A COVID-19-ready public health surveillance system: The Food and Drug Administration's Sentinel System.

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post-market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID-19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID-19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi-pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID-19, validated a diagnosis-code based algorithm for identifying patients with COVID-19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID-19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID-19 prevention and treatment.

Public-private partnerships in transplant drug development.

The Transplant Therapeutics Consortium (TTC), a public-private partnership (PPP) led by the Critical Path Institute (C-Path), recently published a whitepaper titled "The Importance of Drug Safety and Tolerability in the Development of New Immunosuppressive Therapy for Transplant Recipients" by Stegall et al in the American Journal of Transplantation. As staff members of the Food and Drug Administration's (FDA), Center for Drug Evaluation and Research (CDER), Office of New Drugs and Office of Translational Science, and the Oncology Center of Excellence, we would like to provide our perspective on the TTCs efforts and the whitepaper.

Accelerating regulation in response to COVID-19.

Regulators are finding ways to support the expedited development and distribution of novel coronavirus-related vaccines, tests and treatments. Gary Humphreys reports.

FDA postmarketing safety labeling changes: What have we learned since 2010 about impacts on prescribing rates, drug utilization, and treatment outcomes.

PURPOSE: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. METHODS: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study. RESULTS: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. CONCLUSIONS: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications.

Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials: a consensus report from the Non-adherence Academic Research Consortium (NARC).

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

Current state of U.S. Food and Drug Administration regulation for cellular and gene therapy products: potential cures on the horizon.

Cellular & Gene Therapies (CGTs) are complex products, which have been key foci of the International Society for Cell & Gene Therapy (ISCT). For this ISCT North American Legal & Regulatory Affairs Committee review publication, CGTs include but are not limited to somatic cell-based therapies, pluripotent cell-derived cell-based therapies, gene- or non-gene-modified or gene edited versions of these cell-based therapies, in vivo gene therapies, organ/tissue engineered products, and relevant combination products. These products are regulated by the Food and Drug Administration (FDA) in the United States. This publication reviews selected laws, regulations, guidance, definitions, processes, types of meetings and submissions, and other key factors that the FDA follows and implements to regulate and support development of these types of products. These factors may be considered in order to help current and potential product developers/sponsors/applicants navigate through FDA regulatory pathways. We also review expedited programs including types of Designations available at the FDA, and their specific eligibility criteria. We include FDA and other stakeholder resources to consider regarding CGT regulation, to help prepare for CGT development and subsequent FDA approval.

Anatomy of Risk Evaluation and Mitigation Strategies (REMS).

This Chapter provides an introduction and overview of the U.S. FDA REMS program and applicable regulatory aspects. Topics covered include the 2015 Draft Guidance, organization structure and functions, a discussion on pharmacovigilance and adverse event reports, and a discussion of the applicability of REMS in oncology.

Checks and Balances on FDA's Authority.

In this Viewpoint, the authors refute recent suggestions that the US Food and Drug Administration (FDA) is not accountable for its decisions, pointing out the legal, legislative, and executive checks and balances on the agency.

Response to the US FDA LeadCare Testing Systems Recall and CDC Health Alert.

On May 17, 2017, the Food and Drug Administration issued a safety recall for the Magellan Diagnostics' LeadCare Testing Systems due to the potential for inaccurately low blood lead test results when used with venous blood samples. Concurrently, the Centers for Disease Control and Prevention (CDC) issued a health alert with retesting recommendations for specific high-risk populations. The purpose of the CDC retesting recommendations was to help identify high-risk individuals so that those potentially impacted by falsely low test results could be retested and receive appropriate follow-up care. The CDC's Lead Poisoning Prevention Program sought to understand how the recall and recommendations impacted state and local public health agencies. Childhood lead poisoning prevention programs (CLPPPs) in state and local public health agencies collect blood lead test results for children and had a lead role in identifying children for retesting. Case studies are presented that highlight the experiences of 4 state CLPPPs in responding to the recall and recommendations. Collectively, the case studies point to several lessons learned, including the importance of (1) having a well-functioning surveillance system in place prior to a serious incident; (2) having a clear understanding of the roles partners play in the continuum of care for children potentially exposed to lead; and (3) ensuring effective communications with all staff, both internal and external, to public health agencies that have a role in responding to a serious incident. The ability to respond to public health emergencies or other serious incidents takes the combined effort of federal, state, and local public health agencies as well as others in the health care delivery system. The CDC will continue to support state and local lead poisoning prevention programs so that they have the information and tools they need to address and prevent the health effects of lead exposures in communities.

Evaluation of the Implementation of CDC's Health Alert Related to the FDA LeadCare Recall From the State Health Department Perspective.

On May 17, 2017, the Food and Drug Administration (FDA) issued a safety recall for the Magellan Diagnostics' LeadCare Testing Systems due to the potential for inaccurately low blood lead test results when used with venous blood samples. The Centers for Disease Control and Prevention (CDC) announced a health alert with retesting recommendations because those with a blood lead level of concern may have been missed and not connected to the appropriate follow-up services. A qualitative evaluation of 9 state childhood lead poisoning prevention programs' experiences is presented in this report. Interviewees reported using a variety of media and notification methods to inform key stakeholders about the recall and recommendations. Challenges experienced by programs in responding to retesting recommendations include incomplete and out-of-date lists of LeadCare users; missing or inaccurate information in their surveillance database; not having large laboratories and hospitals consider contacting persons for retesting to be within their purview; and having limited staff members to conduct emergency response activities. Two of the 9 states report subsequent challenges with their retesting rates. The retesting recommendations were generally viewed positively. The interviewees' comments provide insight into steps CDC might take to better serve state and local lead programs. Programs' experiences have led to a better understanding of the roles of their program when emergency events occur, their relationship with stakeholders as related to the blood lead testing and reporting process, and areas of improvement in surveillance databases. Public health agencies at all levels have important roles to play in preventing lead exposures and providing needed services when exposures occur. Programs may achieve long-term benefits by improving surveillance systems and having a better understanding of laboratory practices. CDC will continue to provide timely information and recommendations to state and local public health agencies to inform both routine and emergency response activities.

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

New Cancer Drug Approvals From the Perspective of a Universal Healthcare System: Analyses of the Pan-Canadian Oncology Drug Review Recommendations.

Background: FDA approvals do not consider cost, but they set the tone for regulatory approvals worldwide, including in countries with universal healthcare where cost-effectiveness, utility, and adoption feasibility are considered rigorously. Methods: Data from the pan-Canadian Oncology Drug Review (pCODR), a national drug review system that makes evidence-based funding recommendations to Canada's provinces and territories, were collected. Our objectives were to assess (1) temporal trends in cost and efficacy of drugs reviewed, (2) correlations among magnitude of benefits, cost, and pCODR decisions, and (3) predictors of approvals. Results: A total of 60 drugs for 91 indications were reviewed by pCODR from January 2012 to January 2018. Of the 91 reviews (approved previously by FDA), 18 received negative recommendations on the grounds of inadequate clinical benefits; 87% (64/73) of those approved were conditional on improvement in cost. Surrogate outcomes were used to support approvals in 83% of the reviews, which were not correlated with overall survival (rSpearman = +0.16; P=.24). Median cost/quality-adjusted life years (QALY) increased by 36% per annum (quantile regression, P=.0029), although benefits in overall and progression-free survival were stable (P=.21 and .65, respectively). Median-based incremental cost-effectiveness ratio (ICER) of new drugs was $186,403 CAD (range, $7,200 to $2.1 million). Higher ICER was a strong predictor of a negative pCODR recommendation (P<.01). Conclusions: A substantial number of cancer drugs that are FDA approved for public use do not meet Canadian standards for efficacy. Cost of cancer drugs increases by a third annually in Canada, but the benefits-measured mostly with surrogates that did not correlate with survival-are stable. With finite resources to share among multiple societal priorities, such as education and preventive health, cancer drug cost may be unsustainable despite price regulation.

Patient-Reported Outcome Measures in the Food and Drug Administration Pilot Compendium: Meeting Today's Standards for Patient Engagement in Development?

BACKGROUND: In 2016, the Food and Drug Administration (FDA) released a Pilot Clinical Outcome Assessment Compendium (COA Compendium) intended to foster patient-focused drug development (PFDD). However, it is unclear whether patient perspectives were solicited during development or validation of the included patient-reported outcome (PRO) measures. OBJECTIVE: To examine the pedigree of a sample of measures included in the COA Compendium. METHODS: PROs included in chapters 1 or 2 of the COA Compendium were extracted and three reviewers independently searched PubMed and Google to identify information on measure pedigree. Data on method and stage of measure development where patient engagement took place were documented. RESULTS: Among the 26 evaluated PRO measures, we were unable to identify information on development or validation on nearly half the sample (n = 12). Among the remaining 14 measures, 5 did not include any evidence of patient engagement; 2 engaged patients during concept elicitation only; 1 engaged patients during psychometric validation only; and 6 engaged patients during both concept elicitation and cognitive interviewing. Measures either previously qualified or submitted for qualification were more likely to include patient engagement. CONCLUSIONS: For the FDA Pilot COA Compendium to fulfill its purpose of fostering PFDD, it needs fine-tuning to reflect today's standards, improving transparency and facilitating clear identification of included measures so that the level of patient engagement, among other factors, can be properly assessed. Suggested improvements include identifying clinical trials that correspond to the COA Compendium's use in drug development; more clearly identifying which measure is referred to; and including only those measures that already qualified or undergoing qualification.