Post-marketing Requirements Research Articles

Bridging the gap: FDA diversity-related postmarketing requirements.

e13608 Background: Historically, pre-market clinical trials have lacked enrollment of racial and ethnic minority patients that represent the population intended to be treated with the approved drug in the US. The Food and Drug Administration (FDA) has several programs and initiatives designed to enhance diversity in oncology clinical trials, such as the Oncology Center of Excellence’s (OCE) Project Equity, FDA Guidance documents, and submission of Diversity Plans from industry. Under the code of federal regulations and/or statute, the FDA can issue post-marketing requirements (PMR) to fulfill accelerated approval requirements for confirmatory studies; for assessing safety signals; or for conducting dedicated studies in pediatric patients. FDA may also issue post-marketing commitments (PMC) to generate additional clinical evidence. PMRs and PMCs have been used to obtain additional information on under-represented populations. The objectives of this analysis were to identify oncology PMRs/PMCs issued with a specific focus on racial and ethnic minority populations and examine the trend over the 10-year period. Methods: We searched FDA’s publicly available database of PMR/PMCs, inclusive of drugs and biologic products, and internal agency databases for PMR/PMCs issued between 2012-2022. The PMR/PMC search was further narrowed down by keywords to capture all PMRs/PMCs relevant to races and ethnicity. The PMRs/PMCs were then manually reviewed for duplication and applicability to malignant indications. Results: In a 10-year period, 34 PMR/PMCs focused on race and ethnicity were issued across 461 oncology approvals (initial marketing approvals = 164, new indications = 297). Twenty-two were issued with the initial marketing approval and 12 with supplemental efficacy approvals. All PMR/PMCs were issued in the last 3 years (2019-2022). PMCs accounted for 55.9% (n = 19) and PMRs 44.1% (n = 15). Nine of the 15 PMRs requesting additional information on underrepresented populations were included with the accelerated approval PMRs. Six of the 34 PMR/PMCs were issued to obtain additional PK or dosing information in the underrepresented population. The most common PMR/PMC indications issued were lymphoma (n = 13, 38.2%), multiple myeloma (n = 8, 23.5%), and non-small cell lung cancer (n = 4, 11.8%). Although PMR/PMCs that mentioned a specific race were limited, African American/Black (n = 8) and Asian (n = 1) were occasionally identified. All studies identified in this analysis are ongoing except for one, for which the product was withdrawn. Conclusions: Our analysis highlights the trend and increased emphasis on race and ethnicity in post approval oncology studies. While progress has been made to promote studies that are representative of the US population through these PMRs/PMCs, diversity plans, and FDA guidance over the course of the past 10 years, more efforts are needed to better enhance diversity in clinical trials moving forward.

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 -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 -test always requires a post-market clinical trial. If the -value from the pre-market clinical trial is , 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 -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 -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.

US FDA Postmarketing Requirements and Commitments: A Systematic Assessment of Clinical Pharmacology Studies and Their Impact on US FDA Prescribing Information.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

A review of pregnancy and lactation postmarketing studies required by the FDA.

Since pregnant and lactating women have historically been excluded from drug development trials, safety studies need to be conducted postapproval. This study evaluated FDA's Post Marketing Requirements for pregnancy and lactation studies from 2007 to 2020, and identified trends and potential future opportunities. The number of studies required to be conducted in the postmarketing setting was compared with the number of new drugs approved during the same time period. We excluded drugs that were approved for use in men, children, or postmenopausal women. Since 2007, there has been an increase in pregnancy and lactation studies required to be conducted postapproval. However, only 16% of drugs that may be used in females of reproductive potential were issued a postmarketing requirement for a pregnancy and/or lactation study. The most common type of required pregnancy safety study was a pregnancy registry (37%), followed by a descriptive pregnancy safety study (27%), and a retrospective cohort study (26%). In conclusion, there is a need for more comprehensive data collection in pregnant and lactating individuals to better inform prescribers and patients about the safety of medication use during pregnancy and lactation so that they can make a fully informed decision about medication use.

Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities. Methods: We re-examined clinical trial data prior to and after the introduction of revised treatment guidelines; we analysed spontaneous adverse drug reaction (ADR) reports submitted to the EudraVigilance database in 2019/2020 regarding their completeness; and we performed a survey of treatment centres in Germany that have been qualified for the use of commercial CAR-T cells. Results: Lower combined incidences of severe cytokine release syndrome (CRS) as well as neurotoxicity occurred following CAR-T-cell treatment after a revision of management guidelines, suggesting earlier intervention compared to before (12.6% vs. 20.5%). Numerous post-marketing ADR reports lacked information important for case assessment. Full details on treatment indication, CRS onset, outcome, and grading were available for just 38.3% of CRS cases. Survey responses support the majority of regulatory requirements for centre qualification. Time investment was highest for training of healthcare professionals, which required an average of 6.5 staff members (range 2–20) and lasted more than 2 days per person in half of the facilities. The need to harmonize the regulatory requirements for the different CAR-T-cell therapeutics was emphasized. Conclusion: Defined regulatory measures can support the safe and effective use of new therapies and are indicated for structured recording of post-marketing data, and the evaluation of such measures appears to be necessary for the continuous improvement.

Safety of Deferiprone in Patients with Myelodysplastic Syndromes: Results from the Deferiprone US Safety Registry and a Compassionate Use Program

Background: Myelodysplastic syndromes (MDS) are a heterogenous group of hematopoietic stem cell malignancies characterized by ineffective blood cell production. Treatment can include frequent blood transfusions, which may lead to iron overload and subsequent complications. Several treatment guidelines recommend iron chelation therapy (ICT) for lower-risk patients with MDS based on transfusion burden, ferritin level, or iron overload imaging studies. However, ICT options are limited for patients with MDS because deferoxamine is administered parenterally and requires a burdensome infusion regimen that may reduce treatment adherence. Deferasirox is administered orally and requires closely monitoring a patient's renal and hepatic function; deferasirox is contraindicated in patients with significant renal impairment (estimated glomerular filtration rate <40 mL/min/1.73m2), a frequent comorbidity in the primarily geriatric population of patients with MDS. Deferiprone (DFP) is an oral ICT approved for transfusional iron overload in thalassemia, sickle cell disease, and other anemias. Although DFP has no contraindication or dosing adjustment based on renal function, it requires close patient monitoring and laboratory testing, since its use is associated with severe neutropenia (absolute neutrophil count <0.5x109/L) in 1-2% of patients. While existing studies have evaluated the effects of DFP in patients with MDS, limited data on its safety are available for this patient population. Objective: To evaluate the DFP safety profile in patients with MDS from a US safety registry and a compassionate use program. Methods: The DFP US safety registry was established to meet FDA postmarketing requirements following DFP approval in the US in 2011. The registry assessed all reports of adverse events (AEs) in all patients, including those with MDS, from 2011 to 2021. The compassionate use program included patients in the US and Canada from 1996 to 2015. All AEs were assessed in all patients with MDS who received this chelator. In both the safety registry and the compassionate use program, DFP was administered at doses that ranged from 75 - 99 mg/kg/day. AEs were assessed irrespective of a causal relationship with DFP. Results: The US safety registry included 115 adults with MDS (mean ± SD age: 77.7 ± 9.0 y; 61.7% males). Mean ± SD DFP exposure was 1.1 ± 1.4 y (range: 0-7.9 y), with 59 (51.3%) patients receiving DFP for > 6 mo and 34 (29.6%) for > 12 mo. Reasons for discontinuation (> 1 patient) included death (n=30), physician direction (n=26), adverse reaction (n=16), hospice care (n=12), nonresponsive patient (n=6), insurance issues (n=4), and switching to another chelator/formulation (n=3). Observed AEs are summarized in Table 1. The most common AEs were diarrhea (n=34), nausea (n=32), vomiting (n=26), and fatigue (n=26). No deaths were attributed to DFP. In 3 patients, neutropenia was reported in temporal association with fatal outcome, but none were attributed to DFP. Four patients (3.5%) reported severe neutropenia/agranulocytosis: 2 events resolved; 1 case outcome was not reported; and 1 case was ongoing at last follow-up. The compassionate use program included 15 adults with MDS (mean ± SD age: 67.9 ± 10.4 y; 60% males). Mean ± SD DFP exposure was 1.2 ± 2.3 y, with a median (range) of 0.7 y (0-9.1 y). Reported AEs are summarized in Table 2. The most common AEs were nausea and decreased neutrophil count (n=3 each). There were 2 cases of severe neutropenia/agranulocytosis; both resolved. Conclusions: The findings of the safety registry and a compassionate use program suggest the DFP safety profile in MDS is potentially consistent with that of thalassemia, sickle cell disease, and other anemias. No unexpected AEs and no new safety concerns were found. The frequency of the most serious AE associated with DFP, severe neutropenia/agranulocytosis, was 3.5% within this population; of reported outcomes, all resolved. In the compassionate use program, 13.3% of patients reported agranulocytosis, which is higher than what has been shown in patient populations without MDS (2%); however, it is not clear if this percentage is higher than other ICT agents used in MDS, due to the patients' primary disease, or the relatively small sample size. While acknowledging these limitations and observational nature of the data, DFP may be a viable ICT for patients with lower-risk MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016

This cohort study used the Drugs@FDA database to identify new drugs approved by the US Food and Drug Administration (FDA) and assess fulfillment of postmarket commitments and requirements.

Clinical pharmacology information in regulatory submissions and labeling: A comparative analysis of orphan and non-orphan drugs approved by the FDA.

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non-orphan drugs, were analyzed for recommendations and information available related to food-drug interaction, drug-drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non-orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non-orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non-orphan drugs were established; with most difference observed for drug-drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non-orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non-orphan drugs.

Regulation of Molecular Diagnostics.

Molecular diagnostic tests enable rapid analysis of genomic and proteomic markers. These tests are subject to diverging premarket access and postmarket surveillance requirements and mechanisms in the United States and the European Union. Each of these jurisdictions has its own challenges in keeping the regulations up to date with technological developments. A specific area of attention is that of laboratory-developed tests in the United States and health institution in-house-produced tests in the European Union, for which the United States and the European Union have markedly different regulatory approaches. Both jurisdictions have specific but differing requirements for the use of test samples and test-related data under their rules regarding the protection of (personal) health data, which can cause complexity when moving samples or sample-related data from one jurisdiction to the other.

Trends in FDA Transporter-Based Post-Marketing Requirements and Commitments Over the Last Decade.

Characterizing interactions between new molecular entities (NMEs) and drug transporters is a critical element of drug development that helps in assessing potential transporter-based drug-drug interactions (DDIs). However, not all NME new drug applications (NDAs) include a full characterization of NMEs transporter-based DDIs, which necessitates the issuance of post-marketing requirement (PMR)/post-marketing commitment (PMC) by the US Food and Drug Administration (FDA) to characterize these potential interactions. The objective of this analysis is to identify trends in transporter-based PMRs/PMCs issued by the FDA between 2012 and 2021. A decrease in the number of transporter-based PMRs/PMCs was observed from 2012 to 2016 and an increasing trend in the number of PMRs/PMCs was observed after 2017. The majority of these transporter-based PMRs/PMCs requested clinical evaluation (48%), some requested in vitro assessment (38%), and 2.5% requested modeling and simulation assessment. Most of the PMRs/PMCs requested evaluation of NMEs as perpetrator with the efflux transporters, P-gp and/or BCRP (53%). Forty-eight percent of the PMRs/PMCs were fulfilled with 67% resulted in labeling updates. On average, 2.5 years were needed for the information related to PMRs/PMCs to show in NMEs labeling. In conclusion, this analysis highlights the increased emphasis from the FDA on proper characterization of transporter-based DDI and call for the need of early characterization of NMEs-transporters interaction before initial NDA approval.

Amivantamab and Mobocertinib in Exon 20 insertions EGFR Mutant Lung Cancer, Challenge To The Current Guidelines

In 2021, the US Food and Drug Administration (FDA) approved two drugs targeting exon 20 directly: amivantamab and mobocertinib, under the accelerated approval pathway, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. Here we discuss questions regarding the core question of an “unmet need” within the accelerated approval pathway, contending that equipoise remain between the new compounds and previously existing options. Second, the NCCN's guidelines are currently recommending to sequence both drugs, a recommendation that is not based on any data. Last, post-marketing requirements may not shed clarity in the setting of these approvals. Our analysis has implications beyond patients with exon 20 insertion. In an era with growing identification of new and rarer molecular entities, misguided incorporation of new compounds into practice may obstruct trial enrollment in decisive clinical trials.

Post-Marketing Requirements for Cancer Drugs Approved by the European Medicines Agency, 2004-2014.

To address unresolved questions about drug safety and efficacy at the time of approval, the European Medicines Agency (EMA) may require that manufacturers conduct additional studies during the postmarketing period. As a growing proportion of new cancer drugs are approved on the basis of limited evidence of clinical benefit, timely completion of postmarketing requirements is important. We used publicly available regulatory documents to evaluate key characteristics of pivotal studies supporting EMA‐approved cancer drugs from 2004–2014 and assessed completion rates of postmarketing data collection requirements after a minimum of 5 years. From 2004–2014, 79% (45/57) of EMA‐approved cancer drugs had to fulfill postmarketing requirements. Pivotal trials supporting the approval of cancer drugs with postmarketing requirements were less likely to have randomized designs (41/61, 67% vs. 11/11, 100%), include an active comparator (20/61, 33% vs. 10/11, 91%), or measure overall survival as the primary study end point (18/61, 30% vs. 6/11, 55%) compared with pivotal trials for drugs without postmarketing requirements. Among 200 postmarketing requirements, almost half were designed to assess drug safety. After a minimum of 5 years, 60% (121/200) of requirements were completed, 10% (19/200) were ongoing, and 30% (60/200) were delayed. About half (40/75, 53%) of postmarketing requirements for new clinical studies were completed on time. Delays in the completion of postmarketing requirements often did not impact the likelihood of drugs receiving permanent marketing authorization (87%, 39/45) after 5 years. Our findings highlight the need for EMA to better enforce its authority to require timely completion of postmarketing requirements and studies.

Rationale and design of ON-TRK: a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib

BackgroundTropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods.MethodsON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients < 18 years old will be enrolled under a ‘pediatric’ cohort regardless of tumor type and will be followed for 5 years to evaluate the risk of potential long-term adverse effects of larotrectinib on their growth and development. The effectiveness of larotrectinib in the overall study population as well as in patient subgroups will also be evaluated. Procedures avoided in patients with infantile fibrosarcoma (e.g., amputation) and the number of patients who were able to undergo surgery with a curative intent (excluding amputation) because of the use of larotrectinib will be described. Larotrectinib treatment patterns in real-world practice, including dosing and duration of treatment, will be described.DiscussionThe FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA.Study registrationThis study is registered at ClinicalTrials.gov (NCT04142437).Protocol versionv2.5, 25 March 2021.

Analysis of Supportive Evidence for US Food and Drug Administration Approvals of Novel Drugs in 2020

In recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. Drug names, date of approval, indication on labeling, and clinical and regulatory details. Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. The 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. These findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may benefit from a revised approach that better balances time to market with ensuring that approved drugs show evidence of efficacy.

The RACE for children act at one year: progress in pediatric development of molecularly targeted oncology drugs

ABSTRACT Background The Research to Accelerate Cures and Equity (RACE) for Children Act of 2017 authorized the Food and Drug Administration (FDA) to require pediatric clinical trials for new oncology drugs with relevant molecular targets. This study reviewed oncology drug approvals within the first year after the new legislation came into effect, to evaluate the impact on development of molecularly targeted oncology drugs for pediatric cancers. Research design and methods For new oncology drugs approved by the FDA between 08/18/2020 and 08/18/2021, drug approval packages, letters, and prescribing information were reviewed for the submission and approval dates, indication, and molecular target of the drug, and post-marketing requirements that included pediatric clinical trials. Results Within the 1-year period, 17 new oncology drugs were approved, but only 5 had been submitted after 08/18/2020. Three of the 5 (60.0%) had requirements for pediatric trials under the RACE Act. None of the 12 submitted prior to 08/18/2020 had pediatric trial requirements, but 10 (83.3%) had molecular targets that would have made them candidates under the RACE Act. Conclusions Early evidence suggests that the RACE Act was effective at closing the loopholes of previous legislation and creating new opportunities for innovation in developing therapies for childhood cancers.

Investigation of Factors Associated With Immunogenicity Labeling Updates and Characteristics of Biologics License Applications.

Immunogenicity, the potential to elicit an antidrug immune response, is a critical concern in developing biological products, but its consequences are difficult to predict with animal studies. The aims of the present study are to investigate the evolution of immunogenicity information in labeling and to identify attributes associated with immunogenicity labeling updates. Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research, US Food and Drug Administration between 2008 and 2017 were studied. A majority of BLAs described the incidence/prevalence of antidrug antibodies (ADAs) (94.9%) and neutralizing antibodies (NAbs) (68.4%) in their original labeling documents. However, less than one third of the BLAs mentioned the impact of ADAs/NAbs in the original (20.3%) and most recent (29.1%) labeling documents. BLAs with a priority review status (57.4% vs. 33.3%), orphan designation (61.5% vs. 34.2%), or a mention of ADA impact in the latest label (69.6% vs. 38.9%) had higher percentages of applications with postmarketing requirements (PMRs) directly related to immunogenicity concerns in comparison with applications without those characteristics. Among the BLAs with updated immunogenicity information, the mean time to the first update was 1,077days, while that for BLAs with accelerated approval was shorter (709.1±492.2days vs. 1173.8±661.8days). The results suggest that there is a substantial amount of critical information lacking in the original labeling documents and an overdependence on PMRs for more evidence. Additional efforts should be made to investigate the impact of ADAs to provide timely information for improved patient care.

A review of medical device regulations in India, comparison with European Union and way-ahead.

Indian healthcare sector is a fast-growing industry which is expected to reach $280 billion by 2025. Medical devices market in India is one of the top 20 medical device markets in the world. It is currently valued at $5.2 billion and is expected to reach $50 billion by 2025. However, India does not manufacture many devices indigenously and still imports approximately 70% of its medical devices. Manufacturing and monitoring of medical devices are highly regulated activities. In India, there were no specific medical device regulations and devices were regulated under the Drugs and Cosmetics Act, 1940. To fulfill this gap, Central Drug Standard Control Organization released Indian Medical Device Rules, 2017, which are the new regulations for medical devices in India. Keeping pace with the requirements, these were amended as Medical Devices (Amendment) Rules, 2020, which has come into force in April 2020. These rules cover various aspects of device related regulations, including classification, registration, manufacturing and import, labeling, sales, and postmarket requirements, etc. The rules are a positive step and encompass most of the European Union (EU) approval process, which mandates that the devices are safe and performs its intended function. However, with rapid advancements in medical device technology, much is desired in clarity and revamping of the current regulatory system to harmonize standards to be in-line with advanced regulations like EU.

Postmarketing requirements for drugs approved by the Food and Drug Administration for the treatment of solid tumor cancers, 2010-2019.

e13597 Background: In recent years, efforts to improve the efficiency and speed of drug development and approval have driven a surge of Food and Drug Administration (FDA) approvals for cancer drugs. For many cancer therapies, the serious or life-threatening nature of the condition and unmet medical need confers eligibility for expedited programs. Many cancers are also rare diseases, and the increasing use of precision medicine principles to define cancer types further contributes to smaller trial sizes. With limited clinical evidence at the time of approval, cancer drugs may be subject to a greater burden of postmarketing requirements (PMRs). We analyzed PMRs for solid tumor therapies approved by the FDA over the past decade. Methods: The FDA’s novel drug approvals (2010-2019) were reviewed to identify drugs receiving primary approval for solid tumor indications. Approval letters were accessed via the Drugs@FDA database and analyzed for PMRs required under accelerated approval (AA), the Pediatric Research Equity Act (PREA) and the FDA Amendments Act of 2007 Section 505(o) (505(o)). Data are presented using descriptive statistics. Results: A total of 60 drugs received primary approval from the FDA for solid tumor indications between 2010 and 2019 (20 [33.3%] received AA, 33 [55.0%] received orphan designation, and 45 [75.0%] received Fast Track or Breakthrough Therapy designation). The proportion of drugs receiving AA doubled between the period 2010-2014 and 2015-2019 (Table). Of the 60 drugs approved, 52 (86.7%) received a total of 180 PMRs. All 20 drugs approved under AA received PMRs, with a total of 25 PMRs issued under AA. Data from new clinical trials were required for 22 (88.0%) of the 25 PMRs. No PMRs were issued under PREA. Additional safety data required under 505(o) comprised the largest proportion of PMRs; 155 total PMRs (86.1% of all PMRs) were issued for 45 (75.0%) of the drug approvals. Pharmacokinetic or other clinical safety data were required for 96 (61.9%) of the 155 PMRs. Conclusions: More than three-quarters of the cancer drugs approved for the treatment of solid tumors in the past 10 years were issued PMRs, with the majority requiring new safety data. The results of this study indicate that PMRs represent a critical mechanism by which FDA collects safety and efficacy for solid tumor therapies, and underscore the importance of PMR fulfillment. Post-marketing requirements (PMRs) for solid tumor drugs approved 2010-2019.[Table: see text]

Optimal dose selection in oncology biologics development: Need for a paradigm shift.

3093 Background: In oncology, the recommended phase 2 dose (RP2D) is typically selected from the first-in-patient (FIP) dose escalation and then carried forward to late stage trials. The RP2D is often informed by limited data from a relatively small number of patients. Further dose optimization in late stage trials is rare as these trials often evaluate only one dose/dosing regimen. Traditionally oncology development relied on establishing an MTD with the expectation this dose would ultimately provide an optimal benefit/risk profile. However, for biologics there are clear examples suggesting a need to reconsider this approach to dose selection during drug development. The present review attempts to evaluate the dose selection approaches for approved oncology biologics to identify opportunities for improved dose optimization of future oncology drugs. Methods: The dose selection steps for oncology biologics approved by the USFDA from 2010 to 2020 were reviewed. The primary focus of the review was RP2D selection based on early clinical data, doses tested in pivotal trials, exposure-response and dose justification for the proposed dose, and post-marketing requirements (PMR) or post-marketing commitments (PMC) related to dose optimization. Results: The dose selection process for a total of 22 biologics was analyzed. Among these, 17 (77%) did not identify MTD during the FIP trial, and 6 (27%) tested more than one dose in the registration trials. In the initial approval, 2 (10%) had PMR or PMC for further dose optimization. For majority of the biologics the dose justification was based on 1) receptor occupancy 2) biomarker response 3) early clinical activity and 4) target efficacious concentration based on xenograft data. The majority of biologics had shown a shallow exposure-response relationship in safety or efficacy end points which partly can be attributed to the common practice of testing single dose level in the registrational trial. The dose recommended in the FDA label appears to be highly correlated to the RP2D determined in FIP studies. Conclusions: Oncology biologics have heavily relied on pharmacodynamic, early signs of efficacy, and safety data from the limited number of patients in the FIP dose escalation to identify the dose for pivotal trials. In most cases, there have been no dose ranging or optimization based on the final therapeutic outcome. While integration of relevant biomarker, PK, and PD data for optimal dose selection is an important aspect, there is a need to change the paradigm to consider more robust dose optimization, especially in early stage development. Dose ranging assessments incorporating therapeutically relevant endpoints and adequate sample size should be considered, ideally prior to pivotal trials.