name and contact number of the responsible person, name of the cosmetic product, cosmetic category, ingredient listing, product listing number (if any) and type of submission), FDA requests submission of a list of optional information, including but not limited to parent company name (if applicable); type of business (manufacturer, packer, or distributor); image of the label; product webpage link.

The draft guidance describes the mandatory elements that must be included in the registration and listing.  For both the registration and listing, FDA describes optional information that FDA would like to get.  In addition, FDA requests that a party submitting the information, attest to the accuracy and veracity of the information submitted.”

FDA is developing an electronic portal for registration and listing submissions that will be available in October 2023.  On the same day that FDA issued the draft guidance, the Agency issued a request for (nine) volunteers to participate in a pilot program on the electronic registration and listing program.  Although FDA strongly encourages electronic registration, it is developing a paper form as an alternative to electronic registration.

FDA states that is intends to make relevant information from cosmetic product facility registration and listing available to the public to the extent permitted by law.  Under the law, FDA may not disclose the product listing number, registration number, and brand names under which cosmetic products are sold.

Comments on the draft guidance may be submitted until Sept. 7, 2023. (Instructions for submission of electronic and paper comments are included here).

On August 3rd, FDA issued 11 warning letters to foreign facilities registered as OTC drug manufacturers.  For each of these facilities, FDA did not conduct an on-site inspection of the facility prior to issuing the warning letter.  Instead, FDA issued a request for records pursuant to Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA).

Section 704(a)(4) was added to the FDCA by the Food and Drug Administration Safety and Innovation Action (FDASIA) in July 2012.  This section grants FDA the authority to request records regarding drug products remotely, without an on-site inspection:

Any records or other information that the Secretary may inspect under this section from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection, within a reasonable timeframe, within reasonable limits, and in a reasonable manner, and in either electronic or physical form, at the expense of such person. The Secretary’s request shall include a sufficient description of the records requested.

Remote review of records in lieu of an inspection is known as a “paper inspection” or, in FDA guidance, a “remote regulatory assessment.”

Of the 11 warning letters, 6 of the warning letters identified cGMP issues in the records reviewed (see, e.g., Warning Letter to Suhan Aerosol).  As a result of the cGMP issues identified, the 6 firms were placed on Import Alert 66-40, which requires detention of products from “a firm that is not operating in conformity with [cGMP].”  The other 5 warning letters identify the firm’s failure to furnish records after multiple records requests from FDA (see, e.g., Warning Letter to Daxal Cosmetics Private Limited).  These firms were placed on Import Alert 66-79, which applies to “foreign establishments refusing FDA inspection.”

Despite FDA having the authority to conduct paper inspections since the statutory provision was added to the FDCA by FDASIA in 2012, FDA did not issue a warning letter citing Section 704(a)(4) until January 2021.  FDA’s new use of Section 704(a)(4) starting in early 2021 was the result of FDA’s inability to conduct on-site inspections of foreign facilities during the height of the COVID-19 pandemic.  FDA has resumed on-site inspections of foreign facilities focused on current Good Manufacturing Practices (cGMP) but has continued issuing records requests under Section 704(a)(4), which spurred this latest round of warning letters.

In July 2022, FDA issued a draft guidance titled Conducting Remote Regulatory Assessments, which explains that FDA adapted its field operations to continue to provide regulatory oversight of manufacturing facilities during COVID-19, through the use of remote regulatory assessments (RRAs).  The draft guidance defines RRAs to include records requests under Section 704(a)(4).  As described in the draft guidance, FDA learned through its experience during the COVID-19 pandemic that there are “significant benefits in using RRAs” and FDA intends to continue to use RRAs “to assist FDA during and beyond the COVID-19 pandemic.”

The warning letters issued on August 3^rd demonstrate that FDA is indeed continuing to take advantage of its authority to conduct paper inspections, even when an on-site inspection may be feasible.  There are obvious efficiencies with remote review of records in conserving agency resources.  It allows FDA to identify manufacturing facilities with flawed cGMP procedures without traveling to a facility for a multi-day inspection.  It may also allow FDA to review the cGMP practices of more facilities than it would otherwise.

However, there is of course the possibility that a firm may have adequate procedures, but is not following those procedures at the facility, which could only be discovered in person.  As FDA continues to issue records requests under Section 704(a)(4) it will be interesting to see if FDA will allow remote records review to replace a routine on-site inspection, or if FDA will follow up on an adequate records review through an on-site inspection.

If a patient presents a paper prescription for a controlled substance to a pharmacy and the pharmacy cannot fill it, the patient can take that prescription to another pharmacy.  However, electronic prescriptions for controlled substances (“EPCS”), which a practitioner transmits directly to a pharmacy, do not allow the patient such an option.  Instead, the patient must request that the prescriber send a new prescription to a different pharmacy.  That is until August 28th when DEA’s final rule becomes effective.  DEA explained its chief reasons for amending its regulations to allow the transfer of EPCS for initial filling are to provide patients with the option of transferring to prevent treatment delays, reducing patient burden and stress, as well as minimizing opportunities for diversion.  Transfer of Electronic Prescriptions for Schedule II-V Controlled Substances Between Pharmacies for Initial Filling, 88 Fed. Reg. 48365, 48369 (July 27, 2023).  DEA also recognized the potential diversion if the prescriber transmits a new prescription to a different pharmacy and fails to cancel or void the original prescription.  Id. at 48366.

DEA has amended its regulations to allow, upon request from a patient, the transfer of an EPCS between retail pharmacies for initial filling on a one-time basis only.  Id. at 48379 (to be codified at 21 C.F.R. § 1306.08(e)).  Any authorized refills included on schedule III-V prescriptions transfer with the original prescription.  The pharmacy must transfer the EPCS in its electronic form and cannot convert it to another form (such as paper or facsimile) for transmission.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(1)).  The content and prescription information elements required by 21 C.F.R. § 1306.06 cannot be altered during the transmission.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(2)).  Two licensed pharmacists must directly communicate the transfer.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(3)).  The transfer of EPCS for initial dispensing is permissible only if allowable under existing State or other applicable law.  Id. (to be codified at 21 C.F.R. § 1306.08(g)).

Patients wishing to transfer EPCS to another pharmacy should confirm that the receiving pharmacy has the ability to fill the prescriptions before requesting the transfer.

The transferring pharmacist must update the EPCS prescription record to note the transfer.  That pharmacist must also update the prescription record with:

• Name, address, and DEA registration number of the pharmacy to which the prescription was transferred;
• Name of the pharmacist receiving the transfer;
• Name of the transferring pharmacist; and
• Date of the transfer. Id. (to be codified at 21 C.F.R. § 1306.08(f)(4)).

The receiving pharmacist must document:

• The word “transfer” to the electronic prescription record;
• Transferring pharmacy’s name, address, and DEA registration number;
• Name of the transferring pharmacist;
• Date of the transfer; and
• Name of the pharmacist receiving the transfer.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(5)).

The transferring or receiving pharmacy’s prescription processing software may, if capable, capture the required information from the EPCS and automatically populate the corresponding data fields documenting the transfer.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(6)).  The transferring or receiving pharmacist must ensure that the populated information is complete and accurate.  Id.

As with other required controlled substance records, electronic records documenting EPCS transfers must be maintained for two years from the transfer date by both the transferring and receiving pharmacies.  Id. at 48379-80 (to be codified at 21 C.F.R. § 1306.08(h)).  DEA’s final rule does not alter or revise any other prescription or electronic prescription requirements.

DEA’s allowing patients to request a pharmacy to transfer an EPCS for initial filling to another pharmacy not only provides flexibility when medication may be needed most, but it actually reduces the potential for diversion by a prescriber duplicating the prescription without canceling or voiding the original prescription.

Please sing to the tune of “Honesty,” by Billy Joel:

Nitrosamines, it’s such an ugly word,

In pharmaceuticals’ impurity.

Nitrosamines are hardly ever good,

Now FDA has issued policy.

Failure to detect nitrosamines, failure to notify FDA when nitrosamines appear in finished drug products, failure to identify impurities in drugs that may be nitrosamines, even having a deviation in pH of an Active Pharmaceutical Ingredient that might conceivably contribute to the formation of nitrosamines in a finished drug product.  All of these deviations discussed in FDA inspectional observations and Warning Letters have caused serious issues for manufacturers of APIs or finished drug products.

Now, just two weeks after we blogged on nitrosamines, and a week before a PharmaConference where we will talk about the importance of impurities in FDA enforcement, FDA has issued a final guidance, entitled, “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs).”  NDSRIs are a particular focus for FDA, because they are a nitrosamine subcategory that share structural similarity to drug API.

The Guidance, which provides details about nitrosamines and FDA’s experience regulating them, explicitly applies to all finished drug products (including Rx, OTC, and unauthorized drugs), to “prescription and OTC drug products in clinical development,” and to both API and drug manufacturers.  In other words, it’s a sweeping application across the industry.  An earlier FDA guidance, revised in 2021. urged manufacturers to conduct risk assessments for nitrosamines in APIs and drug products; (2) conduct confirmatory testing if risks are identified; and (3) report changes in formulation or manufacturing as required in approved and pending NDAs and ANDAs.  There were tables in each guidance that appear to be consistent where they overlap, but also include different nitrosamines/NDSRIs (FDA guidances are not generally binding law, but, rather, express FDA policy.)

The new final guidance, by its own terms, establishes “a recommended framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs.”  It further defines the AI as being “a level that approximates an increased cancer risk of one additional case in 100,000 people based on a conservative assumption of daily exposure to the impurity over a lifetime (70 years).”

The Guidance then goes on to categorize the types of NDRSIs and to suggest the appropriate acceptable intake limits for drugs, and sets a timetable for manufacturers – or those with pending applications – to review their drug products and take appropriate action.

This second half of this guidance beginning with the “Flowchart to Predict the Carcinogenic Potency Category of an NDSRI and Identify an Associated Recommended AI Limit” takes one back to basic organic chemistry and breaks down the key structural and electronic considerations into a step-by-step guide.  The substitution of the α-carbons and the electronic effects of the “Deactivating” or “Activating” groups yield tangible scores that one can apply to determine a “Potency Score” and therefore the recommended acceptable intake.  Perhaps most importantly, the guidance concludes with examples of how manufacturers would apply this framework to Nitroso compounds.

All drug manufacturers and API manufacturers would be well served to examine the guidance, and perform analysis suitable for their products, to determine whether further assessment is necessary.

The Center for Devices and Radiological Health (CDRH) offers learning opportunities for new and experienced CDRH staff through the Experiential Learning Program (ELP). Through ELP, CDRH staff visit sites that provide formal training and enhance understanding on topics such as how products are developed and how they fit into the larger healthcare system. Site visits can also provide the opportunity to engage with patients on various topics, such as prototyping, trial design and conduct, and product launch and understand the challenges related to quality systems development and management in the product life cycle.

The visits are intended purely to provide a training perspective, and not for CDRH staff to opine on any regulatory functions.

Participation is encouraged from:

• Companies
• Academia
• Clinical facilities
• Medical device incubators and accelerators
• Health insurers
• Health technology assessment groups
• Others, including previous participants in the ELP or the FDA’s other site visit programs.

One noticeable difference from years past is the option for virtual site visits. These allow CDRH to participate during times when the ability to travel is limited while expanding participation from CDRH staff.

Those interested in submitting a proposal to host CDRH staff should:

1.  Complete a Site Visit Request (Sample Site Visit Request).

a.  Ensure that proposals have only one Training Area of Interest.

b.  Include the Identifier Code with the Area of Interest.

2.  Complete a Site Visit Agenda (Sample Site Visit Agenda).

a.  Identify the site visit duration. (Most common are one- or two-day site visits.)

b.  Indicate ability to host a virtual site visit.

3.  Submit proposal documents by email to ELP Proposal Submissions by September 5, 2023 at 12 PM ET.

ELP Proposals will be selected based on a variety of factors such as applicable areas of interest, CDRH resource availability, and logistical considerations.

As a former participant, it was beneficial to me to engage with companies in person at their place of business and see the equipment used in manufacturing the medical devices that are reviewed by FDA. It was also helpful to hear first-hand the practical challenges companies navigate in bringing products to market. Companies may want to consider submitting a proposal so they can meet the CDRH staff who will be working with them on the review of their regulatory submissions. On the other hand, companies may not want to participate if they are not prepared to host FDA and answer questions, or do not meet one of the areas of interest identified on FDA’s webpage.

Anabolic steroids that include testosterone, methyltestosterone, nandrolone decanoate and oxandrolone are schedule III controlled substances with currently accepted medical uses in the U.S.  Other anabolic steroids are approved only for use in veterinary medicine.  Because anabolic steroids are also abused to enhance athletic performance and increase muscle strength, Congress has enacted three laws regulating anabolic steroids: the Anabolic Steroid Control Acts of 1990 and 2004, and the Designer Anabolic Steroid Control Act of 2014 (“DASCA”).  Congress felt that the laws prior to DASCA failed to sufficiently curtail the misuse of anabolic steroids.  So, through DASCA, Congress targeted those who would circumvent the Controlled Substances Act (“CSA”) by manufacturing anabolic steroids with slightly different chemical structures from those expressly controlled by the CSA but which are intended to cause the same potentially harmful effects.  Implementation of the Designer Anabolic Steroid Control Act of 2014, 88 Fed. Reg. 50,036 (Aug. 1, 2023).

DASCA amended the CSA by revising and adding specified substances to the definition of “anabolic steroid,” providing for the temporary and permanent scheduling of anabolic steroids and adding labeling requirements for products containing anabolic steroids.  DASCA became law, amending the CSA, on December 18, 2014.  The Drug Enforcement Administration (“DEA”) issued a final rule on August 1st whose sole purpose is to codify DASCA’s CSA amendments in DEA’s regulations, taking effect immediately and not requiring public comment because it “merely conforms the DEA’s regulations to the statutory amendments to the CSA that have already taken effect, and does not add additional requirements.”  Id.

Definition of “Anabolic Steroid”

To address exploitation of the earlier narrow statutory definition of “anabolic steroid,” DASCA controlled anabolic steroids by name that had emerged after 2004 under the CSA and expanded the definition of “anabolic steroid” to control such steroids that would emerge in the future.  Id. DASCA amended the CSA definition of “anabolic steroid” by adding 22 new substances to the prior list.  Id. at 50,037 codified at 21 C.F.R. § 1308.13(f).

DASCA expanded the definition of “anabolic steroid” to include a drug or hormonal substance chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids and dehydroepiandrosterone) that brings to 86 substances now listed in 21 C.F.R. § 1308.13(f).  Id. at 50,039 codified at 21 C.F.R. § 1300.01(b).

A drug or hormonal substance, other than estrogens, progestins, corticosteroids, and dehydroepiandrosterone not listed in 21 C.F.R. § 1308.13(f) and “is derived from, or has a chemical structure substantially similar” to an anabolic steroid in that provision is considered an anabolic steroid if:

• The drug or substance has been created or manufactured with the intent of producing a drug or other substance that either promotes muscle growth, or otherwise causes a pharmacological effect similar to that of testosterone; or
• The drug or substance has been, or is intended to be, marketed or otherwise promoted in any manner suggesting that consuming it will promote muscle growth or any other pharmacological effect similar to that of testosterone. Id. at 50,040 codified at 21 C.F.R. § 1300.01(b)(2)(i).

The definition excludes anabolic steroids intended for administration through implants to cattle or other nonhuman species that have been approved by the Secretary of Health and Human Services (“HHS”) for such administration.  Id. at 50,039-40 codified at 21 C.F.R. § 1300.01(b)(1)(i).  Also not considered to be a drug or hormonal substance for purposes of the new definition is an herb or other botanical; a concentrate, metabolite, or extract of, or a constituent isolated directly from an herb or other botanical that is a dietary supplement for purposes of the Federal Food, Drug, and Cosmetic Act (“FDCA”).  Id. at 50,040 codified at 21 C.F.R. § 1300.01(b)(2)(ii).

Administrative Scheduling

DASCA authorizes DEA to issue a temporary scheduling order adding a drug or substance to the list of anabolic steroids in schedule III for up to two years that can be extended six additional months if the agency finds that the drug or substance satisfies criteria as an anabolic steroid and will assist in preventing abuse or misuse of the substance.  Id. at 50,041 codified at 21 C.F.R. §§ 1308.50(a)-(b).  The temporary scheduling cannot take effect until 30 days after publication in the Federal Register.  Id. at 50,041 codified at 21 C.F.R. § 1308.50(b).  DEA must also transmit the notice of a proposed order to HHS and take into consideration comments from that agency.  Id. at 50,041 codified at 21 C.F.R. § 1308.50(c).  In addition, DASCA gave DEA authority to issue a permanent order adding a drug or substance to the definition of “anabolic steroid” if it satisfies the criteria for being considered an anabolic steroid.  Id. at 50,041 codified at 21 C.F.R. § 1308.50(f).

Labeling Requirements

DASCA also added a labeling requirement in the CSA to identify products containing anabolic steroids.  It is now unlawful to import, export, manufacture, distribute, dispense, or possess with intent to manufacture, distribute, or dispense an anabolic steroid or product containing an anabolic steroid, unless the product bears a label clearly identifying it as such by International Union of Pure and Applied Chemistry (“IUPAC”) nomenclature.  Id. at 50,040 codified at 21 C.F.R. § 1302.08(a).

DASCA exempts IUPAC labeling if the product is labeled under the FDCA or is the subject of an approved new drug application under 505(b) or (j) of the FDAC or is exempt as a new drug intended solely for investigational use and is being used solely for purposes of a clinical trial subject to a new drug application.  Id. at 50,040 codified at 21 C.F.R. § 1302.08(b).

Civil Fine Provisions

In addition, DASCA added civil fine provisions to the CSA of up to $500,000 for each instance an importer, exporter, manufacturer, or distributor, and up to $1,000 for each violation at the retail level, that fails to comply with labeling requirements.  21 U.S.C. §§ 842(c)(1)(C) and (D).  DEA may take failure to comply with labeling requirements into consideration when issuing or revoking a DEA registration.  Id. at 50,038.

****

Again, the anabolic steroid requirements have been in effect in the CSA since December 2014.  The final rule does not change the legal status of the anabolic steroids.  It amends and merely updates DEA regulations for consistency with DASCA’s amendments to the CSA.

President Barack Obama signed the Comprehensive Addiction and Recovery Act of 2016 (“CARA”) intended to reverse serious prescription drug abuse trend in the United States on July 22, 2016.  CARA amended the Controlled Substances Act (“CSA”) to enable physicians or patients to request pharmacists to partially fill prescriptions for schedule II substances including opioids and to allow remaining quantities to be filled up to 30 days after issuance of the prescription (up to 72 hours for emergency oral prescriptions).  With the amendment by CARA, the CSA allows for partial dispensing of schedule II prescriptions if not prohibited by state law, is requested by the patient or prescriber and the total quantity dispensed in partial fillings does not exceed the total quantity prescribed.  21 U.S.C. § 829(f)(1).

Over a year later in a December 22, 2017, Congress in a bipartisan letter noting that “[l]arge amounts of unused medications are a key contributor” to the nationwide opioid crisis and that between 67% and 92% of surgery patients “reported they had unused opioids remaining after the procedures,” urged the Drug Enforcement Administration (“DEA”) to quickly update its regulations on the partial filling of schedule II prescriptions.  Letter from Congress of the United States, to Robert Patterson, Acting Administrator, DEA (Dec. 21, 2017).  Three years after that letter, DEA proposed a rule to amend its regulations consistent with CARA on December 20, 2020.  Partial Filling of Prescriptions for Schedule II Controlled Substances, 85 Fed. Reg. 78,282 (Dec. 4, 2020).

Now, in July 2023, DEA has finally issued its final rule amending its regulations for partial filling of prescriptions for schedule II substances.  Partial Filling of Prescriptions for Schedule II Controlled Substances, 88 Fed. Reg. 46,983 (July 21, 2023).

Partial Filling of Schedule II Prescriptions Historically

Pharmacists generally have been able to partially fill prescriptions for most schedule III-V controlled substances and non-controlled substances but have been permitted to partially fill prescriptions for II substances only in very limited circumstances.  Pharmacists could partially fill a schedule II prescription if the pharmacy is unable to supply the full quantity of a written or emergency oral prescription.  21 C.F.R. § 1306.13(a).  In addition, a pharmacist could partially fill a schedule II prescription issued to patients in a Long Term Care Facility or who have a terminal medical illness diagnosis.  21 C.F.R. § 1306.13(b).

The Final Rule

a.  General Requirements

DEA’s final rule allows the partial filling of a prescription for a schedule II substance at the request of either the prescribing practitioner or a patient.  Consistent with CARA, a pharmacist may partially fill a prescription for a schedule II controlled substance if:

(1) Not prohibited by state law;

(2) The prescription is written and filled in accordance with the CSA, DEA regulations, and state law;

(3) Partial filling is requested by the patient, by a person acting on behalf of the patient (a caregiver of an adult patient authorized in a medical power of attorney or a parent or legal guardian of a minor patient), or by the practitioner who wrote the prescription; and

(4) The total quantity dispensed in all partial fillings does not exceed the total quantity prescribed.  Id. at 47,001-02 (codified at 21 C.F.R. § 1306.13(b)(1)).

b.  Time Limits

If all of these conditions are met, remaining portions of a partially filled schedule II prescription, if filled, must be filled not later than 30 days after the date the prescription is written.  However, the remaining portions of a partially filled emergency oral prescription for a schedule II controlled substance, if filled, must be filled not later than 72 hours after the prescription is issued.  Id. at 47,002 (codified at 21 C.F.R. § 1306.13(b)(2)).

c.  Practitioner’s Partial Fill Request

A practitioner issuing a schedule II prescription who wants it to be partially filled must specify the quantity to be dispensed in each partial filling on the face of a written prescription, in the written record of an emergency oral prescription, or in the record of an electronic prescription.  After consulting with a pharmacist, a practitioner may also authorize a partial fill after the date the prescription was initially issued but the prescription cannot be filled later than 30 days after it was written.  The pharmacist must note the subsequent request.  All required information, except authorization for partial filling at a later date, must be included on the prescription with all other required elements at the time the practitioner signs the prescription.  For an emergency oral prescription, the prescribing practitioner must communicate the information to the pharmacist during the oral communication.  Id. (codified at 21 C.F.R. § 1306.13(b)(3)).

d.  Patient Request

A patient may also request that their prescription for a schedule II substance be partially filled.  A caregiver named in an adult patient’s medical power of attorney or a parent/legal guardian of a patient who is a minor under age 18, may also request that a prescription be partially filled.  If a practitioner has requested partial filling of a prescription, neither the patient nor one acting on behalf of a patient may request partial filling in an amount greater than what has been requested by the practitioner.  A request by or on behalf of a patient may be made in person; in writing if signed by the patient, caregiver, or parent/legal guardian; or by a phone call to the pharmacist from the patient, caregiver, or the parent/legal guardian.  Id. (codified at 21 C.F.R. § 1306.13(b)(4)).

e.  Recording Required Information

(1)  At the Request of a Prescriber

The pharmacist, upon partially filling a prescription at the request of the prescribing practitioner when the prescriber issued the prescription, must note the quantity dispensed on the face of the written prescription or in the pharmacy’s electronic records, in the written record or the pharmacy’s electronic records of the emergency oral prescription, or in the record of the electronic prescription.  When the pharmacist partially fills a prescription, after the prescriber has conveyed the request during consultation with a pharmacist, the pharmacist must note: “Authorized by Practitioner to Partial Fill,” practitioner’s name, discussion date and time, with the pharmacist’s initials.

In addition, for each partial filling whether requested by the prescriber on the prescription or during consultation with the pharmacist, the pharmacy must maintain a dispensing record of each dispensing date, name or initials of the individual dispensing, controlled substance name and dosage form, date filled, and quantity dispensed.  For electronic prescriptions, the quantity dispensed, date dispensed, and the dispenser must be linked to each electronic prescription record.  Id. (codified at 21 C.F.R. § 1306.13(b)(5)(i)).

(2)  Record at the Request of a Patient

For partially filling a prescription at the request of a patient or by a caregiver or parent/legal guardian, the pharmacist must note on the face of the written prescription or in the pharmacy’s electronic records, in the written record or the pharmacy’s electronic records of the emergency oral prescription, or in the record of the electronic prescription: “The [patient, parent or legal guardian of a minor patient, or caregiver of an adult patient named in a medical power of attorney] requested partial fill on [date such request was made]” and the quantity dispensed.

In addition, for each partial filling, the pharmacy must maintain a record that includes the date of each dispensing, the name or initials of the individual who dispensed the substance, controlled substance name and dosage form and date filled.  For electronic prescriptions, the quantity dispensed, date dispensed, and the dispenser must be linked to each electronic prescription record.  Id. (codified at 21 C.F.R. § 1306.13(b)(5)(ii)).

Effective Date

The final rule is effective on August 21, 2023, over seven years after CARA became law, five and a half years after the congressional letter urging DEA to quickly update its regulations and more than two and a half years after the proposed rule.

We need to talk about nitrosamines.  Recent industry comments submitted to FDA and new, international efforts against these nefarious, potentially carcinogenic organic compounds have the shifting state of regulation here back in the news.

What are nitrosamines?

Nitrosamines are chemicals that can form during drug manufacturing, known by their scientific names as N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA).  N-nitrosamine drug substance-related impurities (NDSRIs) are a pernicious form of nitrosamines that possess structural similarity to active pharmaceutical ingredients (API).

In addition to human drugs, processed foods that contain nitrates and nitrites such as cured meats and alcoholic beverages may contain nitrosamines.  OTC products are also susceptible; testing has revealed nitrosamines in heartburn remedies containing ranitidine.

The evolving upswing in NDSRI regulation is due to their link to cancer.  According to several studies, nitrosamines are a potentially potent carcinogen, depending on the length and depth of exposure.

What is FDA doing about NDRSIs?

The canary in the coal mine for nitrosamines was their 2018 appearance in blood pressure medications called sartans.  That discovery set off a global response, that included a series of recalls, a number of FDA-issued guidances, public advisements, mitigation strategies, and warnings, and generally created the current regulatory focus that CDER Director Patricia Cavazzoni has recently called a priority for CDER.

Aside from its publications, FDA is continuing to investigate the presence of NDSRIs in drug products, which may lead to more inspections or, at least, heightened expectations for industry.  The Agency is trying to meet manufacturers a point where testing standards on how to identify and control NDSRIs become more standardized.  Yet, currently, how the Agency plans to handle nitrosamines is unclear, which has led to the delay in approval of many drugs with no path forward for many of these companies.

As FDA and industry continue to grow their respective understandings about NDSRIs, more of them are turning up.  In May, FDA published a Federal Register request for “collaborative efforts to develop NDSRI data,” and said that as companies are implementing risk assessments recommended in FDA’s 2020 Nitrosamine Guidance, the Agency has unsurprisingly “received an increasing number of reports of NDSRIs that had formed in drug products across multiple drug classes.”  And FDA has had numerous with meetings with individual stakeholders seeking a better understanding of their approach to nitrosamines.  Seek, and ye shall find, so FDA hopes.

Upcoming Deadlines and New International Guidances

Responses to the May 2023 request for comments were due to FDA in early July, as FDA originally hoped that industry would collectively detail its best practices by October 1, 2023.  However, discovering NDSRI-producing gaps in manufacture is so tricky, FDA is considering giving industry an extension on its homework project.  When asked in the Federal Register Notice if a one-year extension would be useful, the response was a resounding “yes!”  Respondents also asked FDA to align its standards to the emerging new guidances and ongoing global efforts to root out NDSRIs.  In addition to the FDA’s efforts, agencies in the E.U., Canada, Australia, and Malaysia have also recently updated their policies and recommendations.

The global search for nitrosamines is rapidly becoming a complex game of Three-Dimensional Chess, as international regulators try to work together to find solutions, walking hand-in-hand with the industry they must all oversee.  Meanwhile, manufacturers are on the hunt to find their quarry before their customers do it for them.  We’ll report back as this complex regulatory structure continues to take shape.

Neither Jazz Pharmaceuticals nor Avadel CNS Pharmaceuticals has taken the battle of sodium oxybate—a drug approved to treat narcolepsy—lying down.  After suing each other in patent litigation and Avadel’s suit against FDA challenging the Agency’s authority to compel patent certifications, it’s Jazz’s turn to sue FDA.  This time, rather than use codes and patent certifications, the fight is over orphan drug exclusivity (“ODE”), with Jazz challenging FDA’s clinical superiority decision concerning sodium oxybate in the treatment of narcolepsy.  Specifically, FDA determined that Avadel’s Lumryz can “break” Jazz’s ODE because it is “clinically superior” based on Lumryz’s “major contribution to patient care,” rendering it not “the same drug” under the Orphan Drug Act.  With that decision, Jazz lost its ODE, allowing Avadel’s sodium oxybate product to compete with Jazz’s long before the expiration of the ODE covering Jazz’s most recent product, Xywav, in 2027.

Approximately six weeks after FDA approved Lumryz and issued its clinical superiority decision, Jazz filed a Complaint against FDA in the District Court of D.C. asking the Court to set aside FDA’s approval of Lumryz, alleging that FDA did not have statutory authority to use clinical superiority to break ODE and that FDA’s approval of Lumryz was arbitrary and capricious.  Like in the multitude of Orphan Drug Act cases preceding this one, Jazz alleges that FDA’s authority under the Orphan Drug Act was limited by the statutory language.  Its main argument is that Congress included only two exceptions to FDA’s restriction barring FDA from granting new approvals during the ODE period: the inability to provide sufficient quantities of a drug and consent from the ODE holder.  Though the Orphan Drug Act (now) includes a clinical superiority clause, Jazz argues that it is not a third exception to ODE.  Jazz also argues that, notwithstanding the language that instructs FDA to promulgate regulations implementing the clinical superiority provisions at 21 U.S.C. § 360cc(c), the statute does not permit FDA to promulgate regulations to use clinical superiority to break ODE.

Taking another stab at the plain language of the statute, Jazz argues that FDA does not have the authority to interpret the term “same drug” in its implementing regulations, as the term is not ambiguous.  Specifically, Jazz notes that the clinical superiority provisions in the Orphan Drug Act “does not authorize FDA to use a determination of clinical superiority as a basis to find that two drugs are not ‘the same drug’ for purposes of [ODE].”   In other words, Jazz states, the “‘different drug’ fiction is the linchpin of OOPD’s [ODE] analysis,” but the distinction between “same drug” based on clinical superiority is “inconsistent with the statute. . . .”

More specific to the facts of this case than the governing statute, Jazz argues that OOPD’s determination that Lumryz is clinically superior to Xywav is inconsistent with FDA’s regulations.  Essentially, Jazz argues that FDA’s determination is based on “greater efficacy,” which is not supported by the types of evidence FDA requires for such a determination—namely, head-to-head comparative studies.  Though FDA framed its clinical superiority decision as a Major Contribution to Patient Care (“MC-to-PC”) superiority finding, Jazz believes that it is actually a greater efficacy argument in disguise.  Because the premise of FDA’s determination—that not needing to awaken to take a second dose will provide medical benefits to narcolepsy patients by improving their sleep architecture and reducing disrupted or fragmented sleep—it must be a comparative effectiveness finding.  And, because comparative effectiveness claims must be supported by substantial evidence—one or more adequate and well-controlled clinical trials—FDA’s decision cannot stand as Avadel never conducted a comparative clinical trial of Xywav and Lumryz.  Thus, Jazz argues, there is no evidence that Lumryz is more effective than Xywav.

Perhaps the most notable assertion is that FDA deviated from Agency policy with respect to clinical superiority in determining that a drug need not be comparable in safety to break ODE on efficacy or MC-to-PC grounds.  In the ODE determination, FDA explained that “one drug can demonstrate a [MC-to-PC] over a previously approved drug even if the drug is not as effective or safe in every respect as the previously approved drug.”  Jazz believes that FDA precedent precludes that position and thus FDA departed from established policy, which FDA denied ever existed.  Jazz, however, cites to the preamble to the 2011 revised implementing regulations for the Orphan Drug Act, which states that MC-to-PC is a narrow category that is applicable and “meaningful only when the subsequent drug [product] provides safety or effectiveness comparable to the approved drug.”  Thus, Jazz contends that FDA has had a longstanding policy that comparable safety is necessary for an MC-to-PC clinical superiority finding.  Jazz points to several other examples of such a requirement, including Procysbi (the brief states that OOPD “observed that an ‘[i]nherent’ part of a major contribution to patient care finding was a threshold requirement that the new drug ‘would maintain a similar or improved adverse event profile and similar efficacy’”) and Ravicti (which, the brief states, FDA rejected the MC-to-PC request “because there was ‘a lack of objective evidence to support [the sponsor’s] claim that [Ravicti] would have comparable safety and effectiveness profiles as those of [the existing phenylbutyrate products].’”

Jazz also asserts that FDA failed to disclose or explain three prior memos in the Lumryz administrative record that found that Lumryz does not provide a MC-to-PC.  In rejecting Avadel’s argument for Priority Review, Jazz explains that FDA must have determined that Lumryz did not represent a “significant improvement” over existing therapies, including Xywav, and thus the clinical superiority determination conflicts with the Priority Review determination.  Jazz argues, essentially, that the change in position was the product of a pressure campaign within the Agency.  But rather than disclose these conflicting analyses, Jazz contends that FDA “conceal[ed] the existence” of these prior determinations.

Finally, Jazz argues that the ODE determination was arbitrary and capricious and an abuse of discretion because FDA ignored relevant scientific considerations.  FDA did not seek input from Jazz or Avadel, and neither had an opportunity to “comment on FDA’s thinking because FDA did not share it.”  Consequently, FDA made its determination without informed comments from the affected stakeholder, which Jazz says is “an indispensable feature of well-reasoned agency decisionmaking.”  The record also does not reflect consultation with the requisite experts, and FDA ignored some of the risks associated with elevated sodium intake, which is precisely the benefit provided by Xywav.  Additionally, Jazz says, FDA exaggerated the importance of once-nightly dosing because the idea that Lumryz allows narcolepsy patients to achieve “normal” sleep is scientifically baseless and unsupported.

Avadel has intervened as a Defendant, and neither FDA nor Avadel has yet to respond to the Complaint.  Our best guess is that FDA will argue that it has broad authority to interpret the provisions of the Orphan Drug Act and interpret “clinical superiority” and “same drug” as it sees fit.  Though FDA has a losing streak when it comes to the Orphan Drug Act, this case is a bit of an uphill battle for Jazz because Congress did include a clinical superiority provision in the Orphan Drug Act as of 2017, and FDA has broad discretion to categorize the basis of its clinical superiority decisions (i.e. greater efficacy, greater safety, or MC-to-PC), and even wider discretion to make MC-to-PC determinations, “which are evaluated on a case-by-case basis for each drug product.”  Such discretion is typically carte blanche for FDA in these types of cases, but again FDA’s track record with the Orphan Drug Act is pretty bleak.  We will keep on watching, as this case is one that might keep us up at night.

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The Office of Pharmaceutical Quality (OPQ), located within FDA’s Center for Drug Evaluation and Research (CDER), uses global inspection, surveillance, policy, and research activities to set quality standards for drugs.  Among its top priorities, OPQ’s Director Mike Kopcha has recently said that OPQ is focused on quality problems that contribute to drug shortages.

Consistent with that initiative, OPQ recently issued its 2022 Annual Report on the State of Pharmaceutical Quality.  The report reiterated a commitment to maintain the supply chain and provides more context about how OPQ—and FDA, more generally—are approaching quality and enforcement as we continue to hurtle past the COVID-19 public health emergency (PHE).

Here’s a breakdown of some of the more interesting highlights, statistics and graphics from the FY 2022 report.

Geography of Manufacturing Sites

OPQ reports that as of October 2022, CDER’s manufacturing site catalog listed 4,814 facilities, a 12% increase over 2018.  Forty percent of those sites are in what CDER terms the “No Application” sector, meaning that those sites make over the counter (OTC) products, unapproved drugs, and homeopathic products, all sold without premarket approvals.  That leaves 60% that manufacture at least one application product.  Those include biological products licensed under Biologics License Applications (BLAs), approved drugs under New Drug Applications (NDAs), and generic products under approved Abbreviated New Drug Applications (ANDAs).

As one might expect, the lion’s share of the registered facilities—over 2,000 of the total—are located here in the U.S.  But the Report helps emphasize the global challenges FDA faces trying to ensure quality.  After the U.S., the most prominent site for facilities was India, with over 600 sites.  China was third with over 430 sites, and after that, several countries in Europe and in Asia each had over a hundred catalog sites, including Germany, Canada, Italy, France, Japan, the U.K., and South Korea.

Table: Inventory Shift Over FY2018-FY2022 for Countries (Greater Than 50 Sites)

Drug Products

In addition to a catalog of manufacturing sites, OPQ reports that CDER also keeps a drug product catalog that contains over 140,000 entries.  Of those, a whopping 123,000 are non-application products that have a unique national drug code number, leaving around 17,000 products covered under BLAs, NDAs, and ANDAs.  For these covered products, voluntary reports to MedWatch increased by seven percent for 2022, but other monitoring such as Field Alert Reports, Consumer Complaints, and Biological Product Deviation Reports showed declines in reporting.  OPQ attributes that in part to the decrease in the use of injectable products as the PHE waned.  The PHE also had a dramatic effect on import alerts.  FDA issued 28 quality-related import alerts in 2022, and most of those 28 alerts were for hand sanitizers that contained impurities or had other defects.

Recalls

Recalls hit a five-year peak in 2022.  OPQ reported that 166 catalog sites generated 912 recalls.  Four specific kinds of events comprised over a third of the 900+ recalls.  Temperature problems were the primary leaders, as the leading event was temperature abuse at 130 recalls, followed by 100 recalls related to products held outside appropriate storage temperature conditions.  CGMP deviations caused 56 recalls, and excipient manufacturers performed 51 recalls due to contamination.

Warning Letters

Non-sterile, non-application products received most warning letters issued in 2022, according to OPQ.  FDA issued 72 CGMP-related warning letters to pharmaceutical manufacturing sites, and over two-thirds of those went to makers of non-application products.  That number is notable because those sites comprised only 30% of inspections.  Again, the effects of the PHE lingered in this area, as FDA targeted hand sanitizer manufacturers with 31 of those 72 letters.  The top-five CGMP issues in 2022 were related to 1) quality control units, 2) production record review/investigations, 3) written procedures/deviations, 4) equipment cleaning and maintenance, and 5) testing and release procedures.

Sampling

While the 2022 Report does not specify what specific circumstances might prompt FDA to take samples for testing, of those that FDA collected, 892 of 1,552 samples—57%–tested at FDA laboratories were out of specification or non-compliant.  FDA’s PHE-focused testing found more troubles with sanitizers, as all the non-compliant COVID tests came from hand sanitizer products that were either subpotent or contaminated with impurities. 2022 marked the fifth straight year that FDA labs found an increasing level of noncompliance.

Table: Laboratory Sample Compliance Rates by Fiscal Year

Conclusions

OPQ faces increasingly global challenges as it seeks to protect the drug supply chain.  Rest assured that 2023 will see FDA continue to direct resources away from the PHE and into other quality initiatives on an international scale.

One of the most important questions FDA has to answer is whether a given product is appropriately characterized as a drug, biologic, device, food, cosmetic, or something entirely different.  As we have explained before, that distinction is critical to assigning a particular product to the appropriate regulatory scheme.  While it is exceedingly obvious that some products, like eyeshadow for example, are cosmetics, or a pacemaker is a device, it can get thorny where the distinction is based on a very fine line—like the number of amino acids in a given active ingredient.  That line becomes even more blurred where it’s not entirely obvious what constitutes the active ingredient.  And, like it has before, the District Court of D.C. recently grappled with this very question in Ipsen v. Becerra.

To set the stage for this case, we need to go back to March 2020, when a new definition of “biological product” threw the world of protein products into a tizzy.  As a result of the Biologics Price Competition and Innovation Act (BPCIA) passed in 2010, the definition of a “biological product” expanded to include “proteins.”  FDA further defined the term “protein” so that it includes any peptide product that has an amino acid sequence greater than 40 amino acids.  FDA also published a list of products anticipated to “transition” from a drug approved under an NDA (FDCA § 505) to a biological product deemed approved under a BLA (PHS Act § 351), and, in March 2020, products meeting the definition of “protein” officially transitioned to BLAs.

But, as is inevitable, there were some disputes about whether certain products should have transitioned, including several that resulted in litigation against FDA for continuing to regulate given products as drugs rather than biologics.  In one such lawsuit, Ipsen sued FDA arguing that the Agency’s decision to regulate its Somatuline Depot (lanreotide acetate) product as a drug rather than a biological product was “arbitrary, capricious, an abuse of discretion, and contrary to law.”  More specifically, Ipsen argued that Somatuline Depot is a “protein,” and therefore, pursuant to the March 2020 transition, should be regulated a biologic rather than a small molecule drug.

Approved in 2007 for the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy, with several indications added in the subsequent years, Somatuline Depot is a synthetic octapeptide available as ready-to-use prefilled syringes for deep subcutaneous injection.  Importantly, as an octapeptide, Somatuiline Depot is a “protein” but consists of only eight amino acids linked in a polypeptide chain.  However, Ipsen argued, Somatuline still meets FDA’s definition of a protein—more than 40 amino acids—because it contains multiple copies of its active ingredient that are linked together “in a manner that occurs in nature” to form a “nanotube” greater than 40 amino acids long.  Should the nanotube not constitute a biologic, Ipsen also argued that Somatuline Depot is at least “analogous” to a protein under the statute.   Thus, Ipsen asked the Court to direct FDA to transition the NDA to a deemed BLA.

FDA, on the other hand, argued that the finished product form—i.e., the nanotube—is irrelevant, as it is the “active ingredient” that matters for purposes of classifying the product as a drug or biologic.  Thus, FDA’s position is that a drug is a “protein” only if its “active ingredient” is composed of at least 40 amino acids.  That is not Somatuline Depot, which has only eight amino acids, and thus Somatuline Depot is not a biologic.  FDA also took the position that Somatuline Depot is not “analogous” to a protein because “it would not be appropriate to interpret the statutory term . . . in a way that would include amino acid polymers that are specifically excluded by the interpretation of the term ‘protein’ set forth in FDA’s Biological Product Definition Final Rule.”

As in most cases, the Court first addressed standing.  In one of the most plainly stated declarations we’ve seen in an FDA APA case, the Court clearly stated the principle of competitor standing.  In other words, the Court found that “Ipsen has sufficiently shown that it suffered a competitive injury because the FDA’s decision to regulate Somatuline Depot as a drug, rather than a biologic, allowed InvaGen to compete with Ipsen using the Drug Act’s § 505(b)(2) pathway. That option would not have been available to InvaGen had the FDA instead determined that Somatuline Depot and InvaGen’s product were biological products.”  Because FDA’s refusal to regulate Somatuline Depot as a biologic was the “but-for” cause of Ipsen’s competitive injury, and because “that injury flowed directly and inextricably from the FDA’s decision to regulate Ipsen under the [FDCA],” the Court found a causal nexus between FDA’s action and Ipsen’s competitive injury.  Thus, the threat of competition is enough to confer standing.

While Ipsen had standing, however, the Court pretty clearly found that FDA’s determination that Somatuline Depot is not a biologic was consistent with the regulation’s plain language and reflects rational decision making.  Though Ipsen argued that FDA should look at the finished drug product—the nanotube with far more than 40 amino acids—rather than the substance with only eight amino acids to assess whether the product is a drug or a biologic, the Court explained that “[n]either the statute nor the regulatory definition of a ‘protein’ requires the FDA to consider the size of the active ingredient as it appears in the final drug product, rather than standing alone” (emphasis in the original).  Instead, FDA’s decision to discern the active ingredient based on what “confers [its] pharmacologic activity” and thus FDA’s decision to analyze just the lanreotide acetate rather than the nanotubes “was unambiguously correct”—and even if it weren’t, the Court stated it would “defer to the FDA’s interpretation as reasonable” because it falls within FDA’s area of special expertise.   Ipsen’s alternative argument—that Somatuline Depot is “analogous” to a protein—was also rejected by the Court.  Thus, as expected the Court deferred to FDA, and left the determination as to whether a product is a drug or a protein to the active ingredient rather than the finished drug product.

Ipsen recently appealed this decision to the D.C. Circuit.  No briefs have been filed yet, with the initial submissions due the end of July.  The D.C. Circuit has previously addressed questions of drug versus device, finding against the Agency based on the plain language of the statute, so this is not entirely unfamiliar territory.  We’ll be watching to see what happens next.

It takes a significant amount of time, cost, and effort to prepare a premarket notification 510(k) submission.  But that is only the beginning.  After a firm submits a 510(k) to FDA, FDA will request still more information after a first-pass review.  According to the 2^nd Quarter FY2023 MDUFA V Performance Report, FDA issued a request for additional information (AI request) on the first FDA review cycle for 63% to 68% of 510(k)s submitted in FY2018 to FY2022.  In this blog post, we will first briefly outline the procedural steps in the 510(k) review process for medical devices.  We will then present an effective strategy to address FDA’s AI request in a timely manner.

Understanding the Traditional 510(k) Review Timeline

There are three types of Premarket Notification 510(k)s: Traditional, Special, and Abbreviated.  The most common type is the Traditional 510(k), therefore this section summarizes the timeline of the FDA review process for a Traditional 510(k).  However, the strategy of addressing the AI request presented in the next section of this blog post applies to all three types of 510(k)s.  Table 1 below shows the 510(k) submission process based on the MDUFA III Performance Goals.

Table 1. Traditional 510(k) Submission Process.

FDA aims to make the MDUFA Decision (i.e., SE or NSE decision) for 95% of 510(k)s by FDA Day 90 to achieve the performance goals under MDUFA V.  A best-case scenario for a firm would be that FDA does not place the submission on hold and clears it within 90 total calendar days (or less) to reach the SE decision.  However, the reality is usually different.  The 2^nd Quarter FY2023 MDUFA V Performance Report shows that 63% to 68% of 510(k)s submitted over the past five years received an AI request.  As demonstrated by the statistics over the past five years (Table 2), the average number of Total Days (FDA Days + Industry Days) ranged from 127 to 159 calendar days.

Table 2. 510(k) Time to MDUFA IV Decision. Note that days are in calendar days.

When a firm submits a Traditional 510(k), FDA first performs the acceptance review to determine whether a submission is administratively complete, or passes the technical screening for an electronic submission submitted using the eSTAR.  If the submission passes the acceptance review, the firm will receive the first good news from FDA via email that the submission has been accepted for substantive review.  In this case, the FDA clock start date is determined as the date of receiving the submission by the Document Control Center (DCC).  Note that the FDA clock uses calendar days.

FDA then conducts a substantive review.  To achieve the 510(k) performance goals under MDUFA V, FDA aims to make the Substantive Interaction (SI) decision by Day 60 for 95% of 510(k) submissions.  The SI communication could be great news for the firm if FDA notifies that it will continue to resolve any outstanding deficiencies via Interactive Review.  In this case, the FDA’s clock continues to forward without placing the submission on hold.  FDA may issue “real-time” requests by sending an email to the firm with a list of relatively minor questions to resolve.  In such email correspondence(s), FDA may indicate the response due date (usually very tight timelines) and the firm may provide its response by sending an email to the FDA lead reviewer by the indicated response due date.

If FDA issues an AI letter, it could be stressful news for the firm and a very different scenario will play out.  In this case, FDA’s email includes a PDF attachment that lists deficiencies that FDA identified in the submission.  There are two types of deficiencies: major and minor.  If major deficiencies are not adequately resolved, they may preclude a favorable decision on the 510(k).  Minor deficiencies can be resolved in a straightforward manner, but they need to be addressed to meet regulatory requirements or to prevent potential misbranding or adulteration.  When FDA issues an AI request, it places the submission on hold and the FDA clock stops.  The firm has a maximum of 180 calendar days to respond.  The CDRH Portal will highlight the response due date.

The stakes are high.  The firm has a maximum of 180 calendar days to respond, or FDA will treat the 510(k) as terminated.  That deadline seems generous, but it can come quickly if the firm needs to engage with FDA to further clarify the deficiencies, receive feedback on the plan to address the deficiencies, or the firm needs to perform additional testing to adequately respond.  All of these activities must be completed within the 180-day timeframe.  Worse, the firm only has one bite of the apple.  The AI response package must respond completely to all parts of the deficiencies and include all information needed to address the deficiencies; in other words, a firm cannot submit a partially completed response package and plan to submit another AI response package at a later date to address remaining deficiencies.

If the response to an AI request does not successfully address all deficiencies, FDA will issue an order declaring a device not substantially equivalent (NSE) to a legally marketed predicate device (NSE letter).  At this point, if the firm wishes to pursue clearance for its device, it has two options: it may either request supervisory review (i.e., an administrative appeal) under 21 CFR 10.75 or submit a new 510(k) application, which will be reviewed within a new 90-day timeframe.  It is crucial, therefore, to develop a comprehensive response strategy as soon as possible after receiving an AI request.  In the next section of this blog post, we will explore effective approaches to addressing 510(k) AI request to optimize the chances of success.

Comprehensive Analysis of FDA Deficiencies

What is FDA’s guiding principle for generating deficiencies?  The Least Burdensome Provisions, amended by the Food and Drug Administration Safety and Innovation Act (FDASIA) and the 21st Century Cures Act, provide the following principle of generating deficiencies: “Whenever the Secretary requests information to demonstrate that devices with differing technological characteristics are substantially equivalent, the Secretary shall only request information that is necessary to making substantial equivalence determinations. In making such request, the Secretary shall consider the least burdensome means of demonstrating substantial equivalence and request information accordingly.” Federal Food, Drug, and Cosmetic Act, Section 513(i)(1)(D)(i).

Per FDA’s guidance documents, Developing and Responding to Deficiencies in Accordance with the Least Burdensome Provisions, each FDA deficiency should include the following four elements: (1) what was submitted, (2) identification of a specific issue or concern, (3) statement of basis for the deficiency, and (4) explicit request for the additional information needed.  We suggest a firm thoroughly review and analyze the AI letter to understand the FDA’s rationale behind the deficiencies and the FDA’s “ask.”

These AI requests often address complicated scientific scenarios in which a submitter has already provided some information, but FDA is not completely satisfied.  Under the guidance, the AI request must summarize the state of play based on the information submitted so far, and then define what would be necessary to resolve the issue.  It is not as easy to formulate this type of request as the firm might think, and as a result, FDA’s AI requests can sometimes seem convoluted.  Not infrequently, a request is lengthy, with multiple subparts.  So the first task is to thoroughly understand each deficiency and map out what will be needed to address it.  This process can require a great deal of time and collaboration as further described below.

Collaborative Planning and Execution

In the AI letter, deficiencies are arranged according to review areas, such as administrative information, 510(k) summary, performance data, engineering performance, biocompatibility, sterilization, software validation, clinical data, and labeling.  An AI letter typically begins with the most significant deficiencies.  There is a wide range of the number of deficiencies−it could be just one major deficiency about one of these review areas.  The AI letter could also present 20 major deficiencies covering multiple review areas and another 30 minor deficiencies.  There is no limit to the number of deficiencies that FDA may generate and include in the AI letter.

Upon receiving the AI letter, appoint a lead person and disseminate the letter among team members for review.  This approach would be particularly helpful if the AI letter covers a wide range of subject matter expertise.  It is typical that a regulatory expert would take the lead.  A spreadsheet may be helpful to track deficiencies, response strategies (e.g., if additional testing is required or justification would suffice), responsible individuals, proposed timelines, and any clarifying questions for FDA.  Team meetings with subject matter experts can be scheduled to discuss response strategies for deficiencies that require extensive clinical, scientific, or engineering input.  If necessary, the firm may engage with third-party laboratories early on to address deficiencies about, for example, but not limited to, biocompatibility, electromagnetic compatibility, or electrical safety and determine timelines for conducting and completing the testing.  When contacting third-party testing laboratories, we suggest discussing the FDA deficiencies with the laboratory personnel so that they understand FDA’s concerns and can generate the data required to address the deficiency as efficiently as possible.  Working with third-party testing laboratories will be effective only if the corresponding deficiency is clearly understood.  If any deficiency is confusing to the firm, we suggest the firm correspond with FDA first to clarify it before planning or conducting any additional testing.

Effective FDA Correspondence Strategy

After a thorough review of the AI letter, the team should consider whether each deficiency is fully understood.  When in doubt, take advantage of FDA’s standard offer of a 10-day call to clarify one or more of the deficiencies.  A list of questions should be prepared and sent to the FDA lead reviewer 48 hours prior to the call.  As this is a 30-minute call, questions should be prioritized in the order of importance to ensure there is time for discussion of key issues.  The 10-day call is intended only to clarify the deficiencies and not to receive FDA’s confirmation on the adequacy of a firm’s plan to address the deficiencies.  It is our experience, however, that some FDA review teams generously offer a quick response to confirm the firm is on the right track in addressing certain deficiencies.  While formal meeting minutes are not mandatory for a 10-day call, it is beneficial to draft minutes and include them in the AI response.

If the scope of the questions submitted for the 10-day call is extensive or if discussion of plans to address the deficiencies is needed, a Submission Issue Request (SIR) pre-submission can be used to seek FDA feedback on proposed approaches to address deficiencies.  If a SIR pre-submission is submitted within 60 days of the AI letter, FDA targets providing meeting or written feedback in 21 days from a request, to the extent resources permit.

Thus, it is beneficial to determine early whether a SIR is needed and to submit as soon as possible within the first 60 days.  If the 60-day mark is missed, FDA may provide meeting or written feedback from a request in 70 days as resources permit.  Note that the method of feedback for a SIR is meeting or written feedback, not both.  However, in our experience, there are some occasions that FDA has offered both written feedback and a meeting for a SIR, and FDA is generally able to respond to follow-up questions interactively via e-mail once the meeting has been held or written feedback provided.  Whether a firm used the 10-day call and/or an SIR, it should include any prior feedback from those interactions with FDA in the AI response and describe how and where in the AI response package the prior feedback was addressed.

Streamlining the AI Response Preparation

The Guidance recommends a response format which entails restating the identified issue and providing one of the following: (1) the requested information or data, (2) an explanation of why the issue does not impact the marketing authorization decision, or (3) alternative information that adequately addresses the issue.

To ensure a comprehensive and timely response within the given 180-day timeframe, it is a good idea to begin drafting responses early on.  This approach not only allows the response to be submitted promptly upon receipt of the last reports or other information, but can also be helpful to identify any gaps in the planned approach and to ensure the team is addressing all aspects of the response.  If the AI response becomes extensive, it can be organized with a table of contents, list of attached files, list of figures, and/or list of tables to facilitate ease of review.  In each response, a firm should include a clear explanation as to how the response addresses the FDA’s concerns.

Tips for Facilitating FDA Review

When providing new test data, a firm should provide a clear narrative description of the goals, protocols, and how the data address FDA’s concerns.  Avoid simply referencing attachments without additional context or descriptions and letting FDA “figure out” the data.  Such responses may lead to reviewer confusion and delay.

When referencing documents within the AI response, cite location within the 510(k) supplement (e.g., Attachment number) and document name or description as appropriate.  When discussing specific information within a referenced document, also include the page number where the specific information may be found.  For labeling documents and the 510(k) summary, FDA often requests both clean and redlined versions.  If a firm provides an editable version of the 510(k) summary to FDA, it may be helpful to facilitate editing and finalizing the 510(k) Summary with FDA.  In the AI response package, hyperlinks can be used to help the reviewer get to the referenced information quickly.  If a response to one deficiency addresses other deficiencies, it is best to refer back to the previous response and avoid redundancy or the potential for inconsistency.

During the recent Regulatory Education for Industry (REdI) Annual Conference, June 6-10, 2022, FDA presented “Tips from a Lead Reviewer” for the presentation titled “Detangling the 510(k) Process.”  In this presentation, FDA suggested the following tips.

Tip #1: Keep in mind that your file will be reviewed by a human

• Keep your file organized
• Must be submitted in English

Tip #2: Check your email often

• Work to get you a decision as soon as possible, within MDUFA deadlines
• Sometimes, this makes it necessary to issue communications during non-business hours
• Don’t forget about your spam folder!

Final Remarks

An FDA AI letter can be lengthy – it is not unusual for AI letters to exceed 10 pages – and therefore challenging to address.  Take a deep breath and address them one by one.  We have had many successful experiences addressing challenging AI requests with the strategic approach discussed here and hope this approach may help your next 510(k) clearance.