Attorney East Hampton

By McKenzie E. Cato & Deborah L. Livornese —

As surveyed in detail by our colleagues in an earlier blog post, FDA’s PDUFA VII goals letter, for fiscal years 2023-2027, is full of announcements and new agency initiatives.  One of those announcements is a commitment to create a new process for reviewing sponsor-initiated requests for release from postmarketing requirements (PMRs).

The process outlined in the goals letter begins when a sponsor submits a request to FDA summarizing its rationale for why an existing PMR is no longer needed, including all necessary supporting data and information.

The relevant FDA review division or office will initiate review of the request, and will notify the sponsor of any additional information considered necessary to evaluate the request within 45 days of receipt.  FDA will then respond to the sponsor with a decision on the PMR release request within 60 days of receipt of the original request, or within 60 days of receipt of the additional information requested by FDA, whichever is later.

FDA’s decision will take the form of an “agreement letter” or a “non-agreement letter.”  In the case of a non-agreement letter, FDA will provide its rationale for the decision.

If FDA’s response is a non-agreement letter, the sponsor has the option of submitting a request for reconsideration with justification, and any additional information and/or data if appropriate.  The process as outlined in the goals letter does not include a deadline for when such a request for reconsideration must be submitted.

Upon receiving a reconsideration request, the review division/office will discuss with the appropriate internal committee that includes senior agency leadership (e.g., Medical Policy and Program Review Committee, Medical Policy Coordinating Committee, and Pediatric Review Committee).  The review division/office will issue a written response to the reconsideration request within 45 days of receipt.  As with the original request for release from the PMR, FDA’s decision will be an agreement letter or a non-agreement letter, and if a non-agreement letter, will include FDA’s rationale for the decision.

Today, sponsors are able to submit requests for release from PMRs.  FDA may respond to these requests by arranging a teleconference to discuss and/or providing a decision in the form of a General Advice Letter.  However, there is currently no formalized timeline or review process.  There is also no guarantee that FDA will provide any rationale for its decision to deny a request for PMR release.

The new review process announced in the PDUFA VII commitment letter will bring much-needed consistency and predictability to requesting release from PMRs.  Additionally, the commitment to include FDA’s rationale in a non-agreement letter will provide sponsors another opportunity to address FDA’s concerns in the form of a reconsideration request.

We look forward to the roll-out of this new process, but it will be some time until we see it in action.  This new process will be incorporated into relevant agency procedures and guidances beginning FY 2023, and will be finalized by the end of FY 2027 and are not subject to PDUFA performance goals.  So, FDA may not begin implementing this new process immediately, but it may be a potential avenue for sponsors starting in late 2022 or early 2023.

By Faraz Siddiqui —

Last week, we blogged about a growing list of drug manufacturers that have refused to follow a 2010 guidance issued by the Health Resources and Services Administration (“HRSA”), which permits 340B covered entities to contract with multiple pharmacies to dispense drugs to covered entity patients.  Because of concerns that these contract pharmacies, which include some of the largest chains in the U.S., are diverting drugs purchased at low 340B prices to non-340B patients, the companies are declining to sell drugs to 340B covered entities that use multiple contract pharmacies.

When HRSA threatened enforcement action and penalties, several companies sued the HHS in federal district courts in Maryland, Indiana, Delaware, New Jersey, and the District of Columbia to enjoin those enforcement actions (see list below). These lawsuits were filed between January and June of 2021.

On May 31, 2021, even as the contract pharmacy dispute was playing out in federal courts, the Arkansas legislature enacted Act 1103 of 2021, entitled the “340B Drug Pricing Nondiscrimination Act.” See Ark. Code Ann. § 23-92-604(c)(1), (2). Among other things, Act 1103 makes it unlawful for pharmaceutical manufacturers to prohibit pharmacies from contracting with a 340B covered entity by denying the pharmacy access to its drugs and makes it unlawful for pharmaceutical manufacturers to deny or prohibit 340B drug pricing for Arkansas-based community pharmacies that receive drugs on behalf of a 340B covered entity. Id.

On September 29, PhRMA sued Arkansas in federal court for declaratory and injunctive relief, seeking to stay the enforcement of Act 1103 pending resolution of the 340B lawsuits in federal courts. This follows PhRMA’s July 2021 petition to the Arkansas Insurance Department, the agency charged with the implementation and enforcement of Act 1103, for a Declaratory Ruling relating to the state’s ability to enforce these two provisions. According to PhRMA, Arkansas effectively seeks to add Arkansas pharmacies as a sixteenth type of covered entity into a federal 340B statute that defines fifteen covered entities.

PhRMA seeks a declaration that pharmaceutical manufacturers need not offer price discounts to contract pharmacies in Arkansas because Ark. Code Ann.§ 23-92-604(c) is both preempted by the federal 340B statute (conflict and field preemption), and because it is unconstitutional under the dormant commerce clause (having the practical effect of regulating commerce occurring wholly outside that State’s borders). PhRMA also requests an injunction barring Defendants from implementing and enforcing Act 1103 against PhRMA and its members.

In response to PhRMA’s petition to the Arkansas Insurance Department, the Commissioner of the Department immediately stayed the enforcement of Act 1103 for 90 days, until October 26, 2021. It remains to be seen if the Department will renew the stay after it expires later this month.

[The currently pending lawsuits in federal court are AstraZeneca Pharmaceuticals v. Becerra, No. 1:21-cv-00027-LPS, 2021 WL 2458063 (D. Del. Jan. 12, 2021); Eli Lilly & Co. v. Cochran, No. 1:21-cv-00081-SEB-MJD (S.D. Ind. Jan. 12, 2021); Sanofi-Aventis U.S., LLC v. HHS, No. 3:21-cv-00634-FLW-LHG (D.N.J. Jan. 12, 2021); Novo Nordisk Inc. v. HHS, No. 3:21-cv-00806-FLW-LHG (D.N.J. Jan. 15, 2021); Novartis Pharms. Corp. v. Becerra, No. 1:21-cv-01479 (D.D.C. May 31, 2021); United Therapeutics Corp. v. Espinosa, No. 1:21-cv-1686-DLF (D.D.C. June 23, 2021); PhRMA v. Cochran, No. 8:21-cv-99198-PWG (D. Md. Jan. 22, 2021).]

The American Bar Association has published a guide to food law that was co-authored by a number of practitioners in this growing field. The book is billed as having been “written by practicing lawyers for practicing lawyers, with a focus on information that is both practical and actionable.” The book includes chapters on federal regulation, food litigation, safety and recalls, nutrition programs, international law, use of block chain in the industry, securing the food system during the pandemic, and intellectual property. HPM’s Ricardo Carvajal contributed the chapter that provides an overview of federal regulation.

By Karla L. Palmer —

The tale of “David versus Goliath” is never a dull skirmish.  This time, “David” consists of a cast of seven compounding pharmacies and their amicus curiae supporters.  And the “David” cast of characters has successfully challenged FDA’s promulgation of its final Memorandum of Understanding (“MOU”) intended to “address” shipments of compounded medications interstate.  See Federal Food, Drug, and Cosmetic Act (“FDCA”) Section 503A(b)(2).

The U.S. District Court’s opening sentence of its Memorandum Opinion captures the historical essence of compounding:

Evoking Victorian apothecary scales and porcelain mortars and pestles, compounded drugs are formulated by pharmacists to create medicines tailored for individual patients.

Plaintiffs challenge FDA’s attempt—through promulgation of the MOU—to redefine compounding and the distribution of compounded formulations interstate in a manner that violates the procedural requirements of the Regulatory Flexibility Act (“RFA”).  See 5 U.S.C. § 603-604.  Remanding the MOU to FDA to engage in that required RFA analysis, or certify why it is not necessary, the Court deferred ruling on Plaintiffs’ substantive claims concerning whether the MOU—in particular its redefinition of the terms “distribute,” “dispense” and “inordinate amounts” and “shall issue regulations” clause—violates FDCA Section 503A.  The District Court spent 30 pages of its 38 page opinion detailing exactly why the Court has standing to adjudicate the aggrieved Plaintiffs’ claims, which standing arguments were briefed in excruciating detail by the government.

The matter involves a “decades old skirmish” dating back to the late 1990s, (and previously blogged about here and here) when Congress passed the Food and Drug Administration Modernization Act (“FDAMA”), which created Section 503A.  Section 503A’s language requires FDA to promulgate a MOU to “address” the “distribution” of “inordinate amounts” of compounded drugs interstate and that it “shall issue regulations” to do so.  Pharmacies located in states that choose to not sign the non-negotiable MOU are limited to an interstate distribution limit of 5% of their compounded formulations.  In signatory states, compounding pharmacies are subject to a 50% “threshold” and certain reporting requirements.  To date, two states have signed the MOU.  Notably, FDA recently extended the time period for states to sign the MOU until October 2022, at which time FDA would commence enforcement of its provisions.

FDA’s MOU drafts were the subject of various iterations over the past two decades, evoking comments from thousands of interested parties.  FDA finally settled on a “final” MOU a year ago, and a coalition of compounding pharmacies immediately filed suit.

The Plaintiffs’ complaint alleges both substantive and procedural violations in FDA’s development of the MOU.  Plaintiffs  claim that, because the MOU is a legislative rule, its promulgation violated the RFA due to FDA’s failure to analyze the economic impact of the regulation on pharmacies.  Plaintiffs also plead a substantive violation—that FDA exceeded its statutory authority under Section 503A in defining several key statutory terms.

The Court stated, “by defining key statutory terms in Section 503A that have binding legal consequences, FDA has evinced its intent to speak with the force of law in the MOU.” Mem. Op. at 32.  Furthermore, FDA’s “ultimate decision has significant binding legal consequences for plaintiffs and pharmacies across the country, and it signals a substantive change in the current legal regime governing interstate compounding.” Mem. Op. at 37.

Determining that the MOU is indeed a legislative rule, the Court ruled in favor of the pharmacies on the procedural issue, but deferred on the critical substantive issue: in essence, whether the MOU improperly defines “inordinate amounts,” conflates the acts of “dispensing” and “distribution,” and violates the “shall issue regulations” requirement in Section 503A.

Given Plaintiffs’ successful procedural challenge, the Court has remanded the matter back to FDA.  The Court ordered the Agency either to prepare the required regulatory analysis or certify that the MOU “rule” will not have a “significant impact on a substantial number of small entities.”  Mem. Op. at 37 (citing the RFA, 5 U.S.C. § 605(b)).  This blogger is interested in that analysis, especially because all of the Plaintiffs submitted declarations concerning the economic impact of the rule.  The Court will request a progress report from FDA in 60 days.  Does this take FDA back to the MOU drawing board, for the fourth time in 21 years?  And, after the Agency complies with the Court-ordered RFA requirement, will the Court then turn to the substantive merits addressing the significant remaining definitional issues raised by Plaintiffs?  Stay tuned.

By Faraz Siddiqui —

The 340B drug pricing program has been booming, according to the Health Resources and Services Administration (“HRSA”), the agency under the U.S. Department of Health and Human Services (“HHS”), which reported that discounted purchases totaled $38 billion in 2020, a 27% increase compared to 2019.  The 340B program, authorized under Section 340B of the Public Health Services Act and administered by HRSA, imposes a ceiling price on pharmaceutical manufacturer sales to “covered entities,” which are certain health clinics that receive federal funding and certain types of safety net hospitals to provide them drugs at lower prices.  Manufacturers may choose not to participate in this program, but the federal government will not reimburse for their outpatient drugs under Medicaid or Medicare Part B if they do not.

A growing list of drug manufacturers are claiming that the discounts meant for low-income patients of 340B covered entities are instead contributing to profits for pharmacies that contract with covered entities to dispense 340B drugs.

Use of contract pharmacies ballooned after  a guidance issued by HRSA in 2010 allowed covered entities to use multiple contract pharmacies to dispense drugs to covered entity patients. By 2014, the HHS Office of Inspector General (“OIG”) found that the rise of contract pharmacy arrangements resulted in duplicate discounts and drug diversion, and a lack of access to 340B pricing at the contract pharmacies. A 2018 report by the Government Accountability Office (“GAO”) found similar issues, as well as contract pharmacy noncompliance and poor federal oversight.

Drug Manufacturers Fight Back Against Proliferation of Contract Pharmacy Arrangements

Drug manufacturers raised their concerns about the 340B program with HRSA with no success. Starting August 2020, several drug manufacturers announced that they would offer 340B prices only to covered entities that have an in-house pharmacy or contract with a single contract pharmacy, essentially reverting to a 1996 HRSA guidance. The companies asserted that their position fully complied with applicable law, and objected  that the practice of using multiple contract pharmacies, based on HRSA’s nonbinding interpretive guidance, has resulted in widespread contract pharmacy noncompliance, and has affected costs, distorted prescribing decisions, and hurt patient care.

In response to this trend, the HRSA general counsel issued an Advisory Opinion (“Opinion”) on December 30, 2020 reaffirming that the 340B program allows covered entities to distribute discounted drugs through multiple contract pharmacies—and that manufacturers are required to sell them those drugs. HRSA based its opinion on the statute and agency precedents over the last 25 years. In January 2021, several companies and the Pharmaceutical Research and Manufacturers of America (PhRMA) sued the agency on various statutory and procedural grounds.  See, e.g., AstraZeneca Pharmaceuticals v. Becerra, No. 1:21-cv-00027-LPS, 2021 WL 2458063 (D. Del. Jan. 12, 2021).

Despite the ongoing legal proceedings, HRSA sent letters to the drug companies on May 17, 2021 stating that their 340B restrictions violated the 340B statute and that they “must immediately begin offering its covered outpatient drugs at the 340B ceiling price to covered entities through their contract pharmacy arrangements.” (see for example, this letter to Astra Zeneca).  The letters also stated that a refusal to do so may result in civil monetary penalties of around $5,883 for each instance of overcharging—over and above repaying the covered entity the amount overcharged. In AstraZeneca v. Becerra, the company requested, but the Court refused to an administrative stay of these fines until the lawsuit was settled. According to AstraZeneca’s court filings, the fines alone would accrue to the tune of $530 million per month.

Federal Court Found HRSA’s Advisory Opinion Was Based on Faulty Legal Grounds

On June 16, 2021, the District Court of Delaware issued a memorandum opinion denying HRSA’s motion to dismiss AstraZeneca’s case, finding that the Advisory Opinion was based on faulty legal grounds. Judge Stark found that, although HRSA’s interpretation of the statute was permissible, the Advisory Opinion unjustifiably assumed that Congress imposed this interpretation as a statutory requirement. According to the court, the relevant language of the Act was ambiguous and neither the plain meaning of the statute, nor the context of the statutory provisions or the legislative intent, explicitly supported HRSA’s Opinion (or, for that matter, AstraZeneca’s position). Because “the agency wrongly believes that interpretation is compelled by Congress,” the court refused to give agency deference to HRSA. The court also disagreed with HRSA’s arguments regarding longstanding agency precedents. The court noted that HRSA “dramatically expanded how covered entities may purchase 340B drugs” in the past 25 years. In fact, the Advisory Opinion was the first agency document to explicitly conclude that manufacturers are required by statute to provide 340B drugs to multiple contract pharmacies. According to the court, “because the government has changed what covered entities may do,” HRSA “has consequently changed what drug manufacturers must do” (emphasis in original).

Two days after the court’s opinion, HHS withdrew the December 30, 2020 Opinion, but the parties agreed that the lawsuit was not moot because HRSA did not withdraw the May 17 letters and continued to maintain that companies must sell to covered entities through contract pharmacies.  AstraZeneca was permitted to amend its complaint to focus on the unlawfulness of the May 17 letters instead of the Advisory Opinion.  As of this writing, the court is still deliberating on the relief to be granted to the manufacturer.  A decision is expected in the coming months.

HRSA Ploughs on With Enforcement Despite Federal Court Decision

Despite the ongoing litigation, on Wednesday, September 22, 2021, HRSA signaled its continued intention to enforce its own interpretation of the 340B program requirements by referring the alleged violations of six drug companies to the HHS OIG. In its letters to the companies informing them of the referral, HRSA notes that, “given [the companies’] continued refusal to comply, HRSA has referred this issue to the HHS Office of Inspector General (OIG) in accordance with the 340B Program Ceiling Price and Civil Monetary Penalties Final Rule.”  OIG enforcement would provide HHS another opportunity to impose fines and restitution while avoiding the procedural issue of lack of notice-and-comment rulemaking. The OIG will nevertheless have to account for the federal court’s conclusion that the requirement to sell 340B drugs to multiple contact pharmacies is not contained in the statute.  The drug companies can be expected to challenge any OIG penalties.

At some point, Congress may cure the statutory ambiguity by clarifying the scope of permitted contract pharmacy use under the 340B program, but such a clarification does not appear in the White House drug pricing plan (summarized here) or the major drug pricing bills currently being considered by Congress.

The American Conference Institute (“ACI”) is sponsoring its 16th Annual Paragraph IV Disputes Conference on November 9-10, 2021 in New York, NY (Livestream Option Available) at the Sheraton New York Times Square Hotel.  And, unlike a lot of conferences over the past year-plus, the ACI conference format will be a live, in-person event (though an interactive, virtual livestream is also available).

ACI’s Paragraph IV Disputes Conference provides invaluable professional development opportunities, meaningful networking, and vital “take-aways” for legal strategies and cost analysis for every aspect of this complex form of litigation

A “Who’s Who of the Food Law Bar” will give you critical insights in sessions like:

• “Forecasting the Future of Pharmaceutical Patent Litigation: Trends, Legal Analyses and Business Prognoses Post-Covid”
• “Spotlight on Delaware: District Court Judges Address Brand and Generic Concerns”
• “The PTAB Live! Practice, Policy, and Procedure in the New World of Pharmaceutical Patent Validity Challenges”
• “The Ethical Practice of Paragraph IV Litigation: New Developments Impacting Professional Responsibility in the Hatch-Waxman Arena”

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be speaking at a “Regulatory Think Tank” session, titled “Analyzing the Effect of the Latest FDA Initiatives on Generic Drug Access and PIV Disputes.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-895-895AX04. You can access the conference brochure and sign up for the event here. We look forward to actually seeing you at the conference.

By Kalie E. Richardson —

On September 24, 2021, the owner of a pharmacy in Puerto Rico pleaded guilty to participating in a felony conspiracy to convert government property and to commit health care fraud in connection with the illegal vaccination of minors between the ages of 7 to 11 with the Pfizer-BioNTech COVID-19 vaccine.  The U.S. Attorney’s Office (USAO) for the District of Puerto Rico and the Department of Health and Human Services, Office of Inspector General (HHS-OIG) announced both the charge and the plea on Monday.  To the best of our knowledge, this is the first time anyone has been federally charged for administering the COVID-19 vaccine to an unauthorized population.

From approximately May 28, 2021 through June 22, 2021, the pharmacy owner and her employees conspired to knowingly and willfully administer the Pfizer-BioNTech COVID-19 vaccine to a total of 24 children aged 7-11 and to submit corresponding claims to the Pharmacy Benefit Manager (PBM) for Medicaid in Puerto Rico.  A full dosage (30 µg) of the vaccine was administered to the children; no serious medical conditions have been identified to date as a result of the illegal vaccination.  The Pfizer-BioNTech COVID-19 vaccine received emergency use authorization (EUA) for the prevention of COVID-19 disease in individuals aged 12-15 in May 2021.  While Pfizer and BioNTech recently announced positive results from a pivotal trial of its COVID-19 vaccine in children ages 5-11, it has not yet received an EUA for this age group.  Additionally, this recent trial studied a two-dose regimen of 10 µg administered 21 days apart, a much smaller dose than the 30 µg dose used for individuals 12 and older.  The Pfizer-BioNTech COVID-19 vaccine, now marketed as Comirnaty, has received full approval for the prevention of COVID-19 disease in individuals 16 years of age and older, and is available under EUA for children 12-15.

The use of an approved drug for a use that was not approved by FDA, commonly known as “off-label” use, is typically a decision left to individual healthcare providers.  However, that is not necessarily the case within the specific context of the COVID-19 vaccines.  Currently, all COVID-19 vaccine used in the United States has been purchased by the government for administration exclusively by enrolled providers through the CDC COVID-19 Vaccination Program.  Eligible pharmacies participating in the program must comply with all FDA requirements, including the vaccine’s EUA or approval.  COVID-19 vaccines must be free to the patient, but vaccination providers may seek reimbursement for vaccine administration fees from the applicable private or public payor.  By administering the vaccine to children aged 7-11, which is not an age group authorized under the EUA, the pharmacy illegally conspired to “convert” the government’s property (i.e., the vaccine itself).  “Conversion” is a common law tort that may occur when one intentionally interferes with a person’s right to property without the owner’s consent and without lawful justification.  By billing the PBM for the administration of the vaccine to an unauthorized population, the pharmacy committed health care fraud.  In Monday’s statement, the USAO and HHS-OIG said that the unlawful activity was “identified quickly” by the Puerto Rico Department of Health.

Under the terms of the plea, the pharmacy owner voluntarily agreed to be excluded as a provider for Medicare, Medicaid, and all federal health care programs for a period of five years.  She also faces a maximum penalty of 5 years in prison, a fine of up to $250,000, and 3 years of supervised release.  The pharmacy itself was suspended from the COVID-19 vaccination program and all funds received for the corresponding Medicaid billings were repaid.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Jeffrey Shapiro and Serra Schlanger will present at this year’s Food and Drug Law Institute virtual Advertising and Promotion for Medical Products Conference on October 13–15.  This conference will analyze the latest regulatory issues related to advertising and promotion of human and animal drugs, medical devices, and biologics.  Jeff will participate in a session on Drug and Device Uses of Digital Health Tools: Considerations for Advertising and Promotion, focusing on how pharma and device companies should approach labeling and other promotional materials for digital health tools, including software apps and digital therapeutics.  Serra will moderate a session on the Impact of Telehealth on Advertising and Promotion, addressing marketing issues and opportunities associated with virtual health care.

We can offer our readers a discount of 15% off registration using code AP15.  We look forward to seeing you at this virtual conference.

By Charles Raver & James E. Valentine —

Few FDA publications are as eagerly anticipated in the drug development world as the twice-a-decade PDUFA Reauthorization Performance Goals and Procedures (hereinafter the “goals letter”). When FDA published the fiscal years (FY) 2023-2027 goals letter at the end of August, making known their commitments and planned initiatives for the coming years, we were both excited by many of the announcements, while recognizing the real success will come from how the Agency implements them. From new initiatives to facilitate faster reviews for new indications under the Split Real Time Application Review (STAR) pilot program, to bringing new meetings under PDUFA goals, to continued support for rare diseases and incorporation of the patient voice, the goals letter revealed a good number of welcome announcements.

Perhaps the most welcome commitment, both the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) plan to hire significantly more drug review staff under PDUFA VII than we had seen under PDUFA VI. The targets for FY 2023 are 132 new hires for CBER and 77 for CDER, representing a tripling and quintupling, respectively, of the equivalent hiring targets for the first FY under PDUFA VI. In total for all FYs, the hiring commitments would equal a jump from 171 (PDUFA VI) to 228 (PDUFA VII) new staff in CBER and 32 (PDUFA VI) to 123 (PDUFA VII) in CDER. However, the hiring targets drop dramatically in both centers in each subsequent FY after FY 2023. We have seen first-hand the difficult task faced by CBER review staff to keep up with the flood of innovative cell and gene therapy products, as well as the taxing influx of COVID-19 pandemic related applications requiring review resources in both Centers. Our hope is that expanding review capacity will have the secondary effect of maintaining staff retention, as there are real concerns over retention from burnout, especially with a large retirement-eligible workforce.

A lasting impact of the COVID-19 pandemic can also be seen in the FY 2023-2027 goals letter. When travel restrictions and public health precautions halt facilities inspections, many sponsors are left wondering how FDA will complete pre-approval inspections and meet their products’ respective PDUFA dates. In response, FDA memorialized its intention to use some of the new tools explored during the pandemic and potentially make them more permanent fixtures of facility inspections (e.g., requesting records in lieu of an inspection, use of information shared by trusted foreign regulatory partners).

While FDA’s plan to use new tools in facilities inspection may be welcome news to those who saw their PDUFA dates extended due to a pending inspection during the pandemic, a far more disappointing consequence of the pandemic can also be seen in the goals letter. FDA appears to be more readily equating in-person with virtual (videoconference) face-to-face meetings. Several small textual changes as well as a footnote buried amidst the meetings goals show FDA using “face-to-face” meetings to mean both in-person and virtual platforms. As our colleagues, Deborah L. Livornese and Josephine M. Torrente, explained in a previous post, in-person meetings create important opportunities for building rapport, and lead to more robust dialogue and collegial relationships between the Agency and sponsors. We echo this sentiment and hope this will merely be an artifact when the pandemic risks subside, which we certainly hope will be before the end of PDUFA VII in 2027.

Meeting requests should still include a statement with “the sponsor’s proposal for either a face-to-face/virtual/teleconference meeting or a written response.” While it’s not clear whether this inclusion of both “face-to-face” and “virtual” was an intentional distinction from earlier references in the goals letter only to “face-to-face” as opposed to an oversight, those who share our concern will have opportunities to voice such concerns during two public meetings. FDA will discuss the goals letter and field public comments, on September 28, 2021 (announcement here), as well as a separate workshop on meetings management practices, which is to be held by July 30, 2024. On the other hand, given that virtual PDUFA meetings held during the pandemic, even when over videoconference platforms like Zoom or WebEx, have been absent of video (with the exception of a few senior officials), we hope that during the time that virtual meetings continue to be necessary, that the intent of this commitment letter to allow them to include video.

Pandemic influences aside, the FY 2023-2027 goals letter contained many notable new initiatives, announcements, and commitments. Some of these will be subjects of more detailed posts in the future and readers should keep an eye on the blog for additional coverage. Below we provide an overview of some of the goals letter’s most notable contents such as new initiatives as well as some large-scale enhancements to programs that have already been in the works. Programs like Advancing Real-World Evidence (RWE) and new commitments to patient focused drug development (PFDD) represent evolutions and formalizations of existing commitments, whereas examples such as STAR and Type D meetings are entirely new. As such, we present these programs and initiatives roughly in order of the newest and most substantial changes to more minor.

1.  Split Real Time Application Review (STAR) Pilot Program – FDA announced this new two-stage split review program, which is similar to the existing Real Time Oncology Review (RTOR) but applicable to efficacy supplements across all therapeutic areas. STAR aims to facilitate earlier access to novel uses of existing therapies for patients with a serious condition with unmet medical needs. In brief, the process begins with a request for a presubmission informal teleconference (or alternatively, a discussion as part of a pre-sNDA or pre-sBLA meeting). If FDA accepts the application, the sponsor can then submit their supplement in two parts.

The sponsor then gets the review ball rolling by submitting all of the efficacy supplement minus the final clinical study reports and clinical summaries. Part 1 can be submitted as much as 2 months (but no more than 3 months) before completing the application with the submission of Part 2, containing the finalized clinical study reports and summaries. Although the PDUFA review timeline begins with submission of Part 2, FDA will set an action date to be at least 1 month earlier than the normal 6-month goal date for a priority review application.

Notable Dates and Timelines – Program opens, beginning of FY 2023; Expediting reviews fully implemented, by FY 2024; Webpage with detailed criteria for acceptance and participation, October 1, 2022; Interim assessment, end of FY 2025; Public workshop, end of Q2 FY 2026.

2.  Rare Disease Endpoint Advancement (RDEA) Pilot Program – The challenges of establishing substantial evidence of efficacy for a rare disease treatment (small patient populations, slow disease progression, heterogenous or even variable disease presentation) manifest long before providing a final efficacy analysis to FDA reviewers. Establishing efficacy endpoints is perhaps the biggest obstacle to successfully developing therapies for patients with rare diseases. The Agency acknowledged that the current methods by which sponsors and reviewers at FDA interact “are not structured to provide repeated, intensive interactions” in the ways necessary to advance endpoint development for rare diseases.

The RDEA Program is a pilot that will provide an opportunity to submit a proposal for one or more endpoints associated with a development program in an active IND or pre-IND, or in the absence of an active development program, a natural history study. The endpoints must be novel (i.e. never been used to support drug approval) or substantially changed from a previous use. Preference will be given to those proposals for exploring endpoints that may have broad applicability to several diseases, those that reflect different types of endpoints, and, for surrogate endpoints, those with novel approaches to collecting data pre-market to accelerate validation of the endpoint.

RDEA will accept a maximum of one proposal in FY 2023 and a maximum of one proposal per quarter, capped at three per year, in each of the remaining fiscal years of PDUFA VII. Acceptance into the RDEA Program will provide sponsors with 4 meetings (in addition to any other meetings associated with their product development program) focused on developing the endpoint. However, sponsors should understand (1) that participation will require a public disclosure agreement specifying, which aspects of an endpoint development program FDA may disclose publicly, and (2) that advice given during RDEA meetings is neither a regulatory decision nor is it binding. The public disclosure agreement is important for participation in RDEA as the FDA plans to discuss endpoints developed in the program during public workshops, in guidance and on its website, potentially prior to drug approval. The Agency will hold as many as three public workshops during PDUFA VII related to rare disease endpoint development.

We commend the recognition of the increased attention needed to foster drug development in rare diseases, and believe that more iterative interactions may be able to help advance novel endpoints for use in evaluating effectiveness.  At the same time, we hope that this process will be implemented in a way that embraces the need for expediency and appropriate flexibility in rare diseases, rather than instead use this heightened oversight to serve to shift these endpoint development programs into a process more akin to the Clinical Outcome Assessment (COA) Qualification Program, which is known to be slow and burdensome, such that few endpoints make it through the process.

Notable Dates and Timelines – Applications open, Q4 of FY 2023.

3.  CMC Development and Readiness Pilot (CDRP) and Support for Accelerated Development Programs – Acknowledging that drug development programs eligible for accelerated clinical development (i.e. those that address a serious condition with unmet medical needs) through tools like Breakthrough Therapy Designation may not result in more timely approval if CMC development does not keep pace, FDA announced plans aimed at addressing this mismatch. First, CDER will publish a new MAPP (the Manual for Policies and Procedures, meant to guide CDER staff in their review activities and interactions with sponsors) describing: (1) early engagement with sponsors and (2) “science- and risk-based approaches” for CMC development that “may be warranted and utilized . . . based upon the anticipated clinical benefit of earlier patient access to the product.”

In addition, a new CMC pilot program, CDRP, will provide an opportunity for additional meetings and Agency feedback during product development under an IND. Sponsors accepted into the pilot will receive “two additional CMC-focused Type B meetings and an additional limited number of CMC-focused discussions based on readiness and defined CMC milestones.” Few details regarding the CDRP’s procedures or additional eligibility criteria are available until FDA publishes a notice in the Federal Register announcing the program, except that FDA plans to accept 8-10 proposal per FY over a 4-year period.

Both the new MAPP and the CDRP program are intended to assist sponsors with CMC development associated with products that have accelerated development timelines by facilitating better understanding about how to demonstrate and achieve CMC readiness for their products. Although the additional approaches expected in the MAPP will be helpful, the increased communication under the CDRP to provide direct feedback to sponsors about CMC earlier in development will be crucial to fulfilling FDA’s goal.

We have seen first-hand that our clients would benefit from earlier focused engagement with the Agency on their CMC plans. Such engagement should help to avoid discovering only late in a review cycle or even in the context of a complete response letter that their process controls or potency assay are not sufficient, especially in the context of complex products like cell and gene therapies. The Agency also intends to use lessons learned during the CDRP to further improve processes, which will be discussed in a public workshop and potentially inform revisions to MAPPs, SOPPs or guidance documents. The Agency will publish a strategy document following the workshop detailing how they intend to incorporate the lessons learned from the program.

Notable Dates and Timelines – New MAPP published, by Dec. 31, 2022; Publish notice of the CDRP program, by Dec. 31, 2022; CDRP start, FY 2023; Public workshop, by July 31, 2025; Strategy document published, by April 30, 2026.

4.  Other CMC Enhancements (Four-Part Harmony Information Requests (IRs), Inspections Tools, Plans to Advance Innovative Manufacturing) – Beyond the initiatives targeted at CMC programs with accelerated clinical timelines above, the PDUFA VII goals letter contained several additional CMC-targeted enhancements including a new structure for IRs (Four-Part Harmony), continued use of tools developed during the pandemic for facilities inspections, and plans to develop a strategy for advancing the use of innovative manufacturing. The first of these CMC-related announcements, the Four-Part Harmony IR, is meant to improve efficiency and clear communication of information requests during application review. The IR format should clearly indicate (a) what information was provided, (b) what is the issue or deficiency, (c) what is needed, and (d) why it is needed.

As mentioned at the outset, the pandemic forced FDA to use alternatives to in-person visits to conduct facilities inspections. These alternative tools have included requesting records and other information from facilities/sponsors, using information and inspection reports from foreign regulatory authorities, and alternative technology platforms. Informed by experiences during the pandemic and likely in acknowledgement of the potential for future travel restrictions, FDA plans to issue new draft guidance. This guidance will lay out the Agency’s plans and intentions regarding carrying these alternative inspection tools and technologies forward.

To improve adoption of innovative manufacturing techniques, FDA plans to hold a public workshop to discuss the following: best practices and lessons learned from the CDER Emerging Technology Team and the CBER Advanced Technology Team, case studies from sponsors, barriers to adoption, regulatory strategies to improve adoption, and science- and risk-based approaches to development. The discussion and public comments during this workshop will inform a new strategy document with actions the Agency will take during PDUFA VII to advance the utilization of innovative manufacturing technology.

Notable Dates and Timelines – Inspection tools draft guidance, by Sept. 30, 2023; Public workshop on advancing innovative manufacturing technology, by end of FY 2023; Publish advancing innovative manufacturing technology strategy document, by Sept. 30, 2024.

5.  Advancing Real-World Evidence (RWE) Program – The 21st Century Cures Act mandated that FDA develop a program for using RWE to support approval of new indications for approved drugs and support or satisfy postapproval study requirements. While elements of an RWE program to satisfy this statutory mandate have been underway for a few years now, the PDUFA VII goals letter proposal for a process to submit RWE proposals and gain direct feedback from the Agency prior to study initiation appears promising. Similar to the RDEA program, described above, the drawback is that participation is contingent upon willingness and agreement with the Agency about public disclosure of elements of the RWE proposal.

Although a formal announcement of the program is expected by end of 2022, the rough description of the program is as follows – (a) FDA solicits applications twice per year; (b) Applications should describe the regulatory question that the RWE is intended to answer, the RWE study design, and the intended sources of real-world data (RWD) (for the unfamiliar reader, think of RWD as the building blocks and components that make up RWE , similar to the way data from a particular clinical outcome is one component of the clinical evidence of a drug’s safety or effectiveness that a clinical study may provide); (c) FDA will evaluate and rank the applications, accepting one to two applications per cycle for the first two years and one to four per cycle thereafter; (d) Sponsors may then request up to four meetings under the program to discuss data, design, and regulatory issues with FDA staff from across review divisions as well as other offices and senior leadership with RWE expertise. As the program is intended to both support sponsors directly through interactions, as well as broadly inform FDA practices and guide industry when adopting RWE approaches, the Agency will publish annual reports containing application details that have been aggregated and anonymized, hold a public workshop, and update existing RWE guidance documents or publish new guidance.

While use of RWE has largely been focused on the postapproval setting, it remains to be seen if prior experience with RWE under prior PDUFAs will provide the comfort needed to extend the use of this data more broadly into the preapproval setting.  This would be of particular value to the development of drugs for rare diseases where it is incredibly valuable to triangulate safety and efficacy data from multiple sources to gain confidence in the findings.

Notable Dates and Timelines – Initiation of the pilot program, by December 31, 2022; Annual reports, starting by June 30, 2024 and at least annually thereafter; Public workshop, by December 31, 2025; Revise RWE guidance documents and/or publish new guidance, by December 31, 2026.

6.  Patient Focused Drug Development (PFDD) – FDA continues its legacy of PFDD (see our previous coverage here) when it announced that it will continue its efforts to incorporate the patient voice into drug development and regulatory decision-making in several ways. First, the Agency committed to continued internal staff training and outreach to industry and patient groups to facilitate integration of PFDD methods into regulatory decision-making, as well as use the Intergovernmental Personnel Act to leverage outside expertise to support review of patient experience data. The Agency also announced that it will issue a Request for Information soliciting “public input on methodological issues, including the submission and evaluation of patient experience in the context of benefit-risk assessment and product labeling” and plans for two public workshops to discuss these methodological issues, culminating in a report on the findings of the RFI and public workshops and how these will inform priorities for PFDD work in the future. Other PFDD announcements include continued development of a virtual catalog of standard core Clinical Outcome Assessments (COAs) and Related Endpoints, continued work to understand how patient preference may inform benefit-risk determinations, and the intention to use public input to understand stakeholder perspective on priority areas for both core COA development and incorporation of patient preference in regulatory decision-making. Finally, FDA plans to publish a new draft guidance on use and submission of patient preference information (PPI).

While this PFDD commitment sounds much more lackluster than the original PFDD meetings under PDUFA V and the subsequent PFDD guidance series under PDUFA VI, this commitment feels like the prudent approach.  The PFDD meeting initiative, including its expanded externally-led PFDD meeting program, continues on.  Further, the Agency is still finalizing the drafts of the full PFDD guidance series, such that using PDUFA VII to reflect on the application of these programs and guidance is the right approach, while providing the Agency resources through PDUFA to keep these earlier programs running.

Notable Dates and Timelines – RFI announced, by end of June 2023; RFI summary published, by end of December 2023; Two public workshops, by end of FY 2024 and FY 2025, respectively; Summary of RFI and public workshop learning with new priorities, by end of FY 2026; Publish new PPI draft guidance, by Sept. 30, 2026.

7.  Changes to Pre-Approval and Post-Approval Postmarketing Requirements (PMRs) Communications – The goals letter contained new plans and timelines to improve Agency communications with sponsors regarding anticipated PMRs during the review cycle as well as adding new procedures for sponsors to request a review of and release from a PMR post-approval. As our HPM colleagues plan to spell out the details more fully in a subsequent post, we will briefly note that the PDUFA VII commitments require the Agency to communicate detailed thinking about potential PMRs no later than 8 weeks, for standard review, and 6 weeks, for priority review, ahead of the action date for NME NDAs and original BLAs. PMRs can require significant additional time and resource commitments on the part of drug sponsors after already investing years and millions of dollars getting a product successfully to the end of the review cycle and to approval. As such increased communication and predictability, both pre-approval and post-approval, will be a welcome development for sponsors and patients to know that PMRs are both thoughtfully planned and released.

Notable Dates and Timelines – Expect revisions to MAPPs, SOPPs and guidance, starting in FY 2023.

8.  Expansion of INTERACT Meetings, New Type D Meeting, and Meeting Follow-up Questions – Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meetings first started in CBER in 2018 as an informal way for sponsors to get pre-pre-IND advice on innovative biological products with new and unique challenges. Sponsors with novel questions, those for which there is no existing FDA guidance, will now be able to use the INTERACT meetings to seek FDA guidance for products regulated in both CDER and CBER (previously, the ‘C’ in INTERACT stood solely for CBER). In effect, this program aims to reduce bottlenecks in the IND-enabling phase by answering questions about, for example, appropriate preclinical models and toxicology studies for novel drugs, design of proof-of-concept studies, or adequate CMC testing to demonstrate safety for first-in-human studies. Direct feedback earlier in development will help get sponsors to the pre-IND meeting with fewer major questions and better equipped to launch the clinical phase of their development programs.  However, as the INTERACT meeting framework is rolled out more broadly, we have seen a recent an increase in these meetings being denied by CBER and the sponsor asked to wait to request a Pre-IND meeting, so it will be important for the Agency to more clearly describe more clearly elucidate when an INTERACT is appropriate.

PDUFA VII also brings a new meeting type to the drug development armamentarium: the Type D meeting. These meetings will be available when a sponsor needs input on a narrow set of questions such as a follow-up question that raises new issues after a formal meeting. However, the sweet spot for the scope of such a question is one that would be narrower than spanning multiple disciplines but broader than just a clarifying question. FDA will limit Type D meetings to no more than 2 topics and questions that require input from no more than 3 disciplines or Divisions.

Even narrower in scope than the Type D meeting question, FDA also added follow-up opportunities or questions in the form of a Request for Clarification to the goals letter. This memorializes a more recent practice adopted by the Agency given the increased use of WRO meetings during the COVID-19 pandemic, allowing follow-up questions to clarify the Agency’s feedback in a WRO or something captured in meeting minutes.  Now formalized, this request should be submitted by a sponsor within 20 calendar days of receipt of the meeting minutes or WRO. Similarly, FDA committed to responding to such requests within 20 days.

Finally, FDA will hold a public workshop on meeting management. In addition to issues applicable to all meeting types such as submission of meeting requests, time management, and coordinating agenda and development of meeting background packages, the workshop will discuss lessons learned while implementing the two new meeting types as well as those learned during the COVID-19 pandemic.

Notable Dates and Timelines – Response to meeting requests, Type D 14 days, INTERACT 21 days; Meeting scheduled or WRO Issued, Type D 50 days, INTERACT 75 days; Submission of meeting background, at time of request (both); Preliminary responses sent; 5 days before meeting (both); Meeting minutes issued, 30 days (both but INTERACT meeting preliminary responses will only be annotated and resent if necessary); Publish revised formal meetings guidance, by September 30, 2023; Public workshop, by July 30, 2024.

9.  Enhanced CBER Capacity for Cell and Gene Therapy Products – FDA looks to expand the Cell and Gene Therapy Program (CGTP) primarily by increasing CBER staff capacity (hiring targets discussed above) and hinted at potential reorganization by stating “[t]he current CGTP organization will be evaluated, with input from external consultants, to determine the optimal organization to effectively integrate new staff and facilitate operations and customer service.” New hires and organizational changes will be aimed towards “direct review activities, indirect activities (e.g., policy, external outreach, postmarket safety), and supporting activities in the CGTP.” Many of the indirect activities include fostering industry development activities through external outreach, workshops, public meetings, webinars, as well as updating guidance and SOPPs, amongst others.

The goals letter specifically called out continuing commitments in key several areas of interest for cell and gene therapy (CGT) sponsors – advancing manufacturing, testing and implementation of new technologies, continued use of surrogate endpoints, RWE, complex innovative designs and disease natural history, as well as new approaches to establish safety and efficacy for rare and ultra-rare diseases. FDA committed to CGT specific workshops and public meetings: (1) a PFDD workshop focused on understanding patient perspective regarding benefit and risk with CGTs and involvement in study design and execution (in addition to the two PFDD workshops noted above), (2) approaches to capturing post-approval safety and efficacy data, and (3) leveraging knowledge from across therapeutic contexts to facilitate CGT development and review. Novel approaches to development will receive additional attention through public-private partnerships to understand challenges to development of CGTs such as novel endpoints, less defined natural histories, and other challenges common to individualized therapies and rare diseases.

FDA committed to publish new guidance on (1) evaluation of efficacy in small patient populations using novel trial designs and statistical methods (and how to apply these methods to more common diseases), (2) question and answer (Q&A) format for FAQs and on common issues from CGT sponsors, (3) approaches for gathering post-approval safety and efficacy data for CGTs, and (4) leveraging prior knowledge regarding CMC, non-clinical and clinical development across therapeutic contexts to facilitate CGT development and BLA review. The Agency also committed to revising the existing guidance Expedited Programs for Regenerative Medicine Therapies for Serious Conditions.

Notable Dates and Timelines – PFDD workshop on CGTs, by end of FY 2023; PFDD workshop report, by mid FY 2024; Draft guidance on efficacy in small patient populations, end of FY 2025; Draft Q&A guidance on common CGT issues, end of FY 2024; Draft guidance on post approval safety and efficacy data, end of FY 2024; Revised guidance Expedited Programs for Regenerative Medicine Therapy for Serious Conditions, end of FY 2025; Public meeting on leveraging knowledge across therapeutic contexts, end of FY 2025; Draft guidance on leveraging knowledge, end of FY 2026.

10.  Allergenic Extract Products Added to PDUFA Review – Although few additional details are available, review of allergenic extract products will be added to PDUFA and benefit from all performance goals, procedures, and commitments. Those allergenic extract products added to PDUFA under PDUFA VII and licensed after October 1, 2022 will generally be included in user fees.

Although we provide this overview of our top ten major changes, commitments and program enhancements, the PDUFA VII goals letter contained several other notable changes. Check back for new posts on the FDA Law Blog as our HPM colleagues take a deeper look at certain programs of interest, address topics excluded from this overview (e.g., safety initiatives, combination product review, digital technology enhancements), and update our readers on ongoing developments regarding PDUFA VII.