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

Jill Wechsler

In the face of a host of contentious and controversial policy decisions, President Biden appears poised to bring in an experienced and well-regarded hand to lead FDA. The agency has lacked a permanent leader for more than eight months, as the White House has been unable to identify a new commissioner acceptable to politicians and interest groups on all sides.

So as the clock has ticked down on the Nov. 15 deadline for Janet Woodcock to vacate her acting commissioner role, potentially forcing Biden to appoint another acting commissioner, word is out that the White House will name cardiologist and research pro Robert Califf to the top job, a position he held for almost a year at the end of the Obama administration.

Califf’s appointment will bring much-needed stability to FDA as it contends with a host of difficult policy decisions involving vaccines, new anti-COVID therapeutics, access to e-cigarettes, accelerated approval programs, and budget priorities. Califf may face opposition in the Senate, as partisan politics has come to the fore on all sides. Although he wins plaudits for his experience in medical research and his familiarity with FDA operations and requirements, some consumer advocates and liberals criticize his close ties to industry and pro-development attitude. He will need support from Republicans, which may be more tenuous in today’s hotly divisive climate on Capitol Hill.

Another factor driving the FDA nomination is the recent announcement of retirement plans by Francis Collins, long-time director of the National Institutes of Health (NIH). Biden will want to name a new leader for NIH before the end of the year, and that provides an opening to bring a woman scientist into the administration’s health and science leadership cadre.

Hopefully, the politicians will recognize the importance of experienced leadership for the nation’s leading health agencies and put aside partisan politics to agree on a new FDA commissioner, and then a new leader at NIH. FDA has been well-served by acting commissioner Woodcock, but her tenuous position has exposed her to criticism and second-guessing on all sides. With a global pandemic still raging, a seasoned hand is needed to stabilize FDA’s exhausted workforce, ensure funding continuity, and steer debate and decisions on many difficult scientific and policy issues.

Articles

After months of deliberation, Biden plans to appoint cardiologist Robert Califf as FDA commissioner.

Can Califf Bring Clarity and Enhanced Credibility to FDA?

In an important step for modernizing drug formulation and biopharmaceutical development, FDA is launching a program to test the safety and suitability of novel excipients for use in new drugs and biologics. This final initiative, first proposed two years ago, will support a pilot program to test up to four novel excipients likely to improve the effectiveness and safety of important new drugs (1). The aim is to encourage sponsors of clinical trials to test new drugs formulated with excipients that FDA finds acceptable for use under this program.

FDA announced the pilot program Sept. 7, 2021, and spelled out the application process in a Federal Register notice (2). The notice explains that the pilot is open to novel excipients that have not been used previously in food or in FDA-approved products. Excipient manufacturers seeking to participate in the pilot should submit information on the novel inactive ingredient and its potential for enhancing health by offering pharmacokinetic characteristics important to developing new drugs, as described in an outline for an initial proposal (3). The sponsor also must show it can produce a complete information package in the set time frame for weighing pilot proposals. Initial pilot review proposals are due at FDA by Dec. 7, 2021.

FDA defines a novel excipient as an inactive ingredient that is not fully supported by existing safety data related to a proposed level of exposure, duration of exposure, or route of administration. Manufacturers should describe how the product addresses a public health need and advances drug development, such as by increasing solubility for an oral formulation taken chronically. Sponsors also, should describe available quality and toxicology information that support the product’s safety, such as pharmacokinetic/toxicokinetic data and other nonclinical information, as presented in FDA guidance issued in 2005 (4).

From these submissions, FDA will select four products for full review under the pilot, planning for two during the first year. Selected participants then should provide a full data package of toxicology and chemistry, manufacturing, and controls (CMC) quality data, as required for excipients. If the excipient passes muster, FDA will determine that it may be used in the formulation for an experimental drug undergoing clinical trials, provided that the sponsor demonstrates that it is safe to use in that therapy. After FDA approves a new drug or biologic utilizing the new excipient, that excipient would then be added to FDA’s Inactive Ingredient Database, making it available for use by other manufacturers, including those producing generic drugs.

Manufacturers of drugs and biologics, as well as excipient developers, have long sought a process for FDA to evaluate new inactive ingredients prior to use in a new drug or biologic. A perennial difficulty is that new drug sponsors are reluctant to delay or complicate FDA review and approval of an investigational new drug (IND) for an experimental therapy due to the need to assess an untried inactive ingredient in the product formulation. Yet, these firms increasingly face difficulties in formulating innovative products with available, established excipients. Biopharma companies have expressed support for the pilot as a way to address these development challenges, such as the need for new ways to stabilize proteins for bioavalability in new formulations. Excipient makers similarly acknowledge that they would be more willing to invest in production, controls, and characterization of novel excipients if it’s possible to gain FDA review of the product’s benefits outside of clinical testing for a new molecular entity.

FDA first proposed this process for evaluating novel excipients separate from new drug applications in a Federal Register notice posted in December 2019 (5). That draft plan asked manufacturers to comment on the proposed program, its definitions and scope, and FDA sought to address these issues in this final proposal.

It appears fitting that FDA is launching this novel excipients pilot program as the International Pharmaceutical Excipients Council, IPEC-Americas, marks its 30th anniversary. IPEC held its first meeting in March 1991, with the aim of harmonizing excipient standards set by different pharmacopeias and to address worldwide issues important to excipient use. Manufacturers of these essential ingredients in pharmaceutical formulations note that many well-known excipients that have been used for decades are not suited to the novel dosage forms and parenterals under development today (6). Industry also would like to see an update of FDA’s 2005 guidance on excipient safety testing, mentioned previously. These initiatives, as well as ongoing efforts to set international standards for excipient use, have potential to enhance drug formulation and support modern manufacturing and quality control efforts.

Novel Excipient Review Pilot Program, FDA.gov

Center for Drug Evaluation and Research Office of New Drugs Novel Excipient Review Pilot Program

Novel Excipient Review Pilot Program Initial Proposal Model Content Online, FDA.gov.

Guidance for Industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients

Novel Excipient Review Program Proposal; Request for Information and Comments

, Federal Register, 84 FR 66669, Dec. 5, 2019.

Jill Wechsler is Pharmaceutical Technology’s Washington editor, 


Volume 45, Number 10
October 2021
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, “FDA Moves to Advance Innovative Excipients

A new program will test the safety and suitability of new inactive ingredients to encourage the accelerated adoption of FDA-accepted excipients in drug development.

FDA Moves to Advance Innovative Excipients

Demand for more efficient and faster development of medical products is prompting regulatory authorities to incorporate additional sources of information into the research and approval processes, notably data provided by patient registries and medical records able to inform traditional clinical trials. FDA and the European Medicines Agency (EMA) are looking to tap real-world data (RWD) and real-world evidence (RWE) more broadly to accelerate the research and market approval process.

A notable advance was FDA’s recent reliance on RWE to approve an added indication for an important medicine. In July 2021, 

the agency extended the use of Astella’s liver transplant drug, Prograf, to also prevent the rejection of lung transplants

, which was based on data from a US registry of lung transplant recipients. FDA determined that this non-interventional “study” with historical controls met FDA standards for being adequate and well-controlled and precluded bias as an explanation of results, explained John Concato, associate director for RWE analytics in the Office of Medical Policy at the Center for Drug Evaluation and Research. Concato also described at the Sept. 13 & 14, 2021, Convergence meeting sponsored by the Regulatory Affairs Professionals (RAPS) how FDA demonstration projects are advancing the use of RWD/RWE in different types of studies.

 advises sponsors on strategies for accessing RWD from electronic health records (EHRs) and medical claims to help demonstrate the safety and effectiveness of a drug or biological product to support regulatory decisions. While such records are used to track medical product safety and to support additional uses and post-approval study requirements, the diversity and limitations of this information have stymied broader adoption for documenting drug effectiveness. Now, FDA is asking biopharmaceutical developers to weigh in on strategies utilizing RWD to support regulatory decisions and to help define treatment exposure, outcomes, data quality assurance, and data quality control procedures.

The potential for wider use of RWD and RWE in drug development has moved up on FDA’s agenda since it was featured in the 21st Century Cures Act of 2016 to support the approval of new indications for a drug and for meeting post-approval study requirements. 

FDA published a framework for wider evaluation of RWE in regulatory decision making in 2018

guidances on using data from EHRs in submissions and on submitting RWD and RWE in applications

. The agency also expanded its Sentinel surveillance system to help assess how health system data can inform research projects. FDA efforts to streamline clinical research during the pandemic have highlighted the potential for wider use of RWE to inform research protocols, identify research subjects, and track outcomes and responses remotely. Upcoming revisions in the Prescription Drug User Fee program (PDUFA VII) further expand the use of RWE in these and other initiatives.

Similarly, EMA looks to make wider use of RWE in regulatory submissions. At the recent RAPS meeting, EMA director of surveillance and epidemiology, Xavier Kurz, described a new study on the issue, noting the frequent use of information from disease registries and hospital records, while also acknowledging limitations in the data and confusion over terminology and methods.

Concato and other FDA officials have addressed these developments at numerous meetings and conferences this past year. At a July 2021 symposium on how RWE is changing scientific standards, experts also noted the limitations and need for caution in interpreting studies utilizing RWE. Long-time RWD skeptic, Steven Nissen of the Cleveland Clinic, warned that RWE is a “dangerous delusion” and should not be viewed as providing “conclusive evidence” on a treatment—citing the failure of early claims of cardiovascular benefits to women of hormone replacement therapy. He argued that wider use of RWE largely aims to save money on clinical development and that a better strategy is to find more efficient ways to conduct randomized trials.

Most experts, however, look to more advanced data analytical methods to validate data in this area. The rising demand for highly personalized therapies to treat very small patient populations, such as for rare conditions and neonatal populations, makes it vital to devise methods for the accurate assessment of RWE. In addition, efforts to include more data on patient minorities and other sub-populations in biomedical research look to tap RWD to make research more inclusive and representative.

FDA and EMA are looking to tap real-world data and real-world evidence more broadly to accelerate the research and market approval process.

FDA to Rely on Real World Data and Evidence for Future Research and Market Approvals

Despite the agency’s remarkable success in speeding vital new vaccines and therapies to patients to combat the COVID-19 pandemic, while also continuing to advise on and approve a broad range of vital medicines, FDA officials have been under attack. The regulators either are acting too fast and risking public safety or too slow, mired in rules while ignoring important scientific findings.

A main difficulty is that the agency has lacked a confirmed leader for the past 10 months, making it difficult to set priorities and explain actions within the Biden administration and to the public and policymakers. As acting commissioner, Janet Woodcock has maintained a steady hand on this diverse agency that oversees a vast range of products vital to public health. In addition to vaccines and new drugs, FDA has been in the spotlight recently over its efforts to limit marketing of e-cigarettes to halt the dangerous vaping epidemic among young people. The agency is responsible for assuring the safety of much of the nation’s food supply, veterinary medicines, and dietary supplements. Plus, its regulation of cannabis products and cosmetics is under debate. FDA’s oversight of medical devices and diagnostics has put it in the hot seat for shortages of critical products for protecting medical personnel and for providing fast and accurate public testing for COVID infection. And there’s the continuing wave of false claims about popular treatments to combat the pandemic, some dangerous and most ineffective.

Earlier in the year, it looked likely that Woodcock would become FDA’s permanent commissioner, but that was sidelined by some Democrats and public health officials upset by the agency’s earlier approval of what turned out to be deadly opioid pain killers that are easily abused. As the long-time head of drug development and approval at the Center for Drug Evaluation and Research (CDER), Woodcock also was accused of working too closely with biopharma companies in accelerating the development and marketing of important new therapies, some turning out to have limited long-term benefits and many posting high price tags. Although patient advocates and research groups have championed Woodcock for providing strong leadership in shifting FDA away from a more risk-averse stance, that approach has been challenged. The result is that the White House has delayed in selecting an FDA commissioner, even though federal rules require Woodcock to vacate her acting position by mid-November unless the administration nominates a new commissioner, permitting her to continue on during the Senate confirmation process.

The situation has hampered FDA in articulating future priorities and pushing back against miscommunications and outside complaints. The recent debate over approval of booster shots for anti-COVID vaccines is a case in point, with FDA compelled to manage President Biden’s promise to provide third shots by late September amidst highly publicized internal agency dissension on the issue. Leading FDA vaccine officials contended that the agency was ignoring the scientific evidence in authorizing booster shots and that such a policy was inappropriate when initial vaccines were desperately needed by much of the Third World.

That dispute over vaccines followed an even more blistering debate over FDA approval of a costly new treatment for Alzheimer’s disease, Biogen’s Aduhelm, based on questionable and very limited clinical evidence. The approval decision by CDER officials was blasted by members of Congress, the medical community and even some patient groups, but justified by the reviewers as likely to provide some benefit to some patients who lacked any alternative treatment for this devastating disease. Continued charges of FDA officials caving to industry pressures, though, prompted Woodcock to seek an independent review of the approval process for the drug from the Health and Human Services (HHS) Inspector General.

These developments have generated media reports on tumult and dissension at FDA and continued criticism about the agency putting industry interests above the needs of public health. The Aduhelm decision was blamed for undermining FDA’s “gold standard” for ensuring drug safety and efficacy and linked to the agency’s dependence on industry-paid user fees for shifting the balance away from careful oversight and toward too-speedy approvals.

Such charges gain support from several departures of long-term agency. Most visible was the recent announcement of retirement by top vaccine approval officials, Marion Gruber and Phillip Krause, director and deputy director of the Office of Vaccine Research & Review (OVRR) in the Center for Biologics Evaluation and Research (CBER). At the same time, many leading staffers who have been at FDA for decades have announced retirement plans, such as Theresa Toigo, CDER associate director for drug safety operations.More departures are expected, as many FDA officials past retirement age are exhausted from the pressures of the past year and now seek to move on after postponing their departures during the height of the public health emergency. Public scorn for the agency’s efforts to evaluate reams of data as fast as possible has tipped the balance in favor of leaving the public spotlight.

Meanwhile, agency veteran Woodcock has worked with her staff to keep review and regulatory decisions on track. Industry leaders have supported her for the top job but went quiet as the administration signaled that would not occur. Woodcock opened the recent annual “Convergence” conference sponsored by the Regulatory Affairs Professionals Society (RAPS) by citing FDA’s efforts to ensure access to needed diagnostics, vaccines, and therapeutics during the health emergency, and in meeting the challenges in conducting clinical trials, inspecting drug and food facilities, and issuing “reams of guidances” to facilitate emergency use authorizations for vital vaccines, drugs and diagnostics, while also keeping up with the usual volume of premarket reviews of innovative products.

Woodcock concluded by expressing hope that these efforts in dealing with the pandemic will create “at least among some people” a “renewed appreciation for the importance of science, technology, and data.” She said she looks forward to a greater understanding of the “essential role [played] by the FDA and other public health agencies” in responding to this crisis and in protecting and promoting public health.

The lack of a new permanent commissioner has hampered FDA in articulating future priorities and pushing back against miscommunications and outside complaints.