Post-marketing Requirements Research Articles

Characteristics of Postmarketing Studies for Vaccines Approved by the US Food and Drug Administration, 2006-2020

This cross-sectional study uses data from the US Food and Drug Administration (FDA) to review the postmarketing requirements and commitments attached to new vaccines approved for use in the past 15 years in the United States.

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

Overview of the Premarketing and Postmarketing Requirements for Drugs Granted Japanese Conditional Marketing Approval.

For drugs that are intended to fill unmet medical needs, such as the treatment of rare diseases or a subtype of cancer, it can take a long time to conduct confirmatory clinical trials due to limited patient availability. Delayed access to these drugs increases the risk of mortality of patients with these diseases. To address this issue, the Ministry of Health, Labour, and Welfare of Japan has decided to implement the Conditional Early Approval System with issuing the Ministry Notification in 2017. Drugs eligible for conditional early approval are those that are indicated for the treatment of a serious disease, have proven safety and efficacy, and cannot be examined easily by confirmatory clinical trials. When the benefit of immediate availability outweighs the risk of having less comprehensive data with which to confirm the clinical benefit of a product in the premarketing phase, products can be approved under the Conditional Early Approval System, accompanied by postmarketing regulatory requirements to manage postmarketing risks and, if needed, conduct postmarketing confirmatory clinical studies. Overview of the pre‐approval and post‐approval regulatory considerations will promote to more efficiently develop pharmaceutical products that fill unmet medical needs, leading to the prompt delivery of safe and effective drugs to patients who often have few therapeutic options available. As of March 2020, four drugs had been approved under the Conditional Early Approval System. In this review, we describe the premarketing and postmarketing requirements of these drugs and discuss the regulatory landscape around the Conditional Early Approval System.

Use of real-world data for HPV vaccine trial follow-up in the Nordic region

Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501–015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14 years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.

Impact of FDA-Required Cardiovascular Outcome Trials on Type 2 Diabetes Clinical Study Initiation From 2008 to 2017

Background:Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events—including the implementation of the CVOT requirement—may have precipitated any observed changes.Methods:We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents.Results:The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies.Conclusions:These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.

A Regulatory Overview of Hip And Knee Joint Replacement Devices

Objective: Medical device acceptance of patients has grown considerably in recent years. This has question the effectiveness of the current regulatory frameworks to ensure the performance, safety, and quality of new devices. This article focuses on the methodical overview on hip and knee joint replacement medical devices evaluating the procedure and proper analysis of medical device regulation in three jurisdictions i.e. the United States of America (USA), EUROPE and INDIA, exploring reforms been laid to stabilize and meet the requirements of existing systems, and further analyse the additional actions which should be employed to fully meet this ultimate goal. Method: We analysed the hip and knee joint replacement medical device regulation system through a secondary research in United States, Europe and India in compliance with the updated national regulatory authority’s legislative documents and requirements. Result: These three regulatory systems vary in their working, organization, acceptance for their specific pre- and post-market evidence requirements, and transparency of process. The most challenging factor remains the same for the countries which are to make sure safety and effectiveness of devices, proper monitoring of its use and important compliance information readiness employing quality management system towards new findings and acceptance for the users. A case study of Johnson & Johnson ASR Implant was also studied, highlighting the major reforms required and the reforms introduced in the United States, Europe and India. Thus, quality and safety reforms are made to strengthen the premarket compliance requirements, enhancing the need of post-market regulation through proper traceability and monitoring of devices by employing the functioning medical device registry. Conclusion: Recent reforms address the major challenges in device regulation, highlighting the need to create connecting points between the device identifier system and existing data collection tools, such as electronic health records, and maintaining effective and up to date use of registries to ensure post-market use of new and existing devices.

Pharmaceutical Drugs of Uncertain Value, Lifecycle Regulation at the US Food and Drug Administration, and Institutional Incumbency.

Policy Points The US Food and Drug Administration (FDA) has in recent years allowed onto the market several drugs with limited evidence of safety and effectiveness, provided that manufacturers agree to carry out additional studies while the drugs are in clinical use.Studies suggest that these postmarketing requirements (PMRs) frequently lack transparency, are subject to delays, and fail to answer the questions of greatest clinical importance. Yet, none of the literature speaks directly to the challenges that the FDA—as a regulatory institution—encounters in enforcing PMRs.Through a series of interviews with FDA leadership, this article analyzes and situates those challenges in the midst of political threats to the FDA's public health mandate. ContextModern pharmaceutical regulation is premised on a rigorous examination of a drug's safety and effectiveness prior to its lawful sale. However, since the 1990s, the US Food and Drug Administration (FDA) has gradually shifted to a model of “lifecycle” regulation that increasingly relies on postmarketing requirements (PMRs) to encourage studies of drug safety and effectiveness following regulatory approval. This article examines the range of legal, institutional, and political challenges that FDA faces in the context of lifecycle regulation.MethodsDocument‐based legal and policy analysis was combined with a set of semistructured interviews of current and former FDA officials (n = 23) in order to explore the implications of the FDA's use of PMRs. The median interview time per official was 61 minutes, with a range of 24 to 227 minutes. All of the officials interviewed occupied positions of leadership and influence within the FDA, such as directors of an FDA center or office, key legal counsel on agency‐wide policy initiatives, and the commissioner of the FDA.FindingsInsufficient resources and coordination within the FDA, inadequate legal authorities, and the political economy of withdrawing an approved indication in the face of opposition from companies and patients all contribute to the observed shortcomings in the FDA's use and enforcement of PMRs. Further, the FDA is fully aware of these challenges, yet is seemingly resigned to and resistant to criticism of its use of PMRs.ConclusionsThis study of the FDA's shift toward lifecycle regulation reveals not simply an agency in transition, but rather an agency on guard against a set of larger political threats to its mandate. This can be characterized as a state of institutional incumbency in which the agency is engaged in an effort to reproduce key features of the regulatory system—in concert with regulated industries and others—while simultaneously sanctioning significant changes to the regulatory standards the FDA has long applied, to the detriment of public health.

Impact of FDA-Required Cardiovascular Outcome Trials on Type 2 Diabetes Clinical Study Initiation From 2008 to 2017.

Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events-including the implementation of the CVOT requirement-may have precipitated any observed changes. We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents. The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies. These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.

Lower-dose prescriptions in the post-marketing situation and the influencing factors thereon.

The dosage of pharmaceuticals is determined through the process of clinical development and approval review based on clinical trial results; however, the information obtained from clinical trials before approval is limited. Some pharmaceutical products are used at doses lower than those approved for post-marketing use. The aim of this study was to reveal the actual state of lower-dose prescriptions for post-marketing clinical use of pharmaceuticals. We investigated the factors related to the deviation based on therapeutic area, detailed statement of the approved dosage, clinical data package, and post-marketing requirement. Among the new molecular entities approved in Japan between January 2005 and December 2014, we identified products that are orally administered and have the same daily dose for different indications, if any. For these products, we collected information on the actual daily dose from the medical information databases of Medical Data Vision Co., LTD. and JammNet Co., LTD. Products whose dose was lower than the approved dose (maintenance dose excluding the initial dose) in ≥ 30% prescriptions in 2015 were defined here as “lower-dose prescription drugs.” We identified 27 lower-dose prescription drugs out of 113 products investigated. The results of the multivariate analysis revealed that factors related to the Anatomical Therapeutic Chemical classification and the detailed statement of the approved dosage significantly influenced the occurrence of lower-dose prescription, whereas the factors related to clinical data package and post-marketing requirements did not. These results suggest the limitation in determining an optimal dosage for the actual clinical use of a drug based on the information obtained from clinical trials conducted before approval, emphasizing the importance of reexamining the optimal dosage that is applicable to a greater number of patients after marketing, if necessary. We believe that the utilization of real-world data could be of help in this regard.

2334-PUB: Evolution of the Designs of the Sitagliptin (SITA) Pediatric Clinical Studies

Approved antihyperglycemic therapies for pediatric patients with T2D are currently limited to metformin (MET) and insulin. SITA is being evaluated in 3 studies in patients 10-17 years of age with T2D: SITA as initial oral therapy, MK-0431 P083; SITA as add-on to MET administered as a fixed dose combination (FDC), MK-0431A P170; and SITA as add-on to MET extended-release administered as a FDC of SITA and MET XR, MK-0431A XR P289. The studies, conducted to fulfill post-marketing requirements, and a Pediatric Investigation Plan (EU), were initiated between 2011 and 2013; enrollment completed in 2018. Study protocols were amended since initiation to accommodate regulatory agency requirements, reduce patient burden related to study conduct, and improve patient accrual. Major amendments to the protocols, their rationales, and their impacts are summarized (Table) and demonstrate the flexibility that may be required to enroll such studies. The impact on enrollment of 2 amendments common to all 3 studies were quantifiable. Of patients randomized after approval of an amendment that broadened the A1C entry criterion (from lower limit of 7.0% to 6.5%), ∼34% in P083, ∼20% in P170 and ∼20% in P289 had a baseline A1C between 6.5% and 6.9%. Of patients randomized after approval of an amendment to include patients on background insulin, 11% of patients in P083, 22% in P170, and 19% in P289 enrolled on background insulin. Disclosure R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck & Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. V.P. Pozharskaya: Employee; Self; Merck & Co., Inc. K. Leight: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. A. Deeb: None. R. Garcia: None. C.A. Rosario: None. C.K. Saha: Research Support; Self; Indiana University School of Medicine. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Y. Samoilova: None. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. Funding Merck & Co., Inc.

033 Effects of Alcohol Administered with Flibanserin in Healthy Premenopausal Women: A Randomized, Double-Blind, Single Dose, Seven-Way Crossover Study

Flibanserin is a serotonin 5-HT1A agonist and a 5-HT2A antagonist approved in the US and Canada for the treatment of HSDD in premenopausal women. Upon approval in the US, the FDA requested several postmarketing requirements, including an alcohol interaction trial. The purpose of this trial was to evaluate the safety of concomitant administration of flibanserin with relevant concentrations of ethanol due to concerns about the increased risk of severe hypotension and syncope. This postmarketing study was primarily designed to evaluate the pharmacodynamic effect of flibanserin 100 mg co-administered with varying doses of ethanol on dizziness, syncope, and hypotension in healthy premenopausal women. In this single-center, randomized, double-blind, single-dose crossover study, participants were randomly assigned to 1 of 12 sequence groups to receive each of 7 treatments: flibanserin 100 mg or placebo with ethanol 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg, or flibanserin 100 mg only. The primary endpoint was the proportion of subjects who experienced dizziness, syncope or hypotension. Secondary endpoints included subject’s self-assessment of drowsiness by a 100 mm visual analog scale (VAS). Safety endpoints included orthostatic vital signs. In compliance with the study site’s standard operating procedures, subjects were not permitted to stand for measurement of orthostatic vital signs if their supine blood pressures were <90/40 mmHg, or if they exhibited symptoms of possible hypotension after dosing.

An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate

Approximately one-third of cancer drugs are approved based on response rate (RR)-the percentage of patients whose tumors shrink beyond an arbitrary threshold-typically assessed in a single-arm study. To characterize RR end points used by the US Food and Drug Administration (FDA) for cancer drug approval. A retrospective review of FDA-approved drug indications in oncology from 2006 to 2018. Data related to cancer type, line of therapy (first-line, second-line, or third-or-later-line treatment for advanced/metastatic disease), type of FDA approval pathway, trial design, sample size, and level of innovation were extracted. The primary outcome was the RR used as the basis for FDA approval. The secondary outcome was rate of complete response. Eighty-five indications for 59 cancer drugs were identified, 32 (38%) received regular approval, and 53 (62%) were granted accelerated approval. Twenty-nine (55%) accelerated approvals were later converted to regular approval. Of these, 6 (21%) approvals showed overall survival benefit, 16 (55%) later established progression-free survival benefit, and 7 (24%) continued to use RR but gained regular approval. The median RR among the 85 indications was 41% (interquartile range [IQR], 27%-58%). Among them, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%. The median complete RR for 81 participants was 6% (IQR, 2%-22%). The median sample size among studies leading to approval was 117 (IQR, 76-182; range, 18-1052 participants). Drugs with accelerated approval pending confirmatory data had lower RR compared with drugs that have completed most postmarketing efficacy requirements (median, 28%; IQR, 15%-50% vs median, 42%; IQR, 31%-58%; P = .02). Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates. Most premarket studies accrue more than 100 patients. Some of these drugs could potentially be tested in premarket randomized clinical trials measuring directly end points that demonstrate clinical benefit.

Analysis of Postapproval Clinical Trials of Therapeutics Approved by the US Food and Drug Administration Without Clinical Postmarketing Requirements or Commitments

The US Food and Drug Administration (FDA) can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics. Pharmaceutical companies can also agree to conduct nonmandated clinical trials as postmarketing commitments. However, when therapeutics are approved by the FDA without postmarketing requirements or postmarketing commitments, it is not well known how often pharmaceutical companies voluntarily conduct trials and report results monitoring safety or efficacy after approval. To characterize postapproval clinical trials sponsored by pharmaceutical companies of therapeutics initially approved by the FDA without clinical postmarketing requirements or commitments. This cross-sectional analysis included postapproval clinical trials conducted with at least 1 site in the United States sponsored by pharmaceutical companies of therapeutics first approved by the FDA from 2009 through 2012. Analyses were conducted June 11, 2018, to November 30, 2018. Postapproval clinical trials registered on ClinicalTrials.gov generating safety or efficacy data, characteristics including whether trials focused on approved or unapproved indications, study design elements, and rates of study completion and results reporting. From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications, of which 37 novel therapeutics for 39 indications did not have postmarketing requirements or commitments for new clinical studies at the time of first approval. For 31 therapeutics (83.8%), there were 600 postapproval clinical trials sponsored by pharmaceutical companies. Most trials investigated therapeutics for new indications (363 [60.5%]) or expanded populations of the originally indicated disease (122 [20.3%]). Trials were often small (median [interquartile range] enrollment, 44 [21-131] participants), nonrandomized (359 [59.8%]), unblinded (455 [75.8%]), and lacked comparators (381 [63.5%]). Approximately half of the trials (311 [51.8%]) assessed at least 1 clinical outcome. Of 300 terminated or completed trials, 204 trials (68.0%) had reported results on ClinicalTrials.gov a median (interquartile range) 16 (13-25) months after their primary completion date. For the 96 trials (32.0%) without reported results, a median (interquartile range) 35 (13-62) months had passed since their primary completion date. Pharmaceutical companies frequently conducted clinical trials after approval, even when there were no clinical postmarketing requirements or commitments at approval. However, most of these trials evaluated new indications or expanded patient populations rather than monitored approved uses, and nearly half of the trials remained incomplete more than 5 years after original therapeutic approval.

PCP60 - EVOLVING STRATEGIES FOR GENERATING, SYNTHESIZING, AND VISUALIZING REAL WORLD EVIDENCE IN RARE DISEASES

RWE for rare diseases is often unavailable. While registries can provide valuable data, these are commonly used to satisfy post-marketing approval requirements and can have limited access and chart data completeness. Non-registry RWE are commonly in the form of case reports. Given the limitations with available RWE in rare diseases, decision-makers often resort to expert opinion. However, rigorously analyzed and synthesized published data can help provide a more objective and complete picture of disease burden. Our objective is to present approaches for generating, synthesizing, and visualizing literature-based evidence rare diseases. We began by developing a structured framework to guide approaches to using rare disease RWE from the literature. This included consideration of: how to identify and collect the data; which data are appropriate to include (given that more severe cases and outcomes are more likely to be reported); how to handle exposure time and number at risk; ways to visualize patterns in patient presentation; and how to integrate expert opinion. We applied and refined the framework using published RWE from case reports from >500 patients with hypophosphatasia. The framework, and how the case report data informed strategies of interest to HEOR practitioners, will be presented. Strategies included tabulating the occurrence of key clinical events; using Kaplan-Meier curves to estimate time-to-event, accounting for censoring; and approaches to identify patterns in clinical data. A checklist for analytic and visualization features useful in displaying these data will also be presented. In the absence of large-scale data collection, methods to understand the epidemiology, burden-of-illness, and outcomes in rare diseases are needed. Several methods exist for synthesizing and visualizing published data to answer HEOR-related research questions, to supplement data from registries and expert opinion. While these methods have promise, it is important to consider potential limitations inherent in using data collected in a non-standardized fashion.

Development of Post-Marketing Risk Management Plan Requirements: The Singapore Experience

Historically, global drug safety regulations were generally reactive and post-marketing safety monitoring comprised mainly spontaneous adverse event reporting. As a strategic move towards proactive pharmacovigilance, several drug regulatory agencies have introduced requirements for risk management plans (RMPs) since the early 2000s. The aim of this paper is to share the process on how the Health Sciences Authority (HSA), the national drug regulatory authority of Singapore, conceptualised and implemented its local RMP requirements, drawing upon the experiences of international regulatory agencies. Some of the steps taken include the incorporation of local RMP requirements into HSA’s guidance documents for the pharmaceutical industry, consultation with industry stakeholders on the proposed updates to these requirements, and strengthening of the enforcement of RMP requirements through relevant enactments in legislation. We also compared our requirements with that of other regulatory agencies to ensure that they were aligned with global regulatory standards. Based on our experience in developing the regulatory framework for RMP requirements in Singapore, we put forth recommendations which could be useful for other regulatory agencies embarking on the implementation of RMP requirements in their countries.

Factors That Influence FDA Decisions for Postmarketing Requirements and Commitments During Review of Oncology Products.

With the recent use of expedited drug development and approval programs for several oncology products in the United States, the importance of postmarketing plans to confirm clinical benefits and safety is increasing. To discuss postmarketing requirements (PMRs) and postmarketing commitments (PMCs) required for oncology products approved in the United States, we investigated the factors that influenced the US Food and Drug Administration (FDA) decisions for PMR/PMCs during FDA review. Characteristics of new drug approvals and PMR/PMCs for oncology products (new molecular entities and new therapeutic biologic products) in the United States between 2008 and 2015 were analyzed. Of the 58 oncology products analyzed, PMR/PMCs were required for 54 products. The proportion of approvals that required confirmatory PMR/PMCs was 100% for accelerated approval (AA) and was 39% for regular approval (RA). Median development times for AA and RA were 7.41 and 7.50 years, respectively. Randomization, number of patients, and end point in pivotal studies were identified as key potential factors that influenced the decision to require PMR/PMCs for both confirmatory and clinical safety studies. Robustness of the pivotal study design was identified as one of the key factors for the decision by the FDA to require PMR/PMCs-in particular, significant PMR/PMCs, such as those for confirmatory studies. That is, the FDA approved products with surrogate markers and smaller studies but required PMR/PMCs to fully prove the risk-benefit profile in the postmarketing period.

Statistical Considerations for Cardiovascular Outcome Trials in Patients with Type 2 Diabetes Mellitus

ABSTRACTThis is the second article written by the American Statistical Association Biopharmaceutical Section Safety Working Group. In the first article, we reviewed the drugs approved by the United States Food and Drug Administration to treat type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. We discussed different strategies to address premarketing and post-marketing CV risk requirements and raised some questions that required further research. The main objective of this article is to outline statistical challenges encountered at the design and analysis stages of cardiovascular outcome trials (CVOTs). We discuss statistical challenges and strategies for testing multiple endpoints, populations, and doses; choosing an event window; addressing premarketing and post-marketing requirements for CV events with group-sequential and adaptive designs; designing a CVOT for noninferiority and superiority testing; assessing effects in subgroups; and evaluating patient's retention and missing data challenges.

Evolving oncology clinical pharmacology strategies oncology: An analysis of approved small molecule cancer drugs by the FDA 2011-2016.

e18130 Background: Understanding the clinical pharmacology properties of new drugs is essential, enabling correct prescribing with respect to dose, interactions and organ impairment. In the era of targeted therapy and resurgence in oncology R&amp;D there is a need to consider how and when to define clinical pharmacology, since many drugs are given accelerated reviews, limiting the development time. This assessment was undertaken to understand how FDA review the clinical pharmacology components of NDAs. Methods: The Clinical Pharmacology and Biopharmaceutics Review documents of small molecule approvals in oncology by FDA from 2011 -2016 were analysed. Information regarding clinical pharmacology studies, in addition to post marketing requirements (PMR) was analysed. Results: Of 42 small molecules identified, 35 had clinical pharmacology review information. There were 16 accelerated approvals and in only 3 approvals were there no PMRs issued. A particular issue concerns the dose, 14 NDAs had identifiable issues in review, resulting in a 10 PMRs which include conducting a further pivotal study with additional doses. The majority of submissions (33) included clinical assessment of drug effect on the QTc interval. 7 PMRs were issued, 4 requesting completion of ongoing studies. A number of PMRs (24) were issued to assess organ impairment and DDI assessment (12). In all orally administered drugs a food interaction study was conducted with 1 PMR issued. In 32 submissions an excretion balance study was conducted, only 1 of the remaining 3 drugs was issued a PMR. Conclusions: Whilst a number of PMRs for clinical pharmacology studies were issued it is encouraging that these did not limit approval, ensuring patient access. For accelerated approvals, there will be insufficient time to complete many studies prior to filing. However, there were a significant number of PMRs regarding dose, reflecting FDA concerns that there is inadequate characterisation of the dose. Clinical pharmacology characterisation of NMEs is still required, but could be conducted through PMRs to enable early patient access. A major focus for sponsors should be a clearer understanding of the dose response relationship.

Balancing innovation and medical device regulation: the case of modern metal-on-metal hip replacements.

Due to problems with wear particle generation and subsequent loosening using conventional metal-on-polyethylene total hip replacements, there has been a shift toward alternative bearing systems, including metal-on-metal (MoM), for younger, more active patients with degenerative joint disease. Based on positive results from early short-term clinical studies, MoM hip replacements were readily adopted by orthopedic surgeons with thousands being implanted worldwide over the past decade. Unacceptably high revision rates reported by two national joint registries called into question the rigorousness of the regulatory approval process for these implants, particularly with respect to premarket data requirements to prove safety, effectiveness, and the appropriateness of the regulatory pathway chosen. The purpose of this review was to investigate the balance between facilitating the introduction of new medical technologies and the need to ensure safety and effectiveness through comprehensive regulatory assessment. The case of MoM hip replacement devices was used to frame the investigation and subsequent discussions. The regulatory approval processes and post-market surveillance requirements associated with three common MoM hip replacements (two resurfacings: the Birmingham and articular surface replacement and the articular surface replacement XL total hip replacement) were investigated. With respect to modern MoM hip replacement devices, the balance between facilitating the introduction of these new medical technologies and the need to ensure safety and effectiveness through comprehensive regulatory assessment was not achieved. The lessons learned from these experiences have application beyond joint replacements to the introduction of new medical technologies in general, particularly for those who have a significant potential for harm. In this regard, a series of recommendations have been developed to contribute to the evolution of the medical device regulatory process.

A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities.

The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure–response modeling methods.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2931-4) contains supplementary material, which is available to authorized users.