Unleashing the Power of Reliance for Post-Approval Changes: A Journey with 48 National Regulatory Authorities.

Post-approval changes (PACs) to marketed products are routinely introduced to continuously enhance the product lifecycle management. However, bringing a chemistry, manufacturing and control (CMC) change through the global health authorities can be a complex and lengthy process taking up to several years, therefore negatively impacting supply continuity. In order to accelerate the review and approval of regulatory submissions and ensure continuous supply to patients, the World Health Organization (WHO) is strongly supporting the implementation of reliance among National Regulatory Authorities (NRAs). While some promising developments have been made with the use of reliance pathways for initial marketing authorizations, reliance is still not widely used for PACs. With the support of the European Medicines Agency (EMA) and WHO, Roche launched a reliance pilot based on EMA approval to file a supply critical variation for a monoclonal antibody. The variation constitutes major changes to the approved manufacturing process. Sameness of the product is ensured by submitting to all participants the same variation package as in the EU. The objectives of the pilot are to ensure continuous supply of this critical medicine by targeting global approval in 6.5 months, to promote regulatory convergence by waiving country specific requirements, and enhance greater transparency by sharing EMA Committee for Medicinal Products for Human Use (CHMP) final assessment report and Q&As to participating NRAs. Globally 48 NRAs have agreed to join the pilot. This article outlines the process of establishing the pilot project, including a planning phase and an engagement phase with the EMA, WHO and the participating NRAs.

Understanding the Regulatory Pathways Used to Develop, Evaluate, Authorize, and Approve New Drugs and Vaccines in the United States.

The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the primary focus of this review.

Translational Aspects of 3D and 4D Printing and Bioprinting.

Three-dimensional (3D) printed medical devices include orthopedic and craniofacial implants, surgical tools, and external prosthetics that have been directly used in patients. While the advances of additive manufacturing techniques in the production of medical devices have been on the rise, clinical translation of living cellular constructs face significant limitations in terms of regulatory affairs, process technology, and materials development. In this perspective, the current status-quo of 3D and four-dimensional (4D) (bio)printing is summarized, current advancements are discussed and the challenges that need to be addressed for improved industrial translation and clinical applications of bioprinting are highlighted. It is focused on a multidisciplinary approach in discussing the key translational considerations, from the perspective of industry, regulatory bodies, funding strategies, and future directions.

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

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

The United States Food and Drug Administration's Platform Technology Designation to Expedite the Development of Drugs.

Drug development costs can be significantly reduced if proven "platform" technologies are allowed to be used without having to validate their use. The most recent US Food and Drug Administration (FDA) guideline brings more clarity, as well as a greater focus on the most complex technologies that can now be used for faster drug development. The FDA has highlights the use of lipid nanoparticles (LNPs) to package and deliver mRNA vaccines, gene therapy, and short (2-20 length) synthetic nucleotides (siRNA). Additionally, monoclonal antibody cell development is targeted. The FDA provides a systematic process of requesting platform status to benefit from its advantages. It brings advanced science and rationality into regulatory steps for the FDA's approval of drugs and biologicals.

From Drug Discovery to Drug Approval: A Comprehensive Review of the Pharmacogenomics Status Quo with a Special Focus on Egypt.

Pharmacogenomics (PGx) is the hope for the full optimization of drug therapy while minimizing the accompanying adverse drug events that cost billions of dollars annually. Since years before the century, it has been known that inter-individual variations contribute to differences in specific drug responses. It is the bridge to what is well-known today as "personalized medicine". Addressing the drug's pharmacokinetics and pharmacodynamics is one of the features of this science, owing to patient characteristics that vary on so many occasions. Mainly in the liver parenchymal cells, intricate interactions between the drug molecules and enzymes family of so-called "Cytochrome P450" occur which hugely affects how the body will react to the drug in terms of metabolism, efficacy, and safety. Single nucleotide polymorphisms, once validated for a transparent and credible clinical utility, can be used to guide and ensure the succession of the pharmacotherapy plan. Novel tools of pharmacoeconomics science are utilized extensively to assess cost-effective pharmacogenes preceding the translation to the bedside. Drug development and discovery incorporate a drug-gene perspective and save more resources. Regulations and laws shaping the clinical PGx practice can be misconceived; however, these pre-/post approval processes ensure the product's safety and efficacy. National and international regulatory agencies seek guidance on maintaining conduct in PGx practice. In this patient-centric era, social and legal considerations manifest in a way that makes them unavoidable, involving patients and other stakeholders in a deliberate journey toward utmost patient well-being. In this comprehensive review, we contemporarily addressed the scientific leaps in PGx, along with various challenges that face the proper implementation of personalized medicine in Egypt. These informative insights were drawn to serve what the Egyptian population, in particular, would benefit from in terms of knowledge and know-how while maintaining the latest global trends. Moreover, this review is the first to discuss various modalities and challenges faced in Egypt regarding PGx, which we believe could be used as a pilot piece of literature for future studies locally, regionally, and internationally.

Strength of Statistical Evidence for the Efficacy of Cancer Drugs: A Bayesian Re-Analysis of Randomized Trials Supporting FDA Approval.

OBJECTIVE: To quantify the strength of statistical evidence of randomised controlled trials (RCTs) for novel cancer drugs approved by the Food and Drug Administration (FDA) in the last two decades. STUDY DESIGN AND SETTING: We used data on overall survival (OS), progression-free survival (PFS), and tumour response (TR) for novel cancer drugs approved for the first time by the FDA between January 2000 and December 2020. We assessed strength of statistical evidence by calculating Bayes Factors (BFs) for all available endpoints, and we pooled evidence using Bayesian fixed-effect meta-analysis for indications approved based on two RCTs. Strength of statistical evidence was compared between endpoints, approval pathways, lines of treatment, and types of cancer. RESULTS: We analysed the available data from 82 RCTs corresponding to 68 indications supported by a single RCT and seven indications supported by two RCTs. Median strength of statistical evidence was ambiguous for OS (BF = 1.9; IQR 0.5-14.5), and strong for PFS (BF = 24,767.8; IQR 109.0-7.3*106) and TR (BF = 113.9; IQR 3.0-547,100). Overall, 44 indications (58.7%) were approved without clear statistical evidence for OS improvements and seven indications (9.3%) were approved without statistical evidence for improvements on any endpoint. Strength of statistical evidence was lower for accelerated approval compared to non-accelerated approval across all three endpoints. No meaningful differences were observed for line of treatment and cancer type. LIMITATIONS: This analysis is limited to statistical evidence. We did not consider non-statistical factors (e.g., risk of bias, quality of the evidence). CONCLUSION: BFs offer novel insights into the strength of statistical evidence underlying cancer drug approvals. Most novel cancer drugs lack strong statistical evidence that they improve OS, and a few lack statistical evidence for efficacy altogether. These cases require a transparent and clear explanation. When evidence is ambiguous, additional post-marketing trials could reduce uncertainty.

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

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

Evaluating cardiac lead safety using observational, real-world data: EP PASSION proof-of-concept study.

BACKGROUND: Traditional post-approval study (PAS) designs have been accepted by regulatory authorities to fulfill postmarketing requirements for cardiac leads, but they have several limitations. OBJECTIVE: We conducted a proof-of-concept study of alternative methods that use real-world data (RWD) to evaluate lead safety in large populations of patients. METHODS: Abbott patient device databases were linked with Medicare Fee-For-Service (FFS) claims to identify lead complications in patients implanted with Abbott Optisure lead. A 1:1 comparison between the PAS method and RWD method of detecting mechanical lead-related complication events was conducted in 444 PAS participants who were enrolled in Medicare FFS. Agreement between methods was evaluated by McNemar test and Cohen κ. Survival free from complications at 3 years was compared between the PAS and RWD cohorts with an equivalence acceptance criterion of ±2.5%. RESULTS: There were 1171 PAS patients and 5804 Medicare FFS patients who received an Optisure lead between August 27, 2014, and June 14, 2016. Patients were observed through December 31, 2018. Complete agreement was found between PAS-reported and claims-detected complications (McNemar P value = 1; Cohen κ = 1). Survival free from complications at 3 years by the RWD method was 98.4% (95% confidence limit, 98.0%-98.7%), which was within the acceptable range of the PAS 98.4% (95% confidence limit, 97.6%-99.0%). CONCLUSION: These results show a close agreement between RWD-detected and PAS-reported lead complication rates, which highlights the potential benefits of RWD-based methods to enhance the generation of clinical evidence for lead safety.

Making Drug Approval Decisions in the Face of Uncertainty: Cumulative Evidence versus Value of Information.

BACKGROUND: The COVID-19 pandemic underscored the criticality and complexity of decision making for novel treatment approval and further research. Our study aims to assess potential decision-making methodologies, an evaluation vital for refining future public health crisis responses. METHODS: We compared 4 decision-making approaches to drug approval and research: the Food and Drug Administration's policy decisions, cumulative meta-analysis, a prospective value-of-information (VOI) approach (using information available at the time of decision), and a reference standard (retrospective VOI analysis using information available in hindsight). Possible decisions were to reject, accept, provide emergency use authorization, or allow access to new therapies only in research settings. We used monoclonal antibodies provided to hospitalized COVID-19 patients as a case study, examining the evidence from September 2020 to December 2021 and focusing on each method's capacity to optimize health outcomes and resource allocation. RESULTS: Our findings indicate a notable discrepancy between policy decisions and the reference standard retrospective VOI approach with expected losses up to $269 billion USD, suggesting suboptimal resource use during the wait for emergency use authorization. Relying solely on cumulative meta-analysis for decision making results in the largest expected loss, while the policy approach showed a loss up to $16 billion and the prospective VOI approach presented the least loss (up to $2 billion). CONCLUSION: Our research suggests that incorporating VOI analysis may be particularly useful for research prioritization and treatment implementation decisions during pandemics. While the prospective VOI approach was favored in this case study, further studies should validate the ideal decision-making method across various contexts. This study's findings not only enhance our understanding of decision-making strategies during a health crisis but also provide a potential framework for future pandemic responses. HIGHLIGHTS: This study reviews discrepancies between a reference standard (retrospective VOI, using hindsight information) and 3 conceivable real-time approaches to research-treatment decisions during a pandemic, suggesting suboptimal use of resources.Of all prospective decision-making approaches considered, VOI closely mirrored the reference standard, yielding the least expected value loss across our study timeline.This study illustrates the possible benefit of VOI results and the need for evidence accumulation accompanied by modeling in health technology assessment for emerging therapies.

Development of sleepiness in professional truck drivers: Real-road testing for driver drowsiness and attention warning (DDAW) system evaluation.

All new vehicle types within the European Union must now be equipped with a driver drowsiness and attention warning system starting from 2022. The specific requirements for the test procedure necessary for type approval are defined in the Annex of EU Regulation C/2021/2639. The objectives of this study were to: (i) investigate how sleepiness develops in professional truck drivers under real-road driving conditions; and (ii) assess the feasibility of a test procedure for validating driver drowsiness and attention warning systems according to the EU regulation. Twenty-four professional truck drivers participated in the test. They drove for 180 km on a dual-lane motorway, first during daytime after a normal night's sleep and then at nighttime after being awake since early morning. The results showed higher sleepiness levels during nighttime driving compared with daytime, with a faster increase in sleepiness with distance driven, especially during the night. Psychomotor vigilance task results corroborated these findings. From a driver drowsiness and attention warning testing perspective, the study design with sleep-deprived drivers at night was successful in inducing the targeted sleepiness level of a Karolinska Sleepiness Scale score of ≥ 8. Many drivers who reported a Karolinska Sleepiness Scale ≥ 8 during the drives also acknowledged feeling sleepy in the post-drive questionnaire. Reaching high levels of sleepiness on real roads during daytime is more problematic, not the least from legal and ethical perspectives as higher traffic densities during the daytime lead to increased risks.

Resmetirom: The First Food and Drug Administration-Approved Medication for Nonalcoholic Steatohepatitis (NASH).

OBJECTIVE: To review the literature leading to the Food and Drug Administration (FDA) approval of the first medication, resmetirom, for the treatment of nonalcoholic steatohepatitis (NASH), including the pharmacology, pharmacokinetics, clinical studies, dosing, and adverse effects. Relevant data will be used to discuss how resmetirom impacts clinical practice. DATA SOURCES: A literature search was conducted using MEDLINE from database inception to May 12, 2024. Keywords included non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, and resmetirom. Study selection, data extraction and all English-language studies involving the use of resmetirom for nonalcoholic fatty liver disease (NAFLD)/NASH were included. DATA SYNTHESIS: Resmetirom, a thyroid hormone receptor agonist, is administered at daily doses of either 80 mg or 100 mg. The drug was shown to provide NASH resolution as assessed by the NAFLD activity score, 80 mg-24.2%, 100 mg-25.9% compared to 14.2% with the placebo group (P < 0.001). Resmetirom, improved liver fibrosis, 80 mg-25.9%, 100 mg-29.9% compared to 9.7% with the placebo group (P < 0.001). Resmetirom's ability to improve fibrosis in patients with F2-F3 fibrosis offers valuable benefit for patients at risk of progressing to cirrhosis. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Resmetirom expands the medication options available to treat patients with NASH which can be given alongside other medications to optimize metabolic factors such as glucagon-like peptide-1 and hydroxymethylglutaryl-coenzyme A reductase inhibitors. Resmetirom was well tolerated in studies. CONCLUSION: Resmetirom serves as an attractive option in patients diagnosed with NASH with evidence of advanced fibrosis (F2-F3) in combination with exercise, diet, and other multimodal therapies targeting metabolic risk factors.

Recent and anticipated novel drug approvals (Q2 2024 through Q1 2025).

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. SUMMARY: Selected drug approvals anticipated in the 12-month period covering the second quarter of 2024 through the first quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. New cellular and gene therapies for cancers continued to strengthen the pipeline, in addition to new drugs targeting previously untreatable conditions. Several novel drugs are being developed for rare and ultra-rare diseases such as hemophilia, Niemann-Pick disease type C, hereditary angioedema, and aromatic L-amino acid decarboxylase deficiency. CONCLUSION: The current drug pipeline includes new drugs with various indications for cancers and rare diseases as well as diabetes, acute coronary syndrome, chronic skin disorder, and chronic obstructive pulmonary disease.

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

Background: 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. Methods: We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Results: 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. Conclusion: 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.

International comparison of availability for orphan drugs: focused on approved orphan drugs in South Korea.

Introduction: In this study, we aimed to comparatively analyse the indicators of availability to orphan drugs in South Korea, the United States of America, Europe Union, and Japan. Methods: For 169 drugs designated as orphan drugs in South Korea between 2012 and 2021, information on the drugs designated as orphan drugs from each jurisdiction was extracted by country. Then, the availability indicators (approval time, drug lag time, and designation gap) were analysed for the drugs approved in each jurisdiction. Results: The approval rate of drugs designated as orphan drugs were 11.22% and 6.31% in the USA and EU, respectively, which was lower than that of orphan drugs in South Korea and Japan. The highest number of approved drugs was in the USA (87 drugs), EU 27 drugs, Japan 22 drugs and Korea 21 drugs. Furthermore, the approval time significantly differed between South Korea and the other countries. South Korea had a significantly different drug lag time and designation gap compared with the USA and EU. Conclusion: Our findings show that to fundamentally improve the access to treatments for rare disease, a policy of regulatory science that can comprehensively support the early stages of research and development and commercialisation is needed.

Pharmaceutical company funding of cancer patient advocacy organizations in the Netherlands.

BACKGROUND: Financial conflicts of interest (FCOI) of medical professionals and associated organizations with pharmaceutical companies (pharma) might contribute to the use of low value oncological treatments. Value criteria for oncological drug approvals in the Netherlands have recently become more stringent leading to objections by cancer patient advocacy organizations (cPAOs). Considering the importance of cPAOs input in cancer patient care we analyzed whether pharma funding of cPAOs occurs in the Netherlands. METHODS: The cPAO websites and available annual reports were evaluated for disclosure of pharma funding for the years 2021 and 2022. Also, data from the Dutch Healthcare Transparency Registry (DHTR) were extracted. RESULTS: Twenty-one of 34 (61.8 %) cPAOs received pharma funding (with 20 registered in the DHTR), and for 13 (29.4 %) cPAOs no reporting of pharma funding could be found. Three of the cPAOs disclosed pharma funding directly on their main website. Online educational material was available from 22 cPAOs on their websites with pharma funding disclosed on the educational material in 5. The total registered amount of pharmaceutical funding was €667,232.00 in 2021 and €536,098.00 in 2022. The median (and interquartile ranges) DHTR registered amount of support per cPAO that received funding in the studied period was €23,799.50 (14,823.75-84,663.30). The most common funding category as defined in the DHTR was project sponsorship. CONCLUSIONS: Financial support by the pharmaceutical industry is common for Dutch cPAOs. Given the importance of cPAOs and their objective input in the societal debate on the availability of cancer drugs, the potential influence of pharma sponsoring should be critically evaluated.

Reflections on the regulatory field covering the development of paediatric medicinal products: a brief overview of current status and challenges.

Many medicinal products are initially developed and tested in adults, and often, only a limited amount of data on their safety and efficacy in children exist. Consequently, paediatric healthcare providers sometimes need to make informed decisions about using medicinal products in children based on available fragmentary data. Ethical guidelines emphasise the importance of protecting children and ensuring they receive safe and effective medical treatments. Paediatric clinical trials should be conducted to provide evidence-based care with specific attention to minimise risks to children. This highlights the dilemma of finding a balance between protecting children and adolescents (and avoiding unnecessary clinical trials) and obtaining reliable, robust and justified data to treat them adequately and not in an off-label manner with unknown risks. For years, paediatricians maintained that children and adolescents are not treated based on up-to-date scientific knowledge and justification. The slogan "children are not small adults" summarised the concerns in a catch phrase. Different stakeholders have taken a variety of actions to address this concern.

Protocol-in-a-Day Workshop: Expediting IRB Approval for Junior and Senior Faculty.

Delays in research protocol development may be a single factor that hinders the career progression of academic faculty. Structured educational guidance during this phase proves crucial in mitigating setbacks in Institutional Review Board (IRB) approval and expediting trial implementation. To address this, the Protocol-in-a-Day (PIAD) workshop, a comprehensive 1-day event involving members from six critical facets of RO clinical trial implementation, was established, offering significant input to individual protocols. Efficacy and satisfaction of the PIAD workshop were assessed through a 5-question survey and the average time from submission to IRB initial approval. The normality of the data was analyzed using the Shapiro-Wilk Test. Nonparametric data was analyzed using a Mann-Whitney U test for significance. A total of 18 protocols that went through the PIAD workshop were activated. The mean time to IRB approval for protocols that went through PIAD was 39.8 days compared to 58.4 days for those that did not go through the PIAD workshop. Based on survey results, 100% of PIAD participants said the PIAD workshop was useful and 94% of participants stated that the PIAD workshop improved the overall quality of their protocol. Participant surveys further highlighted substantial improvements in trial quality, language, and statistical design and revealed that all participants found the workshop helpful. Therefore, both junior and senior faculty benefitted from this educational program during protocol development, as both groups demonstrated shorter times to IRB approval than non-participants. This acceleration not only fosters efficient trial implementation but also supports academic faculty in their career development.