Scientific considerations in the regulatory approval of generic (or biosimilar) version of enoxaparin sodium - A lifesaving carbohydrate polymer.

Enoxaparin sodium (Clexane®/Klexane®/Lovenox®) is one amongst the few drugs that have assumed a central role as drug of treatment and/or prevention against thromboembolic complications during COVID-19. The increase in demand resulting in many generic (or biosimilar) versions entering the market has increased the risks of quality and safety (including immunogenicity) related issues. Under the circumstances, development of stringent regulatory approaches has received much attention as investigation of new drug delivery systems for improved therapeutic activity. As one of the measures to increase quality testing and ensure uninterrupted supply of this life-saving drug globally, determination of enoxaparin molecular weight (MW) has been added in the United States Pharmacopoeia (USP) monograph for enoxaparin sodium. In addition, the presence of a unique 1,6-anhydro-ring structure at the reducing end of about 15-25% of the poly (oligo) saccharide chains of the generic (or biosimilar) product has been set as a mandatory requirement. This article presents an overview of the scientific considerations in the quality manufacturing and testing of the generic (or biosimilar) enoxaparin for regulatory review and approval. In certain cases of strong analytical similarity (structural and functional), abandonment of in vivo testing in animals and humans represents a major advancement in the approval of generic (or biosimilar) version of innovator enoxaparin sodium (lovenox®, injections).

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 2.3 years. 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.

HTA Barriers for Conditional Approval Drugs.

BACKGROUND: Conditional approval pathways facilitate accelerated marketing authorisation based on immature clinical evidence for drugs that address an unmet medical need in a life-threatening or chronically debilitating condition. Lowering evidence requirements for marketing authorisation results in higher clinical uncertainty, which may present challenges for the health technology assessment (HTA) of these products. OBJECTIVES: The objective of this study is to assess whether conditionally approved drugs face higher probabilities of HTA rejection or delays in HTA approval relative to drugs with standard marketing authorisation. METHODS: This paper adopts a mixed-methods approach to provide a meta-analysis of HTA outcomes across 80 drug-indication pairs in France, England, Scotland and Canada. Differences in the characteristics (i.e. disease rarity and clinical trial design) of conditionally approved drugs and drugs with standard marketing authorisation and drivers of HTA outcomes are assessed through logistics regressions. Delays in HTA approval are assessed through a survival analysis. RESULTS: Relative to standard approval drugs, conditionally approved drugs are less likely to include phase III trial designs, less likely to include clinical endpoints and less likely to include an active comparator. Uncertainties in clinical and economic evidence are raised more frequently by HTA agencies for conditionally approved drugs, which have a marginally lower probability of receiving HTA approval relative to drugs with standard approval. Conditionally approved drugs face moderate delays (an average of 6 months) in receiving HTA approval relative to standard approval drugs. CONCLUSIONS: Overall, conditionally approved drugs likely face increased barriers at the HTA level.

Spending by the Centers for Medicare & Medicaid Services Before and After Confirmation of Benefit for Drugs Granted US Food and Drug Administration Accelerated Approval, 2012 to 2017.

Importance: Accelerated approval by the US Food and Drug Administration (FDA) grants market authorization for drugs based on clinical trials using surrogate end points likely to anticipate a clinical benefit. The FDA requires postapproval trials to confirm benefit, after which the accelerated approval is converted to a standard approval or is withdrawn. However, trials frequently fail to assess clinical benefit, and expenditure for these drugs may be substantial. Objective: To evaluate spending by the Centers for Medicare & Medicaid Services (CMS) on drugs granted FDA accelerated approval before and after confirmation of benefit. Design and Setting: This was a cross-sectional study of CMS spending on drugs granted FDA accelerated approval for original indications from 2012 to 2017, with follow-up through 2020. Using data from the Drugs@FDA database and a validated methodology, the characteristics of new drugs granted FDA accelerated approval were identified and analyzed, including indication area, type of drug, type of confirmatory trial end point, orphan designation, number of supplemental indications, and conversion status. Main Outcomes and Measures: Overall and annualized spending by Medicare Parts B and D and Medicaid from 2012 to 2020, before and after conversion to standard approval. Analyses were conducted from June 30, 2021, to March 21, 2022. Results: From 2012 to 2017, the FDA granted accelerated approval to 38 drugs for 42 original indications. Through 2020, CMS spending for these drugs was $67.9 billion (median [IQR], $329.3 million [$54.4 million-$1.6 billion]). For 22 drugs (58%) that were converted to standard approval on the basis of clinical trial results, annualized spending increased substantially after conversion ($35.0 million vs $199.0 million), and spending after conversion accounted for $51.0 billion (75%) of overall spending. However, only 6 conversions (27%) of the 22 were supported by confirmatory trials evaluating clinical outcomes as primary end points. Drugs evaluated using surrogate end points accounted for $40.3 billion (59%) of CMS spending. Conclusions and Relevance: The findings of this cross-sectional study indicate that most of the drugs granted FDA accelerated approval for original indications from 2012 to 2017 lacked confirmatory trials evaluating clinical outcomes to support conversion to standard approval. Automatic coverage mandates produced substantial CMS spending for drugs with unproven clinical benefits.

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

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

Premarket assessment of molecular alterations in drug targets: a case study of 2020 drug approvals.

Aim: Molecular alterations in drug targets may result in differential drug activity. Therefore, the authors aimed to characterize how molecular alterations in drug targets were assessed during drug development. Materials & methods: The authors analyzed nonclinical and clinical study reports submitted to the US FDA for novel drugs approved in 2020 to determine if in vitro studies, animal models or clinical studies assessed molecular alterations in the drug target. Results & conclusion: Assessment of the impact of molecular alterations in drug targets on drug activity varies considerably depending on the type of assessment and therapeutic area. Premarket assessment of drug target molecular alterations is common in the oncology setting, less frequent in the genetic disease setting and rare for other diseases.

Japan's Special Approval for Emergency System During the COVID-19 Pandemic.

The development of drugs for coronavirus disease 2019 (COVID-19) is a global challenge. In Japan, remdesivir was approved in May 2020 for COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In February 2021, a vaccine against COVID-19 was approved. These two approvals were made using the Special Approval for Emergency system in Japan. This Japanese system was started in 2010 and has been used to approve four drugs to date, including remdesivir and the Pfizer COVID-19 vaccine. This paper discusses future challenges for Japan's Special Approval for Emergency system and organizes what can be learned from experiences to date. As a result, I would like to point Out the following issues. (i) Special Approval for Emergency is a system for approving drugs approved overseas, not a system for approving drugs originally developed in Japan. A system to approve drugs that have not been approved in foreign countries needs to be considered. (ii) In the Special Approval for Emergency system, it is necessary to ensure that postmarketing activities are conducted in accordance with the Risk Management Plan and the conditions of approval, to disclose the results in a timely and speedy manner, and to judge the appropriateness of continued approval based on the results of postmarketing activities.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

Implementation of 21st Century Cures Act Expanded Access Policies Requirements.

The US Food and Drug Administration (FDA) expanded access pathway allows patients with life-threatening or serious conditions to access investigational drugs outside of trials, under certain conditions. The 21st Century Cures Act ("Cures Act") requires certain drug companies to publicly disclose their expanded access policies. We characterized the proportion of applicable US biopharmaceutical companies, with an oncology related drug, implementing Cures Act requirements for expanded access policies and whether available policies contain the information described in the Act. We found about one-third of applicable biopharmaceutical companies (32%, 140/423) implemented the Cures Act requirement to have a public expanded access policy. Less than one-third of public policies contained all described information (31%, 44/140). Larger companies and those with at least one drug receiving an FDA expedited designation (59% vs. 21%; P < 0.001), or at least one FDA-approved drug (57% vs. 28%; P < 0.001) were more likely to have a public policy. Our results suggest the Cures Act may be having a limited impact on its goals of supporting timely medical decisions and closing informational gaps for patients and doctors around expanded access to investigational oncology therapies, especially for products sponsored by smaller and newer companies.

Assessment of adverse events associated with remdesivir use for coronavirus disease 2019 using real-world data.

Background: Remdesivir has been used for treating patients with moderate to severe coronavirus disease 2019 (COVID-19) although there is conflicting evidence regarding its usefulness. Data regarding its safety largely come from the clinical trials conducted to support its emergency use authorization (EUA). This study aimed to identify the adverse events of remdesivir with disproportionately high reporting using real-world data.Research design and methods: The adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) by health-care professionals for drugs that have received EUA or approved for the treatment of COVID-19 in the US were studied. Adisproportionality analysis was performed to determine adverse events more frequently reported with remdesivir compared with other COVID-19 drugs in the database.Results: Elevated liver enzymes, acute kidney injury, raised blood creatinine levels, bradycardia, cardiac arrest, and death had disproportionately higher reporting with remdesivir as asuspect drug compared with other drugs. There is no significant difference in the reporting of these events based on patient sex or age.Conclusions: Our study confirms the drug label information regarding liver enzyme elevation. The renal and cardiac safety signals identified necessitate reevaluation for potential drug-labeling changes.

Evaluation of Drug Trials in High-, Middle-, and Low-Income Countries and Local Commercial Availability of Newly Approved Drugs.

Importance: Clinical research supporting US Food and Drug Administration (FDA) drug approvals is largely conducted outside the US. Objective: To characterize where drugs were tested for FDA approval and to determine how commonly and quickly these drugs received marketing approval in the countries where they were tested, both overall and by country income level and geographical region. Design, Setting, and Participants: This cross-sectional analysis of trials supporting FDA approval of novel drugs in 2012 and 2014, sponsored by large drug companies, did not involve human participants. The settings were the countries hosting trials supporting US drug approval. Data sources included Drugs@FDA, ClinicalTrials.gov, PubMed, Google Scholar, EMBASE, and drug regulatory agency websites. Data analysis was completed March through September 2020. Main Outcomes and Measures: The primary outcomes were the proportion of drugs approved for marketing in the countries where they were tested for FDA approval within 1, 2, 3, 4, and 5 years of FDA approval and the proportion of countries contributing participants to trials supporting FDA approvals receiving market access to the drugs they helped test within 1, 2, 3, 4, and 5 years of FDA approval. Results: In 2012 and 2014, the FDA approved 34 novel drugs sponsored by large companies, on the basis of a total of 898 trials, 563 of which had location information available. Each drug was tested in a median (interquartile range [IQR]) of 25 (18-37) unique countries, including a median (IQR) of 20 (13-25) high-income countries, 6 (4-11) upper-middle-income countries, and 1 (0-2) low-middle-income country. One drug was approved for marketing in all testing countries within 1 year of FDA approval and 15% (5 of 34 drugs) were approved in all testing countries within 5 years of FDA approval. Of the 70 countries contributing research participants for FDA drug approvals, 7% (5 countries) received market access to drugs they helped test within 1 year of FDA approval and 31% (22 countries) did so within 5 years. Access within 1 year occurred in 13% (5 of 39) of high-income countries, 0 of 22 upper-middle-income countries (0%), and 0 of 9 lower-middle-income countries (0%), whereas at 5 years access rates were 46% (18 of 39 countries), 9% (2 of 22 countries), and 22% (2 of 9 countries), respectively. Approvals were faster in high-income countries (median [IQR], 8 [0-11] months) than in upper-middle-income countries (median [IQR], 11 [5-29] months) or lower-middle-income countries (median [IQR], 17 [11-27] months) after FDA approval. Access was lowest in African countries. Conclusions and Relevance: These findings suggest that substantial gaps exist between where FDA-approved drugs are tested and where they ultimately become available to patients, raising concerns about the equitable distribution of research benefits at the population level.

Does biomarker use in oncology improve clinical trial failure risk? A large-scale analysis.

PURPOSE: To date there has not been an extensive analysis of the outcomes of biomarker use in oncology. METHODS: Data were pooled across four indications in oncology drawing upon trial outcomes from www.clinicaltrials.gov: breast cancer, non-small cell lung cancer (NSCLC), melanoma and colorectal cancer from 1998 to 2017. We compared the likelihood drugs would progress through the stages of clinical trial testing to approval based on biomarker status. This was done with multi-state Markov models, tools that describe the stochastic process in which subjects move among a finite number of states. RESULTS: Over 10000 trials were screened, which yielded 745 drugs. The inclusion of biomarker status as a covariate significantly improved the fit of the Markov model in describing the drug trajectories through clinical trial testing stages. Hazard ratios based on the Markov models revealed the likelihood of drug approval with biomarkers having nearly a fivefold increase for all indications combined. A 12, 8 and 7-fold hazard ratio was observed for breast cancer, melanoma and NSCLC, respectively. Markov models with exploratory biomarkers outperformed Markov models with no biomarkers. CONCLUSION: This is the first systematic statistical evidence that biomarkers clearly increase clinical trial success rates in three different indications in oncology. Also, exploratory biomarkers, long before they are properly validated, appear to improve success rates in oncology. This supports early and aggressive adoption of biomarkers in oncology clinical trials.

A Systematic Assessment of US Food and Drug Administration Dosing Recommendations For Drug Development Programs Amenable to Response-Guided Titration.

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end-of-phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response-guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA-sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.