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

Jill Wechsler

The President’s Emergency Plan for AIDS Relief (PEPFAR) is celebrating 20 years of providing vital therapies to poor nations in Africa and other regions to combat the spread of this lethal disease. The program was introduced by President George W. Bush and approved by Congress in 2003 to distribute antiretroviral drugs to third-world nations, where HIV/AIDS was threatening the survival of many populations. In recent weeks, policy makers and the public health community have applauded PEPFAR’s broad impact, highlighting its success in greatly reducing the spread of HIV—and in demonstrating the effectiveness of US international aid programs.

But despite long-standing bi-partisan support for the program, conservatives often have complained that PEPFAR funding to local health care agencies also supports family planning and abortion services. With Republicans controlling key House committees that authorize funding for international programs and foreign aid, right-to-life advocates are working to add anti-abortion provisions to legislation reauthorizing US international health programs, including PEPFAR. The

has threatened to block funding for the program unless it includes provisions to clarify that its funds cannot support abortion and related care.

Separately, the House Appropriations Committee added an anti-abortion provision to its recently approved FDA funding bill for fiscal year 2024. Republicans pushed through language that would limit telehealth prescribing for the abortion pill mifepristone, a policy adopted during the COVID-19 pandemic but now targeted by right-to-life proponents.

FDA plays an important role in PEPFAR by approving generic versions of patented and expensive AIDS treatments, but only for distribution outside the United States until domestic patents expire. This conditional approval process has enabled 

distribution of the most effective therapies

 to third-world countries without undermining markets at home and in other industrial nations. FDA has 

 under PEPFAR and maintains a database to provide prescribing and use data.

In recognizing PEPFAR’s 20 years of success in greatly reducing the spread of HIV/AIDS, the Biden administration moved to map out next steps for the initiative. In the fall of 2022, it issued a report on 

Reimagining PEPFAR’s Strategic Direction

, with the stated aim of ending the AIDS pandemic by 2030. The analysis calls for reducing new HIV infections, particularly in girls and young women, and strengthening the capacity of local governments and public health systems to lead and manage the program. Critics of PEPFAR have cited its language for supporting public health programs in Africa that advance family planning, despite adamant denial of those charges by State Department officials. The fear is that fearing the debate will delay the five-year reauthorization of PEPFAR under review by Congress.

Jill Wechsler is Washington reporter for 

Articles

There is concern that debates will delay the five-year reauthorization of PEPFAR under review by Congress.

Long-Admired PEPFAR Program Caught in Abortion Debate

Confusion recently arose over whether and how Medicare will cover new Alzheimer’s treatments, but the fine print indicates that reimbursement for such medicines still will occur only with the completion of studies to support full FDA approval. And even with that imprimatur from FDA, the Centers for Medicare and Medicaid Services (CMS) will limit reimbursement to patients who enroll in physicians’ registries. While one treatment for this widespread condition may gain full approval next month, accelerated approval status remains insufficient to support reimbursement by the federal government.

 on June 1, 2023 that Medicare will cover drugs in this new class of Alzheimer’s treatment that receive “traditional approval” from FDA. However, the fine print stipulated that coverage will only apply to those who participate in a registry to collect real-world data that can further assess the usefulness of these drugs for elderly patients. CMS ignited controversy in 2022 when it decided to only pay for treatment of those few patients participating in confirmatory studies, under its coverage-with-evidence-development program.

The first drug likely to qualify for full approval is Leqembi from Eisai, which is scheduled for an 

of its confirmatory studies on June 9. FDA granted accelerated approval for the treatment in January, but CMS limited coverage to those patients enrolled in confirmatory trials, as it did earlier with Biogen’s Aduhelm. In addition, Eli Lilly hopes to provide sufficient data to gain full approval for its Alzheimer’s therapy by year-end.

 Alzheimer’s Association protested CMS’ requirement 

for registry enrollment as erecting “an unnecessary barrier” to coverage. While patient registries are “important tools for gathering much needed real-world evidence” to improve patient care, they should not be used to limit access to an FDA-approved treatment, the patient advocates stated.

(BIO) described CMS’ policy as reinforcing criticism of FDA accelerated approval and raised concerns that these challenges to accelerated approval will limit patient access to treatment and curb future innovation.Some members of Congress and patient groups agree with FDA on the importance of permitting broad access to potentially beneficial treatments, especially for severe conditions affecting small patient populations.

It really all comes down to money: the high cost of new Alzheimer’s treatments and potentially millions of patients likely to seek treatment would run up Medicare prescription drug budget exponentially.

Reimbursement for Alzheimer's medicines still will occur only with the completion of studies to support full FDA approval.

Medicare Still Won’t Pay for Alzheimer’s Drugs without Confirmatory Data

After more than a decade of debate and discussion, FDA has published a new system for providing basic and essential information on patient use of drugs and certain biologic products. A 

new one-page Patient Medication Information (PMI) guide

 would replace the more complex and lengthy Patient Package Inserts (PPIs) now distributed in pharmacies dispensing prescription medicines.

The aim of the new program is to reduce drug misuse and adverse reactions by providing accurate information on product indications and uses to help people take prescription medicines safety and effectively,

in unveiling the new proposal May 30, 2023. Currently, the different types of information on prescription drugs as now required can be confusing and prompt patients to stop taking medications or to use them inappropriately, leading to treatment failures, hospitalizations and even deaths.

a one-page document that highlights essential information on product use and would be given to patients with their medications, including certain biological products provided in outpatient settings. The information also will be available online for public access. FDA anticipates that by reducing duplicative information, the new system will be more cost-efficient for drug and biotech manufacturers. The new format also will support translation of PMI to other languages and facilitate the use of technologies to convert the information to additional formats. FDA estimates that its proposal would cost approximately $20 million a year to implement, but would yield greater benefits and savings, largely from safer and more appropriate use of medicines.

To realize such gains, sponsors of new drugs will seek FDA approval of PPIs as part of new drug applications (NDAs) or biologics licensed applications (BLAs). In addition, manufacturers of already approved medicines will have to revise existing patient information documents and file supplemental applications to gain PMI approval. The greater burden on industry will involve updating systems for printing and packaging PMIs with medicines, an undertaking that has generated objections to previous FDA proposals for revising required information for patients. To facilitate these changes, the agency outlines a five-year implementation schedule, as it calculates that sponsors would have to submit labeling supplements for more than 2600 existing drugs and more than 1600 new drug applications.

Generic-drug makers face added complexities in converting current medication information to the new format, as they will have to refer to new PMIs of their reference listed drugs, once those are submitted to and approved by FDA. The agency says it will facilitate this process by creating PMI templates for approved abbreviated new drug applications if the reference drug has been withdrawn or lacks an approved PMI.

In recognition of the issues raised from past proposals, FDA requests comments from industry on the usefulness and appropriateness of this latest patient information plan, the accuracy of the agency’s estimate of the burden and cost of providing the requested information, ways to improve the PMI proposal, and strategies for a reducing the burden of collecting the requested information. Industry has six months to submit comments.

FDA has published a new system for providing basic and essential information on patient use of drugs and certain biologic products. 

FDA Proposes Streamlined Medication Handouts

The continued surge in applications to FDA for testing new gene therapies is taxing the agency’s resources and highlighting the need for new policies and updated operations to fully realize the promise of these cutting-edge treatments. FDA authorized accelerated approval for a new amyotrophic lateral sclerosis (ALS) treatment, Biogen’s Qalsody (tofersen), based on years of testing to demonstrate the drug’s potential for blocking production of a protein believed to give rise to ALS in some 500 of approximately 30,000 ALS patients with a specific gene mutation (1). Meanwhile, bluebird bio is seeking approval of a new treatment for a certain form of sickle cell disease (SCD), a lovo-cel gene therapy that is injected into the patient’s blood to produce anti-sickling hemoglobin (2).

To further such advances, officials in the Center for Biologics Evaluation and Research (CBER) seek added resources and new approaches for quickly bringing innovative therapies to patients. In numerous presentations in recent months, CBER Director Peter Marks has lamented the slow pace and high cost of developing and testing new gene therapies. FDA has approved about a dozen of these cutting-edge treatments so far, he pointed out in a webinar on April 4, 2023 sponsored by the Alliance for a Stronger FDA (3). But after two decades of effort in this area, he urged changes to approve more than a handful of new products each year. “I don’t think we have a really long time to play around,” Marks commented, but need to “transform the environment” for developing these treatments through accelerated endpoints and regulatory flexibility.

One recent change is the formation of a new “super” Office of Therapeutic Products (OTP) in CBER to replace the smaller Office of Tissues and Advanced Therapies (OTAT). OTP has six offices overseeing 14 divisions and 33 branches, designed to house an expanded staff able to quickly assess new research programs and steer promising therapies through the regulatory process. The latest version of the user fee program for drugs and biologics provides added funding to support an increase in experts assigned to gene therapies, advanced manufacturing technologies, and related programs (4).

Marks also has proposed that CBER adopt some of the innovations established by FDA’s Oncology Center of Excellence (OCE), including FDA’s accelerated approval pathway for promising therapies. While acknowledging that not all fast approvals will confirm benefits later, he is optimistic that this approach can provide many seriously ill patients with access to important treatments faster than otherwise. A related plan is to launch a new version of Operation Warp Speed for rare diseases to support the development of gene therapies for conditions affecting small patient populations, starting with a few high-need programs that could benefit from more constant contact with FDA. The tension between approving a potentially important new therapy for children with a debilitating rare genetic disease based on preliminary evidence, or waiting for further clinical trials to confirm benefits, was paramount in the recent debate over accelerated approval for Sarepta’s new treatment for Duchenne muscular dystrophy, which an FDA advisory committee approved by a close 8–6 vote last month.

In addition, CBER is working to advance international cooperation among regulatory authorities in vetting and regulating new gene therapy applications to expand the global pool of patients testing and receiving treatment. This involves applying elements of OCE’s Project Orbis program to provide a framework for regulators to cooperate in reviewing concurrent submissions for biotech products outside the oncology area.

The high cost of producing gene therapies for small patient populations, however, presents the highest hurdle for CBER and manufacturers to bring more innovative gene therapies to patients. While FDA doesn’t consider cost in assessing the safety and efficacy of a medicine for market approval, Marks has voiced concerns about the long timeframe and expensive
methods for producing treatments for only 30 to 40 patients a year—a process that he recognizes is very different from manufacturing monoclonal antibodies for thousands of people. Some gene therapies make it through clinical development, he noted, only to be dropped by sponsors due to high production costs that make these new treatments “commercially non-viable” and put clinical trial sponsorship out of reach of small companies and nonprofit disease organizations and foundations.

A priority for Marks is to reduce the bottlenecks in gene therapy production processes and to provide added
assistance to sponsors struggling with manufacturing issues. The expanded OTP has three chemistry, manufacturing, and controls (CMC) offices—for gene therapy, cell therapy and human tissue, and for plasma protein therapeutics—to accommodate more staffers with expertise in biotech manufacturing able to provide timely, accurate information in this area.

CBER also has scheduled virtual “town hall” meetings for OTP staffers to clarify expectations on specific technical components required for investigational and market applications for cell and gene therapies. At presentations in September 2022 and in April 2023, reviewers from OTP’s Office of Gene Therapy CMC addressed questions on guidance documents, assay qualification and validation, product characterization and release testing, and stability studies at different stages of product development and use (5). Another session on June 8, 2023 will focus on CMC for cell and tissue products (6).

Marks sees a two-to-three-year window to move forward and transform the environment and manufacturing process for gene therapies. Under current methods, these new products will continue to raise challenges in the cost and pricing arena, as seen in Biogen’s price tag for its new ALS drug of almost $200,000 a year for treatment. “If we get it right,” Marks says, FDA will realize some of its goals for advancing gene therapies, which will make a “huge difference in the bio-economy,” while also impacting patients’ lives sooner.

FDA Approves Treatment of Amyotrophic Lateral Sclerosis Associated with a Mutation in the SOD1 Gene.

bluebird bio. bluebird bio Submits Biologics License Application (BLA) to FDA for lovotibeglogene autotemcel (lovo-cel) for Patients with Sickle Cell Disease (SCD) 12 years and Older with a History of Vaso-Occlusive Events. Press Release. April 24, 2023.

Alliance for a Stronger FDA Webinar with Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research. April 4, 2023.

FDA. Establishment of the Office of Therapeutic Products. 

OTP Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls–April 2023. Town Hall. 

OTP Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls–June 2023. 

 Washington editor, jillwechsler7@gmail.com.

When referring to this article, please cite it as Wechsler, J. FDA Eyes New Strategies to Spur Gene Therapy Development. 

An increase in applications for gene therapies is putting stress on FDA’s resources.

FDA Eyes New Strategies to Spur Gene Therapy Development

Recent challenges to certain controversial approval decisions have prompted FDA officials to reexamine of the role and composition of the agency’s many advisory committees and to explore options for change. With more than 50 panels composed of academics, scientists, and various interested parties, the program has become overly complex and sometimes contentious, with some up-or-down votes on important approval decisions appearing at odds with ultimate decisions by agency reviewers.

Commissioner Robert Califf has been calling for changes to improve the operations and composition of its advisory panels for several months. In a 

 on May 17, 2023, at the annual meeting of the Food and Drug Law Institute (FDLI) in Washington, D.C., Califf emphasized the need for the agency to strengthen committee structure and methods to be “more efficient, flexible, and effective in the exercise of our regulatory responsibilities".He noted the value of interchange among FDA experts and those outside the agency, particularly on complex scientific issues, and that transparent discussion is important. But he also said that the advisory committee system “can be improved” to enable FDA scientists to “get the best advice possible.”

Similarly, Patrizia Cavazzoni, director of the Center for Drug Evaluation and Research (CDER), cited plans at the FDLI meeting for advisory committee “modernization” among numerous key initiatives for her office in the coming months. The process will include efforts to refine the selection of advisors so that their “expertise applies precisely to the matters under consideration.” That may involve adding to advisory panels more temporary members with special knowledge about the drug or disease under discussion and taking steps to ensure diversity in geographic areas represented.

Cavazzoni also noted the need for FDA to improve how it communicates about advisory committee operations and their relationship to the agency. This involves emphasizing to the public that these panels play an advisory role to the agency—and that FDA retains ultimate decision-making authority.

FDA’s interest in updating advisory committee composition and operations has become more visible in recent months, stemming from the uproar that resulted when FDA granted accelerated approval in 2021 to Biogen’s Alzheimer’s treatment, Aducanumab, despite a near-unanimous vote against approval at an advisory meeting in November 2020. Three panel members resigned in protest, and Medicare limited coverage to those patients participating in ongoing clinical trials.

That controversy, and subsequent heated debates over the approval of other treatments for critical diseases with questionable efficacy data, has prompted FDA officials to reconsider the advisory committee process, including the composition of the panels and the issues identified for discussion. A main change would be to shift away from “gladiator votes”—yes-or-no decisions on specific applications—and to provide more nuanced opinions on the main issues. But in some cases, the absence of up-or-down votes on key questions may generate confusion as to what the committee experts actually recommend. In the recent consideration of Sarepta’s new gene therapy to treat Duchenne’s muscular dystrophy, the advisory committee supported approval by a very slim margin. However, the patient advocate on the panel made a strong case for FDA to approve the drug as another treatment option for this devastating condition. FDA staff has gone back to the drawing boards, indicating it may limit treatment to a very young age group pending further clinical results.

Interchange among outside experts on scientific and technologic questions is important, Califf emphasized at the FDLI meeting. Such debate “makes our decisions better,” he noted, and “adds a level of transparency.” However, the commissioner also raised concerns about the steady stream of “misinformation and disinformation” in society that can undermine public confidence in science and “weaken faith in governmental and other institutions, including the FDA.”

Public debate among expert advisors can both support sometimes controversial decisions by FDA staffers, but also raise challenges to agency actions. The advisory committee process is one element in this ongoing debate that appears open to improvement, and Califf advised the regulatory community to “stay tuned for developments in this area.”

Challenges to approval decisions have prompted FDA officials to reexamine of the role and composition of the agency’s many advisory committees and to explore options for change.

FDA Eyes Advisory Committee Reform to Enhance Credibility

As policy makers continue to scrutinize and criticize high drug prices, manufacturers are eager to shift some of the blame to pharmacy benefit managers (PBMs), hitting them for demanding high rebates and discounts that boost consumer costs. PBMs, in turn, insist that their efforts save money for health plans and patients by keeping outlays for medicines under control.

Now Congress is stepping in with a range of legislative proposals to further manage PBMs and the pharma market. Pharmaceutical companies, meanwhile, aim to sideline measures that would ratchet down certain drug prices, limit patents, and revise tax policy. In what has been a busy week on Capitol Hill, the legislators also discussed bills to advance generic-drug competition, to revise corporate tax policy, and to lower prices on diabetes therapies for all patients.

Vermont independent Bernie Sanders led the charge at a hearing before the Senate Health, Labor, Education and Pensions (HELP) committee 

. Both Democrats and Republicans appeared receptive to price-lowering promises from leading diabetes drug makers Eli Lilly, Sanofi, and Novo Nordisk, and ready to criticize executives from leading PBMs—CVS, Express Scripts, and Optum Rx—for huge profits and limited transparency. A telling issue was unfavorable PBM coverage of new biosimilars and charges that the middlemen serve their insurance corporate interests—and not patients. An ongoing complaint of too-low reimbursement from community pharmacists fueled Republican support for curbing PBM operations that appear to shift business to their own mail-order pharmacy operations and away from local retailers.

As a result, the HELP committee approved an extensive PBM reform bill along with three other measures involving FDA and drug policies. Two support generic drug development by curbing citizen petitions to FDA designed to delay competition (S. 1067) and by limiting “parking” strategies that similarly thwart competitive generic drug marketing (S. 1114). The RARE Act (S. 1214) addresses abuses of the seven-year exclusivity period for orphan drugs. And the hefty Pharmacy Benefit Manager Reform Act (S. 1339) swipes at multiple PBM practices, including “spread pricing” and the failure to pass rebates and fees to plans and patients.

These proposals follow similar House and Senate Committee efforts to curb PBM practices. The 

Senate Finance Committee held a hearing on PBM

 practices in March and issued a framework for legislation to curb abuses that limit access to affordable drugs. Similarly, the House Energy & Commerce Health Subcommittee has heard testimony on dozens of legislative proposals to “increase transparency and competition in health care,” including measures requiring PBMs to disclose more detailed information on drug costs, coverage and rebates.

As the legislators have advanced reforms related to PBMs and other drug pricing issues, manufacturers, insurers, and PBMs have escalated their attacks on each other. The Pharmaceutical Research and Manufacturers of America (PhRMA) recently launched a wave of anti-PBM television ads highlighting how the middlemen limit patient access to needed medicines and fail to pass on discounts to consumers. Conversely, America’s Health Insurance Plans (AHIP) has financed a million-dollar campaign blaming pharma companies for high drug costs. And the PBMs’ Pharmaceutical Care Management Association (PCMA) is airing ads to highlight the benefits of their operations and the need for drug patent reform.

At this point, it seems that pharma is winning the policy and rhetoric campaign against PBMs, as support has increased among both Republicans and Democrats for legislation requiring these drug middlemen to be more transparent about their operations, particularly rebates negotiated with manufacturers and how they set payments to retail pharmacists. And more is slated to come from the Federal Trade Commission, which continues an investigation into whether PBM practices limit competition.

Congress have initiated a range of legislative proposals to further manage PBMs and the pharma market.