Food And Drug Administration Decision Research Articles

Food and Drug Administration (FDA) Approvals of Biological Drugs in 2023.

An increase in total drug (small molecules and biologics) approvals by the Food and Drug Administration (FDA) was seen in 2023 compared with the previous year. Cancer remained the disease most targeted by monoclonal antibodies (mAbs), followed by autoimmune conditions. Our data reveal the prevalence of approvals for biologics even during years when the total number of authorizations was low, such as in 2022. Over half the drugs that received the green light in 2023 benefited from expedited programs, as the incidence of many diseases increased. In addition, over half of the biologics approved received Orphan Drug Designation from the FDA. This narrative review delves into details of the most significant approvals in 2023, including mAbs, enzymes, and proteins, explaining their mechanisms of action, differences from previous drugs, placebo, and standards of care, and outcomes in clinical trials. Given the varying number of drugs authorized annually by the U.S. health authority, this review also examines the limits of external influences over the FDA's decisions and independence regarding drug approvals and withdrawals.

Seventeen years since rimonabant's downfall: reassessing its suicidality risk profile.

Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference thiswith the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.

Characterization of accelerated approval status, trial endpoints and results, and recommendations in guidelines for oncology drug treatments from the National Comprehensive Cancer Network: cross sectional study

ObjectivesTo evaluate National Comprehensive Cancer Network (NCCN) guideline recommendations for oncology drug treatments that have been granted accelerated approval, and to determine whether recommendations are updated based on the results...

A new era for food in health? The FDA announces a qualified health claim for yogurt intake and type 2 diabetes mellitus risk reduction

IntroductionOver the last two decades research has grown regarding dairy intake and health. It has been reported by many that yogurt intake may be associated with reduced risk of type 2 diabetes mellitus (T2D). In this report, the United States Food and Drug Administration (FDA) decision to announce a qualified health claim for yogurt products regarding reduced risk of T2D in response to a Danone North America petition is discussed. MethodsRelevant literature cited in the petition along with supporting evidence from PubMed and Google Scholar databases until April 1st, 2024 were used. Literature was found using relevant keywords. ResultsOn March 1st, 2024, the United States Food and Drug Administration (FDA) announced the first ever qualified health claim, stating that eating yogurt regularly may reduce the risk of T2D according to limited scientific evidence. The enforcement discretion letter was critically reviewed and discussed regarding its future implications for people with T2M and public health. ConclusionsIt is unclear how this FDA decision will affect public health and nutrition in the long-term. Limited scientific evidence suggests that at least 3 servings of yogurt per week may reduce the risk of T2D incidence for the general population. Yogurt will not cure or treat people with T2D.

Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines.

The Covid-19 pandemic highlighted the need to examine public trust in the U.S. Food and Drug Administration (FDA) vaccine approval process and the role of political influence in the FDA's decisions. Ensuring that the FDA is itself trustworthy is important for justifying public trust in its actions, like vaccine approvals, thereby promoting public health. We propose five conditions of trustworthiness that the FDA should meet when it reviews vaccines, even during emergencies: consistency with rules, proper expert or political decision-makers, proper decision-making and noninterference, connection to public preference, and transparency of both reasons and procedures. The five conditions provide a road map of procedural and substantive requirements, which the FDA has variably implemented, focused on ensuring appropriate influence of political interests. While being a trustworthy agency cannot guarantee the public's trust, implementing these conditions builds a groundwork for public trust.

Improving Food and Drug Administration-Centers for Medicare and Medicaid Services Coordination for Drugs Granted Accelerated Approval.

The Food and Drug Administration (FDA)'s accelerated-approval pathway expedites patient access to promising treatments. However, increasing use of this pathway has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We examined approaches to improve coordination between the FDA and Centers for Medicare and Medicaid Services (CMS) for drugs granted accelerated approval. We argue that policymakers have focused on expedited pathways at the FDA without sufficient attention to complementary policies at the CMS. Although differences between the FDA and CMS decisions are to be expected given the agencies' different missions and statutory obligations, procedural improvements can ensure that Medicare beneficiaries have timely access to novel therapies that are likely to improve health outcomes. To inform policy options and recommendations, we conducted semistructured interviews with stakeholders to capture diverse perspectives on the topic. We recommend ten areas for consideration: clarifying the FDA's evidentiary standards; strengthening FDA authorities; promoting earlier discussions among the FDA, the CMS, and drug companies; improving Medicare's coverage with evidence development program; tying Medicare payment for accelerated-approval drugs to evidence generation milestones; issuing CMS guidance on real-world evidence; clarifying Medicare's "reasonable and necessary" criteria; adopting lessons from international regulatory-reimbursement harmonization efforts; ensuring that the CMS has adequate staffing and expertise; and emphasizing equity. Better coordination between the FDA and CMS could improve the transparency and predictability of drug approval and coverage around accelerated-approval drugs, with important implications for patient outcomes, health spending, and evidence generation processes. Improved coordination will require reforms at both the FDA and CMS, with special attention to honoring the agencies' distinct authorities. It will require administrative and legislative actions, new resources, and strong leadership at both agencies.

Physician Perspectives on the Food and Drug Administration's Decision to Grant Accelerated Approval to Aducanumab for Alzheimer's Disease.

In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval to aducanumab, a monoclonal antibody indicated for the treatment of Alzheimer's disease. The accelerated approval decision was controversial due to concerns about the use of an unvalidated surrogate measure, beta-amyloid, as the basis for approval and a lack of clinical outcome benefit. Between October 2021 and September 2022, we conducted a survey of a nationally representative group of internists, medical oncologists, and cardiologists to understand perspectives around aducanumab's approval and how this FDA decision may influence trust in other drugs approved through the accelerated approval program. Among 214 physician respondents familiar with the accelerated approval of aducanumab, 184 (86%) would not prescribe or recommend aducanumab. Further, 143 (67%) physicians reported losing trust in other drugs approved through the accelerated approval program due to the FDA's decision with aducanumab. As a growing number of similar novel Alzheimer's disease treatments are on the horizon, the first of which, lecanemab, already has received accelerated approval in January 2023, our survey findings provide insight into the impact of the FDA's regulatory decisions on the perspectives and prescribing behavior of physicians concerning these novel drug treatments.

An insider's perspective on FDA approval of aducanumab.

Aducanumab was approved in 2021 by the US Food and Drug Administration (FDA) under the accelerated approval pathway. Since then, there have been many misconceptions about the approval decision despite multiple publications from the FDA to explain the rationale. Even though the FDA's final decision was accelerated approval, the Office of Clinical Pharmacology recommended regular/full approval based on its own analyses. Exposure-response analyses were conducted to quantify the relationship between aducanumab longitudinal exposure and responses (standardized uptake values ratios for amyloid beta and various clinical endpoints) in all clinical trials. To explain the difference between aducanumab and other compounds with negative results in the past, publicly available data were combined with the aducanumab data to demonstrate the relationship between amyloid reduction and clinical endpoint change across multiple compounds with similar mechanism of action. The probability to observe the overall positive findings in the aducanumab program was quantified under the assumption that aducanumab is ineffective. Positive exposure-response (disease progression) relationship for multiple clinical endpoints from all clinical trials was identified. Positive exposure-amyloid reduction relationship was established. Consistent amyloid reduction-clinical endpoint change relationship across multiple compounds was observed. If aducanumab is assumed to be ineffective, it is extremely unlikely we would observe the overall positive findings in the aducanumab program. These results provided convincing evidence to support aducanumab's effectiveness. In addition, the observed effect size in the studied patient population represents a clinically meaningful benefit given the magnitude of disease progression within the trial duration. Totality of evidence supports the Food and Drug Administration (FDA)'s approval decision for aducanumab.Different opinions were clearly explained in the FDA's public reviews from different disciplines.Readers are encouraged to read the FDA's reviews to understand the FDA's rationale to approve aducanumab.

Development of Monoclonal Antibody Therapeutics for Alzheimer's Disease

Background: In a previous review article in the Taiwanese Journal of Psychiatry (Takeda and Tagami: Taiwanese J. Psychiatry 2020; 34: 152-61), we gave the development status of drugs for Alzheimer's disease, presented a relatively pessimistic view, and highlighted the difficulties in their development. Methods: Since I have witnessed some encouraging development of monoclonal antibody therapeutics against Alzheimer's disease, I have decided to contribute this article. I reviewed new data from published journals and from internal reports of pharmaceutical companies. I have also offered some explanations and comments. Results: In 2021, I saw promising clinical trial results reporting the use of aducanumab, a monoclonal antibody treatment against amyloid β protein, and the U.S. Food and Drug Administration (FDA) announced a decision for expedited approval of aducanumab. But the results of aducanumab's phase III clinical trials were considered by some to be insufficient for the approval, and the FDA's decision was controversial. The European and Japanese regulatory authorities did not approve aducanumab. In September 2022, however, more promising results were announced from Phase III clinical trials of another monoclonal antibody, lecanemab. Conclusion: In this review, I have recounted the state of the arts of drugs for treating dementia and highlighted remarkable recent progress in the development of monoclonal antibody therapeutics for Alzheimer's disease.

Unwanted Advice? Frequency, Characteristics, And Outcomes Of Negative Advisory Committee Votes For FDA-Approved Drugs.

Substantial controversy arose in 2021 when the Food and Drug Administration (FDA) approved the Alzheimer's disease drug aducanumab (Aduhelm) under its accelerated approval program despite a nearly unanimous negative advisory committee vote. Advisory committees are convened before some FDA decisions to provide insight for the agency's decision-making process. To understand the frequency, characteristics, and outcomes of cases in which the FDA authorizes a drug against the recommendations of an advisory committee, we reviewed all FDA advisory committee referrals for new drugs approved during the period 2010-21. The fraction of approved drugs that had been referred to an advisory committee decreased from 55percent to 6percent annually, with FDA approvals of negatively reviewed drugs occurring about once a year. Qualitative analysis of committee meetings revealed variability in the substance and wording of key voting questions. Reforms such as transparent criteria for when a drug should be subject to external scrutiny, consistent wording of voting questions, and clear regulatory responses to negative recommendations can better ensure public confidence in the FDA approval process.

Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer.

Alzheimer disease (AD) is a progressive disorder common among older adults and culminating in profound cognitive impairments and high mortality risk. The US Food and Drug Administration (FDA) recently provided accelerated approval for Aduhelm, a medication for AD treatment. Aduhelm (Biogen Inc., Cambridge, Massachusetts) has been described as the first disease-modifying treatment for AD but has not been demonstrated to improve patients' cognitive or functional outcomes. In this commentary, we describe why Aduhelm approval was controversial and aspects of the current evidence of special pertinence to epidemiologists. The FDA decision was based primarily on 2 randomized controlled trials (RCTs), both terminated early, with conflicting findings about the cognitive benefits of Aduhelm. Both RCTs showed important adverse effects of the medication. The FDA cited the documented reduction in brain amyloid, an AD biomarker hypothesized as a surrogate outcome, to justify accelerated approval. Despite lack of racial/ethnic diversity in the RCT participants, concerns about health disparities have been invoked to argue for public funding of this expensive medication. The Centers for Medicare and Medicaid Services recently made a "Coverage with Evidence Development" determination for Aduhelm and similar medications. We end by describing how innovative study designs could accelerate postapproval research and evaluate the proposed surrogate outcomes.

U.S. Food and Drug Administration Reasoning in Approval Decisions When Efficacy Evidence Is Borderline, 2013-2018.

The U.S. Food and Drug Administration (FDA) has substantial flexibility in its approval criteria in the context of life-threatening disease and unmet therapeutic need. To understand the FDA's evidentiary standards when flexible criteria are employed. Case series. Applications submitted between 2013 and 2018 that went through multiple review cycles because the evidence for clinical efficacy was initially deemed insufficient. Information was obtained from the approval package (available on Drugs@FDA), including advisory committee minutes, FDA reviews, and complete response letters. Of 912 applications reviewed, 117 went through multiple review cycles; only 22 of these faced additional review primarily because of issues related to clinical efficacy. Concerns about the end point, the clinical meaningfulness of the observed effect, and inconsistent results were common bases for initial rejection. In 7 of the 22 cases, the approval did not require new evidence but rather new interpretations of the original evidence. No FDA decisions cited reasoning used in previous decisions. The conclusions rely on the authors' interpretation of the FDA statements and on a series of "close calls." The FDA has no mechanism to find or tradition to cite similar cases when weighing evidence for approvals, resulting in standalone, bespoke decisions. These decisions show highly variable criteria for "substantial evidence" when flexible evidential criteria are used, highlighted by the recent approval of aducanumab. A precedential tradition and suitable information system are required for the FDA to improve institutional memory and build upon past decisions. These would increase the FDA's decisional transparency, consistency, and predictability, which are critical to preserving the FDA's most valuable asset, the public's trust. U.S. Food and Drug Administration.

Pancreatic Islets Quality and Potency Cannot be Verified as Required for Drugs: Reflection on the FDA Review of a Biological License Application for Human Islets.

Dear Editors Human pancreatic islets are regulated as a drug in the United States, requiring a biologic license application (BLA) approval for allotransplantation outside of clinical trials.1 The goal of the BLA is to prove that drug manufacturing consistently provides a well-defined, high-quality product, with verified characteristics that assure the desired clinical effect. Such verification is considered essential for clinical safety and efficacy of any drug. No US academic institutions have been capable of submitting a BLA for pancreatic islets over the last 20 y, which led to a gradual demise of the field.1 Recently, a private company has filed a BLA for human islets and the Food and Drug Administration (FDA) Advisory Committee members reviewed the application on April 15, 2021.2 Herein, we share findings from that meeting as they have major implications for the field of islet transplantation. FDA advisors confirmed that islet transplantation has a favorable benefit-risk profile for certain patients with type 1 diabetes. This conclusion is not surprising to the transplant community, as favorable clinical outcomes have been well documented over the last 20 y.1 However, the main question: whether the BLA should be approved, was not asked and remains unanswered. Moreover, during the meeting, the FDA presented its own analysis of the BLA data. FDA concluded that “the quality and potency of the human islets may not be reliably defined, and critical quality attributes of the islets (islet characteristics based on the release criteria) did not correlate with islet function.”2 Basically, this means that the main goal of the BLA has not been achieved. Thus, BLA approval has no merit. However, the final FDA decision is yet to be made. Based on the scientific evidence, we call on the FDA to reach the most rational decision: reject the BLA and allow human pancreatic islets to be included into the definition of human organs under the OPTN Final Rule. This will result in proper islet regulation, as with any other organ for transplantation. This was proposed in recent publications and directly to the FDA and Health and Human Services.3,4 Unfortunately, an FDA representative recently renounced our proposition.5 Alternatively, an FDA decision to reject the BLA but continue holding the same drug-related requirements would inevitably prevent any clinical use of human islets indefinitely in the United States. On the other hand, the FDA approval of a clearly deficient BLA would be detrimental. The BLA-holding commercial entity would be authorized to sell human islets of unverifiable quality and potency. Transplant centers will have no choice but to purchase and transplant them in patients. Such regulation would compromise patient safety and FDA credibility. Moreover, it would be impossible to verify the islet manufacturer performance, even when islet graft fails, since the ultimate reason for failure cannot be established. These new FDA findings provide further strong evidence that islets do not fit into drug regulatory framework and should be instead included into the organ for transplant regulations by the Health and Human Services Secretary.

New Visualization Models of Designation Pathway and Group Categorization of Cell-Device and Protein-Device Combination Products in the United States.

The developer and sponsor of new cell-device and protein-device combination products in the United States needs to forecast which classification and designation to the regulatory scheme of biological products or devices would be required for the new products by the Food and Drug Administration (FDA). To improve the predictability and acceptability of the designation of new cell-device and protein-device combination products for innovators, developers, and sponsors, and to encourage the development and early access of new combination products, we proposed new visualization models of the designation pathway and group categorization. We searched the website of the FDA and the Alliance for Regenerative Medicine (ARM) on May 3, 2021 to identify the regulatory scheme of the FDA's capsular decision cases of cell-device and protein-device combination products, and of the tissue-engineered products approved by the FDA. By introducing a new definition of the primary intended use (PIU) of developers and sponsors extracted from the classification factors of primary mode of action (PMOA), as well as drug-device and biologic-device combination products, we developed new visualization models of the designation pathway and the two-dimensional model of group categorization, and proposed a new group categorization of cell-device and protein-device combination products, focusing on the device component function. The new visualization models and the group categorization proposed in this study may increase the predictability and acceptability of the classification of newly developed cell-device and protein-device combination products to regulatory schemes in the US for innovators, developers, and sponsors.

The Problem of Aducanumab for the Treatment of Alzheimer Disease.

Ideas and OpinionsSeptember 2021The Problem of Aducanumab for the Treatment of Alzheimer DiseaseG. Caleb Alexander, MD, MS and Jason Karlawish, MDG. Caleb Alexander, MD, MSJohns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, Baltimore, Maryland (G.C.A.)Search for more papers by this author and Jason Karlawish, MDUniversity of Pennsylvania, Philadelphia, Pennsylvania (J.K.).Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-2603 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail On 7 June 2021, the U.S. Food and Drug Administration (FDA) approved aducanumab for the treatment of Alzheimer disease. Biogen, the owner of the drug, will sell it as Aduhelm. The FDA's decision to approve aducanumab is among its most controversial ever. In this article, we examine the decision's implications for clinical research and patient care.Reverberating Problems With Drug Approval and ResearchAducanumab was approved despite the concerns of scientists and regulatory experts about its efficacy. Notably, an FDA statistician and an advisory committee on which one of us served (G.C.A.) reviewed the product at a November 2020 hearing ...

FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib.

On March 10, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The recommended approved dosage was nivolumab 1 mg/kg i.v. plus ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks. The approval was based on data from cohort 4 of CheckMate 040, which randomized patients with advanced unresectable or metastatic HCC previously treated with or who were intolerant to sorafenib to receive one of three different dosing regimens of nivolumab in combination with ipilimumab. Investigator-assessed overall response rate (ORR) was the primary endpoint, and ORR assessed by blinded independent central review (BICR) was an exploratory endpoint. BICR-assessed ORR and duration of response (DoR) form the primary basis of the FDA's regulatory decision, and BICR-assessed ORR was comparable in all three arms at 31%-32% with 95% confidence interval [CI] 18%-47%. The DoR ranged from 17.5 to 22.2 months across the three arms, with overlapping 95% CIs. Adverse events (AEs) were generally consistent with the known AE profiles of nivolumab and ipilimumab, and no new safety events were identified. This article summarizes the FDA review of the data supporting the approval of nivolumab and ipilimumab for the treatment of HCC. IMPLICATIONS FOR PRACTICE: Nivolumab and ipilimumab combination therapy is another option for patients with advanced hepatocellular carcinoma who experience radiographic progression during or after sorafenib or sorafenib intolerance. No new toxicities were identified, but, as expected, increased toxicity was observed with the addition of ipilimumab to nivolumab as compared with nivolumab alone, which is also approved for the same indication. Whether to administer nivolumab as a single agent or in combination with ipilimumab is expected to be a joint decision between the oncologist and patient, taking into consideration the potential for a higher likelihood of response and the potentially higher rate of toxicity with the combination.

#Mesh: Social Media and Its Influence on Perceptions in Hernia Repair.

Social media can influence public perception in health care. By 2016, social media discussion against the use of transvaginal mesh influenced changes in Food and Drug Administration (FDA) regulations. We propose that the fate of hernia mesh will follow that of transvaginal mesh. Thus, we compare the trend of social media discussion of hernia and transvaginal mesh. Posts on Twitter and public Facebook groups were tracked for keywords "hernia," "hernia mesh," and "pelvic/vaginal mesh." Posts were categorized based on sentiment. On Facebook, 16 public groups with 14526 members expressed negative sentiments in 95% of their 750 daily posts. Meanwhile, of the 1.1million tweets on Twitter, those about hernia mesh were more negative (36.5%) than those about pelvic/vaginal mesh (29.2%). Three of the 5 top tweeters about hernia mesh and pelvic/vaginal mesh were linked to law firms involved in mesh-based lawsuits. The negative sentiments and steering of social media discussion by lawyers may directly affect surgical care. As surgeons, we may adapt our informed consent to acknowledge our patients' apprehensions about mesh. We may also be more involved in social media discussions ourselves. Meanwhile, we await FDA decisions in the regulation and availability of hernia mesh.

Retail violations of sales to minors on e-cigarettes and cigars

ObjectivesThe finalized ‘Deeming Rule’ extended the Food and Drug Administration (FDA) authority to regulate e-cigarettes, cigars, and other newly deemed tobacco products. We seek to assess the neighborhood characteristics associated with retail violations of sales to minors (RVSM) by tobacco product. Study designWe collected national inspection data on tobacco retailers during August 8, 2016, and May 31, 2018, from the FDA compliance check database. MethodsA web scraping tool was applied to text mine the FDA decision letters and extract information on the tobacco product involved in RVSM. Separate logistic regression models with random effects were performed to examine the association between zip code-level neighborhood characteristics and RVSM by tobacco product. ResultsOf 268,317 minor-involved compliance inspections, 35,403 (13.2%) were identified as RVSM. Among 23,352 warning letters included in the final analysis, e-cigarettes, cigars, cigarettes, and smokeless tobacco accounted for 20.0% (n = 4673), 40.4% (9439), 35.6% (8303), and 4.0% (937) of RVSM, respectively. Flavored tobacco products were abundant among underage sales. For e-cigarettes, RVSM were more likely to occur in zip codes with a larger proportion of youth population aged 10–17 years (adjusted odds ratio [AOR] = 1.17 [1.02–1.34]). A larger proportion of African Americans was associated with a higher risk of RVSM for cigars (AOR = 1.09 [1.07–1.11]) but a lower risk of RVSM for e-cigarettes (AOR = 0.90 [0.87–0.93]). ConclusionsRetail violations of underage sales for cigars and e-cigarettes are prevalent and neighborhood characteristics associated with violations differ by tobacco product. Continued inspections with tailored strategies to reduce RVSM of all tobacco products are needed.

Disagreements Between FDA and its Oncologic Drugs Advisory Committee (ODAC).

Cases of discordance between the US Food and Drug Administration (FDA) and its advisory committees are uncommon. Due to the importance of oncology therapies, we sought to identify and discuss instances of disagreement between the regulatory decision made by FDA, and the recommendation made by its Oncologic Drugs Advisory Committee (ODAC) via committee vote. Public databases (Oncologic Drugs Advisory Committee Meeting Materials, Drugs@FDA) as well as publicly available documents from ODAC meetings were reviewed to discern cases of disagreement between the two bodies. This review of public data yielded six (6) instances in which FDA's ultimate regulatory decision went against the recommendation of the ODAC. The six cases are briefly discussed and key drivers for or against an approval decision are outlined. In cases where FDA's decision was less conservative than that of the ODAC, the value of therapies with novel mechanisms of action which provide new options for patients, as well as regulatory precedent were observed as key drivers for regulatory decision-making. In cases where FDA took a more conservative approach than the ODAC, the importance of appropriate clinical trial design, clinically relevant trial endpoints, and the integrity of the data collected were stressed as driving the ultimate regulatory decision.

Advancing structured decision-making in drug regulation at the FDA and EMA.

The recent benefit-risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit-risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit-risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators.