As readers of this blog know (see, e.g., here), the Affordable Generics (and Biosimilars) Act has been floating around in Congress for the better part of two decades. That bill, addressing drug (and later biological product) patent settlement agreements (pejoratively referred to as “reverse payment agreements” by their opponents), was first introduced by Senator Herb Kohl (D-WI) in June 2006 as S. 3582—well before the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) established the biosimilar biological product licensure pathway, and years 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 originally proposed, the legislation would have amended the Federal Trade Commission Act (“FTC Act”) to effectively kill drug patent settlement agreements by providing that:

It shall be considered an unfair method of competition affecting commerce under subsection (a)(1) for a person, in connection with the sale of a drug product, to directly or indirectly be a party to any agreement resolving or settling a patent infringement claim in which—

(A) an ANDA filer receives anything of value; and

(B) the ANDA filer agrees not to research, develop, manufacture, market, or sell the ANDA product for any period of time.

Though the bill also included narrow exceptions:

Nothing in this subsection shall prohibit a resolution or settlement of patent infringement claim in which the value paid by the NDA holder to the ANDA filer as a part of the resolution or settlement of the patent infringement claim includes no more than the right to market the ANDA product prior to the expiration of the patent that is the basis for the patent infringement claim.

S. 3582 went nowhere; and many additional unsuccessful attempts to get a similar bill passed followed over the years. For example, see our posts here, here, here, and here.

The push for legislation—restyled as the Preserve Access to Affordable Generics and Biosimilars Act with the enactment of the BPCIA—seemed to have waned a bit in recent years, perhaps coinciding with an end to the Federal Trade Commission’s (“FTC’s”) annual reports on “Agreements Filed with the Federal Trade Commission under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003” and waning activity from FTC in the space (according to information published on FTC’s website).  But like cockroaches, some pieces of legislation are resilient and never seem to die.

The latest iteration of the Preserve Access to Affordable Generics and Biosimilars Act making its way through Congress is Senator Amy Klobuchar’s (D-MN) S. 142.  Like previous iterations of the bill, it would amend the FTC Act to add new Section 27, which provides, in part, that:

(A) In general.—Subject to subparagraph (B), in such a proceeding, an agreement shall be presumed to have anticompetitive effects and shall be a violation of this section if —

(i) an ANDA filer or a biosimilar biological product application filer receives anything of value, including an exclusive license; and

(ii) the ANDA filer or biosimilar biological product application filer agrees to limit or forgo research, development, manufacturing, marketing, or sales of the ANDA product or biosimilar biological product, as applicable, for any period of time.

And like its predecessor bills, S. 142 includes narrow exceptions:

(B) Exception.—Subparagraph (A) shall not apply if the parties to such agreement demonstrate by clear and convincing evidence that—

(i) the value described in subparagraph (A)(i) is compensation solely for other goods or services that the ANDA filer or biosimilar biological product application filer has promised to provide; or

(ii) the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.

. . . . As well as some exclusions:

(b) Exclusions.—Nothing in this section shall prohibit a resolution or settlement of a patent infringement claim in which the consideration that the ANDA filer or biosimilar biological product application filer, respectively, receives as part of the resolution or settlement includes only one or more of the following:

(1) The right to market and secure final approval in the United States for the ANDA product or biosimilar biological product at a date, whether certain or contingent, prior to the expiration of—

(A) any patent that is the basis for the patent infringement claim; or

(B) any patent right or other statutory exclusivity that would prevent the marketing of such ANDA product or biosimilar biological product.

(2) A payment for reasonable litigation expenses not to exceed—

(A) for calendar year 2023, $7,500,000; or

(B) for calendar year 2024 and each subsequent calendar year, the amount determined for the preceding calendar year adjusted to reflect the percentage increase (if any) in the Producer Price Index for Legal Services published by the Bureau of Labor Statistics of the Department of Labor for the most recent calendar year.

(3) A covenant not to sue on any claim that the ANDA product or biosimilar biological product infringes a United States patent.

In recent years and iterations of the Preserve Access to Affordable Generics and Biosimilars Act, additional provisions have been added (compared to the more ancient versions of the bill).  In particular, provisions have been added to expressly provide for the FTC to obtain forfeiture and civil penalties in an administrative proceeding initiated by the Commission.  The penalty provisions provide, in relevant part:

(e) Penalties.—

(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.

These civil penalty provisions—likely viewed by proponents of the legislation as hallmark provisions—may now be the legislation’s final death knell even if, unlike its predecessors, the bill actually makes it through Congress.  As we noted in a blog post published shortly after the Supreme Court’s decided SEC v. Jarkesy, 144 S. Ct. 2117 (2024) was released, that landmark decision “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.’”

While Jarkesy addressed only the SEC’s authority to impose fines, the underlying jury trial is not limited to that context: It applies to any claims that seek to impose civil penalties or other forms of monetary relief.  As the Court explained in Jarkesy, Congress’s imposition of civil penalties as a remedy is “all but dispositive” in determining that the Seventh Amendment right to a jury trial will attach, including in actions brought by a federal agency.

The Preserve Access to Affordable Generics and Biosimilars Act (S. 142) cannot be squared with Jarkesy’s interpretation and application of the Seventh Amendment.  As discussed above, the 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.

Where does this leave us?  Well, Congress can move forward and pass the bill, but it would likely be immediately challenged in court as unconstitutional.  And with the Jarkesy decision, it seems almost certain that an enacted version of the Preserve Access to Affordable Generics and Biosimilars Act would be invalidated by a court because its entire remedial structure is contrary to the Seventh Amendment.  That means legislators will either have to go back to the drawing board or drop the issue all together.  Hopefully, the cockroach is dead.  After all, as we have written before in other contexts (i.e., the BLOCKING Act), “[I]f you limit a generic drug manufacturer’s ability to settle cases, that manufacturer does not settle fewer cases, it submits fewer Paragraph IV ANDAs.  And fewer ANDAs means less, not more, generic drug competition.”

The American Conference Institute (“ACI”) will hold (virtually) its 4th Annual Passport to Proficiency on the Essentials of Hatch-Waxman and BPCIA from October 8-24, 2024.  This virtual three-week program is designed to give new lawyers and executives a solid foundation in the essentials and intricacies of Hatch-Waxman and BPCIA litigation and regulation.

Gain a comprehensive understanding of Hatch-Waxman and BPCIA essentials—critical competencies for legal and business professionals in the biopharmaceutical sector.  Everyone in the life sciences industry must be well-versed in the regulatory components and intellectual property nuances integral to patenting products.

This year’s co-chairs include Fangli Chen, Ph.D. (Partner, Proskauer Rose LLP) and Jason Murata (Partner, Axinn, Veltrop & Harkrider).  Hyman, Phelps & McNamara, P.C. Director Sara W. Koblitz will speak during Module 5 on various Hatch-Waxman and BPCIA topics.  The series, held virtually on Tuesday and Thursday afternoons on ACI’s interactive platform, will provide an in-depth review of Hatch-Waxman and the BPCIA, as well as other intellectual property basics related to small molecules and biologics. This program lays the groundwork for understanding the patent life cycles of biopharmaceutical products and business development plans.

To learn more about the program and to view the agenda, see here.  FDA Law Blog readers receive a 10% discount (use FDA Law Blog promo code: D10-999-FDA25).

Who says nothing happens in Washington, D.C., in August?  The Drug Enforcement Administration (“DEA”) will announce Thursday in the Federal Register that it will hold a hearing on the proposed rescheduling of marijuana to schedule III at DEA Headquarters in Arlington, Virginia on December 2, 2024.  DEA received over 43,500 public comments in response to the agency’s Notice of Proposed Rulemaking in the Federal Register on May 21, 2024.

“Interested persons,” that is “any person adversely affected or aggrieved by any rule or proposed rule issuable” under the Controlled Substances Act wishing to participate in the hearing must file a written notice of their intention to participate, which DEA will review.

Each notice of intention to participate must:

1. State with particularity the interest of the person in the proceeding;
2. State with particularity the objections or issues concerning which the person desires to be heard; and
3. State briefly the position of the person regarding the objection or issues.

Interested persons can file electronically as a PDF attachment via email to the Drug Enforcement Administration, Attn: Administrator at nprm@dea.gov or in writing to the Drug Enforcement Administration, Attn: Administrator, 8701 Morrissette Drive, Springfield, VA 22152 within 30 days after publication in the Federal Register.

As we said in our earlier post when DEA announced initiation of the rescheduling proposal in May, “buckle up!”

In 1997, Congress wisely amended the Federal Food, Drug, and Cosmetic Act (FDCA) by adding Section 513(f)(2) to establish the De Novo process.  The De Novo process provides a regulatory pathway to classify novel devices for which general controls alone or general and special controls provide reasonable assurance of safety and effectiveness for the intended use.  This amendment allowed sponsors with low or moderate risk devices to proactively employ the De Novo process.

In 2012, the FDCA was modified to allow the submission of a De Novo request without the need for a prior 510(k), and set a target review time by FDA of 120 days.  Before then, to use the De Novo process a sponsor had to submit a 510(k) premarket notification, receive a decision of “not substantially equivalent” due to lack of a predicate device, and then submit a De Novo request for the device.  There was no time limit for De Novos, which meant some requests languished for prolonged periods.  For the first fifteen years after the De Novo program was established, it was basically a failure.

These legislative changes helped.  The average annual number of De Novos granted leapt. (This is a good example of Congress fixing a problem.  Of course, Congress had created the problem in the first instance.)  The average annual number of De Novos granted increased from 5 to approximately 29.

De Novos now play an important role in product advancement.  For example, FDA granted seven De Novos for COVID-19 related indications for use.  Each of these De Novos can represent a clinical advance.  Equally important, once these De Novos are authorized, they can serve as predicate devices in the 510(k) process.  In other words, De Novos serve as springboards for other new devices.

When FDA grants a De Novo, it is supposed to issue a decision summary and classification order.  Sponsors of a new 510(k) device can use the decision summary and classification order affiliated with the De Novo to learn what the De Novo applicant submitted and build the case for substantial equivalence to the De Novo device.  In effect, these documents serve as road signs helping to direct new market entrants.

These summaries can be invaluable to companies that want to get their own clearance, providing the details that can be the key to understanding what the recipient of the De Novo did.  Since 2010, FDA has posted classification orders and decision summaries for devices classified through the De Novo classification process.  The classification order identifies the special controls and therefore is extremely important.  However, the special controls tend to be high level, such as “Electromagnetic compatibility (EMC) and electrical safety testing must be performed for any electrical components” and “Software verification, validation, and hazard analysis must be performed for any software components of the device.”  This high level statement leaves many questions about details.

However, far too often, potential 510(k) applicants get to a fork in the regulatory road and find that no road signs have been posted, metaphorically speaking.  According to the Medical Device Databases webpage, the De Novo database is to be updated weekly.  When we reviewed the De Novos that were granted between CY 2022 and 2024, we saw that only 28% had decision summaries posted:

Dishearteningly, the trend is in the wrong direction.

Breaking this down further, we found that the rate of decision summaries posted varied by offices:

What’s more astonishing is the number of years that have lapsed between De Novos being granted and their decision summaries posted:

For 2024, some De Novos were recently granted and therefore do not reflect badly on FDA—yet.  The same cannot be said for De Novos from January or February.

We further identified the ten De Novos with the greatest number of days elapsed between when they were granted and the lack of a decision summary.  These numbers are accurate as of August 16, 2024:

FDA has not publicly explained why the decision summaries for De Novos are not posted in a timely manner.  FDA has said that these summaries need to go through multiple levels of review, but that cannot excuse delays of 500 days or more.  The agency has done far better in posting 510(k) summaries, which are similar types of documents.  FDA delaying the De Novo decision summary postings is contrary to their promotion of timely access to information, and hinders companies that are trying to get new 510(k)s.  We have had multiple clients who have had to guess what to submit because the De Novo summary was not available, even though the De Novo had been granted long before.

It is important that FDA posts the decision summaries in a timely fashion.  Delays unnecessarily hamper the ability for other companies to efficiently move through the 510(k) process, which also makes the review process less efficient for FDA itself.  Without the decision summaries, companies are left to guess at the study design to satisfy special controls and/or engage with FDA through the pre-submission process to obtain feedback.  FDA’s failure to post decision summaries for 70% of De Novos granted in the last 2.5 calendar years is both inexplicable and deprives patients and clinicians of options.  By taking the simple step of making summaries available faster, FDA can facilitate the clearance of new products, and make life easier for its own reviewers.

Enacted in 2022, the Inflation Reduction Act (IRA) amended the Medicare provisions of the Social Security Act to impose several discount requirements on pharmaceutical manufacturers.  In addition to the widely publicized drug price negotiation program, the IRA established inflation rebate programs under Medicare Part B and Part D.  Since 1991, the Centers for Medicare and Medicaid Services (CMS) has administered inflation rebates in the Medicaid Drug Rebate Program (MDRP), but the IRA brings inflation rebates to Medicare.

The two inflation rebate programs share many features in common, with key differences.  These programs require manufacturers to pay rebates to Medicare if they raise their prices for certain Part B and Part D drugs faster than the rate of inflation.  The programs do not impose additional price reporting requirements on manufacturers; instead, CMS will determine rebates based on prices currently reported under the MDRP and Medicare Part B.  CMS will develop a new online portal for manufacturers to review their reports, submit Suggestions of Error, and make rebate payments.  CMS will provide all manufacturers of Part B and Part D rebatable drugs the respective reports, even if their rebate amount due for an applicable period is $0.  The Part B program applies to calendar quarters beginning with the first quarter of 2023, and the Part D program applies to 12-month periods beginning on October 1, 2022.  Because of the limited time between enactment and the effective dates of the inflation rebate programs, Congress directed CMS to implement these two programs initially through program guidances.  Accordingly, CMS issued first a preliminary guidance on each program, then, after a 30-day comment period, issued revised guidances on December 14, 2023.  On July 31, 2024, CMS published a proposed rule to codify its guidances, with some changes. We have drafted a memorandum that summarizes the main provisions of this proposed rule and notes where the regulation differs from the guidances.

Among other topics, the memorandum summarizes CMS’s proposed regulations for both these Part B and Part D inflation rebate programs, including:

• Key definitions;
• The drugs to which the rebates apply;
• Methods of calculating and applying rebates;
• Processes for reporting, reconciling, and paying rebates; and
• Penalties and enforcement.

We will be watching the development of these inflation rebate programs and will provide an update as the rule progresses.

In the world of patent term extensions, every day considered part of the regulatory review period is important, as that day—either in whole or in part—gets added back to the patent upon approval of the product.  In the veterinary world, where rolling applications are common, the testing phase is usually particularly important because the review phase, which starts only when the last component of the rolling New Animal Drug Application (NADA)—called the Administrative NADA—is submitted, is short, typically around 60 days.  So to maximize patent term restoration, the earlier the start of the testing phase, the better.

As background, under the PTE statute at 35 U.S.C. § 156(g), certain patents covering animal drugs are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review.  As with other FDA-regulated products, such as human drugs and medical devices, the “regulatory review period” is composed of a “testing phase” and a “review phase.”  For animal drugs approved under FDC Act § 512, the “testing phase” begins on the earlier of the effective date of an Investigation New Animal Drug (“INAD”) exemption or the date a major health or environmental effects test on the drug was initiated and ends on the date a NADA is “initially submitted” to FDA under FDC Act § 512(b).  The “review phase” is the period between the initial submission and approval of the NADA.  FDA’s PTE regulations at 21 C.F.R. § 60.22(f) clarify that a marketing application “is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application.”  FDA guidance has been clear that that point for rolling submissions is when the last component has been submitted.

Since 1991, FDA has taken the position that the testing phase starts when the sponsor submits a request to Center for Veterinary Medicine to establish an INAD file and ends when an NADA is submitted.  In February 2018, however, FDA issued a PTE decision determining that the testing phase for a NADA starts only once a Notice of Claimed Investigational Exemption (“NCIE”)—a written notification to FDA under an INAD of the sponsor’s intent to ship an investigational new animal drug—has been submitted.  In that PTE decision, this made a difference of over a year (which could result in an additional 6 months added back onto the patent).  The NADA applicant requested reconsideration, but FDA refused to set the testing phase at the INAD opening and instead used the date that a major health or environmental effects test on the drug was initiated.

In response,  Nissan Chemical Corporation, Intervet, and Merck Sharp & Dohme collectively sued FDA in June 2022 under the Administrative Procedure Act alleging that FDA’s determination of the regulatory review period for its approved NADA for BRAVECTO was arbitrary and capricious and violated due process principles because FDA changed its methodology for determining a drug’s regulatory review period without acknowledging the change or providing fair notice.  In February 2010, an oral formulation of BRAVECTO, a medication to treat and prevent fleas and tick infestation in dogs, was the subject of an INAD submitted to the Agency.  Plaintiffs performed the necessary studies on BRAVECTO and filed an NADA on April 8, 2014; FDA approved the NADA on May 15, 2014.  As required by law, Plaintiffs submitted a request for PTE within 60 days of approval, claiming that the regulatory testing phase began on February 19, 2010, the date in which the INAD was assigned number 11-903 for the investigation of the oral formulation of BRAVECTO.  When the U.S. Patent and Trademark Office consulted with FDA on the appropriate timelines, FDA claimed that the INAD, and thereby the testing phase, was not effective until August 4, 2011 because no NCIE was submitted until then.  After a Request for Reconsideration, FDA determined that the study actually began on June 28, 2011, but rejected the February 2010 date stating that “an INAD file was established when we received the first NCIE” and that the opening of the INAD file on February 19, 2010 was merely a “housekeeping matter” and thus the testing phase did not begin in February 2010.  While Nissan et al. sued FDA, at FDA’s request, the Court remanded the decision back to the Agency, but it came to the same conclusion.  Nissan thus filed an Amended Complaint and each party filed Motions for Summary Judgment.

The District Court for the District of Columbia determined that “the key question at issue in this case” is the appropriate start of the testing phase: February 2010 or June 2011.  The Court pretty quickly determined that “FDA acted arbitrarily and capriciously when applying [the PTE statute] to BRAVECTO because the FDA did not provide fair notice or an adequate explanation of its shift in methodology.”  FDA, since 1991, had publicly signaled that the opening of an INAD file starts the testing phase for a new animal drug.  FDA explicitly said as much in the 1991 preamble accompanying proposed patent restoration regulations.  FDA also consistently interpreted it that way between 1990 and 2007. While FDA had acknowledged this approach, in its 2022 remand decision FDA said that such approach was an “improper application” of the regulation and that the Agency started differentiating the opening of the INAD file from submission of an NCIE in 2009.  Thus, the Agency concluded, the June 2011 date should stand.

On August 8, 2024, the Court granted Nissan et al.’s Motion for Summary Judgment finding that FDA failed to provide fair notice to plaintiffs of the need to submit an NCIE rather than an INAD to trigger the start of the testing phase.  The Court explained that “FDA never publicly acknowledged that it was changing course.”  “It was not until the FDA’s 2022 remand decision that the agency publicly acknowledged these past mistakes and clarified its methodology for determining the testing phase start date.”  FDA was required to provide fair notice that it would no longer use the INAD date to start the testing phase.  The appropriate inquiry was “whether, as of February 2010, plaintiffs would have been ‘able to identify, with ‘ascertainable certainty,’ the standards with which the agency expect[ed] parties to conform’ in order to trigger the start of the testing phase for BRAVECTO.”  Because the Agency did not repudiate its prior contradictory statements and precedents until 2022, “FDA’s regulations, decisions, and statements did not provide fair notice to plaintiffs of the actions they were required to take in order to trigger the start of the testing phase for BRAVECTO, and the FDA’s actions therefore violated the APA.”

With this decision, the testing phase for BRAVECTO began on February 19, 2010, giving Plaintiffs an additional year to be included in its testing phase calculations.  It’s a clean win for the Plaintiffs and yet another hit to FDA’s court losses.  More important for industry, however, is that the case affirmatively puts every NADA filer on notice: the NCIE is now what triggers the start of the testing phase—not opening the INAD.

FDA’s Office of Prescription Drug Promotion (OPDP) has issued two new Untitled Letters this summer after 5 months without any letter activity. The letters are vastly different from one another in subject matter, but together they make a cruel summer of OPDP enforcement against industry. [Editorial note – the Gen X’er included that link first – for the arguably more popular reference, read on.]

The first Untitled Letter was issued to kaleo, Inc. on July 17, 2024 for a social media post published by Instagram influencer Brittany Mahomes (who has 2 million Instagram followers) about AUVI-Q (epinephrine injection, USP) that “entirely omit[ed] all risk information” about the drug. Mahomes, spouse to Kansas City Chiefs quarterback, Patrick Mahomes, is the mother of 2 young children with severe food allergies. Presenting only information about the benefits or efficacy of a prescription drug, like AUVI-Q, without any risk information is considered a false or misleading presentation under the Federal Food, Drug and Cosmetic Act (FDCA), and is considered misbranding of the product.

AUVI-Q is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects… biting insects… allergen immunotherapy, foods, drugs, diagnostic testing substances… and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The approved labeling for AUVI-Q includes warnings and precautions regarding emergency treatment, injection-related complications, serious infections at the injection site, allergic reactions associated with sulfite, and disease interactions.

The Instagram post contained both a video portion and text portion, neither of which mentioned or included any risk information. Instead, the post focused solely on the benefits and efficacy of AUVI-Q, with statements otherwise consistent with AUVI-Q’s approved labeling, such as “Auvi-Q is the only epinephrine autoinjector out there for infants and toddlers” and “AUVI-q® (epinephrine injection, USP) is for life-threatening allergic emergencies.”  The FDA acknowledged that although the post included the statement, “For Important Safety Information, visit @auviq_IS[,]” this “does not mitigate the misleading impression created by the omission of risk information,” (emphasis added). FDA’s stated concern from a public health perspective is that the omission of risk information “fails to provide material information about the consequences that may result from the use of Auvi-Q and creates a misleading impression about the drug’s safety.”  In other words, individuals may not be as vigilant about avoiding allergens if they only hear the benefits of AUVI-Q without understanding there may be safety consequences as well.

Honestly, we are pretty shocked that this social media post slipped through the review committee.  Haven’t we all learned that celebrity endorsements for prescription drugs still need to meet traditional promotional requirements? Thank you, Kim, for paving the way here.

Moral of the story – simply referring consumers (or followers) to a drug’s website for safety information is not enough  – even if you are TSwift’s bestie.

August 2024 Untitled Letter to Mirati Therapeutics Inc.

The second Untitled Letter was issued to Mirati Therapeutics Inc. (Mirati), a Bristol Myers Squibb company, on August 1, 2024 for content on a healthcare provider branded website for its product, KRAZATI (adagrasib), which was approved under FDA’s accelerated approval pathway for patients with certain types of non-small cell lung cancer based on objective response rate (ORR) and duration of response (DOR). The FDA’s accelerated approval pathway can allow for earlier approval of drugs intended to treat serious conditions and fill an unmet medical need where approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit and the predicted clinical benefit is subsequently verified in a post-approval confirmatory trial(s). FDA notes in its letter that it received multiple complaints about the website under its Bad Ad Program.

The letter states the website makes false or misleading claims and representations about the benefits and efficacy of KRAZATI, thus misbranding the product. The website makes numerous clinical efficacy claims for the drug, including claims relating to “depth of response,” “disease control rate” (DCR), and rates of “stable disease” (SD), “partial response” (PR), “complete response” (CR), and “progressive disease” (PD) from Mirati’s KRYSTAL-1 study which was the basis for FDA’s accelerated approval of KRAZATI. However, as FDA points out in its letter, KRYSTAL-1 was a multicenter, single-arm, open-label expansion cohort study that evaluated the effect of KRAZATI on ORR and DOR and thus did not establish that the SD observed in the study was attributable to the effect of the drug; such an assessment would need to be based on the results of a randomized controlled trial. FDA noted similar findings for the website’s presentation of DCR, overall survival (OS) and progression free survival (PFS) results since the KRYSTAL-1 study design was not capable of producing interpretable results on these endpoints. The website also included claims from “data on file” that were based on “pooled DOR” information. FDA stated “[p]ooling data poses analytical problems as differences among studies and study populations can affect the validity and interpretability of such pooled analyses,” and, because the FDA could not verify the presented results, requested Mirati provide data to support its claim for FDA’s review. Additionally, Mirati included disclaimers that the data presented on the website were based on descriptive and post-hoc analyses, which FDA stated is not sufficient to mitigate the overall misleading impression created by the inclusion of the data.

The Mirati letter deals with much more nuanced issues than the letter to kaleo. When dealing with a drug that is approved via the accelerated approval pathway, can efficacy data be presented as consistent with the FDA-required labeling (CFL) and be subject to the “scientifically appropriate and statistically sound” (SASS) standard, generally thought to be a lesser substantiation standard than the traditional regulatory requirements of “substantial evidence” and “substantial clinical experience?”  Even in a CFL world, these presentations likely fall short of the SASS standard where the communication “relies on a study that is inadequate to support the representations or suggestions it presents [and] disclosure of the material limitations of that study does not correct the misleading message conveyed by the communication.”

What these bloggers find interesting about this letter (beyond the CFL analysis) is that because KRAZATI was approved under the accelerated approval pathway, Mirati would have been required to submit all promotional materials for the drug thirty (30) days in advance of the material being used. As FDA did not object to the timing of the submission in the letter, it seems that FDA (likely) received a copy of this website for review, FDA did not comment, and Mirati moved forward with publishing – only to receive an Untitled Letter months later.  Years ago, FDA had much more robust communications about promotional materials with sponsors of accelerated approval products. This Draft Guidance, withdrawn in 2015, outlines FDA’s historical intent to review submissions and provide comments in a timely manner, “usually within 15 working days of the day the materials are received by FDA.” While it is likely not reasonable to maintain this expectation given the volume of materials submitted, it begs the question:  if OPDP cannot review materials and/or provide comments within the thirty (30) day window for accelerated approval products, why bother requiring sponsors to submit their materials in advance in the first place? Just some food for thought.

States better get ready,
Rescheduling may be coming,
You may need to make changes,
You may need to do more,
Than just get on board.
(With apologies to Curtis Mayfield)

By the close of the public comment period for the Drug Enforcement Administration’s (“DEA’s”) proposal to reschedule marijuana two weeks ago, the agency had received over 43,500 comments.  Governors, state cannabis regulators, law enforcement groups and local governments weighed in, as did marijuana advocates and opponents, marijuana industry associations, Members of Congress, federal law enforcement groups, healthcare and human rights groups, unions and trade associations, and private individuals.  Comments ranged from single sentence declarations to lengthy, cogent treatises, expounding on whether to reschedule marijuana from schedule I to schedule III or another schedule under the federal Controlled Substances Act (“CSA”), to leave marijuana in schedule I, or to deschedule altogether.  Regardless of whether DEA holds a public hearing, the issue will not be resolved for some time.

Rescheduling or descheduling from the most stringent schedule under the CSA, should one of those actions occur, would loosen federal manufacturing, import/export, distribution, and security requirements.  Rescheduling out of schedule I would allow for the medical use of FDA-approved prescription drugs dispensed by DEA-registered, state licensed pharmacies pursuant to prescriptions issued by similarly DEA-registered, state licensed practitioners.

While DEA is the primary federal authority that enforces the CSA and its regulations, the states, commonwealths, and territories also regulate marijuana and other controlled substances within their borders.  What has been overlooked is how rescheduling or descheduling may impact how the states and the District of Columbia might have to regulate marijuana.

Every state has enacted its own controlled substances statutes and regulations, many of which mirror the federal CSA and DEA regulations.  While states regulate most controlled substances similarly to regulation at the federal level, DEA and the states often diverge with marijuana.  Marijuana has been in schedule I of the CSA, the most stringent schedule for substances of abuse, since 1970.  21 U.S.C. § 812(c)(c)(10).  Schedule I substances have a high potential for abuse, no currently accepted medical use in treatment in the U.S., and lack accepted safety for use under medical supervision.  21 U.S.C. § 812 (b)(1).  In the most recent eight factor analyses prior to August 2023, in 2016 HHS and DEA concluded that marijuana continued to meet criteria for remaining in schedule I.  Denial of Petition To Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition To Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).

The states, through their own controlled substance authorities, pharmacy boards, departments of health or legislatures schedule and impose regulatory requirements on substances of abuse and the legitimate entities that handle them.  Some states have authorities that regulate marijuana exclusively.  To date thirty-eight states authorize marijuana in different dosage formulations for specific qualifying medical conditions and twenty-four states authorize adult recreational use of marijuana.  Marijuana use remains illegal in a handful of states.

Depending upon the state, substances of abuse are scheduled, rescheduled or descheduled if, as under the federal CSA, they meet certain criteria.  State scheduling criteria, though differing by state, are also generally consistent with CSA criteria.  About half the states require the same eight factor scheduling analysis as the CSA, and while some states require analysis of additional factors, others require analysis of fewer factors.

States’ controlled substances acts generally mirror the federal CSA.  This internal mandate may conflict with the state’s current allowance of marijuana for medical or recreational uses.  Federal scheduling actions may automatically trigger a number of states to control the substance consistent with the federal CSA.  In some states the regulatory authority is required to take action within a certain period of time, say thirty or sixty days following the final scheduling notice appearing in the Federal Register, or the federal action becomes effective in the state.  Some of those states require a public hearing, after which the state publishes its decision to follow or not follow the federal scheduling action.  States required to automatically schedule, reschedule or deschedule based on what DEA does may lack the authority to schedule marijuana more independently.  A number of states have discretional scheduling authority not tied to federal scheduling.

The federal CSA does not preempt state law unless there is positive conflict between one of its provisions and state law such that they cannot stand together.  21 U.S.C. § 903.  DEA has historically taken the position that in conflicts between the CSA and state law, the stricter governs.

DEA rescheduling marijuana in either schedules II or III may not represent a big change for states that already authorize marijuana for medical use.  However, for states that allow for recreational use of marijuana, even federal rescheduling from schedule I to a less restrictive schedule may trigger a sea change and potential culture shift.

At least half of the states currently regulate marijuana as a schedule I substance under their controlled substances act.  Other states variously control marijuana as a schedule III (Minnesota), schedule VI (Arkansas, Massachusetts, North Carolina and Tennessee), schedule VIA (Alaska), or schedule Z (Maine).  There are some states that do not control marijuana, or they regulate it outside of their controlled substances act.

Were DEA to reschedule marijuana to schedule II or III, or leave it in schedule I, and the states regulate it in a less restrictive schedule or allow continued recreational use, how will the U.S. Department of Justice (“DOJ”) and DEA respond?  Will DOJ and DEA continue to exercise the enforcement discretion generally shown since the Cole Memo was issued in August 2013?  Merrick Garland may not be Attorney General if DEA takes scheduling action on marijuana, but if he is, he may have provided a clue during his confirmation.  He said at that time that it was not the best use of DOJ’s limited resources to prosecute those complying with laws in states that have legalized marijuana and are “effectively regulating marijuana.”  Merrick Garland, Responses to Questions for the Record to Judge Merrick Garland, Nominee to be United States Attorney General 24 (Feb. 28, 2021).  We wonder if the Cole Memo was a holding pattern of sorts until DOJ and DEA resolved the federal/state marijuana divide and having done so, determine that states are not “effectively regulating marijuana” if they regulate marijuana less restrictively.

Rescheduling or descheduling, should either occur, will likely not become effective anytime soon.  In the meantime, authorities should take stock of potential federal rescheduling ramifications by assessing and understanding how it may impact how they regulate marijuana their state.

Increasingly the subject of induced infringement litigation, the viability of the carve-out has been questioned for several years now.  But recently, a new challenge was filed in the District Court for the District of Columbia questioning whether modifications to labeling as a result of patent protections—beyond the mere omission of language—are permissible under the section viii carve-out requirements.  In other words, the case asks how “same” a generic drug’s labeling must be as compared to its Reference Listed Drug.

On July 30, brand name drug sponsor Novartis asked the District Court for a Temporary Restraining Order (here and here) enjoining FDA’s approval of a generic version of its ENTRESTO (sacubitril and valsartan) with certain dosing and indication information carved-out or modified.  That modification to the labeling, Novartis argues, “represents a sharp departure from FDA’s statutory and regulatory mandate to require that a generic drug be the ‘same’ as its reference listed drug.”  This is because the generic—sponsored by MSN Laboratories Private LTD—revised the approved ENTRESTO indication rather than simply omitted portions.  Additionally, Novartis alleged that FDA unlawfully permitted the carve-out of critical safety information of a modified dosing regimen.  Each of these issues, says Novartis, “independently renders the agency’s decision unlawful, and invalidates the agency’s approval of the MSN product.”

ENTRESTO was approved by FDA in July 2015 “to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.”  In February 2021, FDA approved a supplement to the ENTRESTO NDA, which changed the indication such that it now reads “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”  As a result, ENTRESTO is now approved to treat all patients with chronic heart failure, whether classified as having reduced ejection fraction or not, and added a new dosing regimen for specific patients.  Novartis has a patent on the new indication, which claims a modified dosing regimen for use in patients with heart failure with reduced ejection fraction.

While denying a Citizen Petition from Novartis asking FDA to refuse to approve any ANDA that omits the new dosing regimen or changes the indication, FDA approved MSN’s ANDA on July 24, 2024.  FDA, in its Citizen Petition Denial, stated that it retains the authority to approve generic labeling that modifies an approved indication and that it could lawfully approve generic labeling that omits the modified dosing regimen in ENTRESTO’s labeling.  To that end, FDA approved the MSN ANDA without the modified dosing regimen and with the indication “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. Left ventricular ejection fraction (LVEF) is a variable measure, so use clinical judgment in deciding whom to treat.”  From the government’s brief, see here.

Upon denial of the Citizen Petition and approval of the MSN ANDA, Novartis filed suit against FDA arguing that FDA’s actions violate the plain text of the FDCA.  FDA should not have approved the modified indication, as the FDCA requires generic labeling to match the current labeling for the reference listed drug—not the 2015 label that has been discontinued.  Novartis further claims that the MSN labeling is unlawful because it violates the statutory requirement that the indications be “the same.”  While Novartis implicitly questions whether FDA’s regulations are consistent with the statute that requires the same labeling, it points to FDA regulations that permit only the “omission of an indication”—not the modification of the product’s currently approved indication.  Novartis asserts that FDA failed to explain “how a full cloth rewriting of the reference drug’s labeling is consistent with the rest of the ENTRESTO labeling” and that the modified labeling, especially considering the omission of the modified dosing regimen, “renders [the MSN product] both less safe and less effective.”

FDA and intervenor MSN vehemently defend FDA’s approval here.  FDA asserts that “there is no legal or logical basis for Novartis’s claim that generic labeling may only omit a patented use by deleting words from (rather than adding them to)” the RLD’s labeling.  FDA regulations explicitly permit “omission of an indication or other aspect of labeling protected by patent,” which is exactly what FDA approved here when it carved out the use of patients with normal ejection fraction.  FDA further argues that Novartis’s implied preclusion against adding words would lead to absurd results, as the availability of a carve-out would depend on stylistic wording choices in the reference labeling.

Meanwhile, MSN argues that Congress designed the “same labeling” statutory requirements to allow for labeling changes by permitting section viii statements to avoid including language that would infringe a patent.  That’s precisely what FDA did here when it approved the modified label.  According to MSN, Novartis’s reading, which would allow only for changes relating to different manufacturers, product names, or company addresses, is so narrow that it would “render meaningless the section viii statutory provisions because it would not allow generic companies to carve any language from the brand label in order to avoid brand company patents.”  The only way that MSN could have omitted the protected language was to make “minor attendant changes to the label,” and to preclude such modifications “would create a precedent where any brand manufacturer could circumvent section viii statements entirely by carefully wording its indications.”

Both FDA and MSN additionally question whether the carved-out data is actually “critical safety information” as concluded by Novartis.  FDA claims that “Novartis overstates [the data’s] significance” while MSN accuses Novartis of asking the Court to “second-guess FDA’s scientific judgment regarding drug safety and efficacy.”  As a determination of fact, MSN argues, FDA’s assessment here should be treated with respect even under Loper, which, MSN highlights, clearly states that “Section 706 [of the Administrative Procedure Act] does mandate that judicial review of agency policymaking and factfinding be deferential.”  FDA, in responding to the Citizen Petition, laid out a highly reasoned and technical analysis that should be afforded deference, concludes MSN.

At its heart, the question at issue here implicates the survival of the carve-out.  While not quite as “on the nose” as the inducement of infringement cases, Novartis is asking the Court to limit FDA’s authority with respect to the carve-out such that the RLD sponsor’s crafting of the indication would dictate whether a carve-out can even be used.  This case further raises questions about whether deference will continue to be afforded to FDA in the scientific and factual context notwithstanding Loper.  This interesting case is certainly one to watch!

The American Conference Institute (“ACI”) held its 11th Annual Summit for Women Leaders in Life Sciences Law at the Seaport Hotel in Boston, Massachusetts on July 25th & 26th of last week.  Several leading ladies in law at HPM attended the conference and, based on their feedback, gave the annual event an A+ rating.  Our very own Director, Anne Walsh, spoke on a panel titled Navigating Today’s Life Sciences M&A Landscape: Charting the Latest Trends and Challenges in Pharma and Biotech Dealmaking.  As we are all aware, the M&A landscape is an ever-changing place, so there is always something new to learn.  Anne and her fellow panelists engaged the audience with timely and thoughtful insights, each addressing their area of specialty (e.g., FDA, IP, and antitrust).

The weather was great in Boston, and so many talented and inspiring women gathered at the Seaport Hotel to speak on the most pressing issues currently in life sciences.

Substantive topics:

• AI – Leveraging AI in Medical Devices, Harnessing Generative AI in Business Operations and Legal Practice.
• GLP-1s – Exploring the Anticipated Compliance and Litigation Risks.
• Advertising Challenges in Life Sciences.

Highlights:

• CEO Spotlight Interviews.
• Women in Government and Judiciary Roundtable.
• “Mistakes – I’ve Made a Few” Overcoming Bumps in your Career Journey…

Not surprisingly, the impact of Chevron being overturned was a recurring theme throughout the two-day conference. We heard multiple speakers acknowledge that Loper Bright will invite more challenges to government regulation and the need for federal agencies to shore up their rules and regulations to protect past actions and reduce the ripple effects for regulated entities.

This annual summit tends to be a standout conference for women in life sciences law and something that is anticipated all year.  Most importantly, the summit guarantees to empower future generations of women in life sciences.  The focus on networking made it very easy to meet colleagues from all over the country and the world.  We will be sure to put it on our calendars for next year, and hope to see fellow Blog readers in Boston too.

There is a growing consensus among legal experts that after Loper Bright, FDA may rely on non-binding guidance to instruct industry with hopes of charting regulatory pathways that avoid litigation. In areas like biologics, biosimilars, and interchangeable biosimilars, where emerging technologies meet regulatory complexities, this is perhaps a wise strategy. The top line from FDA for any cGMP-governed industry like these is always going to be that quality matters. But in the biologics and biosimilar industries, maintaining quality can be a very nuanced—if not difficult—process.

Last week, FDA issued draft guidance to address the potential complications that arise when sponsors seek to modify products, production processes, or quality controls for approved biologics license application (BLA) biosimilar and interchangeable products. Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Questions and Answers Guidance for Industry is intended to be a roadmap that first describes the change notification process outlined in 21 C.F.R. Part 601.12, and then offers additional information and discussion about what FDA expects to see from applicants who are intent on ensuring quality.

The draft guidance first addresses the kinds of information applicants should develop and collect so that they can evaluate the effects that post-manufacturing changes might have on their products’ identity, strength, quality, purity, or potency. Part 601 delineates those changes as being either major, moderate, or minor.

Major changes may have a substantial effect on quality and require a Prior Approval Supplement (PAS). The draft guidance notes that adding a comparability protocol in a PAS that outlines postapproval chemistry, manufacturing, and controls (CMC) changes can be beneficial, potentially paving the way for reduced future reporting if it sufficiently details a minimal risk for adverse effects from the manufacturing changes.

Biosimilar and interchangeable sponsors with moderate post-manufacturing changes can submit a Change Being Effected in 30 Days (CBE-30) supplement. The draft guidance reminds applicants that FDA must approve or note any missing information in a CBE-30 supplement within 30 days before an applicant distributes the product.

Here again though, both the guidance and the regulations describe how a persuasive filing may have advantages for an applicant. A product described in a well-drafted and persuasive CBE-30 might in turn merit immediate distribution, in effect changing a CBE-30 to a CBE-0. The draft refers industry to other guidances on the factors FDA might consider, and the regulation tells us that they include “substantial similarity with a type of change regularly involving a [CBE] supplement or . . . [where] evidence that the proposed change has been validated in accordance with an approved protocol . . . .” In our experience such a change is rare, but perhaps FDA is of the mind here to clarify how this might happen. As for minor changes that have minimal effect of product quality, the draft guidance notes that applicants can document those in their annual report, as opposed to a discreet filing with the agency.

Between the discussion in the draft guidance and the steps described in Part 601, applicants should have useful instruction of how to notify FDA of postapproval changes. But the draft guidance also includes several helpful takeaways for applicants about the kinds of quality data that they should evaluate. For example, it notes that applicants should conduct comparability exercises before and after the manufacturing change and analyze both the data from those exercises as well as their design. That’s because “postchange biosimilar or interchangeable biosimilar product should be evaluated at the process step most appropriate to detect a change in the quality attributes.” As with any cGMP issue, sponsors taking this on also need to focus on process validation.

And since we’re talking about biosimilars and interchangeables, FDA notes that an applicant should include a “well-qualified, in-house reference material.” This is an important “calibration point” for comparability, ideally enabling applicants to evaluate whether the changed product remains sufficiently similar to the reference product.

When applicants introduce a licensed biosimilar or licensed interchangeable product into a multiproduct manufacturing area, they potentially risk cross-contamination, or loss of controls over personnel, process, or materials. The draft guidance notes that in this situation, purity and identity of the product are the key quality attributes at risk. FDA counsels that sponsors evaluate the multiproduct manufacturing risks based on both the type of product and the potential effects of additional controls. In other words, there are no strict guidelines that span across the biosimilar industry.

Finally, the draft guidance describes the CMC information that FDA recommends applicants submit in support of a supplement for a change in dosage form or strength. That information includes adequate comparability data between the original licensed biosimilar or interchangeable and the proposed new dosage form or strength. It also includes an adequate comparative analytical assessment and validated manufacturing data that supports the change.

As is seen here through the myriad regs and guidances we’ve linked, quality assurance for biologics, biosimilars, and interchangeables is a labyrinthine pursuit, and FDA expects to hear about how applicants are ensuring it. We’ll update this post when FDA issues Final Guidance.

In November 2023, FDA published a proposed rule regarding wound products containing antimicrobials. From a legal perspective, the reason for the proposed rule is that these wound products are some of the few remaining medical devices that have not yet been classified by FDA. As a result, they have been coming to market through the 510(k) process as Class II medical devices since passage of the Medical Device Amendments, nearly 50 years ago. While it is well within FDA’s right to formally classify the products, the position it is taking in the proposed rule is not based in science or evidence, and raises serious commercial speech concerns.

Without providing a single piece of evidence, the premise of the proposed rule is that these wound products with antimicrobials are contributing to the spread of antimicrobial resistance (AMR). FDA’s position is that finalizing this rule will lead to a reduction in morbidity and mortality. However, FDA fails to provide any evidence of deaths or serious injuries associated with the long-standing use of these products. Despite the lack of support for its position that these products pose significant risk, FDA is proposing to upclassify certain wound products with antimicrobials to Class III, and for those remaining in Class II, to impose stringent special controls, ranging from an AMR risk assessment to prohibitions on truthful, scientifically accurate speech.

The Washington Legal Foundation graciously published my article analyzing the rule and discussing the implications to industry if finalized. While the comment period has closed, we will be tracking FDA efforts to finalize the rule. If you have questions about how this might impact you, or would like talk about how you can influence FDA before the rule is finalized, please reach out.

The American Conference Institute (“ACI”) is holding its 10th Anniversary Paragraph IV Disputes Master Symposium from October 15-16, 2024, at the Hyatt Regency McCormick Place in Chicago, Illinois.  Each fall, leading pharmaceutical patent litigators for brand-name and generic drug companies gather at the Paragraph IV Disputes Master Symposium in Chicago to receive up-to-the-minute information on the latest developments affecting Hatch-Waxman litigation and participate in significant peer-to-peer networking opportunities.  Join us to address emerging and growing areas of concern, including the implementation of the Inflation Reduction Act, FTC’s—and now a District Court’s—attack on Orange Book patent listings, and the proposed use of the Bayh Doyle Act.

Other key program highlights this year include:

• Examining the Use of Clinical Trials as Prior Art: How to Thread the Needle on Protecting IP and Mandated Disclosures
• Patent Rights and Supply Chain Dynamics: Understanding How Developments in India May Affect Hatch-Waxman- Generic and Brand Perspectives
• Fireside Chat on Future of FDA Initiatives Affect Small Molecules: Regulatory Initiatives, and Agency Developments for Hatch Waxman Practitioners to Watch

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will moderate a panel discussion, titled “Fireside Chat on the Future of the FDA: Regulatory Initiatives, and Agency Developments for Hatch Waxman Practitioners to Watch.”

You can register for the conference here.  FDA Law Blog readers receive a 10% discount off the tuition fee (promo code D10-999-FDA25).

For several years, FDA has requested that sponsors of drug or biologic led combination products identify essential performance requirements (EPRs) related to the device constituent in their applications.  EPRs were usually requested in the context of design controls, although 21 C.F.R. § 820.30 does not use this term.  In various meetings with the Agency and at conferences, FDA was often asked to clarify this term.  Are EPRs the same as “Essential Performance” as defined in IEC 60601-1 Medical electrical equipment – Part 1: General requirements for basic safety and essential performance?  Are EPRs design outputs that are essential for the proper functioning of the device that are required to be identified per 21 C.F.R. § 820.30(d)?  Are EPRs a new term to describe a subset of design input requirements and specific to combination products?

FDA recently released a much-anticipated draft guidance to address these frequent questions:  Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products.  We were thankful to see that the term, EPR, has been replaced with Essential Drug Delivery Outputs (EDDO), which better aligns with terminology and requirements of the Quality System Regulation.

The draft guidance (June 2024) defines an EDDO as the “design outputs necessary to ensure delivery of the intended drug dose to the intended delivery site.  Drug delivery includes successful product preparation and the initiation, progression, and completion of dose delivery.  EDDOs are system level outputs for which device drug-delivery function is dependent on the device design.”   There is a lot to unpack in this definition and the draft guidance includes sections to help sponsors identify and differentiate which design outputs should be considered EDDOs, and includes appendices with examples demonstrating the process of identifying EDDOs as well as an appendix providing examples of potential EDDOs based on product type that includes prefilled syringes, auto-injectors, on body injectors, pen injectors, jet injectors, nasal sprays, metered dose inhalers, dry powder inhalers, nebulizers, vaginal systems, infusion pumps, and subdermal implants.

While the scope of the guidance indicates that it is intended to address information about EDDOs submitted for drug- or biologic-led combination products, the guidance also covers applicability to 510(k)s, PMAs, and IDEs suggesting that the draft guidance may also apply to the device constituent of cross-labeled combination products, or drug delivery devices not associated with a combination product.

With respect to verification and validation of EDDOs, the draft guidance recommends demonstration that the EDDO is met after preconditioning that includes conditions of storage and shipping.  Design verification testing should include risk-based sampling plans and include evaluation over the shelf-life for EDDOs that may change over time or have age-related failure modes.  Design validation may be covered by clinical studies, pharmacokinetic/pharmacodynamic or bioequivalence/bioavailability studies, literature, simulated bench testing, and/or anthropometric data and should include endpoints that have the capability of validating device performance.

A control strategy should be established to ensure that each lot of the final finished product is manufactured to conform to the design outputs.  A risk-based approach can be used for each EDDO to determine the appropriate control strategy.

Information to include in IND, IDE, and marketing applications is also described within the draft guidance.  Common across application types are a description of the device constituent and performance data.  For marketing applications, a summary of the EDDO information is recommended in the device description with reference to performance data and other supportive information.

Although there are some inconsistencies in the scope of the guidance, it overall should be a valuable resource for developers of drug delivery devices when final.  Comments may be submitted by September 30, 2024.

The American Conference Institute (“ACI”) is holding its 2nd West Coast Editionof its Legal, Regulatory, and Compliance Forum on Cosmetics & Personal Care Products from September 25-26 at the Le Meridien Delfina, Santa Monica, California.  Join distinguished counsel and regulatory experts representing the cosmetics and personal care industry, together with government officials, as they share insights on myriad topics, including:

• Preparing for the next stages of the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) implementation
• Analyzing specific California and Washington laws and regulations governing cosmetics and personal care products
• Assessing the latest developments in PFAS legislation and litigation
• Obtaining insights into FTC and NAD Guidelines on Influencers, Consumer Reviews and Endorsements
• Comprehending West Coast product labelling, packaging and recycling laws
• Navigating emerging trends in Clean Beauty and ESG Practices
• Addressing Beauty-Tech and Consumer Privacy protections in the digital era
• Understanding global trade regulations and successfully introducing your products into a dynamic world marketplace
• Implementing IP protections and anti-counterfeiting strategies for your brand

Hyman, Phelps & McNamara, P.C.’s John W.M. Claud will be speaking at the conference in a session titled “Crafting Your Safety Blueprint for Adverse Events and Recalls under MoCRA.”

You can register for the conference here.  FDA Law Blog readers receive a 10% discount off the tuition fee (promo code D10-999-FDA25).