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

Jill Wechsler

Despite the pressures and added regulatory challenges imposed by the COVID-19 pandemic, and the uproar over its surprise approval of Biogen’s new Alzheimer’s therapy Aduhelm, FDA is on track this year to authorize a notable number of new molecular entities (NMEs) and important biotech therapies. In the first half of 2021, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) gave the nod to 29 novel therapies, slightly ahead of last year’s pace that saw the approval of a near-record 53 new drugs.

added up to 27 NMEs and biologics as of June 30, 2021, with several more additions in July. And 

 a new pneumococcal vaccine and new treatments for multiple myeloma and for lymphoma.

Almost half of the new drugs are treatments for cancer and related conditions, many benefitting from priority review and accelerated approval programs. That includes Jazz Pharmaceuticals’ new blood cancer therapy, a treatment for non-small cell lung cancer from Amgen, and Bristol Myers Squibb’s new CART-T therapy for multiple myeloma plus a cell therapy for large B-cell lymphoma.

Important non-cancer approvals also include the first new treatment for vaginal yeast infections in two decades and the first therapy for chronic weight management authorized since 2014, arising from approval of an added indication for Novo Nordisk’s type 2 diabetes injectable Wegovy (semaglutide) for obese or overweight adults. FDA also okayed new therapies for Duchenne muscular dystrophy, lupus nephritis, chronic heart failure, and notably, an extended release injectable to manage HIV, replacing daily pills with monthly injections.

There were advances in the over-the-counter drug world, too. In June, FDA approved the first nonprescription nasal antihistamine to expand treatment options for patients age six and older; younger children still must obtain Bayer Healthcare’s Astepro (0.15% azelastine hydrochloride nasal spray) on a prescription basis.

Important news on the approvals front continued in July, as 

FDA authorized its first interchangeable biosimilar

—Mylan’s Semglee once-daily insulin therapy, biosimilar to Sanofi’s Lantus.

FDA also approved an important treatment for high-risk, early-stage, triple-negative breast cancer, giving the nod to Merck’s Keytruda (pembrolizumab) to be used in combination with chemotherapy for this serious condition.

On the downside, FDA halted use of a treatment approved in February for relapsed or refractory multiple melanoma, Pepaxto, from the Swedish firm Oncopeptides, based on evidence from ongoing clinical studies of higher death rates among patients treated with the new drug versus an earlier therapy. Pepaxto gained accelerated approval, but now 

FDA has alerted patients and health professionals 

to the potential risk and has suspended enrollment in postapproval studies pending further examination of the safety signal.

CDER officials attribute their ability to maintain a fairly normal advise-and-consent process for innovative drugs during the past 18 months on the hard work of its dedicated staff, as well as efficiencies gained from the recent reorganization of its Office of New Drugs (OND). CDER Director Patrizia Cavazzoni noted increases in staff hiring and retention at the May 2021 annual meeting of the Food and Drug Law Institute (FDLI), attributing this surprising development to new remote work flexibilities due to COVID-19 restrictions. She also cited the success of large platform trials and clinical networks, as well as increased sponsor use of decentralized trials. The structural overhaul of OND has resulted in smaller, more flexible review offices with clearer areas of expertise and greater alignment of interrelated disease areas, 

Cavazzoni explained in recent testimony to the House Energy & Commerce Health subcommittee

, which held a hearing to explore the lack of new therapies for neurogenerative diseases.

Articles

In the first half of 2021, the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research approved 29 novel therapies.

New Drug Approvals on Track at FDA

Congressional leaders, as well as regulated industry, want more information from FDA on its strategy for resuming inspections of manufacturing facilities to better assure the quality, safety, and efficacy of medical products. The suspension of in-person field inspections in March 2020 has resulted in a huge backlog of delayed site visits, as FDA sent investigators only to those operations deemed “mission critical.”

FDA Acting Commissioner Janet Woodcock recently confirmed that the agency is returning to normal procedures for domestic inspections, although foreign inspections will still be limited to mission-critical situations. 

 before the Senate Health, Education, Labor and Pensions (HELP) Committee on July 20, 2021, Woodcock outlined FDA’s plan to “transition to standard operations” for US inspections, which means focusing on higher-risk establishments and scheduling postponed surveillance inspections based on risk.

Meanwhile, Congressional leaders continue to demand more information on how and when FDA will resume standard operating procedures for inspections, reflecting concerns that postponed oversight may delay the approval of new drugs and biologics. 

 to Woodcock dated July 22, 2021, Republicans and Democrats on the House Energy and Commerce Committee requested details on the status of foreign inspections; whether delayed inspections are hindering the approval of applications for new drugs, generics, and biosimilars; FDA’s ability to utilize inspection reports from trusted inspectorates; and how FDA’s data modernization initiative will improve its inspection program. The legislators also want to know how much of the $38.3 million provided to FDA to help address the pandemic is being used to support the resumption of domestic and foreign inspections, and the impact of FDA’s decision to preannounce all inspections for the foreseeable future.

FDA normally conducts nearly 1000 foreign and domestic inspections a year for medical products, but has made less than 100 critical site visits in the United States in the last two years, and only a handful overseas. In its “

Resiliency Roadmap for FDA Inspectional Oversight

” issued May 5, 2021, FDA acknowledged that it had postponed most inspections in 2020 due to the pandemic, focusing primarily on manufacturing operations producing drugs needed to prevent critical shortages and to support the approval of novel drugs or treatments for COVID-19. For 2021 the agency has some 15,000 domestic surveillance inspections on its to-do list, most of those involving food and other products, but a third related to drugs.

To better manage this considerable volume of inspection work, FDA aims to enhance the Office of Regional Affairs (ORA) field inspection program through the agency’s data modernization initiative to provide cross-program interoperability, Woodcock reported to the Senate panel. This includes new technology supporting regulatory assessments to improve the receipt, review, and analysis of industry data and records, including a review of inspectional approaches using next-generation assessment technologies.

Furthermore, FDA has established a new agency-wide Inspectional Affairs Council to better coordinate inspection approaches and assessments across product centers. This panel aims to “optimize the inspection process,” explained Judith McMeekin, associate commissioner for regulatory affairs, in a presentation July 14, 2021 to the Alliance for a Stronger FDA (1). McMeekin, who manages ORA’s 5000 inspectors and other staffers, noted that the Council will provide a forum for the leadership of FDA centers to jointly assess strategies and policy issues across operations to ensure optimal use of resources.

McMeekin reported that ORA has conducted about 30 mission critical foreign inspections during the pandemic, which has involved a tremendous effort to mitigate risks to investigators. ORA also worked to facilitate the emergency approval of vital vaccines to combat the pandemic by devising methods to inspect key vaccine clinical research sites, collaborating with the Center for Biologics Evaluation and Research (CBER) to plan the visits. In just four weeks, a team of more than 50 ORA investigators inspected 26 clinical research facilities to ensure the accuracy and reliability of data to be considered by FDA’s vaccine advisory committee. Here, FDA sent in two inspectors, instead of one, to assess data in the shortest amount of time, supplying them with portable projectors able to review documents from a distance.

McMeekin also highlighted ORA’s need for additional funding, particularly to enhance its operations related to drugs and medical products. Only 10% of its budget is supported by user fees, she explained, and most of its appropriated funds are allotted to food safety and oversight. To expand its drug inspection activities, lab capacity, and scrutiny of more imported packages containing drugs, ORA is looking to tap more medical product user fee funds, while also increasing appropriated support to bolster its staff dealing with medical devices and biologics, as well as its cadre of foreign inspectors.

In going forward with scheduling of site visits in the US, FDA is utilizing a rating system to assess the number of COVID-19 cases in the local area and risks to personnel, in consultation with state and local authorities. For now, the agency is pre-announcing domestic inspections to ensure a facility is available and safe for FDA staffers to visit, but FDA officials recognize that it will take some time to restart its foreign drug inspection program due to the more extensive planning required to arrange for safe travel and site visits.

Associate Commissioner for Regulatory Affairs (ACRA) Judy McMeekin (July 14, 1:30-2:30 PM ET)

FDA officials discuss resuming normal facility inspection operations, both domestic and foreign.

FDA Under Pressure to Restore “Normal” Drug Inspections

A broad White House proposal to advance competition in major US industries features several measures intended to make medicines more affordable for patients. The 

 also instructs the Department of Health and Human Services (HHS) to aide consumers by reducing the cost of hearing aids, limiting certain hospital mergers, and clarifying insurance options offering affordable coverage.

With 72 wide-ranging proposals, the initiative challenges multiple areas where curbs on free competition may harm consumers and workers. There are measures designed to help workers negotiate with employers, limit airline fees, curb data collection and surveillance by tech companies, and support open online marketplaces.

To spur competition in the health care arena, HHS is 

within 45 days to map out ways to combat high drug prices and “price gouging” and enhance domestic pharmaceutical supply chains. One item on the list is to revive a rule that requires health marketplaces to offer at least one health plan with a standard benefit to make it easier for consumers to compare coverage options. The Federal Trade Commission (FTC) and Department of Justice (DoJ) also will review merger guidelines to prevent patient harm from certain hospital mergers and assess the need for controversial rules requiring hospitals to disclose the prices they negotiate with health insurance firms.

The FTC also will investigate and take action against “pay for delay” and other agreements between pharma manufacturers found to discourage competition. And regulators will reduce the cost of hearing aids for consumers by permitting over-the-counter sales of these products to inject competition into the market. This puts pressure on FDA to issue proposed rules for over-the-counter (OTC) hearing aids without delay.

The White House also revives support for importing less expensive drugs from Canada, directing FDA to work with states and tribes to establish procedures to obtain lower-cost medicines without imposing risks to public health. Such drug importing proposals have been on the table for more than a decade but have been opposed by Canadian officials and difficult for state and federal agencies to implement. A Trump administration drug importation program prompted two states to develop and seek FDA certification of such importation plans, a process that has been challenged by brand pharma companies. FDA is weighing a citizen petition opposing authorization of state import programs but recently informed industry lawyers that it needs more time to review these “complex issues.”

A related area of focus involves facilitating the development, testing, and approval of generic drugs and biosimilars. The Biden initiative calls on FDA to fully implement agency plans issued in 2017 and 2018 to advance competition in prescription drug markets by clarifying the approval framework for these products, including standards for interchangeability and for biologics licensing. The executive order further advises FDA to implement recent legislation designed to prevent brand manufacturers from limiting access to drug samples needed to test new generic products.

Additionally, HHS should provide effective educational materials and communications to improve the understanding of biosimilars and interchangeable products among healthcare providers, patients, and caregivers. Similarly, FDA and FTC are instructed to identify and address deceptive, false, and misleading statements designed to undermine consumer confidence in the safety and effectiveness of generics and biosimilars. And FDA should collaborate with the Patent and Trademark Office to prevent patent extensions designed to delay competition from generics and biosimilars. The Centers for Medicare and Medicaid Services (CMS), moreover, should prepare for coverage of interchangeable biological products and support new payment models to increase utilization of these products.

Despite offering multiple strategies for tackling high drug prices, the Biden proposal largely leaves it to Congress to move forward on the more contentious proposals, such as granting Medicare authority to negotiate pharma reimbursement. House Democrats are looking to include such measures in the reconciliation bill to approve the federal budget for 2022, now moving through the legislative process.

In the Senate, where broad agreement is needed

 to advance such pricing proposals, the Senate Judiciary Subcommittee on Competition Policy, Antitrust, and Consumer Rights opened the 

discussion of these issues at a hearing this week on “cracking down on anticompetitive conduct in prescription drug markets.” Subcommittee Chair Amy Klobuchar (D-Minn) supported legislation to further limit pay-for-delay and other tactics that keep generics off the market. While representatives of brand manufacturers maintained that existing antitrust policies promote innovation while ensuring appropriate competition, reformers argued that current policies and judicial decisions permit a range of anticompetitive conduct to limit generic marketing such as “product hopping,” blocking patents, and abuse of citizen petitions. 

White House proposal includes measure to make drugs more affordable.

Drug Prices Targeted in Biden Competition Initiative

Facing continued criticism of FDA approval for Biogen’s Alzheimer’s disease treatment, Aduhelm, acting commissioner Janet Woodcock took the unusual step of calling on the Office of the Inspector General (OIG) of the Department of Health and Human Services (HHS) to examine the review process for that drug. In a letter to acting inspector general Christi Grimm last week that was posted on Twitter July 9, 2021, 

Woodcock requested an “independent review and assessment of interactions 

between representatives of Biogen and FDA during the process that led to the approval of Aduhelm.” 

This surprising move reflects Woodcock’s aim to protect FDA’s reputation for maintaining the gold standard for objective and science-based assessment of all new medical products. The action also seeks to distance Woodcock from the Aduhelm approval decision, as she struggles to gain support for leading FDA permanently.

FDA granted accelerated approval for Aduhelm on June 7, 2021

 based on slim evidence that it may provide benefit for some Alzheimer’s patients, gains to be confirmed in post-approval studies. However, the approval decision ignited an eruption of criticism, largely due to a very broad label supporting prescribing for both early and late Alzheimer’s conditions. Biogen’s $56,000 price tag on the drug, moreover, generated outrage that it would bankrupt Medicare, which provides care for most patients likely to use the drug.

Among the loudest critics were members of FDA’s Peripheral and Central Nervous System advisory committee, which had soundly rejected approval of the drug at a meeting in November 2020 due to the sponsor’s failure to provide convincing evidence of the drug effectiveness. Three members of that panel resigned in protest and called for the removal of top officials at the Center for Drug Evaluation and Research (CDER) and relevant new drug review offices.

As members of Congress demanded an investigation into the agency’s review process, FDA sought to stem the attack by releasing documents indicating a thorough analysis of clinical data for the drug. 

CDER officials used the press to further explain their actions

However, the criticism escalated further with the revelation by the STAT website of 

efforts by high-level FDA staffers to find a pathway for approving the Biogen drug 

despite the advisory committee rejection, largely to meet patient demands for any promising treatment. That internal discussion led the agency to decide that the possibility of some potential benefit supported accelerated (but not final) approval of the drug.

FDA supported a move by Biogen to revise the label for Aduhelm

 to limit prescribing to patients with milder forms of Alzheimer’s disease. Such action is highly unusual so soon after product approval and was seen as a way to reduce potential spending on the drug and thus deflect criticism. However, the revision is not expected to limit prescribing noticeably, although it may provide insurers with some flexibility to negotiate reimbursement.

Meanwhile, the House Energy & Commerce Committee and others plan to hold hearings on the issue and Woodcock’s role in the decision. Sen. Joe Manchin (D-WV) called on President Biden to fire Woodcock for permitting the Aduhelm approval, while Democrats are looking to add drug pricing provisions to current budget legislation. It remains to be seen if Woodcock’s request for an OIG investigation will calm the opposition and prevent heads from rolling at FDA.

FDA’s review and approval of Aduhelm triggers controversy and a call for review from within the Agency.