Post-marketing Requirements Research Articles

Deployment of in-body wearable devices in healthcare and at work: closing the EU regulatory gap

Abstract Background In-body wearable devices can protect workers’ health and safety. Moreover, they might provide data that could be capitalized on in the context of the European Health Data Space (EHDS), which aims at fostering a single market for medical devices and high-risk AI systems. Yet, neither EU legislation nor national law regulates the use of in-body wearables at the workplace and the related data protection and safety issues. This regulatory gap impacts on workers’ rights. Methods The study explores whether the EU regulatory framework used in the healthcare sector for medical devices could fit the in-body wearables’ application in employment. The legal and policy analysis takes the perspective of workers’ rights and discusses the application of a key GDPR principle: lawfulness. The research discusses the potential transformations in the EU health data protection framework that could close the regulatory gap. Results The EU regulatory framework for medical devices (focused on product safety, performance, and quality) is not equipped to address the data protection challenges linked to the use of in-body wearables for occupational health and safety purposes. The GDPR’s principle of lawfulness and the related guidance by EU and national data protection authorities lack clarity on employers’ possibilities to apply in-body wearables for occupational health purposes. Filling the regulatory gap is conducive to appropriate qualification and risk-based classification of in-body wearables, which affect pre- and post-market requirements and impact on data protection. Conclusions a. The EU legislator could use its social policy competence to regulate the use of in-body wearables to protect workers’ health while safeguarding their data. b. EU authorities should clarify whether and how the data collected by in-body wearables at the workplace could be shared and (re)used within the EHDS. c. Further input by data protection authorities is needed to close the regulatory gap. Key messages • The EU should regulate the use of in-body wearables to protect workers’ health and safety. • Health data gathered through the application of in-body wearables at the workplace may be an asset for the EHDS.

Addressing Drug-Drug Interaction Knowledge Gaps at the Time of Approval: An Analysis of FDA Postmarketing Requirements and Commitments from 2009 to 2023.

It has become increasingly common for patients to rely on the use of multiple prescription medications. The management of polypharmacy requires careful consideration for how drugs are metabolized and their potential for interaction with other drugs. Drug-drug interaction (DDI) assessments are typically performed in a stepwise manner during drug development, though knowledge gaps can exist at the time of approval. The US Food and Drug Administration can establish postmarketing requirements (PMRs) or postmarketing commitments (PMCs) to address these knowledge gaps. In this study, we systematically evaluated PMRs and PMCs established to new molecular entities (NMEs) at the time of initial approval between 2009 and 2023, for the assessment of pharmacokinetics-based DDIs (i.e., drug metabolizing enzyme- and transporter-related DDIs). We found that 22% of NMEs had at least one DDI-related PMR or PMC, with a total of 263 that were pharmacokinetic based. Of these, 67% were for the assessment of drug metabolizing enzymes, which were established most frequently for their evaluation as a substrate, and 28% for transporters, which were established most frequently for their evaluation as an inhibitor. The 89% of PMRs and PMCs that were considered fulfilled had a revision to the United States prescribing information, the majority of which resulted in updated new instructions for use. This study highlights the value in conducting PMRs and PMCs early in the drug development process allowing broad patient inclusion at the time of initial drug approval.

Post-marketing surveillance framework of cell and gene therapy products in the European Union, the United States, Japan, South Korea and China: a comparative study

BackgroundCell and gene therapy products (CGTPs) often receive accelerated approvals, lacking comprehensive long-term safety and efficacy data, which can raise significant safety concerns. This research aims to study the post-marketing surveillance (PMS) of CGTPs in the European Union (EU), the United States (US), Japan, South Korea, and China, to offer insights for the development of a secure and standardized post-marketing regulatory framework for CGTPs.MethodsRelated regulations and the implementation effect of PMS for approved CGTPs were studied searching PubMed, CNKI, and the official websites of the European Medicines Agency, the US Food and Drug Administration, Japan’s Pharmaceuticals and Medical Device Agency, South Korea’s Ministry of Food and Drug Safety, and the National Medical Products Administration of China.ResultsCompared to those in China, the guidelines of PMS for CGTPs in the EU, the US, Japan, and South Korea was more comprehensive. Notably, the EU had dedicated regulations and supporting guidelines of PMS. Of the 26 CGTPs approved in the EU, 88% were under additional monitoring, 38% received conditional marketing authorization, and 12% were authorized under exceptional circumstances, with 77% designated as orphan drugs. The US had released 34 guidelines specifically for CGTPs which, forming the foundation of post-marketing risk management. Among the 27 CGTPs approved in the US, 22% were required to perform risk evaluation and mitigation strategies, 37% added black box warnings in the package inserts, 63% mandated to post-marketing requirements, and 15% subject to post-marketing commitments. In Japan, stringent supervision measures encompassing all-case surveillance (79%) and re-examination (53%) were applied to the 19 approved CGTPs, with 21% approved through conditional and time-limited approval. The PMS for CGTPs in South Korea, mainly included PSUR, re-examination, and re-evaluation. China had introduced several relevant regulations, which consisted of general statements and lacked detailed guidance.ConclusionsThis study demonstrates that the regulatory policies of PMS for CGTPs in the EU, the US, Japan, and South Korea were comprehensive. The implementation of PMS for CGTPs in the EU, the US, and Japan was well developed. This knowledge holds valuable insights for China’s future learning and development in this field.

The Role of Heuristics and Biases in the Choice of Risk Triggers for Novel Foods and GMOs in the European Union

Abstract In the European Union (EU), novel foods and Genetically Modified Organisms (GMOs) are subject to long and costly authorisation procedures and post-marketing requirements. The regulatory frameworks applicable to novel foods and GMOs come into effect based on perceived factors of risk. These “risk triggers” are characteristics of novel foods and GMOs which differentiate them from traditional foods, creating a presumption of risk. Within the EU, consumer acceptance of genetically modified foods and novel foods like insects or cultivated meat is shaped by heuristics and biases, mainly focusing on the “novelty” and “unnaturalness” of these products, resulting in a predominantly negative perception. This paper investigates the close connection between cognitive biases identified in consumer perception literature and the implementation of specific risk triggers in the regulation of novel foods and GMOs in the EU. It subsequently raises concerns about the appropriateness of these risk triggers in forming a presumption of risk for these innovative products.

Approved medicines for paediatric solid tumours in Europe: Lessons from the life cycle of a paediatric investigation plan

BackgroundDespite the positive changes brought by the Paediatric Regulation in the European Union (EU) in 2007, drug development in children remains challenging. MethodsTo better understand the issues encountered to reach an authorisation for paediatric patients, we reviewed the pathway of the 11 Paediatric Investigational Plans (PIPs) with indications targeting paediatric solid tumours granted by the Committee for Medicinal Products for Human Use (CHMP) between 2007 and 2022. ResultsOn average 5,5 years were necessary to reach approval after a PIP was agreed. All the PIPs underwent at least one modification (median 3 modifications per PIP). The use of single arm trials, in the context of refractory/relapsed disease in absence of standard of care treatment, was supportive for granting a paediatric indication in the majority of the cases. In 6 out of 11 approved products, extrapolation from adults was used. For 2/11 the approval focused on an older population first compared to the initial age group agreed in the PIP due to the development of a suitable formulation for younger children still ongoing at the time of first approval. Scientific advice sought on paediatric development use of extrapolation from adults, major objections raised by CHMP and post-marketing requirements were examined. ConclusionAnalysing the process necessary to reach an authorisation for paediatric patients, we highlight the major challenges faced in the paediatric approval process and the positive examples of successful drug development that reached final approval. Our analysis is expected to provide useful insights to drug developers, investigators and regulators.

Analysing post-marketing requirements for orphan drugs approved by US FDA and EMA

Analysing post-marketing requirements for orphan drugs approved by US FDA and EMA

Assessing Post-Marketing Requirements for Orphan Drugs: A Cross-Sectional Analysis of FDA and EMA Oversight.

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) oversee pharmaceutical regulations, including orphan drugs targeting rare diseases with limited patient populations. Post-marketing studies are crucial for monitoring safety and efficacy, with post-marketing requirements (PMRs) mandated by the regulatory agencies to ensure compliance. This study aims to compare PMR statuses, objectives, and pivotal trial characteristics of orphan drugs approved by the FDA (n = 154) and EMA (n = 79) from 2008 to 2018, shedding light on regulatory differences and their impact on drug development. Contrary to expectations, our analysis found no significant disparity in the proportion of orphan drugs with and without PMRs approved by both the FDA (48.1%) and EMA (55.7%). Safety concerns surrounding orphan drugs post-approval, attributed partly to pivotal trial design, underscore the need for robust post-marketing surveillance. While the FDA primarily focuses on post-marketing safety (36.1%), the EMA places a higher emphasis on both efficacy and safety (47.1%), reflecting distinct approaches to PMR management between the two regulatory bodies. The observed trend of delayed PMRs at the EMA (47.1%) highlights the importance of effective cooperation between regulators and pharmaceutical companies to ensure the timely completion of PMRs and enhance drug safety.

Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used. To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points. This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024. Descriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments. From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication. In this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

Comparative Analysis of Post-Authorization Measures for Advanced Medicinal Products Authorized in the European Union and in the United States of America Between 2009 and 2023.

In the current landscape, regulatory agencies face the challenge of reconciling timely authorizations for novel medicines addressing life-threatening conditions with thorough evaluations of their benefits and risks. This challenge is pronounced with advanced therapy medicinal products (ATMPs), where expedited approval mechanisms and orphan drug designations are often applied, making post-authorization measures a crucial mechanism to address uncertainties. We compared post-authorization measures imposed by the U.S. Food and Drug Administration and the European Medicines Agency on ATMPs approvals, from 2009 to 2023. A systematic extraction of FDA postmarketing requirements (PMRs) and EMA-imposed post-authorization measures (PAMs) from publicly available regulatory documents was conducted. Descriptive analysis focused on post-authorization measure categories, objectives, study designs, and their status and registration rates. A total of 15 ATMPs were approved in both jurisdictions over the study period. For these products, the EMA imposed 53 PAMs (34 Annex II conditions and 19 Specific Obligations), whereas the FDA imposed 27 PMRs. As of December 2023, 15 EMA-imposed PAMs were fulfilled, with no explicit fulfilments indicated for FDA PMRs. Both agencies promoted real-world data use in around half of the imposed PAMs (23 by EMA vs. 15 by FDA), marking regulators' growing recognition of Real-World Evidence for decision-making. This study highlights disparities between imposed PAMs: EMA imposed more PAMs, covering efficacy, safety, and quality aspects, while the FDA required fewer measures focusing on specific safety concerns. These discrepancies primarily reflect distinct regulatory structures and approaches to further post-authorization data collection between the EMA and FDA, rather than disparities in initial benefit/risk assessments.

Analysis of post-marketing requirements for oncology drug conditional approvals in the United States and China

BackgroundConditional approvals, also known as accelerated approvals, have been introduced by many pharmaceutical regulators around the world, allowing innovative drugs to enter the market earlier on the basis of limited evidence. This research aims to systematically analyze and compare the post-marketing requirements for conditional approvals of oncology drugs in China and the United States. By collecting and categorizing different types of post-marketing requirements, this study seeks to elucidate how these requirements are proposed and discern the underlying logic and patterns. MethodsThis study delved into oncology drug approvals, encompassing FDA accelerated approvals (up to December 31, 2022) and NMPA conditional approvals (from 2017 to December 31, 2022). Leveraging review documents from FDA and NMPA, comprehensive data on product characteristics, all post-marketing commitments and requirements, and especially those related to confirmatory requirements were extracted. The analysis incorporated descriptive statistics, visualizations such as Upset plots, and thorough examination of confirmatory requirement timeframes. FindingsThis study examined 168 FDA accelerated approvals and 41 NMPA conditional approvals for oncology indications. Post-marketing requirements displayed diversity: FDA emphasized confirmatory studies, clinical pharmacology studies, and more, while NMPA predominantly focused on confirmatory studies. Confirmatory requirement timeframes indicated higher FDA-required completion times for new confirmatory trials compared to continued completion of original pivotal trials. In contrast, NMPA's requirement patterns were comparatively singular, with relatively fixed timeframes. FDA's evolving trend showed decreasing timeframes over time, suggesting an increasing demand for timely confirmatory data. InterpretationConditional approvals offer a unique approach to bring potentially life-saving drugs to the market faster, despite limited supporting evidence. Our analysis of oncology drug conditional approvals in the U.S. and China reveals diverse post-marketing requirement patterns. This study provides valuable insights for regulatory decision-making in a dynamic pharmaceutical landscape. Balancing the risks and rewards of conditional approvals is crucial in ensuring both patient safety and timely access to innovative treatments.

Role of Clinical Pharmacology in Diversity and Inclusion in Global Drug Development: Current Practices and Industry Perspectives: WhitePaper.

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post-marketing requirements.

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

Post-market study requirements and associations with timely submission and regulatory action for oncology drugs receiving accelerated approval, 2011-2023.

11028 Background: For oncology drugs receiving accelerated approval (AA), the Food and Drug Administration (FDA) enforces Postmarketing Requirements (PMRs) to verify clinical benefit prior to regular approval. Although previous work has characterized the rigor and timeliness of confirmatory studies, the association between specificity and scope of PMR statements and the timeliness of PMR submission and ultimate approval status is not well understood. Methods: We identified 161 oncology indications granted AA between January 2011 and July 2023 using FDA’s Cancer AA database. We linked indications to 181 corresponding PMR statements using the Drugs@FDA database. We analyzed PMR statement scope and specificity based on the presence or requirement of eight characteristics: target population, comparator (active or placebo-controlled), randomization, multicenter trial, blinding (double-blind or open-label), enrollment target, follow-up duration, and endpoints. We used chi-square and t-tests to analyze associations between PMR characteristics and two primary outcomes: indication approval status (regular vs. withdrawn) and PMR timeliness (on time vs. late). We defined “late” submissions as PMRs submitted or withdrawals occurring after an expected PMR Final Report submission date. Ongoing PMRs were excluded from the timeliness analysis unless expected dates occurred before August 2023. Results: Among 181PMR statements, 98% percent specified target population, 81% endpoint (44% overall survival), 63% use of randomization, 54% comparator (40% active; 14% placebo-controlled), 30% follow-up duration 26% enrollment targets, 24% multicenter trial, and 13% double-blinding (and 8% open-label). Among AAs converted to regular approval, 82% of PMRs were submitted on time vs. 24% on-time for withdrawn AAs (p=0.001). Regular approval PMRs were submitted 10.2 months ahead of expected dates, whereas withdrawn AAs were submitted 14.5 months behind expected dates (p<0.001). Compared late PMR submissions, on-time PMR submissions had lower enrollment (400 vs. 665, p=0.01), less blinding (19% vs. 40%, p=0.03), more frequent use of a single trial for both AA and PMR (38% vs. 8%, p=0.001), and primary endpoints other than overall or progression-free survival (36% vs. 5%, p<0.001). Compared to late PMR submissions, on-time PMR submissions more often followed PMR statements that specified follow-up duration (39% vs. 13%, p=0.006) and non-survival primary endpoints (30% vs. 8%, p=0.01). Conclusions: There is marked variability in the contents of PMR statements for oncology AA drugs. Several characteristics of PMRs – including smaller enrollment size, surrogate endpoints, and single trials for AA and PMR – are associated with timely submission. These findings inform the specificity and scope of future FDA PMRs for oncology AA indications.

Clinical trial diversity (CTD) scorecards.

e23042 Background: To ensure safety and efficacy, oncology clinical trials must include adequate participation by age, gender, race, and ethnicity subgroups. In November 2020, the US FDA issued Guidance for Industry to increase clinical trial diversity in pivotal clinical trial programs. CARER Group developed the CTD Scorecard to evaluate demographic diversity in registration trial programs for new drugs. Methods: Based on publicly available data, CTD Scorecard assigns each drug a letter grade (A, B, C, D, F) for demographic subgroups-age, race and ethnicity, as well as an overall grade. Scoring includes percentage of subgroup enrolled relative to US population, number of subgroup receiving study drug, and prevalence of disease in each subgroup. Results: From January 2022 to December 2023, US FDA approved 26 new oncology drugs. In this period, 8 trial programs were rated Grade B, 18 received Grade C. Notably, elderly, and female participation was better represented with 23 (88%) and 19 (90%) with Grade A or B respectively. Two trial programs each received Grade C for these subgroups. Asian representation was high, with 54% of programs scoring Grades A or B. Only one drug received Grade D for this demographic and no programs received Graded F. In contrast, Black and Hispanic populations showed significant underrepresentation. Fourteen (54%) of trial programs for Black and thirteen (50%) for Hispanic populations received Grades D or F. Notably, 20 (77% ) of trial programs had ≤10 Black participants receive study drug, with 6 programs having no Black participants receive study drug. Similarly, 14 (54%) of trial programs included ≤ 10 Hispanic participants receiving study drug, and 3 (12%) programs with no Hispanics receiving study drug. During this time, FDA issued Post-Market Requirements or Commitments (PMR/PMC) for 9(35% ) of oncology drugs due to premarket trial diversity shortfalls. However, by CTDs, 20 (77%) of the 26 approved drugs lacked adequate representation, yet did not receive Post-Marketing Requirements or Commitments. Conclusions: Oncology drug safety and efficacy can vary by age, race, sex, and ethnicity, necessitating diverse demographic participation in clinical trials. Alongside US FDA industry guidance, entities like the National Academy of Sciences, Engineering and Medicine and the GAO Report emphasize the need for trial diversity, bolstered by Federal Clinical Diversity Provision H.R. 2617 enacted in 2022. CARER’s scoring system evaluates clinical diversity age, sex, race and ethnicity, based on FDA data since January 2022. Age ≥65, female gender, and Asian race subgroups were generally well represented in clinical trial programs. Black and Hispanic groups show the lowest representation. Consistent use of PMC and PMR to new drugs may improve demographic inclusivity in trials lacking initial diversity.

An Analysis of Dosing-Related Postmarketing Requirements for Novel Oncology Drugs Approved by the U.S. Food and Drug Administration, 2012-2022.

The FDA's Oncology Center of Excellence's (OCE) launch of Project Optimus signals increased focus on dose optimization approaches in oncology drug development, particularly toward optimization in the premarket setting. Although sponsors continue to adapt premarket study designs and approaches to align with FDA's expectations for dose optimization, including consideration of the optimal dosage(s), there are still instances where questions remain at the time of approval about whether the approved doses or schedules are optimal. In these cases, FDA can exercise regulatory flexibility by issuing postmarketing requirements (PMR) and avoid delaying patient access to promising therapies. This landscape analysis demonstrates that over the past decade (2012-2022), FDA frequently used PMRs to answer additional questions about dosing for novel oncology approvals. We found more than half of drugs (78/132, 59.1%) had a dosing PMR and observed a recent increase in PMRs intended to evaluate whether a lower dose could be more optimal. These results suggest there are opportunities to adapt premarket dose optimization strategies and leverage innovative development tools to ensure timely identification of the optimal dose.

Rare oncology therapeutics: review of clinical pharmacology package of drug approvals (2019-2023) by US FDA, best practices and recommendations.

There are many challenges with rare diseases drug development and rare oncology indications are not different. To understand the regulatory landscape as it relates to application of clinical pharmacology principles in rare oncology product development, we reviewed publicly available information of 39 approvals by US FDA between January 2019 and March 2023. The objective was to understand the expected clinical pharmacology studies and knowledge base in such approvals. Model informed drug development (MIDD) applications were also reviewed, as such approaches are expected to play a critical role in filling clinical pharmacology gaps in rare oncology, where number of clinical trials and size of these trials will perhaps continue to be small. The findings highlighted how clinical pharmacology contributed to the evidence of effectiveness, dose optimization and elucidation of intrinsic and extrinsic factors affecting drug's behavior. Clinical pharmacology studies were often integrated with modeling in many of the NDAs/BLAs. Of the post marketing requirements (PMR) received, 18% were for dose optimization, 49% for DDI, 8% for QTc, 49% for specific population, and 5% for food effect. Two post marketing commitments (PMC) were issued for immunogenicity of the 11 biologics submissions. 15% (6 of 39) of the submissions used maximum tolerated dose (MTD) to advance their molecule into Phase 2 studies. Of them 3 approvals received PMR for dose optimization. 3 + 3 was the most prevalent Phase 1 design with use in 74% of the New Drug Applications (NDA)/Biologic License Applications (BLA) reviewed. Rest used innovative approaches such as BLRM, BOIN or mTPi, with BLRM being the most common. Seamless clinical pharmacology and MIDD approaches are paramount for rare oncology drug development.

Characterization of the US Food and Drug Administration Post-Marketing Commitments and Requirements for Pregnancy and Lactation.

Enactment of the US Food and Drug Administration Amendments Act (FDAAA) in 2007 and the Pregnancy and Lactation Labeling Rule (PLLR) in 2015 are important milestones giving the FDA the authority to request studies in pregnant and lactating women. Our objective was to characterize trends of pregnancy and lactation-related postmarketing commitments (PMCs) and postmarketing requirements (PMRs) for new molecular entities approved by the FDA between 2000 and 2022. Approval letters of original New Drug Applications (NDAs, N = 488) for new molecular entities were obtained from the FDA website. NDAs with pregnancy and lactation-based PMCs/PMRs were identified, and data extracted. Data included: PMC/PMR timelines and attributes of requested study(ies) (type, design elements, and outcomes) when available. Fifty-nine NDAs included 92 PMCs/PMRs related to pregnancy and lactation. Forty-one NDAs had pregnancy-related PMRs/PMCs, 4 had lactation-related PMRs, and 14 had both. Most PMRs/PMCs were for nervous system medications (N = 33). Forty-seven NDAs specified safety data collection in infants in at least the first year of life. All pregnancy-related PMRs were issued after 2008, most PMCs (N = 8) were issued before 2008. Only one PMC requested a pharmacokinetic study in pregnant women. All lactation-related PMRs (N = 18) requested measurement of drug concentrations in breast milk with one also requiring measurement of maternal blood concentrations. Eighty-nine percent of lactation-related PMRs were requested after 2015. There was a steady increase in pregnancy and lactation-related PMRs following enactment of FDAAA and PLLR. Additions involved information collection pertaining to safety of the medication in pregnant and lactating women and children exposed to medications during pregnancy and breastfeeding.

Investigation of Immunogenicity Assessment of Biosimilar Monoclonal Antibodies in the United States.

Immunogenicity is critical for biologics. However, reference biologics labeling documents do not necessarily mention immunogenicity impact, rendering the development of biosimilars more challenging. We aimed to investigate the comparative assessment of immunogenicity profiles between biosimilars and their respective reference biologics in the review reports of the biosimilar monoclonal antibody applications approved by the Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA) as of March 13, 2022, covering 22 applications approved between April 5, 2016, and December 17, 2021. The maximum differences in anti-drug antibody (ADA) and neutralizing antibody (NAb) incidences between biosimilars and reference products mostly fell within ± 15% (-13.6% to 12%) and ± 20% (-17.4% to 17.1%, except extreme values of -23.4% and 66.7%), respectively. In comparison with antineoplastic agents, more immunosuppressants had ADA-positive (11/11, 100.0% vs. 8/10, 80.0%)/NAb-positive (11/11, 100.0% vs. 3/10, 30.0%) subjects, and the distribution of the aforementioned incidence differences was wider. The investigated biosimilars with available data for analysis demonstrated a high degree of consistency with their reference products in terms of the impact on pharmacokinetic parameters. No increase in immunogenicity was found in available switching studies. Most (16/22, 72.7%) biosimilars were issued post-marketing requirements that were not directly related to immunogenicity concerns. The FDA considered the totality of evidence assessing clinical consequences of immunogenicity differences, if any. Additional information on titers and subgroup analysis may be warranted to elucidate the critical attributes of immunogenicity impact and to aid in forming cost-effective strategies for biosimilar development.

FDA Approvals of Oncology Drugs for Tissue-Agnostic Indications.

The development of molecularly targeted oncology drugs for tissue-agnostic indications represents a new paradigm, but marketing authorization may carry additional risks due to uncertainties about extrapolating drug safety and efficacy, and biomarker test accuracy, to unstudied tumor types. To determine tumor types represented and method of mutation identification in trials supporting the US Food and Drug Administration (FDA) approvals of tissue-agnostic drugs, and to describe post-marketing requirements and commitments (PMRs/PMCs) issued for studies to evaluate additional tumor types and to validate companion diagnostic devices. For each tissue-agnostic drug approval identified via the FDA's Hematology/Oncology Approvals and Safety Notifications website, prescribing information, approval packages, and letters were retrieved from the Drugs@FDA website. Characteristics of approvals, details of supporting trials, and PMRs/PMCs for clinical trials and diagnostic tests were extracted. Six drugs were approved for seven tissue-agnostic indications between 2017 and 2022, with 9-15 different tumor types represented in trials supporting approvals. Only one approval prospectively utilized a commercial assay to identify the molecular alteration of interest in tumor samples. All seven approvals were issued PMRs for trials with additional tumor types, and six of seven were issued PMCs for studies to support labeling for companion diagnostic devices. The number of patients and cancer subtypes in trials supporting tissue-agnostic oncology drug approvals varied by mutation. Most drug approvals did not have concurrent approval of a diagnostic test. Post-marketing studies play a critical role in confirming clinical benefit and ensuring companion diagnostic device performance across a broader range of tumor types.

Dosage optimization in drug development: An FDA Project Optimus analysis of postmarketing requirements issued to repair the cracks.

1598 Background: Dosage optimization (DO) is a critical aspect of oncology drug development. Because of this, the US FDA, through Project Optimus, has focused on reforming the DO and dosage selection paradigm for oncology products. When approving products, FDA may determine that although the recommended dosage possesses a favorable benefit:risk (BR) profile, there are significant safety concerns that require evaluation of alternative dosages to potentially improve the BR profile. Such postmarketing requirements (PMRs)—issued as a condition of approval—are examined here to better understand the characteristics and potential limitations of DO studies in the postmarketing setting. Methods: Between Jan. 1, 2010 to Dec. 31, 2022, oncology new molecular entities (NMEs) and original applications for biologics, hereafter referred to as new drugs, approved by CDER with at least one PMR issued for DO were identified in the FDA electronic records database. The designs and results of the associated trials or analyses for these PMRs, along with the status of the PMRs, were collected and evaluated. Results: There were 24 PMRs issued for 21 new drugs (15% of 138 total approved new drugs). The most common drug classes were: tyrosine kinase inhibitors (TKIs) (10), antibody drug conjugates (ADCs) (3), or GTPase Inhibitors (2). The following trials or analyses were planned to address these PMRs: randomized dose-comparison trials (18), non-randomized dose-finding trials (2), food effect trials (2), exposure-response analysis (1), and pending (1). The planned sample sizes for the 18 dose-comparison trials were 3 with <100 patients, 4 with 100 to 199 patients, 7 with 200 to 500 patients, and 4 with >500 patients. The dose-comparison trials used the following (co)primary endpoints: response rate (12), safety (7), OS (3), and PFS (2). Fourteen PMRs were either fulfilled (11) or released (3). Of the 11 fulfilled PMRs, 8 led to dosage changes for 5 new drugs (cabazitaxel, carfilzomib, ponatinib, ceritinib, and pexidartinib), and 3 did not lead to dosage changes. Ten PMRs are ongoing. The median time from issuance to fulfillment or release (not including ongoing PMRs) was 6 years (range: 0.7 to 8.3). Conclusions: A high proportion (15%) of new drugs required a PMR, which generally involved conducting a randomized trial with a substantial patient enrollment to evaluate an alternative dosage(s). This process was slow with a median of 6 years to fulfill a PMR. DO in the premarket setting has the potential to rapidly maximize BR, avoiding both patient exposure to unnecessary toxicity and large, resource-intensive, multi-year postmarketing trials. Project Optimus is working with stakeholders to advance a DO paradigm that occurs early and throughout premarket development to ensure an optimized recommended dosage at the time of approval.