Lessons Learned from Approval of Aducanumab for Alzheimer's Disease.

When the US Food and Drug Administration used the accelerated approval process to authorize the use of the antiamyloid drug aducanumab to treat Alzheimer's disease (AD), many people hoped this signaled a new era of disease-modifying treatment. But 2 years later, aducanumab's failure to launch provides a cautionary tale about the complexities of dementia and the need for a thorough and transparent review of the role that regulatory agencies and various stakeholders play in approving AD drugs. We highlight the events leading to aducanumab's controversial approval and discuss some of the key lessons learned from the drug's failure to deliver the hoped-for benefits. These lessons include the inherent limitations of antiamyloid strategies for a complex disease in which amyloid is only one of several pathological processes, the need for clinical trials that better reflect the diversity of communities affected by AD, the potential pitfalls of futility analyses in clinical trials, the need for greater transparency and other modifications to the approval process, and the dementia field's unreadiness to move from the highly controlled environment of clinical trials to the widespread and chronic use of resource-intensive, disease-modifying drugs in real-world treatment scenarios. People with dementia desperately need effective therapies. We hope that the aducanumab story will inspire changes to the approval process-changes that restore public trust and improve future efforts to deliver disease-modifying therapies to the clinic.

Applying propensity methods to the United States transplant registry for external real-world evidence control arms for 5-year survival in the BENEFIT study.

To address the challenges of assessing the impact of a reasonably likely surrogate endpoint on long-term graft survival in prospective kidney transplant clinical trials, the Transplant Therapeutics Consortium established a real-world evidence workgroup evaluating the scientific value of using transplant registry data as an external control to supplement the internal control group. The United Network for Organ Sharing retrospectively simulated the use of several distinct contemporaneous external control groups, applied multiple cause inference methods, and compared treatment effects to those observed in the BENEFIT study. Applying BENEFIT study enrollment criteria produced a smaller historical cyclosporine control arm (n = 153) and a larger, alternative (tacrolimus) historical control arm (n = 1069). Following covariate-balanced propensity scoring, Kaplan-Meier 5-year all-cause graft survivals were 81.3% and 81.7% in the Organ Procurement and Transplantation Network (OPTN) tacrolimus and cyclosporine external control arms, similar to 80.3% observed in the BENEFIT cyclosporine treatment arm. Five-year graft survival in the belatacept-less intensive arm was significantly higher than the OPTN controls using propensity scoring for comparing cyclosporine and tacrolimus. Propensity weighting using OPTN controls closely mirrored the BENEFIT study's long-term control (cyclosporine) arm's survival rate and the less intensive arm's treatment effect (significantly higher survival vs control). This study supports the feasibility and validity of using supplemental external registry controls for long-term survival in kidney transplant clinical trials.

Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) disorders are a group of ultra-rare, inherited, lysosomal storage diseases caused by enzyme deficiencies that result in accumulation of glycosaminoglycans (GAGs) in cells throughout the body including the brain, typically leading to early death. Current treatments do not address the progressive cognitive impairment observed in patients with neuronopathic MPS disease. The rarity and clinical heterogeneity of these disorders as well as pre-existing brain disease in clinically diagnosed patients make the development of new therapeutics utilizing a traditional regulatory framework extremely challenging. Children with neuronopathic MPS disorders will likely sustain irreversible brain damage if randomized to a placebo or standard-of-care treatment arm that does not address brain disease. The United States Food and Drug Administration (FDA) recognized these challenges, and, in 2020, issued final guidance for industry on slowly progressive, low-prevalence, rare diseases with substrate deposition that result from single enzyme defects, outlining a path for generating evidence of effectiveness to support accelerated approval based on reduction of substrate accumulation [1]. Neuronopathic MPS disorders, which are characterized by the accumulation of the GAG heparan sulfate (HS) in the brain, fit the intended disease characteristics for which this guidance was written, but to date, this guidance has not yet been applied to any therapeutic candidate for MPS. In February 2024, the Reagan-Udall Foundation for the FDA convened a public workshop for representatives from the FDA, patient advocacy groups, clinical and basic science research, and industry to explore a case study of using cerebrospinal fluid (CSF) HS as a relevant biomarker to support accelerated approval of new therapeutics for neuronopathic MPS disorders. This review provides a summary of the MPS presentations at the workshop and perspective on the path forward for neuronopathic MPS disorders.

Life Years Gained From the FDA Accelerated Approval Program in Oncology: A Portfolio Model.

BACKGROUND: Although the FDA Accelerated Approval Program (AAP) has come under scrutiny, the population-level health benefit of the program has not been quantified. Therefore, the objective of this study was to estimate the number of life years gained among patients with cancer that can be attributable to the therapies receiving FDA accelerated approvals in oncology between 2006 and 2022 in the United States. METHODS: The data sources used were FDA listings, FDA approval letters and labels, published clinical trial data and other publications including relative effectiveness estimates, and the Ipsos Oncology Uptake Tool for product uptake. Data for 130 oncology treatments approved by the FDA under the AAP were extracted and validated. We developed a decision analytic model to estimate the survival gain for each indication and to accumulate life years gained for consecutive cohorts of patients receiving the therapies. Life year gains were estimated with and without the AAP, and the incremental life years gained were attributed to the program. RESULTS: The analysis estimated that through December 2022 in the United States, the program gained approximately 263,000 life years across 69 products for which overall survival data were available, for approximately 911,000 patients with cancer. CONCLUSIONS: Policy discussions about the evaluation of AAP cannot be complete without assessing its impact on its most important target outcome: patient survival. To date, there has been no estimation of the life year gain delivered by the AAP. Our research shows that substantial number of life years were gained for patients with high unmet need by the cancer therapies approved through the program.

It Takes 2 to Tango. Setting Out the Conditions in Which Performance-Based Risk-Sharing Arrangements Work for Both Parties.

OBJECTIVES: Faster regulatory approval processes often fail to achieve faster patient access. We seek an approach, using performance-based risk-sharing arrangements, to address uncertainty for payers regarding the relative effectiveness and value for money of products launched through accelerated approval schemes. One important reason for risk sharing is to resolve differences of opinion between innovators and payers about a technology's underlying value. To date, there has been no formal attempt to set out the circumstances in which risk sharing can address these differences. METHODS: We use a value of information framework to understand what a performance-based risk-sharing arrangements can, in principle, add to a reimbursement scheme, separating payer perspectives on cost-effectiveness and the value of research from those of the innovator. We find 16 scenarios, developing 5 rules to analyze these 16 scenarios, identifying cases in which risk sharing adds value for both parties. RESULTS: We find that risk sharing provides an improved solution in 9 out of 16 combinations of payer and innovator expectations about treatment outcome and the value of further research. Among our assumptions, who pays for research and scheme administration costs are key. CONCLUSIONS: Steps should be undertaken to make risk sharing more practical, ensuring that payers consider it an option. This requires additional costs to the health system falling on the innovator in an efficient way that aligns incentives for product development for global markets. Health systems benefits are earlier patient access to cost-effective treatments and payers with higher confidence of not wasting money. Innovators get greater returns while conducting research.

Characteristics of Clinical Trials for the US Food and Drug Administration Accelerated Approval and Subsequent Confirmatory Trials: Implications for Drug Approval in Japan.

The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established to facilitate and expedite access to new drugs for serious or life-threatening conditions. Although many drugs have granted AAs in the US, the number of approvals under the conditional approval system in Japan remains limited. This study aimed to examine whether confirmatory trials after the US AA are conducted in accordance with the design of postmarketing requirements and assess the timing of regular approval (RA) in Japan for drugs that have been granted US AA. Utilizing FDA databases and Japanese regulatory data from 1992 to 2023, we analyzed indications, postmarketing requirements, and clinical trial designs. Our findings indicate that the AA program in the US is well-managed as most AAs were converted to RAs based on confirmatory study data that met the designations. From the Japanese perspective, our findings show that the over half of Japanese RAs can be obtained without waiting for confirmatory trial results. By granting RA, instead of conditional approval, based on exploratory trial data in the US AA, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Therefore, further improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.

NAFLD and NASH biomarker qualification in the LITMUS consortium - Lessons learned.

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Sharing knowledge of such interactions with the scientific community is of paramount importance to increase the chances of qualification of relevant biomarkers that may accelerate drug development, and thereby help patients, across disease indications. A qualified biomarker enables a decision to be made that all understand and support in a common framework.

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

Policy Points The increasing number of drugs granted accelerated approval by the Food and Drug Administration (FDA) has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We recommend several administrative and legislative approaches for improving FDA-Centers for Medicare and Medicaid Services (CMS) coordination around accelerated-approval drugs, including promoting earlier discussions among the FDA, the CMS, and drug companies; strengthening Medicare's coverage with evidence development program; linking Medicare payment to evidence generation milestones; and ensuring that the CMS has adequate staffing and resources to evaluate new therapies. These activities can help improve the integrity; transparency; and efficiency of approval, coverage, and payment processes for drugs granted accelerated approval. CONTEXT: 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. METHODS: 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. FINDINGS: 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. CONCLUSIONS: 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.

Case study using RWD in the context of a pivotal trial for regulatory approval in a rare disease.

Rare disorders impact millions of children worldwide, and developing new medicines in this setting is associated with multiple challenges. In this paper, we share a successful story of how real-world data (RWD) were leveraged to accelerate evidence generation and patient access to a life-changing therapy in patients with severe manifestations of PIK3CA-related overgrowth spectrum who require systemic therapy. Despite all the existing regulatory guidelines considering real-world evidence (RWE), there is limited regulatory precedent of the use of this framework in support of a new indication. Thus, our case study illustrates design innovations based on the use of a compassionate use program, primarily in children, as a RWD source for approval of a new therapy in a rare disorder. We highlight the systematic considerations and mitigation of potential sources of bias in order to transform the data into actionable evidence. Our experience shows that RWE can be successfully used with appropriate study planning and mitigation in the context of a rare disorder with a high unmet medical need. Some lessons learned from this case study can benefit therapeutic development in rare disorders.

Accelerated drug approval: Meeting the ethical yardstick.

Drugs addressing unmet medical needs can change the lives of millions. Developing and validating new drugs can, however, take many years. To streamline the assessment of new drugs, regulatory agencies have long established shortened review pathways. Among these programs, Accelerated Approval (AA) has recently come under scrutiny due to the U.S. Food and Drug Administration's decision to authorize Aducanumab, the first Alzheimer's disease drug. This decision attracted fierce criticism due to the allegedly insufficient evidence about the safety and efficacy of the drug. While considerable scholarly attention has been devoted to this case, the ethical aspects of the AA regulatory pathway have so far remained relatively unexplored. In this paper, we set out to fill this gap. We illustrate six conditions that should be met for AA to be ethically acceptable: moral solicitude, evidence, risk mitigation, impartiality, sustainability, and transparency. We discuss such conditions and suggest practical steps to implement them in regulatory and oversight processes. Taken together, our six conditions represent a benchmark for assessing the ethical validity of AA processes and decisions.

Combining evidence from clinical trials in conditional or accelerated approval.

Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allows earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean χ 2 -test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean χ 2 -test always requires a post-market clinical trial. If the p -value from the pre-market clinical trial is ≪ 0.025 , a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean χ 2 -test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean χ 2 -test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval.

Takeaways from the Recarbrio Conundrum: Has the FDA Jumped the Gun?

Recarbrio is a novel antibiotic approved by US-FDA. It was initially found to be useful in treating various resistant gram negative infections. A recent investigation revealed lack of methodological and scientific integrity behind the process of FDA approval for this drug. This incident is a lesson for us that we shall not consider FDA clearance as the gold standard before approving any drug in the Indian market or start using it before having adequate data from our own clinical settings.

Physician Perceptions of the FDA's Breakthrough Therapy Designation: An Update.

The US Food and Drug Administration developed the Breakthrough Therapy designation to expedite the development and review of drugs that show a clear advantage over available therapy for serious conditions. Prior research has shown that physicians tend to misunderstand that a drug may receive a Breakthrough Therapy designation based on preliminary clinical evidence (eg, effect on a surrogate endpoint or intermediate clinical endpoint that is likely to predict clinical benefit). The objective of this article is to examine whether physicians' familiarity with and interpretation of the Breakthrough Therapy designation have changed since a survey on the topic was published in 2016. We replicated three of the questions in that study and explored beliefs that a Breakthrough Therapy designation automatically qualifies a drug for accelerated approval. We also draw comparisons by specialization (oncologists vs. primary care physicians). In general, physicians remain more likely than not to misunderstand the Breakthrough Therapy designation.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA.

BACKGROUND: Previous research focused on the clinical evidence supporting new cancer drugs' initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. OBJECTIVES: To examine the clinical trial evidence supporting new targeted cancer drugs' initial and supplementary indication approval in the US, EU, Canada, and Australia. DATA AND METHODS: 25 cancer drugs across 100 indications were identified with FDA approval between 2009-2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07-6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38-8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17-5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14-30.65], p < 0.05) than supplementary indications. Initial indications' pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93-0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09-0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01-1.39], p < 0.05). CONCLUSIONS: Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication's differential clinical and economic value.

Clinical development of anticancer drugs can be enhanced using efficacy data of small population clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Although there are accelerated approval pathways based on data of small populations and surrogate endpoints, the concern that these pathways authorize the use of inefficacious drugs based on limited data from earlier phase clinical trials remains. We retrospectively investigated the efficacy of anticancer drugs, which were approved or whose development was terminated in small and large clinical trials, and verified whether small clinical trials could reflect the results for efficacy in large clinical trials. METHODS: All anticancer drugs approved in Japan or whose development was terminated from 2015 to 2019 were searched. The median overall survival (OS), median progression-free survival (PFS), and overall response rates (ORR) between small clinical trials (sample size ≤100) and large clinical trials (sample size >100) with identical target populations and treatment settings were compared. Simple linear regression analysis, Spearman's correlation analysis, and paired sample t-test were performed. RESULTS AND DISCUSSION: A total of 61 comparable small and large clinical trials were identified. For all endpoints, statistically significant linear trends and correlation were detected (p < 0.001). There were no statistically significant differences in the median PFS and ORR between small and large clinical trials. The mean differences of both clinical trials were -0.102 months and -1.531%, respectively. WHAT IS NEW AND CONCLUSION: Even when the sample size of the clinical trial was increased, the efficacy data of anticancer drugs could not be changed significantly. These results supported the accelerated approval pathway based on the promising efficacy data of small populations in anticancer drug development.

Impact of expedited programs in the United States, as foreign regulatory factors, on clinical development time in Japan.

WHAT IS KNOWN AND OBJECTIVE: Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development. METHODS: In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs. RESULTS AND DISCUSSION: The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p = 0.008), FT (p = 0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time. WHAT IS NEW AND CONCLUSION: US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.

Medicaid and Accelerated Approval: Spending on Drugs with and without Proven Clinical Benefits.

Many state Medicaid officials are concerned about rising prescription drug spending, particularly drugs approved through the Food and Drug Administration's (FDA) accelerated approval pathway. The authors examined how much of Medicaid programs' accelerated approval spending is attributable to products that have demonstrated clinical benefits versus those that have not. Their findings provide support for states' concerns that pharmaceutical companies often fail to complete their required postapproval confirmatory studies within the FDA's requested timeline. But the findings also highlight one issue that policy stakeholders have not yet devoted substantial attention to: the use of surrogate endpoints involved in the postapproval confirmatory studies for most of the products in this study's sample. The granularity of the study's results enabled an analysis of the impact of different policy recommendations on both the accelerated approval pathway and Medicaid programs. These findings inform the current policy debate, suggesting that policy stakeholders might focus attention on products converting their approval on the basis of surrogate outcomes rather than on clinical outcomes.

A chronicle of the 17-alpha hydroxyprogesterone caproate story to prevent recurrent preterm birth.

Preterm birth is a substantial public health concern. In 2019, the US preterm birth rate was 10.23%, which is the fifth straight year of increase in this rate. Moreover, preterm birth accounts for approximately 1 in 6 infant deaths, and surviving children often suffer developmental delay or long-term neurologic impairment. Although the burden of preterm birth is clear, identifying strategies to reduce preterm birth has been challenging. On October 29, 2019, a US Food and Drug Administration advisory committee voted 9 vs 7 to withdraw interim accelerated approval of 17-alpha hydroxyprogesterone caproate for preventing recurrent preterm birth because the called for a confirmatory trial, known as the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial, was not confirmatory. The Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial included subjects enrolled in the United States and Canada to ensure that at least 10% of patients would be from North America; however, this trial took 9 years to complete and did not demonstrate significant treatment effects in the 2 primary outcomes of interest. Delivery before 35 weeks' gestation occurred in 122 of 1130 women (11%) given 17-alpha hydroxyprogesterone caproate compared with 66 of 578 women (11.5%) given placebo (relative risk, 0.95; 95% confidence interval, 0.71-1.26; P=.72). Similarly, the coprimary outcome neonatal composite index occurred in 61 of 1093 women (5.6%) given 17-alpha hydroxyprogesterone caproate compared with 28 of 559 women (5.0%) given placebo (relative risk, 1.12; 95% confidence interval, 0.68-1.61; P=.73). There was also a lack of efficacy for 17-alpha hydroxyprogesterone caproate treatment in the analysis of a variety of secondary outcomes. Like the Maternal-Fetal Medicine Units Network trial, the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial was also flawed. Importantly, the Maternal-Fetal Medicine Unit Network trial was the sole justification for treating women in the United States with 17-alpha hydroxyprogesterone caproate for nearly 2 decades. Currently, despite more than half a century, 17-alpha hydroxyprogesterone caproate still has not been found to be clearly effective. In this context, how does the advising physician dependent on scientific evidence advise a patient that 17-alpha hydroxyprogesterone caproate is effective when the evidence to support this advice has repeatedly been found to be inadequate? This clinical opinion is a critical appraisal of the 2 randomized trials examining the efficacy of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth and a chronicle of events in the regulatory process of drug approval to help answer this question. With this examination, these events illustrate the complexity of pharmaceutical regulations in the era of accelerated Food and Drug Administration approval and characterize the financial impact and influence in medicine. In this report, we also emphasize the value of observational studies in contemporary practice and identify other examples in medicine where accelerated Food and Drug Administration approval has been withdrawn. Importantly, the themes of the 17-alpha hydroxyprogesterone caproate story are not limited to obstetrics. It can also serve as a microcosm of issues within the US healthcare system, which ultimately contributes to the high cost of healthcare. In our opinion, the answer to the question is clear-the facts speak for themselves-and we believe 17-alpha hydroxyprogesterone caproate should not be endorsed for use to prevent recurrent preterm birth in the United States.

Evaluation of Serious Postmarket Safety Signals Within 2 Years of FDA Approval for New Cancer Drugs.

BACKGROUND: We examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here. METHODS: We identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns. RESULTS: Fifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval. CONCLUSION: Based on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug. IMPLICATIONS FOR PRACTICE: The majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.

FDA Accelerated Approval of Pembrolizumab for Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma.

On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc., Whitehouse Station, NJ) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Approval was based on Cancer Immunotherapy Trials Network protocol 9, also known as KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% confidence interval: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months. The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for the Food and Drug Administration's accelerated approval of pembrolizumab for the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma, including efficacy and safety information. This approval provides patients and physicians with an additional treatment option for this aggressive and life-threatening carcinoma.