Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

As part of the Biden administration’s ongoing campaign to reduce outlays for prescription drugs, FDA is collaborating with the US Patent & Trademark Office (USPTO) to limit patent extensions for minor changes to a medicine. The initiative aims to promote competition in the biopharmaceutical market by challenging strategies designed to block timely approval of less costly generics and biosimilars to innovator products.

The joint effort was outlined by FDA Commissioner Robert Califf and USPTO Director Kathi Vidal in a statement issued July 6, 2022 on the need to prevent the patenting of “incremental, obvious changes to existing drugs.” The aim is to prevent delays in generic drug competition “based on trivial changes” to a drug product (1). While the “issuance of robust and reliable patents to incentivize pharmaceutical innovators is critical, our patent systems must not be used to unjustifiably delay generic drugs and biosimilar competition beyond that reasonably contemplated by law,” President Biden noted in an Executive Order last year.The two agencies aim to “leverage our collective expertise” in advancing innovation, competition, and the approval of safe and effective drugs.

To ensure that patent examiners have the time and resources needed for thorough review of pharma patent applications, FDA will assist the USPTO by providing patent examiners with training on pharmaceutical and biologics state-of-the-art development to help determine whether similar innovations already exist. FDA will ensure USPTO access to sources maintained by the agency for this purpose, and the two agencies will collaborate on developing policies aimed at protecting and promoting US innovation, a process that will solicit public input in upcoming events and listening sessions.

FDA’s role in addressing patent practices likely to delay competition were described earlier in a September 2021 letter from then-Acting FDA Commissioner Janet Woodcock to her PTO counterpart, urging greater collaboration and engagement between the two agencies to prevent “possible misuse of the patent system” (2). Woodcock outlined how FDA’s Orange Book aims to ensure transparency in patent listings, as does additional similar information on certain licensed biological products. She further described concerns about companies creating “patent thickets” by obtaining multiple patents on different aspects of the same products, as well as patent “evergreening” and “product-hopping” practices designed to forestall competition without advancing innovation.

Woodcock suggested that FDA assist USPTO by offering patent examiners training on its public information and databases that can help identify what is “prior art” to a claimed invention. Joint efforts could cover product eligibility for patent term extensions and information to help USPTO “accurately and fairly” grant patent term extensions where they are appropriate.

The FDA-USPTO collaboration comes as Congress appears to be moving forward with drug pricing legislation, which Democrats hope to include in key budget reconciliation legislation before Congress. The Senate leadership released the text of a bill that updates previous price reform efforts and claims to have support from all 50 Senate Democrats (3). The main proposal requires the Department of Health and Human Services (HHS) to negotiate lower prices paid by Medicare for certain prescription drugs, with the exception of insulin, where separate legislation has been proposed to address the need for significant cost controls. Additional provisions in the Senate bill would cap out-of-pocket spending on drugs by Medicare patients at $2000 a year, and ensure free vaccines to patients. The measure also revises manufacturer rebates on Medical Part B and D and repeals the controversial Part D rebate rule proposed by the Trump administration.

Biotech and pharma innovators have strongly attacked the legislation as a threat to innovation and global competitiveness of US-based firms, predicting big drops in developing new cancer drugs and therapies for rare diseases. At the same time, marketers of generic drugs and biosimilars claim that the revised Medicare negotiating process would undermine the development of lower-cost therapies.

FDA officials acknowledge that the agency plays only an indirect role in drug pricing debates, largely by instituting added efficiencies to drug development and ensuring a transparent and responsive product review process. At the same time, Woodcock noted earlier thatthe agency is “committed to identifying abuses of the system that can impede competition” and to recognizing how pharmaceutical patents impact access to approved medicines.

USPTO, “Director’s Blog: The Latest from USPTO Leadership,” 

Letter from Janet Woodcock to Andrew Hirshfeld

US Senate, KEL22401 13H, Subtitle I—Prescription Drug Pricing Reform Part 1—Lowering Prices Through Drug Price Negotiation.


Vol. 46, No. 8
August 2022
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, “FDA Joins Effort to Curb Drug Patent Abuses,” 

Articles

FDA and the USPTO hope to promote competition by challenging strategies designed to block timely approval of generics and biosimilars.

FDA Joins Effort to Curb Drug Patent Abuses

Oversight of drug manufacturing and quality control will continue to utilize off-site reviews of documents and operations, as FDA moves to make permanent these approaches that proved efficient and effective during the COVID-19 pandemic. FDA says this hybrid inspection model will remain a regular means for supplementing onsite inspections and will be further integrated into the agency’s oversight operations as the agency endeavors to restore its field inspection program. That task faces added difficulties as a large number of vacancies in the agency’s field force has expanded the task of replacing and training more inspectors and compliance officials.

The importance of utilizing remote regulatory assessments (RRAs) was highlighted by Commissioner Robert Califf and Associate Commissioner for Regulatory Affairs Judith McMeekin in a 

 an “optimized approach” for overseeing manufacturers and supply chains “dispersed around the world” [see  RRAs won’t replace site inspections, but these top officials emphasize that they can serve as a practical way to ensure compliance, to verify information submitted to the agency, and to inform key regulatory decisions.

Earlier during the pandemic, FDA officials reported they were utilizing a “wide range of oversight tools” to extend the agency’s regulatory reach where on-site inspections were not feasible. In an 

, McMeekin and then-Acting Commissioner Janet Woodcock highlighted the value of alternative inspectional tools for verifying the quality and compliance of regulated products where on-site examination was not feasible. FDA provided added advice on utilizing this approach in a 

 on its use of remote interactive evaluations of drug manufacturing and bioresearch monitoring facilities during the pandemic.

now provides more specifics on how the agency will utilize RRAs and how these audits will coordinate with and supplement site inspections. In a question-and-answer advisory on 

 published July 22, 2022, the agency says that RRAs will be useful in seeking to confirm information more quickly and efficiently, particularly when FDA is unable to send in staff due to travel restrictions.

The draft guidance clarifies the scope and format of RRAs, the type of situations where they will be requested, and how these approaches will relate to and complement site inspections. The advisory explains how FDA will request an RRA and will carry out the process and notes that there are consequences for a manufacturer that declines to participate in an RRA, even when not mandated.

The guidance also informs stakeholders where compliance with RRA requests is voluntary or is required by statute, a policy that FDA would like to expand. Currently, FDA has stated authority to require compliance with RRA requests by certain food importers and by manufacturers of all human and animal drugs and biological products. Pending legislation, which FDA backs, would extend that policy to all regulated establishments, including food producers, clinical investigators, and manufacturers of medical devices and tobacco products.

Over the past two years, FDA reports that it has utilized RRAs in evaluating more than 1470 domestic and more than 600 foreign operations. These methods have identified unreported adverse events, provided information to support import alerts, evaluated how well companies are correcting issues raised in previous inspections, and assisted in making regulatory decisions on premarket submissions. As with other inspection activities, FDA will continue to utilize a risk-based approach to shape RRA requests, examining the location, inspection history, and complexity of products made at a facility.

FDA’s hybrid inspection model will remain a regular means for supplementing onsite inspections and will be further integrated into the agency’s oversight operations.

FDA Confirms Ongoing Reliance on Remote Inspection Methods 

The approval of certain critical medicines based on preliminary clinical evidence continues to raise questions about reliance on too-weak efficacy data and delays in sponsors submitting confirmatory evidence from postapproval trials. FDA has approved dozens of valuable therapies under the program, many of them able to confirm efficacy through subsequent clinical studies. However, the controversial approval in 2021 of Biogen’s Aduhelm to treat Alzheimer’s Disease by the Center for Drug Evaluation and Research (CDER) continues to haunt the program, triggering widespread scrutiny of accelerated approvals and generating a range of reform proposals to accelerate the conduct of confirmatory studies.

FDA’s Oncologic Drugs Advisory Committee (ODAC) added to the debate with its April 2021 meeting that challenged several “dangling approvals” for cancer therapies. That prompted some manufacturers to withdraw earlier approvals for certain indications and others to renew confirmatory study efforts. The agency 

 another ODAC meeting on Sept. 22 and 23, 2022 to review additional medicines that raise questions about efforts to confirm indications in later studies. The expert panel will assess a multiple-myeloma treatment from Oncopeptides, where a confirmatory trial demonstrated “worse overall survival and failed to verify clinical benefit,” the FDA announcement stated. Also on the agenda is Secura Bio’s lymphoma therapy, which has raised questions about the benefits and risks of overall survival information.

Meanwhile, Congressional leaders have proposed measures to reform the accelerated approval program, as discussed in an article in the 

 urging legislation to halt abuses. A notable change would require sponsors to have confirmatory trials underway before gaining an early approval. Additional 

reforms would ease FDA withdrawal of an approval 

if further study results are not submitted within a certain period of time or grant FDA “automatic withdrawal” authority for drugs that fail to demonstrate efficacy. These and others proposals are included in the FDA 

 recently approved by the House, although its fate in the Senate is not clear.

At the same time, the cancer community and numerous patient disease groups are anxious to retain the accelerated approval program as important for enhancing patient access to therapies likely to have important benefits. These advocates also recognize that FDA should be able to remove those products unable or unwilling to confirm initial efficacy to retain credibility for the program. The 

 at FDA’s Oncology Center of Excellence (OCE) aims to clarify the importance of confirming initial study results following approval to support continued early access to promising new treatments. OCE listings include 85 therapies for cancer and hematologic malignancies that have verified clinical benefit, 65 that have studies ongoing, and 21 where accelerated approvals have been withdrawn. OCE continues to pressure sponsors to provide postapproval data in a timely manner and to withdraw products from the market when confirmatory studies fail to confirm benefit or are not completed with due diligence.

Stricter oversight of the accelerated approval program appears likely, as product costs and benefits remain in the spotlight. An analysis by 

investigators highlights the harmful effects of certain drugs on patients where early indications were not confirmed and patients were unaware of the potential danger from unanswered questions about such therapies. The decision to limit coverage of Aduhelm by the Medicare program, moreover, is prompting health plans and insurers to scrutinize more closely the costs and utilization of drugs with conditional approval status. At the same time, patients suffering from cancer and rare conditions continue to press for early access to therapies that demonstrate limited efficacy. Even with some legislative fixes, FDA will continue to face difficult decisions on product approvals and possible withdrawals.

Scrutiny of accelerated approvals has generated a range of reform proposals to accelerate the conduct of confirmatory studies.

FDA Continues to Grapple with Accelerated Approval Issues

As the timeframe narrows for reauthorizing FDA user fees before the Congressional August recess, legislators are devising strategies for advancing the legislation, while FDA leaders are preparing for the worst. Without reauthorization of new fees for drugs under the Prescription Drug User Fee Act (PDUFA), generic drugs under the Generic Drug User Fee Act (GDUFA), biosimilars under the Biosimilar User Fee Act (BsUFA), and medical devices under the Medical Device User Fee Amendments (MDUFA) by early August 2022, the agency is required to notify staff of possible layoffs and closures several weeks before the current fee authorization expires on Oct. 1, 2022. Although user fee reauthorization bills usually include a range of measures that make significant changes in FDA programs and operations, the stalemate in Capitol Hill now has prompted a leading Senator to propose a slimmed-down, fee-only bill to meet the renewal deadline.

If Congress fails to act before the end of the current fiscal year, FDA would lose its authority to collect fees from manufacturers, along with requirements for meeting certain timeframes and for utilizing agreed-on policies for assessing and approving new drugs and medical products. Just as damaging to the agency, FDA is required to send out pink slip notices to staff who are supported by fee revenues, warning of potential layoffs.

, a significantly different and more extensive measure is on hold in the Senate, as the legislators debate the scope and size of provisions to enhance FDA regulatory authority. 

 (FDA 2022) approved by the House several weeks ago contains a long list of relatively noncontroversial amendments, but focuses on reauthorizing the fees before then (see 

The Senate version of the user fee legislation, the 

FDA Safety and Landmark Advancements (FDASLA) Act

, has drawn opposition from Republicans for including major amendments that overhaul the agency’s regulation of diagnostics, dietary supplements, and cosmetics. Although the full package was approved by the Senate Health, Education, Labor and Pensions (HELP) committee several weeks ago, it drew fire from Sen. Richard Burr (R–NC), ranking Republican on the panel. Burr strongly objected to including such significant policy changes in the user fee bill and recently countered by backing a highly streamlined version that primarily would renew the fee programs. Burr stated in proposing his FDA Simple Reauthorization Act that the Committee’s proposal would undermine drug development for critical therapies by expanding the agency’s authority and fails to hold FDA accountable. His “

 represents the clearest path forward,” he concluded.

 to pass its already-approved user fee bill, or something close to it, to move the process forward. However, observers now are pessimistic that Congress will approve a new user fee package before August, thus requiring the agency to send out furlough notices.

Such a development could not come at a worse time, according to FDA commissioner Robert Califf, who sees enormous implications in delay for funding user fees. FDA will try to review products as quickly as possible, but won’t meet set timelines and commitments, Califf said at a meeting sponsored by the Alliance for a Stronger FDA last week.

He and other FDA officials already are struggling to attract qualified experts to the agency and had anticipated that the added funds and provisions in the new user fee programs would enhance that process. Without approval of new appropriations bills for 2023 and the new user fees, “we’d have to lay people off,” Califf said. And FDA already is “in a period of the ‘Great Resignation’”, he noted, as burnt-out staffers are leaving the agency, worn out from contending with long work hours and extreme pressure to evaluate and approve new vaccines, medicines, and diagnostics under tight timeframes to combat the COVID-19 pandemic. Hiring new staffers will be impossible, Califf noted, as he questioned who would want to work for an organization where jobs may not even exist in the near future.

US legislators are devising strategies ahead of the reauthorization deadline for the FDA User Fee legislation.

Gamesmanship Escalates over FDA User Fee Legislation

FDA has been struggling for more than 10 years to devise policies and operations to facilitate the approval and marketing of over-the-counter (OTC) medications. In a major step forward, two years ago Congress authorized a new approval process for converting drugs from Rx to nonprescription status, along with new user fees to support a more efficient FDA regulatory program for these medicines. Most recently, FDA has proposed a new process to facilitate approval of an additional category of nonprescription medicines that carry certain limitations on use, but don’t require prescriptions from a doctor.

The initiative for modernizing FDA’s oversight of nonprescription drugs has also encouraged pharma companies to seek approval of OTC contraceptives. Perrigo’s HRA Pharma 

that it has filed an application to market its birth control pill Opill on a nonprescription basis. The move involves an Rx-to-OTC switch for this progestin-only daily “mini” pill, which was approved by FDA in 1973, although is no longer widely used in the United States. The application was submitted by Paris-based HRA Pharma, which was recently acquired by Perrigo, a leading global OTC pharmaceutical manufacturer based in Dublin. HRA markets Opill in Britain and Europe and expects FDA’s review of its application to take 10 months, despite calls from Democratic leaders and health advocates to speed up the process.

 of Oakland, Calif. has been working with FDA for several years on switching its Zena combination estrogen-progestin prescription birth control pill to nonprescription status. A main hurdle has been FDA’s usual request for data from an “actual use” clinical trial, a requirement that Cadence may seek to address through a technological educational interface for patients.

These moves to enhance patient access to OTC contraceptives is occurring at a time of much change in FDA nonprescription drug regulation. After years of underfunding the agency’s program for overseeing OTC drug development and approval, Congress enacted major reforms for the program as part of the Coronavirus Aid, Relief and Economic Security Act (CARES), passed in March 2020 to address the pandemic. The legislation authorized FDA to collect user fees from manufacturers of $110 million over five years to help expand the Office of Nonprescription Drugs in the Center for Drug Evaluation and Research (CDER). The aim was to overhaul its stagnant OTC monograph system, which utilized FDA’s rulemaking process to carry out Rx-to-OTC switches, a process that often took years.

Under the new program, FDA has rolled a series of 

for issuing and revising OTC monographs under this more expeditious process, including a high-profile monograph for sunscreens. CDER also has published guidance documents for implementing the program and has several more on its agenda, including those on dispute resolution procedures, various meeting types, and e-data submission procedures.

 to facilitate the development of a new class of medicines that carry an Additional Condition for Nonprescription Use (ACNU). The aim is to enhance access to certain Rx medicines that are found to need 

additional instructions and safeguards to ensure correct selection and safe patient use

, but still warrant easier access than for prescription medicines. The proposal spells out how manufacturers may submit an application proposing a drug with an ACNU that can be implemented to ensure appropriate consumer self-selection and product use, possibly through answering certain questions at a pharmacy kiosk or on a mobile app or automated telephone response system. FDA seeks comments on the potential benefits and potential pitfalls of the proposed system.

A main issue for all OTC products is cost and coverage. While nonprescription drugs often are less expensive than Rx therapies, consumers usually pay for OTC products out of pocket, while health insurance plans cover much of the cost of prescriptions. There is some pressure for payers to pick up more of the tab for certain OTCs, such as contraceptives, as they would save money from fewer doctor office visits and generally lower product prices. Additionally, payment status is murky for “behind-the counter” medicines, an area that may expand noticeably under a recently proposed new rule. The coverage issue will be spotlighted for OTC contraceptives, as the Affordable Care Act requires health insurers to provide coverage for prescription birth control pills but would not necessarily apply to nonprescription products.

Application for OTC contraceptive highlights efforts to broaden access to medicines. 

FDA Regulation of Nonprescription Drugs in Spotlight

The recent Supreme Court decision revoking the legal right to abortion services in the U.S. (Dobbs vs. Jackson Women’s Health Organization) has bolstered efforts in some states to also limit patient access to certain FDA approved medicines and treatments. A main target is mifepristone (Mifeprex), approved by FDA more than 20 years ago as safe and effective means of blocking progesterone production. When taken in combination with a second drug, misoprostol (Cytotec), in the first 10 weeks of pregnancy, this medical treatment halts a pregnancy.

More than half of abortions in the U.S. are brought about by these medicines, now also available as generics. As more states ban abortion services of all types, a major battle is anticipated over the legality of states blocking access to these FDA-approved medicines. In response, 

attorney general Merrick Garland recently asserted

 that states cannot ban the drug based on disagreement with the FDA’s expert judgment. Garland also indicated that the Justice Department is ready to work with lawful authorities to “protect and preserve access to reproductive care.”

FDA approval of mifepristone (also known as RU-486) has been controversial from the start. Manufacturer Danco Laboratories, a small, privately held firm, markets only this one product, which gained FDA approval in 2000 despite strong opposition from right-to-life groups at the time. The agency issued several labeling updates over the years and 

authorized a generic version from GenBioPro in 2019

required Danco to implement a Risk Evaluation and Mitigation Strategy (REMS)

 that limited prescribing to certain qualified physicians and required in-office administration of the pill.

However, FDA relaxed the mifepristone REMS requirements in 2021 to permit its prescribing via telemedicine and mail-order delivery of the drug during the pandemic. That added flexibility will be a target when at some point the declared COVID public health emergency ends and abortion foes look to bring back FDA’s earlier prescribing and dispensing limits in all states.

Meanwhile, with more than 25 states banning abortions completely or moving to adopt such policies, efforts have already intensified to limit access to mifepristone more broadly. Biden administration officials have contested such moves, and manufacturers such as GenBioPro has 

challenged a Mississippi law that blocks telehealth access to mifepristone

. Reproductive health advocacy groups also are establishing systems to assist women in states that ban all abortions to obtain access to these treatments. However, the campaign against medication abortions will only intensify as more states enact laws specifically blocking physicians from prescribing the medicine, as proposed recently in Texas.

A similar confrontation is emerging over access to the “morning after” emergency contraception pill, Plan B One Step and several additional brands. Those drugs, which are not considered abortifacients, are approved to prevent pregnancy when taken within three days of unprotected sex and are available in pharmacies without a prescription. There was a notable spike in demand for these pills following the Supreme Court decision, as many patients looked to stock up on what they feared would become a banned product. While morning-after pills work by blocking ovulation for several days, abortion opponents claim that the pills also prevent egg implantation and thus should be restricted as causing early abortions.

Even more alarming for the health care community are related challenges to widely used contraceptives by staunch right-to-life advocates. Justice Clarence Thomas spotlighted the issue in releasing an opinion in the Dobbs case urging the Supreme Court to “reconsider” past rulings on right to contraception and other practices seen to undermine family relationships. Such proposals may have the added impact of heading off efforts to gain FDA approval of non-prescription status for birth control pills and to strengthen requirements for health insurers to cover contraceptives without added cost-sharing.

An equally troubling issue for medical professionals is the possibility that certain approved drugs for cancer or other serious conditions may harm the fetus or cause a miscarriage when needed to treat a pregnant woman, raising the potential for prosecution under strict abortion bans. The American Association for Cancer Research (AACR) 

 that state legislative actions could limit access to cancer care for patients diagnosed during pregnancy, even to protect the life of the mother. AACR fears that critical care could be denied to patients in certain states where it might also jeopardize development of the fetus.

The legal battle over the right of states to ban access to FDA approved drugs is slated to escalate, with more than 20 states planning or already enforcing limits on mifepristone prescribing and use. To avoid taking action that could be challenged in the courts, some states with strong anti-abortion laws may move to curb the use of a drug to induce an abortion, but not impose an outright ban on products approved by FDA.

Some states look to block access to approved drugs. 