The Winter Solstice, signifying the shortest day of the year, was Saturday, December 21.  Although the earliest sunset of the year was actually in early December, this day also marked another premature sunset – the beginning of the end of the rare pediatric disease priority review voucher program.

As we blogged recently, the program has had scheduled sunset dates from its very beginning, which have been repeatedly extended.  The first sunset date is the authority to grant a priority review voucher to a rare pediatric disease product application for a drug that has not been designated as a drug for a rare pediatric disease.  Although such designations are not typically a prerequisite for a voucher, the law is drafted so that once this first sunset date has passed, only designated programs may receive priority review vouchers for rare pediatric diseases until the program sunsets completely.  As we mentioned in our blog post, this first sunset date was originally in September, but was given a brief reprieve until December 20, 2024, as part of a continuing resolution to keep the government funded until that date.

As December 20 approached, there was a need for another continuing resolution to keep the government funded.  Earlier in the week, it was reported that there was a bipartisan agreement on a bill that would have funded the government and extended the first sunset date for the rare pediatric disease priority review voucher program for nearly 5 years, until September 30, 2029.  However, the bill ran into political challenges, and as the minutes ticked away until a potential government shutdown, the bill that was ultimately passed was stripped of many of the provisions that were originally included, such as the extension to the rare pediatric disease priority review voucher program.

This means that, at the current moment, FDA cannot award any priority review vouchers for rare pediatric disease product applications unless it is for a drug that was designated as a drug for a rare pediatric disease not later than December 20, 2024, and such application is approved not later than September 30, 2026.

Although this is a truly regrettable outcome of what seemed like a promising beginning to the week in this regard, this does not mean that all hope is lost.  Congress has since passed several of the bills that were originally stripped out of the continuing resolution, such as the bill that would transfer the land under RFK Stadium in DC to the DC government for the purposes of building a new football stadium (or other potential enumerated purposes).

Therefore, there remains hope that Congress could still act to extend the program.  As we mentioned in our previous blog post, and as stated by many other stakeholders, this program has been crucially important for rare pediatric disease product development, and it does not cost a single government dollar (although we do not wish to minimize the additional resources a priority review application demands).  If the program were to sunset completely, as currently scheduled, the impact on the development of drugs for rare pediatric diseases would be difficult to overstate.  Although FDA cannot currently award rare pediatric disease priority review vouchers to any applications not currently designated as a drug for a rare pediatric disease, there is no provision that prevents FDA from continuing to grant such designations.  We would strongly urge companies to continue to request, and FDA to continue to grant, such designations in the hopes that Congress can accomplish what it seemed ready to do on a bipartisan basis just a few days ago.  In the meantime, we encourage all stakeholders to keep the pressure on to get this done as soon as possible.

FDA recently released 510(k) Third Party Review Program and Third Party Emergency Use Authorization (EUA) Review which finalizes the draft guidance of the same title issued in December 2023.  We previously discussed the Third Party Review Program in a blog post last year when FDA mentioned its expansion as part of its plan to address the resource gap for review of laboratory developed tests (LDTs) under the LDT final rule.  The final guidance appears not to make any meaningful changes that are actually likely to support or incentivize its increased utilization, which is disappointing, although not unsurprising.

The final guidance looks much like the prior draft and is intended to satisfy FDA’s obligation to issue final guidance on consultations with persons under section 565(i) of the FD&C Act and also to provide clarity on use of third party emergency use authorization (EUA) review. The guidance also addresses FDA’s obligation to provide considerations on third party compensation, information sharing, and conflicts of interest.

Discussion of the early interaction (EI) consult policy and details of a third party review memo, which were previously described on the website, are now included within the guidance.  The guidance also clarifies the criteria for re-recognition of third party 510(k) review organizations and the suspension or withdrawal of recognition and discusses how FDA will audit the Third Party 510(k) Review Program as part of ongoing audit plans under the Quality Management and Organizational Excellence (QMOE) Program which are all Medical Device User Fee Amendments (MDUFA) IV and V commitments.

The Third Party Review Program for EUAs looks different compared to the Third Party Review Program for 510(k)s.  Whereas applicants interact directly with third party 510(k) review organizations, for EUAs, FDA will generally contract with the third party review organization and will send submissions it receives to the third party for review.  FDA may, in certain emergency situations, determine that in vitro diagnostic device EUAs may be submitted directly to the third party EUA review organization.  EUAs may only be submitted following a relevant declaration under section 564 of the FD&C Act justifying emergency use authorization of a product and, because such emergencies are not known, FDA will identify and contract with third parties based on expertise and skills needed in anticipation of or at the time of an emergency declaration.

While FDA may utilize third parties to review EUAs to lessen the burden on internal FDA resources during a public health emergency, this might not offer much in the way of advantage or assistance to a new Sponsors or FDA as compared to other programs put in place during the recent COVID-19 public health emergency.  In April 2020, the National Institutes of Health (NIH) launched the Rapid Acceleration of Diagnostics (RADx) to speed innovation in the development, regulatory authorization, commercialization, and implementation of EUA COVID-19 testing.  Sponsors who applied to the program were put through a highly competitive, rapid three-phase selection process to identify the best candidates for at-home (over-the-counter) or point-of-care in vitro diagnostic COVID-19 tests. All proposals underwent an initial technical, clinical, commercial, and regulatory review before receiving funding and in-kind service support.  Sponsors were provided a RADx interdisciplinary consulting team, including a regulatory consultant who worked closely with the FDA to ensure Sponsors were meeting the Agency’s expectations.  This was especially advantageous to Sponsors who had not previously taken a product through the FDA market authorization process.  The purpose of the RADx project team was to help Sponsors quickly accelerate past development hurdles, provide them with close partnerships with other regulatory agencies (e.g., FDA), and to generate data in a format that would streamline FDA’s review. The program led to 18 over-the-counter COVID-19 EUAs, 2 multiplex COVID/Flu EUAs, and supported De Novo and 510(k) submissions for over-the-counter COVID-19 and multiplex COVID/Flu assays.  A similar support program, instead of or in combination with third party review, could be instrumental in assisting manufacturers of LDTs to validate tests and de-risk regulatory authorizations.

As we have previously discussed, the Third Party 510(k) Review Program is not widely used.  We noted in last year’s post that in Fiscal Years 2018 – 2022, fewer than 100 510(k)s went through the Third Party Review Program annually. Fiscal Year 2023 showed similar performance.  The Agency has reportedly been trying to improve the program, as we discussed in 2018 and 2020.  However, the new final guidance does not appear to do anything to enhance the program or change it in a way that would be likely to lead to increased use by industry.  This appears to be yet another failed attempt to remediate a program that has long underperformed its potential.  As the Agency looks towards reviews of LDTs, a program similar to RADx may provide a better approach to assist manufactures and FDA in meeting the challenges to allow for review and authorization of LDTs.

We recently published the first part of our review of FDA’s draft guidance titled “Frequently Asked Questions – Developing Potential Cellular and Gene Therapy Products.” Questions and Answers Guidance (see previous coverage here).  In this post we focus in on the draft guidance document’s chemistry, manufacturing, and controls (“CMC”)-specific content.  In eight pages we get a string of high-level regulatory questions that provide a nice roadmap for CMC product development, which largely align with opportunities to engage with CBER as you progress through the development of cellular and gene therapies (“CGT”).

As you review these questions and answers, nothing that CBER provides in this guidance is “new.”  In fact, nearly all of the CMC comments are directing us to existing guidance documents.  This does not mean that there is no value in this recent publication. What can be gained from this new guidance from a CMC perspective is more nuanced.  The guidance documents that CBER has issued in recent years in the CGT space have been important steps forward.  Each provides high-level considerations for a field that spans a mind-boggling number of indications and therapeutic modalities that CBER is responsible for reviewing.  This is best exemplified by CBER’s description of characterization tests in this guidance:

The appropriate characterization tests depend on the unique features of the product type. For example, characterization testing of a cell-based product may include extended assessment of cell surface phenotypic markers, such as those associated with immune-cell activation, differentiation, and exhaustion. For adeno-associated viral vectors, examples may include characterization of non vector DNA impurities in capsids by next-generation sequencing, vector genome size analysis, and detection of capsid amino acid modifications by mass spectrometry. For tissue-engineered medical products, examples may include biomechanical testing to assess the ability of a vascular graft to tolerate repeat access without leaking, permeability testing to assess the characteristics of a skin graft, or cellular distribution throughout a cell scaffold construct.”

This broad span of products can limit CBER’s ability to give meaningful details or examples in guidance, leaving the Center to make more general recommendations:

• “FDA recommends that sponsors evaluate a number of product characteristics during early clinical development to help identify and understand CQAs”
• “There is no fixed number of lots recommended for PPQ. In general, a greater understanding and knowledge of the product and manufacturing process can reduce the number of PPQ lots that should be sufficient to qualify the performance of the manufacturing process.”

If you make a tissue product you may produce one lot per patient where a gene therapy may only need a handful of lots through Phase 3.  It is harder to execute full testing programs on lots containing one unit.  As a result, how you approach your PPQ will be drastically different.

Key takeaway for CMC:  What makes a successful CMC section for an IND or BLA looks very different for every development program.  In this draft guidance, CBER is walking sponsors through the options available to them to ask program-specific questions as sponsors will only get one shot at some meeting types (INTERACT, Pre-IND, Pre-BLA). It is important that sponsors do not miss an opportunity to engage with CBER on CMC topics. This is even more so in rare disease CGT programs where clinical development can be more streamlined, so CMC product development is expected to happen at a more rapid rate.  This new guidance will help ensure that sponsors get the most out of their interactions with CBER by ensuring they do not have major blind spots.  From there, it is up to sponsors to take every opportunity to ask product-specific CMC questions to CBER.  As this and other CGT guidance documents illustrate, there is no one-size-fits-all approach to CMC.

Administrative Law Judge (“ALJ”) John Mulrooney conducted a prehearing conference hearing on Monday, December 2nd, to kick off the public hearing on the Department of Justice’s (“DOJ’s”) notice of proposed rulemaking (“NPRM”) to reschedule marijuana.  The NPRM seeks to reschedule marijuana from schedule I of the federal Controlled Substances Act (“CSA”) to schedule III.  The DEA Administrator issued a General Notice of Hearing fixing December 2nd as the commencement date for the hearing.

The purpose of the public hearing “is to receive factual evidence and expert opinion testimony” on whether marijuana should be rescheduled to schedule III.  Prehearing Ruling (Dec. 4, 2024), at 1.  Last week’s prehearing conference set the parameters for the hearing on the merits, scheduled to begin January 21, 2025.  Judge Mulrooney’s prehearing ruling establishes the schedule for the parties’ presentations and established hearing guidelines.  Parties will have ninety minutes to present the testimony of their witness.  Counsel may present a two minute opening statement about their witness and the proposed exhibits that will be sponsored through the witness.  The prehearing ruling encourages parties “to consider whether there is merit in consolidation with other participants that have similar (or complimentary) litigation objectives, witnesses, and/or areas of interest.  Id. at 2.  Consolidated parties are allowed to present testimony of up to two witnesses during the hearing, a presentation up to 120 minutes.  Id.

At the conclusion of a party’s presentation, counsel or the designated representative for the party may present either a ten minute closing argument or submit a brief of up to twenty-five pages within five business days of their witness’ presentation.  Id.  Witness cross-examination will be limited to matters covered on direct examination, but if a party submits an affidavit or letter into evidence from a witness who also testifies in person, cross-examination as to matters referenced in the document may be permitted even if the witness does not refer to them during their direct testimony.  Cross-examination will be limited to twenty minutes for each party on the opposing side.  Id. at 3.

The parties have noticed their intentions to offer into evidence documents they identified in their prehearing statements and must serve each other with a copy of the documents noticed in their prehearing statements no later than January 3, 2025.  Parties are required to lay a foundation “for recognition as an expert” and for every proposed exhibit as a condition precedent for inclusion in the record.  Id.  A limited number of affidavits may be received into the record subject to the evidentiary weight adjustment specified in the regulations.  Id. at 3-4.

The court consulted the parties as to availability of their representatives and witnesses.  A party scheduled to present a witness must be physically present in the courtroom even if the witness appears via video teleconference.  A representative seeking to cross-examine an opposing witness must also be physically present.  Id. at 5.  The hearing on the merits commences January 21st with proceedings each Tuesday-Thursday, except for the week of February 10th, through March 6th.

We learned earlier this week that an allision (a runner-up to Merriam-Webster’s 2024 Word of the Year, polarization) may be poised to occur—perhaps within a fortnight (another runner-up to Merriam-Webster’s 2024 Word of the Year thanks to Taylor Swift)—as Congress considers various pieces of healthcare legislation as part of its year-end package.  As part of that package, we understand that discussions on the latest iteration of the “Bringing Low-cost Options and Competition while Keeping Incentives for New Generics Act” (“BLOCKING Act”) (also known as the “Expanding Access to Low-Cost Generics Act”) have resurfaced and could potentially hit the generic industry.  (Unless the legislative ship can be steered away.)

We’ve railed against passage of the BLOCKING Act since February 2018 when it was made as a legislative proposal in the first Trump Administration’s Proposed Fiscal Year 2019 Budget (pages 22 and 51)—including in blog posts (here, here, here, here, and here) and in Congressional testimony—as antithetical to a primary goal of the Hatch-Waxman Amendments: getting high quality, low-cost generic drugs into the hands of consumers—fast.  After all, the BLOCKING Act would significantly alter the ANDA Paragraph IV 180-day exclusivity incentive.  Specifically, it would further dilute the 180-day exclusivity incentive by amending the Paragraph IV 180-day exclusivity statutory provisions at FDC Act § 505(j)(5) to place new conditions on when a subsequent Paragraph IV ANDA can be approved notwithstanding a first applicant’s eligibility for 180-day exclusivity.

In our May 2023 B-B-B-B-Bad to the Bone post, we highlighted some changes to the original version of the BLOCKING Act, restyled as the Expanding Access to Low-Cost Generics Act of 2023, intended to guard against a subsequent Paragraph IV ANDA gutting the 180-day exclusivity incentive and that would somewhat blunt the negative effective of the legislation.  But we’ve made no bones about our take on BLOCKING and its progeny: “That being said, it’s kind of like putting lipstick on a pig.  In the end, the “Expanding Access to Low-Cost Generics Act of 2023” (S. 1114) is still the BLOCKING Act, and it is still bad to the bone.”

Based on what we’ve heard from the talk on Capitol Hill, the latest version of the BLOCKING Act that is poised for introduction in Congress within the next few days is the same language proposed for inclusion in the never-passed “Food and Drug Administration Safety and Landmark Advancements Act of 2022.”  That’s the version we dissected here, and that is available here.

Given that we’ve already covered the version of the BLOCKING Act apparently on tap for congressional consideration, we won’t do so again here.  But we thought a clarion call would be appropriate now.  After all, as we’ve said before—and it bears repeating over and over again—what generic drug companies would be willing to invest millions of dollars in generic drug development and patent challenges for the potential of a hollow exclusivity incentive?  More ANDA approvals does not necessarily translate into more launches.  Over time, a new exclusivity regime for Paragraph IV ANDAs may mean fewer ANDA approvals and launches.  And that ultimately means more drug shortages of critical medicines, fewer choices for consumers, and higher costs to the U.S. healthcare system.

On Wednesday, December 11, Hyman, Phelps & McNamara, P.C. (HPM) and Riparian LLC will co-host a webinar on an important CMS rule imposing penalties for misclassification of drugs and other reporting errors under the Medicaid Drug Rebate Program.  (See our post on this rule here.)  The Webinar will explore the CMS rule and provide actionable recommendations for manufacturers on how to navigate the new requirements.

Date:  Wednesday, December 11, 2024

Time:  12:00 PM to 1:15 PM ESTfda

Presenters:

•  Alan Kirschenbaum, Director, HPM
•  Jennifer Lospinoso, Managing Director, Riparian LLC
• Lynn Buhl, Managing Director, Riparian LLC

Please click here to register.  Once you register, you’ll receive instructions by email on how to access the webinar.  We hope you’ll join us!

On Wednesday, December 11, Hyman, Phelps & McNamara, P.C. (HPM) and Riparian LLC will co-host a webinar on an important CMS rule imposing penalties for misclassification of drugs and other reporting errors under the Medicaid Drug Rebate Program.  (See our post on this rule here.)  The Webinar will explore the CMS rule and provide actionable recommendations for manufacturers on how to navigate the new requirements.

Date:  Wednesday, December 11, 2024

Time:  12:00 PM to 1:15 PM EST

Presenters:

• Alan Kirschenbaum, Director, HPM
• Jennifer Lospinoso, Managing Director, Riparian LLC
• Lynn Buhl, Managing Director, Riparian LLC

Please click here to register.  Once you register, you’ll receive instructions by email on how to access the webinar.  We hope you’ll join us!

On November 19, 2024, FDA released a draft guidance titled “Frequently Asked Questions – Developing Potential Cellular and Gene Therapy Products.”  As much of the content of this draft guidance for cellular and gene therapy (“CGT”) products is articulated elsewhere, this document serves as a one-stop shop or “Cliffs Notes” for the numerous guidance documents now covering CGT product development.  However, as your high-school literature teacher warned you—to ace the test, you need to read the book, ahem, source regulations, guidance, or other policy documents.

CBER’s approach here was to take FAQs from across sponsor interactions, public workshops, email requests, etc. and create a new guidance to help CGT sponsors more efficiently find their way to the correct answers.  The draft guidance includes FAQs covering topics from across disciplines: regulatory review; chemistry, manufacturing, and controls (“CMC”); nonclinical and pharmacology/toxicology (“PT”); clinical; and clinical pharmacology.  Because this guidance covers such a breadth of information, for Part 1 of our coverage, we will focus on the non-CMC topics and summarize our top takeaways from each section, something of a Cliffs Notes for the Cliffs Notes.

Section #1: FDA Interactions

Given the wide range of sponsors (i.e., academic to industry) involved in developing CGTs, the guidance starts by summarizing some of the fundamentals of opening an IND.  This summary covers everything from format and contents of INDs to their submission and use of the Electronic Submissions Gateway to cross-referencing other applications to FDA’s review of the IND and the associated timelines.  While this section is emblematic of the breadth of coverage of this guidance, it is particularly helpful for any sponsor who is looking to submit an IND for the first time, academic sponsors, and entities who partner with academic sponsors.

Interestingly to us, the draft guidance attempts to again clear up a common source of confusion by describing the differences between INTERACT and pre-IND meetings.  Here, the draft guidance states that the appropriate timing for an INTERACT meeting should be when a sponsor has identified a specific product and has conducted some preliminary proof-of-concept (“POC”) studies but has not yet designed and conducted definitive toxicology studies.  CBER had previously, as recently as July 2024 in its SOPP on regulatory interactions with sponsors (SOPP 8101.1), described that an INTERACT meeting may be appropriate when a sponsor has identified a “specific investigational product or product-derivation strategy to evaluate in a clinical study before requesting an INTERACT meeting” (emphasis added).  In contrast to the scope for INTERACT meetings, the draft guidance describes an example of when a pre-IND meeting would be appropriate as being when the sponsor has completed POC and possibly some preliminary nonclinical safety/toxicology studies and desires to move to the definitive toxicology studies.  The distinction between the INTERACT and pre-IND meeting and the potential narrowing of the scope for INTERACT meetings appears to have moved these two meeting types closer together on the continuum of product development timelines.  It also appears to have continued to shift the focus away from degree of CMC-readiness, although our experience tells us that this continues to be a consideration in CBER’s review of INTERACT meeting requests.

The draft guidance also describes pre-BLA meeting considerations, noting that FDA “strongly recommends” scheduling one.  The draft guidance states that only one 90-minute pre-BLA meeting will typically be granted for a specific product or indication planned for an original marketing application.  Such meetings should also be multi-disciplinary, not discipline-specific.  The draft guidance states that a pre-BLA meeting request should be submitted at least 4 months before the anticipated BLA submission.  The draft guidance recommends that no more than 15 questions are included in the briefing package.  CBER will not commit to reviewing packages greater than 250 pages.

For the many CGT programs intended for rare disease indications, we have found there is immense value in “socializing” pivotal data (whatever “phase” of study they may come from) prior to a pre-BLA meeting. This could occur during an End-of-Phase 2 (“EOP2”) meeting if a Phase 2 study is expected to provide primary evidence of safety and effectiveness.  Even if an EOP2 meeting has occurred, it may help to have a focused clinical/statistical discussion of study results following Phase 3, as an “EOP3” meeting.  This highlights the opportunities that exist for engaging with FDA beyond the opportunities explicitly acknowledged in guidance.

Section #2: Nonclinical Studies

As CBER has indicated in other guidance documents regarding considerations for nonclinical investigations, designing a nonclinical program is highly product and indication specific, which makes uniform design recommendations difficult.  Instead, this guidance highlights questions about species, animal model, and product selection for nonclinical programs as well as several aimed at helping to understand the purpose and importance of POC, toxicity, and biodistribution studies. There is even a tip of the hat to alternative (non-animal) test methods, which have become powerful methods for the assessment of the potential for off-target toxicity and unintended genome editing. To us, some of the most helpful information provided pertains to selection of animal species and the design of pharmacology and toxicology studies, with the  discussion of considerations that are unique to either cellular products or gene therapies.

The draft guidance enumerates key considerations for selecting an animal species for both pharmacology and toxicology studies.  These considerations consist of (1) whether the investigational CGT product is pharmacologically active in the species, (2) the technical feasibility of using the intended clinical delivery device or procedure, (3) comparability of the physiology and anatomy, and (4) the sensitivity of the selected species to potential toxicities.  Additional specific considerations for cell therapies include the ability of the species/strain to support survival and engraftment or availability of an appropriate analogous animal product.  Specific considerations for gene therapies include the susceptibility of the species to the vector, the vector transduction profile, and the pharmacological response to the vector and expressed transgene.

The draft guidance also directs sponsors to consider the biological relevance of a particular animal or disease model for pharmacology studies.  Factors related to the relevance of an animal or disease model to a target patient population include (1) progression of the disease phenotype or injury, (2) the lifespan of each model, (3) the similarities and differences between the animal model and the proposed patient population, (4) the timing of product administration relative to disease onset and progression, and (5) the relevant anatomy and physiology related to the delivery method and target anatomic site(s).  If there is no available animal model, the sponsor should provide supporting data from other sources, which can include in vitro studies, in silico studies, in vivo studies using an analogous animal product, and relevant data from studies evaluating a related product or indication.

Shifting from pharmacology, the draft guidance offers input on design of toxicology studies.  Because many CGT products are single-dose administration products, the duration for pivotal toxicology studies evaluating such a product should be informed by the biodistribution and persistence profile of the investigational product.  The draft guidance describes various methods to assess either cell distribution for cell therapy products or vector biodistribution for gene therapy products.  For cell therapy products, the draft guidance notes that in vivo imaging techniques provide certain advantages.  For gene therapy products, the use of quantitative and sensitive assays such as qPCR are recommended.  Where vector presence is detected, transgene mRNA and/or protein expression levels should also be measured.

Section #3: Human Trials

Finally, the guidance provides a quick overview of clinical study recommendations. Here, CBER focused on high-level questions about study design, providing substantial evidence of effectiveness, endpoint selection (including differences between clinical and surrogate endpoints), and assessing safety in CGT clinical programs.  The draft guidance recommends, when feasible/ethical, the use of a placebo/sham concurrent control, active concurrent control, or dose-ranging concurrent control, as opposed to no-treatment concurrent control or external control, though no guidance is offered as to when such controls are feasible or ethical.  Next, sponsors should consider no-treatment control.  However, the draft guidance notes that in some cases, such as with rare diseases that have a natural history that does not spontaneously improve, a well-conducted natural history study may serve as an acceptable external control.

Consistent with both previous guidance and CBER’s approval decisions and recommendations to sponsors, the draft guidance recommends that for rare diseases, sponsors should consider designing their FIH study to be an adequate and well-controlled clinical study so that it may contribute to meeting the substantial evidence of effectiveness standard or even “serve as a pivotal study to support approval.”  The draft guidance also notes that clinical outcomes in early phase studies could provide confirmatory evidence of effectiveness.

The discussion of endpoint selection, especially with respect to accelerated approval, caught our attention.  It was quite notable to us that, while the guidance mentions both surrogate endpoints and intermediate clinical endpoints, the latter received little attention.  The discussion focused almost entirely on distinguishing clinical and surrogate endpoints, explaining considerations for selection of biomarkers as surrogate endpoints, and the strength of evidence needed to support a surrogate endpoint.  On the other hand, CBER provided no additional guidance as to when a clinical endpoint would be appropriate as an intermediate clinical endpoint to support accelerated approval.  However, CBER just recently granted (to our knowledge for the first time) an accelerated approval based upon an intermediate clinical endpoint (see the November 13, 2024 approval of the gene therapy, Kebilidi).

For safety, the draft guidance emphasizes that close monitoring of subjects immediately after product administration is critical to capture early safety signals for CGT products.  FIH studies should generally employ staggered enrollment and treatment to identify potential safety issues before dosing the next subject.  The staggering interval should be long enough to monitor for acute and subacute adverse events based on observations in animal studies or previous human experience with related products.  Clinical studies of CGT product should have well-designed stopping rules to assure that risks remain reasonable.  Such stopping rules should specify the number of adverse events, as well as the nature/severity of these events, which would trigger such a determination.

Our Concluding Thoughts

While much of this new FAQ guidance reiterates policies and interpretations of FDA’s legal and regulatory authority that are described elsewhere, sponsors will likely find this document helpful for its effective summation of a large breadth of information.  Perhaps, this guidance is best used as a first step before searching across the many and various documents it aims to summarize.  The draft guidance contains a lengthy references section citing to 39 other guidance and procedure documents, not to mention the numerous statutory and regulatory provisions cited throughout, indicating the breadth of sources summarized in this one document.  While the much of the benefit of the guidance comes from its utility as one-stop source of information, its discussion of topics like the narrow distinctions between pre-IND and INTERACT meetings may still be helpful to sponsors, even if this new discussion seem, to us, to push further into development the potential first window during which a CGT product sponsor could interact with CBER.

It is also worth noting that the draft guidance reinforces CBER’s view that sponsors should consider how to maximize the potential for early phase studies to contribute to substantial evidence of effectiveness as one of two adequate and well-controlled studies, as confirmatory evidence, or even as the pivotal study to support a marketing application.  As such, particularly for rare diseases, it is important for sponsors to assess efficacy in these studies, even if only pharmacodynamic measures can be adequately measured. All the while, this efficiency in clinical development requires accelerating CMC by having early-stage studies serve as large stage studies.  However, as we noted above, the CMC topics covered in this draft guidance will be covered in Part 2 of this blog coverage.  Stay tuned for the next iteration of the Cliffs Notes to the Cliffs Notes.

On August 30, 2024, we posted on what was then the most recent version of S. 142, the Preserve Access to Affordable Generics and Biosimilars Act.  Some version of the bill, which addresses patent settlement agreements (pejoratively referred to as “reverse payment agreements” by their opponents), has been floating around in Congress for the better part of two decades—even before the U.S. Supreme Court declined to hold, in FTC v. Actavis, Inc., 133 S. Ct. 2233 (2013), that so-called reverse payment settlement agreements are presumptively unlawful.

As we noted in our prior post, S. 142 includes some new provisions (compared to previous iterations of the bill) to expressly provide for the Federal trade Commission (“FTC”) to obtain forfeiture and civil penalties in an administrative proceeding initiated by the Commission.  In particular, the bill would amend the FTC Act (15 U.S.C. 44 et seq.) to add new Section 27(e), titled “Penalties,” stating:

(1) FORFEITURE.—Each party that violates or assists in the violation of this section shall forfeit and pay to the United States a civil penalty sufficient to deter violations of this section, but in no event greater than 3 times the value received by the party that is reasonably attributable to the violation of this section. If no such value has been received by the NDA holder, the biological product license holder, the ANDA filer, or the biosimilar biological product application filer, the penalty to the NDA holder, the biological product license holder, the ANDA filer, or the biosimilar biological product application filer shall be sufficient to deter violations, but in no event shall be greater than 3 times the value given to an ANDA filer or biosimilar biological product application filer reasonably attributable to the violation of this section. Such penalty shall accrue to the United States and may be recovered in a civil action brought by the Commission, in its own name by any of its attorneys designated by it for such purpose, in a district court of the United States against any party that violates this section. In such actions, the United States district courts are empowered to grant mandatory injunctions and such other and further equitable relief as they deem appropriate. . . .

(3) CIVIL PENALTY.—In determining the amount of the civil penalty described in this section, the court shall take into account—

(A) the nature, circumstances, extent, and gravity of the violation;

(B) with respect to the violator, the degree of culpability, any history of violations, the ability to pay, any effect on the ability to continue doing business, profits earned by the NDA holder, the biological product license holder, the ANDA filer, or the biosimilar biological product application filer, compensation received by the ANDA filer or biosimilar biological product application filer, and the amount of commerce affected; and

(C) other matters that justice requires.

We raised the possibility that these civil penalty provisions—likely viewed by proponents of the legislation as hallmark provisions—may be the legislation’s death knell in light of the Supreme Court’s decision in SEC v. Jarkesy, 144 S. Ct. 2117 (2024) (see our previous post here), in which the Court “ruled that the Securities and Exchange Commission (SEC) may not impose fines to penalize securities in its administrative proceedings because that practice violates the Seventh Amendment ‘right of trial by jury’ in all ‘suits at common law.’”  Specifically, we commented that:

The Preserve Access to Affordable Generics and Biosimilars Act (S. 142) cannot be squared with Jarkesy’s interpretation and application of the Seventh Amendment. . . .  [T]he bill expressly provides for the FTC to obtain civil penalties—the exact type of claims the Supreme Court held are subject to Seventh Amendment protections—without a jury trial at any step of the process.  Rather, the bill is structured so that liability is fully determined by an Administrative Law Judge (“ALJ”) in an administrative proceeding without a jury, with “conclusive” factual findings made by that ALJ.  Then, in a follow-on action in court to impose civil penalties, the liability findings made by the ALJ are treated as “conclusive” and a judge—not a jury—assesses penalties in a bench trial.

That structure directly conflicts with the Supreme Court’s holding in Jarkesy.  First, S. 142 removes the jury entirely from both steps of its delineated process for assessing civil monetary penalties.  Second, by having an ALJ “conclusively” determine liability—and without a jury—it impermissibly takes away from the jury its core function of finding facts.  Just as it is unconstitutional to side-step the jury in an action seeking civil penalties for fraud (as in Jarkesy), so too is it impermissible in an action seeking civil penalties for unfair competition.  Both types of claims are analogous to common-law claims that fall squarely within the scope of Seventh Amendment protections.

Of course, a lot has happened since our August 2024 post.  Not only has a challenge been lodged against FDA in the Central District of California over the Agency’s civil money penalty authority based on Jarkesy (see our previous post here), but a new Administration—and one with a likely very different view of the FTC than the Biden Administration—is on the horizon.  Nevertheless, we are where we are at the moment and Congress is pressing on for passage of the Preserve Access to Affordable Generics and Biosimilars Act . . . and, based on a discussion draft we understand has been circulating on Capitol Hill, that introduces some even newer provisions to the bill.

The heightened discussion concerning Jarkesy and the Preserve Access to Affordable Generics and Biosimilars Act has even caught the attention of a Federalist Society panel.  Indeed, in a recent Federalist Society-sponsored webinar, titled “Does Jarkesy Doom the Preserve Access to Affordable Generics and Biosimilars Act?,” moderator Brian Pandya (Duane Morris LLP) hashes out the interplay between Jarkesy and The Preserve Access to Affordable Generics and Biosimilars Act with Matthew S. Hellman (Jenner & Block), William M. Jay (Goodwin Procter LLP), and Prof. Emily Michiko Morris (The University of Akron School of Law).

While we recommend that folks view the webinar video in its entirety, below are some key comments from the panelists worth noting (to be clear, the Federalist Society simply organized this independent panel of experts with varying opinions and does not take an official view on these issues):

Emily Michiko Morris: “This brings up the Preserve Access Act, which was actually introduced back in 2006 . . . A lot has happened since then of course.  In particular, the Supreme Court has weighed in fairly definitively in its 2013 decision in FTC v. Actavis.  For those of us who study the patent system and in particular the pharmaceutical industry and its use of patents, this raises the question of whether the Preserve Access [Act] is even relevant anymore.”

Matt Hellman: “What that means going forward is that if you happen to be aware of any agency enforcement scheme that allows for civil penalties, and we’ll talk about one that’s in the Act today, there’s a big question of whether or not that’s allowed anymore after the opinion striking down the SEC enforcement scheme in Jarkesy . . . Jarkesy is the lens through which we need to understand and assess what’s going on with the [Preserve Access] Act.”

Willy Jay: “Looking at this through the lens of Jarkesy, does the fact that you have an Article III judge come in at the end of the process change the way we look at this for Seventh Amendment purposes?  I would argue that the answer is no.  If this is a cause of action for civil penalties, it is one that should be treated the same way as in Jarkesy . . . [In the FTC proceedings,] you are certainly never getting an adjudication compliant with the Seventh Amendment . . . nowhere in the ALJ, the FTC, the Court of Appeals, or the district court are you getting a jury.”

Matt Hellman: “Agency findings can’t be a preclusive input into . . . [the Article III] process . . . It’s especially the case talking about treble damages,” which are “the kind of [damages] that the modern court . . . says needs to be awarded by a jury . . . .” “The Act as written is probably not going to fly.”

Emily Michiko Morris: “What’s happened is that the FTC requires that these cases submit their settlement terms to the FTC for review . . . The FTC in a 2020 report . . . reported that the vast majority of settlements . . . involved these kinds of early generic terms . . . I think this is probably the reason that the FTC has stopped publishing these reports . . . Overall, the effect has already been what the Preserve Access Act was presumably hoping to accomplish.”

. . . . And a shout-out to Matt Hellman who provided us with the headline for this post: “If you’ve got legitimate suspenders, don’t have an unconstitutional belt.”

Finally, we want to note one additional comment from Willy Jay.  He commented that “[m]ost agencies when they pursue civil penalties have to refer civil penalty actions to the Attorney General.  The FTC has chipped away at that . . . this legislation would allow the FTC to skip that entirely and give the FTC complete authority to pursue civil penalties . . .  You could in theory have a situation where a holdover FTC brings an action for civil penalties for violating federal law that the chief law enforcement officer of the United States does not think is a legal violation.”

Willy’s comment highlights another constitutional issue that we believe arises from the current discussion draft of the Preserve Access to Affordable Generics and Biosimilars Act circulating on Capitol Hill.  That is, that the FTC may be granted the authority to run to district court without consulting the Department of Justice.  If true, that’s a pretty significant development . . . . though perhaps not a scenario we are likely to see under the 47th President.

We recently blogged on FDA’s draft guidance, Chemical Analysis for Biocompatibility Assessment of Medical Devices, which describes chemical characterization methods that may be used to demonstrate biocompatibility of a medical device as an alternative to conducting certain biological testing.  We noted that the draft guidance’s discussion on determining a device’s contact duration raised concern as it contradicted ISO 10993-1:2018, Biological evaluation of medical devices —Part 1: Evaluation and testing within a risk management process. By way of background, FDA’s general guidance for biocompatibility, Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”, references ISO 10993-1 for identification of a device’s nature and duration of contact, including cumulative effects with repeated use.  The ISO 10993-1: 2018 standard, in turn, describes contact duration as the cumulative sum of single, multiple, or repeated duration of contact, although we are aware that a draft version of the standard (ISO/DIS 10993-1:2024) may be heading in a similar direction to the draft guidance.

As we noted in the previous post, Appendix A of the draft guidance for chemical analysis states that devices with short duration but repeated use are categorized according to the total number of days and not the total amount of time.  As an example, a device used daily for 5 minutes per day over 60 days would have a total contact time of 5 hours but would need to be tested as a device with long-term (> 30 days) contact duration, similar to an implant.  Another device that is used for 20 hours during a single day would be considered to have limited (< 24 hours) contact duration with fewer tests to complete, despite having a contact time four times longer than the first device.

We have seen this come up in many device reviews over the last several years, so we are not surprised to see it make its way to the draft guidance, but the justification for this burdensome approach is not provided and having conflicting recommendations in two related documents (i.e., the new draft guidance and ISO 10993-1: 2018) leads to more uncertainty for sponsors.  Finally putting this calculation method in the draft guidance appears to be a stake in the ground for the Agency to have a document to cite when it attempts to bully sponsors into performing additional testing that was not required of its predicate device.

Another problem this raises is that this method of determining contact duration conflicts with certain product-specific guidance documents (e.g., Latex Condoms for Men – Information for 510(k) Premarket Notifications:  Use of Consensus Standards for Abbreviated Submissions, Hemodialysis Blood Tubing Sets – Premarket Notification [510(k)] Submissions, Premarket Notification (510(k)) Submissions for Electrosurgical Devices for General Surgery, and Class II Special Controls Guidance Document: Topical Oxygen Chamber for Extremities) and will likely cause additional downstream issues for sponsors when attempting to determine which biocompatibility endpoints require testing.

The time needed to conduct additional biocompatibility tests or a chemical analysis with toxicological risk analysis, if FDA disagrees with a device’s contact duration, may exceed the 180-day hold cycle.  Given this and the contradictions between the draft guidance, ISO 10993-1: 2018, and product specific guidance documents, use of FDA’s pre-submission process to align on necessary biocompatibility tests is recommended for devices used for short durations over multiple days or repeated use of the device by a single patient.

*KP Medical Device Consulting LLC

A recent Warning Letter reflects an FDA citation of a company for refusing to permit FDA Investigators to take photographs during an inspection.  We haven’t seen an FDA Warning Letter citing a refusal to permit photographs for years, so, just as FDA is apparently reviving these types of allegations, it is probably time for us to revive blogposts that have discussed this issue for more than a decade now.

The current Warning Letter was issued to a drug manufacturer in China (Tianjin Darentang Jingwanhong Pharmaceutical Co., Ltd.) for multiple violations observed during an inspection that occurred eight months ago.  One of the foremost allegations is that the FDA inspection team attempted to take photos of two filling machines that FDA observed to be “dirty and in an apparent state of disrepair, despite the equipment status being identified as clean.”  Management, according to the Warning Letter, “stated that the investigators were not allowed to take photographs of the equipment as part of the inspection.”  FDA reports that it told the company that “failure to allow photography would be documented as a refusal,” and the company “acknowledged the refusal.”

To be clear, as we discussed in a blogpost back in 2013, the Federal Food, Drug, and Cosmetic Act does not explicitly require companies to permit photographs to be taken.  Section 704 of the Federal Food, Drug, and Cosmetic Act (“FDCA”) (21 U.S.C. §374(a)(1)(B)) has required, for years, FDA-regulated industry to allow FDA “officers or employees” to “inspect, at reasonable times and within reasonable limits and in a reasonable manner,” any facility and “all pertinent equipment, finished and unfinished materials, containers, and labeling therein.”  FDA has always claimed that this gives them the authority to take photographs while conducting an inspection, as reflected in its Investigations Operations Manual (at Section 5.3.4.1), provided that “photos are an integral part of an inspection.”  The Manual also advises inspectors, if plant management refuses photographs, to cite two cases that the Manual claims authorize the taking of photographs, but those cases, in the view of critics like me, actually only authorize use of photographs in court when the investigated entity has not refused to permit photographs to be taken.

Then along came the FDA Safety and Innovation Act (“FDASIA”) (our firm’s summary of the law, which was enacted in 2012, is here).  FDASIA authorized FDA, in Section 707(b), to issue a guidance about what constitutes refusing an authorized FDA inspection, which is a crime under Section 301(f) (21 U.S.C. §331(f)).  In addition to the blogpost above, the resulting draft and then finalized Guidance has been the subject of several blogposts on our authoritative blog (authoritative, at least, in our own minds, as to matters of FDA law) and other articles we’ve authored, including here, here, here, here, and here.

Because the Guidance was required to be issued by FDASIA, it may have more compelling effect than most FDA guidances, which explicitly state that they are not binding law.  On the other hand, they may not be any more compelling than other FDA guidances: the U.S. Supreme Court’s Loper Bright decision limits the deference that courts should afford federal agencies in the agency interpretation of what laws mean (see blogposts here, here, and here).

To be sure, this is not the first time that FDA has included the “Limiting Photography” observation in a Warning Letter.  In August 2017, Homeolab USA received a similar observation, although it was the last substantive observation in the letter (in the recently issued Warning Letter, the allegation ranked near the top).  In September 2016, Nippon Fine Chemical received a similar Warning Letter about an attempt to prevent an FDA Investigator from taking photographs.  And for foreign companies, FDA does not even need to go through the formality of issuing a Warning Letter to get its way.  FDA’s standing Import Alert 66-79 includes a long list of companies whose products can be stopped at the border simply because the foreign company tried to limit photography during an FDA inspection, among other things (the Warning Letter that prompted this blogpost included a warning that FDA would “continue” to block imports from the inspected facility for its enumerated violations.  The addition of a company to an import alert is purely administrative, yet it carries an immediate penalty to companies that dare to limit FDA’s inspections.

So, how to proceed?  If you don’t want to face a battle with FDA, keep “quiet on the set,” an obscure reference to a miniseries subtitled “The Dark Side of Kids’ TV,”, and also the phrase directors would supposedly scream after the advent of “talkies.”  Don’t tell Investigators they can’t take pictures.  Ask them why they think they are entitled to take pictures, ensure that what they are photographing is within the scope of their inspection powers, and then take side-by-side photographs so you can demonstrate later if the FDA photos are misleading.

If you want to challenge FDA investigators for being outside of their inspectional authority, prepare to address an observation in a Warning Letter.  Unfortunately, multiple courts have held that Warning Letters are not final agency action, so it may be hard to judicially challenge FDA’s authority to take photographs during an inspection.

Last May the Department of Justice (“DOJ”) and the Drug Enforcement Administration (“DEA”) issued a Notice of Proposed Rulemaking (“NPRM”) to transfer marijuana from schedule I of the Controlled Substances Act (“CSA”) to schedule III.  Schedules of Controlled Substances: Rescheduling of Marijuana, 89 Fed. Reg. 44,597 (May 21, 2024)..  The NPRM was consistent with the Department of Health and Human Services’ finding that marijuana has a currently accepted medical use in the U.S. and its views about abuse potential and physical or psychological dependence.  The CSA requires scheduling actions through formal notice and comment rulemaking on the record after opportunity for a hearing.

If DEA reschedules marijuana to schedule III, regulatory controls applicable to schedule III controlled substances would apply as well as marijuana-specific requirements and any controls that might be implemented to meet U.S. treaty obligations.  Drugs containing any substance within CSA’s definition of “marijuana” would remain subject to the applicable prohibitions in the Federal Food, Drug, and Cosmetic Act.

DEA announced in August after receiving over 43,500 comments in response to the NPRM that it would hold a public hearing regarding the proposed rescheduling.  Schedules of Controlled Substances: Rescheduling of Marijuana, 89 Fed. Reg. 70,148, (Aug. 29, 2024).  The “preliminary hearing,” which will begin Monday, December 2nd at 9:30 a.m. in DEA’s North Courtroom at its headquarters in Arlington, Virginia, will serve to address legal and logistical issues and future dates for the evidentiary hearing on the merits.  No witness testimony will be offered nor received on Monday.  Only designated participants and credentialed media members may attend.  The public may access the hearing virtually at www.DEA.gov/live.

In a Temporary Rule announced on November 19, 2024, DEA with input from HHS again extended current telemedicine flexibilities, which were first initiated on January 31, 2020 at the inception of the COVID-19 pandemic. The federal telemedicine flexibilities (i.e., temporary exceptions from some of the requirements of the Ryan Haight Act of 2008) are extended for an additional year, until December 31, 2025. All DEA-registered practitioners may continue to prescribe via audio-visual telemedicine encounters schedule II-V controlled substances, and schedule III-narcotic controlled substances that are FDA-approved for opioid use disorder management and treatment.  DEA notes in the Federal Register notice that it received over 38,000 comments to its 2023 proposed rules (35,454 for the general telemedicine flexibilities proposed rule and 2,915 for the buprenorphine telemedicine flexibilities proposed rule), and held two days of public listening sessions addressing industry comments.  It cited that feedback as the impetus to once again give DEA time to consider “a new path forward for telemedicine” and to allow for a “smooth transition” for both patients and practitioners that have relied on the availability of telemedicine for prescription of needed controlled substance medications.  While not stated in the Temporary Rule, telemedicine prescribers and pharmacies should ensure that state laws permit telemedicine prescribing, and should ensure they hold necessary licenses in accordance with state law, especially if prescribing or dispensing across state lines.

As a reminder (and as blogged about here), on March 1, 2023, DEA, together HHS, promulgated two notices of proposed rulemaking (NPRMs), one for general telemedicine prescribing of controlled substances and another for telemedicine prescribing of Buprenorphine (“Telemedicine Prescribing of Controlled Substances When the Practitioner and the Patient Have Not Had a Prior In-Person Medical Evaluation,” here, and “Expansion of Induction of Buprenorphine via Telemedicine Encounter,” here).  The proposed rules, while expanding pre-COVID-19 patient access to telemedicine prescriptions for controlled substances, fell well short of the telemedicine flexibilities that existed during the COVID-19 pandemic. More specifically, the proposed rules leave somewhat limited telemedicine options for both medication assisted treatment (i.e., use of buprenorphine) for opioid use disorder, and for Schedule III-V non-narcotic controlled substances unless the patient receives an in-person examination. In addition, the proposed rules leaves no telemedicine options for Schedule II or Schedule III-V narcotic medications, which would require an initial in-person visit before issuing a prescription. The sole exception to this limitation is for a prescription of buprenorphine for treatment of opioid use disorder, where a patient may receive an initial 30-day telemedicine prescription; but the “refill” (or second prescription) still requires an in-person exam.  For schedule III-V non-narcotic prescriptions, patients similarly would be eligible to receive an initial 30-day telemedicine prescription prior to an in-person exam. Any refill, however, would require an in-person exam either by a “referring” provider or dispensing provider.

Thus, while continuing to review industry feedback, DEA is still working on promulgating a more workable final set of telemedicine regulations.  Notably, the draft telemedicine regulatory framework comes 16 years after passage of the Ryan Haight Act of 2008, in which Congress specifically tasked DEA with crafting a framework that included a DEA registration category for telemedicine providers; and some in Congress have voiced concerns with not only telemedicine’s current nebulous status, but also with this lengthy delay.  We cannot predict with any certainty what effect President Trump’s election will have on HHS’s and DEA’s proposed telemedicine framework, especially when one considers the anticipated DOGE (Department of Government Efficiency) activities commencing with President Trump’s January 2025 inauguration. One undertaking of the DOGE, led by Elon Musk and Vivek Ramaswamy, intends to chop away at the broad-sweeping breadth of existing federal regulations. This blogger questions whether any revised proposed telemedicine regulations will successfully dodge DOGE.  Thankfully, we have until December 31, 2025 to ruminate about it.

FDA recently issued a draft guidance, Chemical Analysis for Biocompatibility Assessment of Medical Devices, which describes chemical characterization methods that may be used to demonstrate biocompatibility of a medical device as an alternative to conducting certain biological testing.  Chemical characterization identifies and quantifies chemicals that may be released from the medical device, while a toxicological risk analysis (TRA) evaluates the risks to the patient associated with the chemicals identified.  Data from chemical characterization studies must be evaluated in a separate TRA following ISO 10993-17 guidelines.

For FDA submissions, this strategy can be used to evaluate the biocompatibility endpoints acute, subacute, subchronic, and chronic systemic toxicity, genotoxicity, carcinogenicity, and reproductive/developmental toxicity.  That is, the biocompatibility endpoints cytotoxicity, sensitization, irritation/intracutaneous reactivity, material-mediate pyrogenicity, implantation, and hemocompatibility are not covered by the approach discussed in the new draft guidance.  Chemical characterization can also be useful in evaluating a change to the materials or manufacturing of a device.

Although the draft guidance states that the approach can be used for limited (< 24 hour), prolonged (1-30 days), or long-term (> 30 days) contact devices and “can reduce the time needed to complete biocompatibility testing by evaluating multiple biocompatibility endpoints at once and can reduce animal testing”, it is rarely going to save sponsors time or money to use chemical characterization in place of biological testing for most limited and prolonged contact devices to support FDA premarket submissions.

Using chemical characterization and toxicological risk analysis to support the biocompatibility of a medical device is not new.  Since the first issuance of FDA’s guidance Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” in 2016, sponsors submitting premarket submissions to FDA have had the option of using these techniques to evaluate certain biocompatibility endpoints.  Many sponsors want to reduce animal testing and, therefore, welcome the approach.  However, the experience in practice has been one of frustration as sponsors have struggled to reach agreement with the Agency on acceptable methods and acceptance criteria for these chemical assessments, despite FDA’s  partial recognition of the ISO 10993-18 and -17 standards that describe methods for chemical characterization and TRA, respectively.  Many sponsors have given up and opted to conduct biological studies instead of chemical assessments given the significant uncertainty with the non-animal based approach. FDA also notes variability in the approaches, inconsistent analytical chemistry reports, and deficiencies in review of premarket submissions as a driver for the draft guidance.

The draft guidance provides recommendations for collection and reporting of chemical characterization data and discusses the topics of information gathering, test article extraction, chemical analysis, and data reporting.  The main body of the draft guidance provides high-level recommendations, and four appendices provide detailed recommendations for test design.  Many of the details provide helpful clarity and it is noted that many of the recommendations in the draft guidance follow feedback FDA has provided to sponsors in Pre-Submissions and deficiencies over the last few years; but for others, FDA’s recommendations feel overly burdensome and not tolerable of any uncertainty or risk.  The following topics stood out as being burdensome and likely areas for FDA scrutiny of a sponsor’s chemical characterization data:

• One such area relates to determining a device’s contact duration. The general guidance for biocompatibility references ISO 10993-1 for identification of the nature and duration of contact, including cumulative effects with repeated use.  The standard describes contact duration as the cumulative sum of single, multiple, or repeated duration of contact.  However, Appendix A of the draft guidance contradicts the standard, stating that devices with short duration, but repeated use are categorized according to the total number of days and not the total amount of time.  Watch for a follow-up post on this particular topic.
• One of the most common issues with chemical characterization studies is that the use of harsh non-polar and semi-polar solvents (e.g., hexane and isopropanol) can be incompatible with many devices, including common polymers like silicones. Exhaustive extraction in these solvents can lead to high levels of product degradation or increased levels of extractables found in the chemical data, which is not expected during clinical use, and can often result in a TRA with a negative or inconclusive outcome.  Although FDA suggests in the draft guidance to investigate use of multiple solvents to find a suitable one, this is sometimes not possible even after many rounds of attempted feasibility studies performed by the labs.  In this regard, FDA states if compatible solvents cannot be identified, then chemical characterization data would not be appropriate to support a TRA and biological testing would be needed.  Although the draft guidance suggests that chemical characterization data can reduce time and animal testing requirements for biocompatibility evaluations, this will not be the case for many medical devices, including some long-term contact devices, for these reasons.  Furthermore, because some animal testing to address long-term endpoints is not practical or feasible to perform, sponsors can find themselves in a very difficult position.  FDA suggests that simulated use/leachables studies to simulate the clinical use (i.e., in a more clinically relevant solvent) and release kinetics data can be helpful; we agree with FDA’s thoughts regarding usefulness of these alternative studies especially in the cases where devices are incompatible with non-polar and/or semi-polar solvents and to more accurately estimate clinically relevant exposures.  We would encourage FDA to consider releasing guidances on both of these topics in parallel with the subject guidance.
• Another area that FDA discusses throughout the draft guidance is that chemical identities of extractables must be “confident” or “confirmed” levels to be used in the TRA. However, it is very common to have “tentative” or “unknown” identifications in chemical characterization studies.  In the draft guidance, FDA illustrates the need for additional orthogonal data (i.e., additional primary detection methods) in the sponsor’s methods to help with identification.  FDA also suggests throughout the draft guidance that information gathering on device materials of construction and the manufacturing process, including chemical additives, processing aids, presence of cohort of concern compounds, etc., can be useful in the development of a device-specific chemical characterization plan and analysis of the resulting data.  We agree with FDA on this point, and recognize that a large gap in the industry may be stemming from the fact that a Biological Evaluation Plan/Report (i.e., BEP/BER or Biological Risk Assessment) per ISO 10993-1 is not required for the majority of FDA pre-market submissions.  We have already seen trends in which FDA has started asking for more material, supplier, and manufacturing information in 510(k)s, submissions for which FDA historically did not require this information to be submitted by the sponsor. We have concerns that FDA’s expectations related to chemical identification levels may be unattainable even despite proper information gathering and additional orthogonal data and represent an unwillingness to accept some residual level of uncertainty in their decision-making process.
• In several places in the draft guidance, FDA illustrates that non-targeted chemical analysis is needed for general screening of unspecified device extractables, but that subsequent use of targeted analysis may be necessary to confirm the identity or refine the quantity of certain chemicals, including cohort of concern compounds, or analyze extractables with high concentrations. FDA also states that non-targeted data is insufficient to conclude that a particular substance is absent from the device extracts.  We have seen cases in which devices with claims of “DEHP-free” or “phthalate-free” do in fact contain these chemicals in the device extracts.
• In Appendix A of the draft guidance, FDA provides suggestions on what is and is not considered “worst case” for the test articles used for testing. FDA suggests that test articles represent the worst-case manufacturing process, and provide the examples that the device undergoes the greatest number of sterilization and/or reprocessing cycles.  It is common that sponsors will perform, for example, testing on 2x EO sterilized devices in order to support manufacturing scenarios in which the device needs to be re-sterilized.  However, reprocessing (cleaning and disinfection and/or sterilization) is typically performed by the end user in a healthcare facility rather than part of the manufacturing process.  FDA’s suggestion to test the maximum reprocessing cycles for reusable devices is aligned with the recommendations in clause 4.8 of ISO 10993-1:2018, but is extremely burdensome and not referenced in the related ISO 10993-18.  We have already seen trends for FDA to request biocompatibility and other testing after maximum reprocessing cycles of each separate reprocessing scheme listed in the sponsor’s labeling, including all combinations of detergent and disinfection chemistries, manual vs. automatic washing methods, sterilization modalities, and different sterilizer cycles/parameters for the same sterilization modality.  As many reusable devices can undergo hundreds or even thousands of cycles, the combination of testing the maximum cycles for each of these variables is extremely time-consuming and cost prohibitive, costing many hundreds of thousands or even millions of dollars.  In addition, the recommendation to test the device after maximum reprocessing cycles appears counterintuitive to the other recommendations in the guidance, which focus on the toxicological concern of chemical additives or manufacturing process aids, including cohort of concern compounds, present on the device that can be extracted.  These chemicals would typically have decreased quantities over the lifetime of a reusable device due to being removed by multiple cycles of reprocessing.  Therefore, FDA’s justification for this burdensome approach is not clear.

Given the current frustrations with chemical assessments and desire to reduce animal tests, the release of the draft guidance is a step in the right direction.  However, additional guidance from FDA is necessary in the related areas of simulated use and release kinetics studies.  In order to be more helpful to industry, reasonable recommendations to reduce animal testing in practice (rather than theory) are still needed.  It is recommended to submit a Pre-Submission to the Agency when considering your chemical characterization strategy, especially for any devices/materials with special considerations or use of alternative strategies and solvents.

FDA is extending the comment period on the notice published September 20, 2024 (89 FR 77162). Submit either electronic or written comments on the draft guidance by December 19, 2024, to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.

*KP Medical Device Consulting LLC

Over the past few days, we’ve been blogging about changes that are sure to come to FDA under Trump 2.0. Calls to more generally gut Federal agencies are everywhere, including from Robert F. Kennedy, Jr., the current nominee to lead the department of Health and Human Services. But shedding regulators in sensitive areas like drug manufacturing—even in the era of influencer-driven medicine—can lead to compromises in safety and efficacy, especially when FDA is already facing a massive inspectional backlog. One occurrence where an adulterated drug leads to injury can change a lot of minds about government’s role and the extent of needed FDA oversight.

Americans’ faith in safe drugs is thanks in no small part to the FDA investigators that conduct preapproval, for-cause, and routine inspections. So what does this all mean for FDA’s inspection workforce? Perhaps presciently, the non-partisan Government Accountability Office (“GAO”) issued a report last week imploring FDA to implement strategies to retain its investigators and address a long-simmering shortfall in their ranks.

According to the report, FDA has employed between 200 and 250 investigators in the years since the COVID pandemic. Over that time the number of vacancies has steadily grown, from 25 in 2021 to 73 in 2023. Those vacancies came while FDA was trying to ramp up inspections, after they fell under the first Trump administration and then cratered during the pandemic. The task before these investigators is daunting. According to FDA data, there are over 4,700 registered drug manufacturing facilities globally, more than half overseas. In 2023, FDA conducted 906 domestic and 768 foreign inspections, still well below pre-pandemic levels. According to FDA, and as reported by GAO, the difference was due to lower investigator capacity, due to the departure of several highly experienced investigators and their replacement with largely novice investigators, who can take years to train up.

There is so little capacity because being an FDA investigator requires immense technical knowledge, almost constant travel, and long hours. Unsurprisingly then, GAO has identified turnover as the key problem plaguing FDA inspectional workforce. This is a consistent finding from GAO, which has noted in past reports that investigators face these difficult professional challenges.

Under the Biden administration, FDA has taken some steps to remedy this problem. However, GAO reports that they have been ineffective as “investigator attrition has generally outpaced hiring and has resulted in a large number of relatively inexperienced investigators.” GAO credits FDA for implementing “action plans” to address investigators’ pay and training, but notes that the agency has not yet implemented any remedies for dissatisfaction over travel, workload, and work-life balance. The report also notes that “the continued loss of experienced investigators is already affecting FDA’s ability to meet inspection goals.” Lower numbers of investigators combine with lack of experience to limit the overall number of inspections FDA can conduct. That, in turn, may compromise FDA’s ability to identify lower manufacturing standards and the failure to comply with FDA and cGMP requirements.

The report concludes that FDA stakeholders should continue to collaborate to identify strategies that appropriately address these issues. Of course, making federal jobs more appealing for current and aspiring FDA investigators is not at the top of the incoming administration’s to-do list.

Is the GAO report a Pollyanna assessment of Federal priorities in the face of the current political bent towards proposed massive cuts to Federal jobs and services? We would say certainly not, as it underscores a critical need to ensure drug safety and efficacy. You are forgiven, however, if you’re skeptical that an RFK Jr.-led HHS would ever enact these recommendations. But in the face of the prevalent headwinds, there is also some reason to believe that this part of FDA’s vital role in ensuring public health will not fall entirely by the wayside under the weight of potential cuts. Even small-government members of the Republican-controlled House have long beat the drum of increasing FDA’s foreign inspection capacity. And we can’t help but wonder if the goals of smaller government aren’t outweighed by the political consequences to an administration potentially pock-marked by recalls, shortages, and outbreaks. Those very negative outcomes may be the fate of the American gold standard of drug safety if the incoming administration decides that oversight and inspections are disposable Federal functions.