Regulatory Submissions Research Articles

Using Innovative Tools and Lean Writing Workflow Processes to Accelerate Regulatory Document Writing

Lean writing workflow processes can streamline development of complex documents, including protocols and other regulatory submissions. This paper outlines standard development timelines and describes useful lean writing workflow methods and tools to reduce protocol development timelines without sacrificing document quality. We present the results of a survey completed by 75 Medical writers (MW) that reveal the strategies used during document preparation and use real case scenarios (protocol development) that illustrate how innovative tools and approaches can be efficiently used to create a lean writing workflow process. Software tools (e.g., proofreading assistance, citation manager, collaborative authoring and reviewing) were widely accepted and used during protocol development according to the MWs surveyed. Most of the surveyed writers (62%) hypothesized a reduction in production time by about 25%. Efficient collaborative work across different time zones had a marked impact on shortening timelines while maintaining production of high-quality documents. Real case scenarios were used to illustrate how innovative tools and approaches can positively impact timelines and efficiently create a lean writing workflow process regardless of therapeutic area. The real case scenarios showed that protocol development time can be decreased by about 26% without compromising the quality of the document. This shows that software tools, templates, checklists, and collaborative writing were more impactful than hypothesized by the MWs included in the survey. With clear workflow processes, roles, and responsibilities backed by innovative software applications, template guidelines, and collaborative work processes, MWs can overcome common development challenges and improve their lean regulatory writing skills.

Generative AI in Clinical Research: Regulatory Submissions, Clinical Data Management, and Beyond

Artificial intelligence and its subsets, such as generative artificial intelligence, have been making headlines due to their potential to accelerate the growth and expansion of various industries, including healthcare. However, the majority of application areas in healthcare revolve around diagnosing diseases, finding lead molecules for potential treatments, optimizing hospital operations, and other related aspects. This means that there are areas where the potential of these technologies is still to be realized. Examples of where such technologies could produce a significant impact across multiple elements are clinical research and its related domains, including regulatory submissions, clinical data management, clinical documentation, and other closely related areas. When artificial intelligence and its related technologies are utilized in these areas, they yield unparalleled outcomes regarding efficiency, consistency, and reproducibility. This, in turn, supports professionals involved in clinical research, like medical writers, statistical programmers, and other stakeholders, to drastically improve the speed by which they produce the initial drafts of various outputs, reduce the risk of errors that could lead to submission rejection, and optimize the overall clinical research workflow. Despite the potential of this area, the number of available solutions that support the aforementioned domains remains low. This is further complicated by the fact that there are even fewer numbers of working solutions.

Metabolite Bioanalysis in Drug Development: Recommendations from the IQ Consortium Metabolite Bioanalysis Working Group.

The intent of this perspective is to share the recommendations of the International Consortium for Innovation and Quality in Pharmaceutical Development Metabolite Bioanalysis Working Group on the fit-for-purpose metabolite bioanalysis in support of drug development and registration. This report summarizes the considerations for the trigger, timing, and rigor of bioanalysis in the various assessments to address unique challenges due to metabolites, with respect to efficacy and safety, which may arise during drug development from investigational new drug (IND) enabling studies, and phase I, phase II, and phase III clinical trials to regulatory submission. The recommended approaches ensure that important drug metabolites are identified in a timely manner and properly characterized for efficient drug development.

Critical Comments by Food and Drug Administration Reviewers on Patient-Reported Outcomes in Food and Drug Administration Regulatory Submissions (2018-2021)

ObjectivesThis article examined the inclusion of patient-reported outcome (PRO) data in new drug applications (NDAs) submitted to the Food and Drug Administration (FDA) and approved from 2018 to 2021. The importance of assessing PROs, which capture patients’ perspectives on the disease and treatment experience, has been underscored by many stakeholders, including regulatory authorities. Despite the increasing inclusion of PRO assessments in registration trials, inclusion of language related to PRO results in approved product labeling varies widely. MethodsThis study examined FDA submission packages for NDAs approved by the FDA from 2018 to 2021 to identify critical reviewer comments related to PROs. Comments were identified and categorized by the type of criticism. Reviewers considered both oncology and nononcology indications. ResultsAssessment of PROs was included in 66.2% of the 210 submissions reviewed. Critical comments were identified in 45.3% of these applications; comments most commonly related to statistical analysis considerations, fit for purpose, and study design. Other categories of critical comment included data quality, lack of treatment benefit, administrative considerations, and miscellaneous issues. Differences were observed between oncology and nononcology NDAs with regard to the number and type of comments included in each of these categories. The findings highlight the importance of planning statistical analyses, establishing content validity, carefully considering study design, maximizing data quality, and demonstrating treatment benefit, among other issues. ConclusionsOverall, this study offers insight into the landscape of PRO data included in recently approved NDAs, along with recommendations for improving the quality and reporting of PROs in clinical trials.

Low temperature vaporized hydrogen peroxide sterilization of 3D printed devices

BackgroundLow temperature vaporized hydrogen peroxide sterilization (VH2O2) is used in hospitals today to sterilize reusable medical devices. VH2O2 sterilized 3D printed materials were evaluated for sterilization, biocompatibility and material compatibility.Materials & methodsTest articles were printed at Formlabs with BioMed Clear™ and BioMed Amber™, and at Stratasys with MED610™, MED615™ and MED620™. Sterilization, biocompatibility and material compatibility studies with 3D printed materials were conducted after VH2O2 sterilization in V-PRO™ Sterilizers. The overkill method was used to evaluate sterilization in a ½ cycle. Biocompatibility testing evaluated the processed materials as limited contact (< 24-hours) surface or externally communicating devices. Material compatibility after VH2O2 sterilization (material strength and dimensionality) was evaluated via ASTM methods and dimensional analysis.Results3D printed devices, within a specific design window, were sterile after VH2O2 ½ cycles. After multiple cycle exposure, the materials were not cytotoxic, not sensitizing, not an irritant, not a systemic toxin, not pyrogenic and were hemo-compatible. Material compatibility via ASTM testing and dimensionality evaluations did not indicate any significant changes to the 3D printed materials after VH2O2 sterilization.ConclusionLow temperature vaporized hydrogen peroxide sterilization is demonstrated as a suitable method to sterilize 3D printed devices. The results are a subset of the data used in a regulatory submission with the US FDA to support claims for sterilization of 3D printed devices with specified materials, printers, and device design 1.

The Role of Model Master Files for Sharing, Acceptance, and Communication with FDA.

With the evolving role of Model Integrated Evidence (MIE) in generic drug development and regulatory applications, the need for improving Model Sharing, Acceptance, and Communication with the FDA is warranted. Model Master File (MMF) refers to a quantitative model or a modeling platform that has undergone sufficient model Verification & Validation to be recognized as sharable intellectual property that is acceptable for regulatory purposes. MMF provides a framework for regulatorily acceptable modeling practice, which can be used with confidence to support MIE by both the industry and the U.S. Food and Drug Administration (FDA). In 2022, the FDA and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop to discuss the best practices for utilizing modeling approaches to support generic product development. This report summarizes the presentations and panel discussions of the workshop symposium entitled "Model Sharing, Acceptance, and Communication with the FDA". The symposium and this report serve as a kick-off discussion for further utilities of MMF and best practices of utilizing MMF in drug development and regulatory submissions. The potential advantages of MMFs have garnered acknowledgment from model developers, industries, and the FDA throughout the workshop. To foster a unified comprehension of MMFs and establish best practices for their application, further dialogue and cooperation among stakeholders are imperative. To this end, a subsequent workshop is scheduled for May 2-3, 2024, in Rockville, Maryland, aiming to delve into the practical facets and best practices of MMFs pertinent to regulatory submissions involving modeling and simulation methodologies.

Ethical considerations for real-world evidence studies.

Real-world evidence (RWE) studies are conducted on patient's data primarily collected for monitoring of health status of patients. The use of real-world data to generate evidence in academic research or for regulatory submission raises a variety of ethical issues such as privacy, confidentiality, data protection, data de-identification, data sharing, scientific design of study, and informed consent requirements. The investigators-researchers and sponsors should adhere to current standards of ethics whilst planning and conduct of RWE studies. The ethics committees should consider ethical issues specific to RWE studies before approval.

Developing and Validating a Model of Humeral Stem Primary Stability, Intended for In Silico Clinical Trials.

In silico clinical trials (ISCT) can contribute to demonstrating a device's performance via credible computational models applied on virtual cohorts. Our purpose was to establish the credibility of a model for assessing the risk of humeral stem loosening in total shoulder arthroplasty, based on a twofold validation scheme involving both benchtop and clinical validation activities, for ISCT applications. A finite element model computing bone-implant micromotion (benchtop model) was quantitatively compared to a bone foam micromotion test (benchtop comparator) to ensure that the physics of the system was captured correctly. The model was expanded to a population-based approach (clinical model) and qualitatively evaluated based on its ability to replicate findings from a published clinical study (clinical comparator), namely that grit-blasted stems are at a significantly higher risk of loosening than porous-coated stems, to ensure that clinical performance of the stem can be predicted appropriately. Model form sensitivities pertaining to surgical variation and implant design were evaluated. The model replicated benchtop micromotion measurements (52.1 ± 4.3µm), without a significant impact of the press-fit ("Press-fit": 54.0 ± 8.5µm, "No press-fit": 56.0 ± 12.0µm). Applied to a virtual population, the grit-blasted stems (227 ± 78µm) experienced significantly larger micromotions than porous-coated stems (162 ± 69µm), in accordance with the findings of the clinical comparator. This work provides a concrete example for evaluating the credibility of an ISCT study. By validating the modeling approach against both benchtop and clinical data, model credibility is established for an ISCT application aiming to enrich clinical data in a regulatory submission.

Development of bioreactor scale-down model using orthogonal projections to latent structures method and CO2 supplementation.

Scale-down model qualification is an important step for developing a large-scale cell culture process to enhance process understanding and support process characterization studies. Traditionally, only harvest data are used to show consistency between small-scale and large-scale bioreactor performance, allowing attributes that are dynamic over the cell culture period to be overlooked. A novel statistical method, orthogonal projections to latent structures (OPLS) analysis, can be utilized to compare time-course cell culture data across scales. Here we describe an example where OPLS is used to identify gaps between small-scale and large-scale bioreactor performances. In this case, differences in the partial pressure of carbon dioxide (pCO2) and lactate profiles were observed between small- and large-scale bioreactors, which were linked to differences in the product-quality attributes fragments and galactosylation. An improved small-scale model was developed, leading to improved consistency in the process performance and product qualities across scales and qualification of the scale-down model for regulatory submissions. This new statistical approach can provide valuable insights into process understanding and process scale-up.

Interoperability of Leigh Syndrome Patient Registry Data with Regulatory Submission Standards

Introduction: Leigh syndrome (LS) is a rare, severe neurometabolic disorder and a type of primary mitochondrial disease. The Cure Mito Foundation is a nonprofit foundation founded in 2018 by parents of affected children. The organization's mission is to unite the global LS community to accelerate patient-centered research, treatments, and cures. Cure Mito has launched a global patient registry for Leigh syndrome in September 2021 to better understand the disease, facilitate clinical trials recruitment, and build a strong global community.&amp;nbsp;Objectives: Patient data is collected in registries for getting a real-world view of patient reported outcomes, and to improve the understanding of the disease. Establishment of interoperability of therapies. The project described here has been undertaken to establish such interoperability for Leigh syndrome patient registry data.Methods: Establishing interoperability consisted of assessment of all data elements and collected data, alignment of data elements and variables with CDASH domains and variables, terminology alignment, data transformation, and compliance assessment.&amp;nbsp;Results: Data assessment has been done, domain map has been developed, and data has been converted to CDASH standard.Conclusion: Cure Mito Foundation and Sumptuous Data Sciences, LLC completed a project focused on interoperability of Leigh syndrome patient registry data with CDISC standards, converting the data to CDASH standards, with SDTM conversion in progress. This project is a key milestone for all stakeholders who collect real world data in rare diseases.

Emergency Approval Mechanisms for Human Vaccines in India.

The coronavirus disease 2019 (COVID-19) pandemic highlighted the world's level of preparedness in managing public health emergencies (PHEs). It revealed the critical need for timely medical therapeutics, especially vaccines. To expedite response, many nations, including India, adopted emergency approval mechanisms and offered new ways of review, such as the rolling review along with the accelerated review procedure. This response resulted in reallocating internal resources and adopting new policies and measures, such as integrating digital technology with regulatory submissions and flexibility in statistical approaches. The present review focuses on the utilization of the New Drugs and Clinical Trials Rules 2019 for granting emergency approval to COVID-19 vaccines by the Drug Controller General of India (DCGI) and explores the legislative basis for such authorization during the PHE. The review aims to elucidate key intricacies and challenges inherent in the existing 'emergency use' framework within the Indian regulatory landscape. It assesses three critical facets of the 'emergency use' paradigm: the definition of the term, establishment of a transparent decision-making process, and formulation of rules governing termination or expiration of the emergency status. It makes policy recommendations regarding the 'emergency use' framework to respond to new, emerging, or re-emerging public health threats of the future.

Evaluating Utilization of Tiny-TIM to Assess the Effect of Food on the Absorptions of Oral Drugs and Its Application on Biopharmaceutical Modeling

Safety and efficacy are the most critical factors for the development of modern medications. For oral drugs, evaluating drug exposure under various conditions is one of the most important outcomes for clinical trials. These data will help to better understand the safety and efficacy of new drugs. Studies involving potential drug-drug interactions, proton pump inhibitors, and intake of food are often conducted to assess the above. Among the above, the influence of food on exposure to the drug is one of the key data sets for regulatory submission. Since food may have either a positive or negative effect on drug exposure, it is important to obtain an early assessment of the food effect. To better forecast and plan for clinical studies, substantial efforts have been made in the industry to develop modeling and in-vitro and in–vivo assays. Despite the efforts, predicting the effect of food on exposure without integrating the dynamic of the gastrointestinal tract in the assessment remains challenging. In this study, we evaluated the utilization of the dynamic Gastro-Intestinal Model (Tiny-TIM) for the food effect of over 20 drugs/formulations in development or on the market that covers all BCS classes. In general, the Tiny-TIM predicted food effects were in good agreement with the reported data in humans. This suggests that Tiny-TIM can successfully capture the impact of physicochemical properties on absorption under the influence of food.

Communicating computational workflows in a regulatory environment

The volume of nucleic acid sequence data has exploded recently, amplifying the challenge of transforming data into meaningful information. Processing data can require an increasingly complex ecosystem of customized tools, which increases difficulty in communicating analyses in an understandable way yet is of sufficient detail to enable informed decisions or repeats. This can be of particular interest to institutions and companies communicating computations in a regulatory environment. BioCompute Objects (BCOs; an instance of pipeline documentation that conforms to the IEEE 2791-2020 standard) were developed as a standardized mechanism for analysis reporting. A suite of BCOs is presented, representing interconnected elements of a computation modeled after those that might be found in a regulatory submission but are shared publicly - in this case a pipeline designed to identify viral contaminants in biological manufacturing, such as for vaccines.

An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report.

This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.

A Review of Meaningful Change Thresholds for EORTC QLQ-C30 and FACT-G Within Oncology

ObjectivesThis literature review provides an overview of meaningful change thresholds for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy – General (FACT-G) used across hematological cancers and solid tumors (melanoma, lung, bladder, and prostate). MethodsEmbase, MEDLINE, and PubMed were searched to identify relevant oncology publications from 2016 to 2021. Label claims from the US Food and Drug Administration and the European Medicines Agency for 7 recently approved drugs (pembrolizumab, atezolizumab, glasdegib, gilteritinib, tisagenlecleucel, axicabtagene ciloleucel, and daratumumab plus hyaluronidase-fihj) were reviewed. ResultsPublications providing guidance on meaningful change thresholds for the QLQ-C30 displayed a growing trend away from broad “legacy” thresholds of 10 points for all QLQ-C30 scales), toward deriving “contemporary” thresholds (eg, subscale specific, population specific). Contemporary publications generally provide guidance on selecting thresholds for specific scales that account for improved or worsening thresholds (eg, QLQ-C30 subscales). This trend was not clear for FACT-G, with less new guidance available. Most clinical trials used in regulatory label submissions have used thresholds of 10 points for the QLQ-C30 subscales and 3 to 7 points for the FACT-G total score. Despite the availability of more recent guidelines, contemporary meaningful change thresholds seem slow to emerge in the published literature and regulatory labels. ConclusionsTrialists should consider using contemporary thresholds, rather than legacy thresholds, for QLQ-C30 endpoints. Thresholds derived for a similar patient-population should be used where available. Further work is required to provide these across a broader range of cancer sites.

A Comparative Analysis of Generic Drug Assessment and Regulatory Approval in the USA, Europe and India.

The Abbreviated New Drug Application (ANDA) is used for the regulatory submission of generic drugs, which are pharmaceutical equivalents to brand-name drugs and distributed without patent protection. Different countries have their own regulatory requirements for the approval of generic drugs, enforced by authorities such as the CDSCO in India, EDQM in Europe, and USFDA in the United States. This review aims to compare the regulatory processes and requirements for generic drug approval in India, Europe, and the US, highlighting key differences and challenges. The involvement of regulatory authorities in the drug development process is crucial for expediting approval and addressing queries, helping to minimize delays. The Common Technical Document (CTD) format is employed across regions to harmonize submission requirements. This study underscores the differences in dossier submission for generics across the three regions, illustrating India's position in the global generic drug approval landscape. By comparing approval requirements, this work provides insight into the hurdles India must overcome to streamline its approval process. The ANDA allows generic manufacturers to submit bioequivalence studies, using the original innovator's safety and efficacy data. However, obtaining approval simultaneously from multiple regulatory authorities remains a challenging task. Careful review of regulatory documents by skilled personnel can reduce regulatory queries, ultimately accelerating the market launch of generic drugs. This review provides a comprehensive overview of the generic drug approval process, emphasizing the need for harmonization and improved efficiency in India's regulatory framework.

Potential value of animal microphysiological systems.

Microphysiological systems (MPS) are designed to recapitulate aspects of tissue/organ physiology in vivo, thereby providing potential value in safety and efficacy assessments of FDA-regulated products and regulatory decision-making. While there have been significant advances in the development, use, and proposals of qualification criteria for human organ MPS, there remains a gap in the development using animal tissues. Animal MPS may be of value in many areas including the study of zoonotic diseases, assessment of the safety and efficacy of animal therapeutics, and possibly reduction of the use of animals in regulatory submissions for animal therapeutics. In addition, the development of MPS from various animal species enables comparison to animal in vivo data. This comparison, while not always critical for all contexts of use, could help gain confidence in the use and application of human MPS data for regulatory decision-making and for the potential identification of species-specific effects. The use of animal MPS is consistent with the replacement, reduction, and refinement (3Rs) principles of animal use by identifying toxic compounds before conducting in vivo studies and identifying the appropriate species for testing.

Traditional Knowledge and Intellectual Property Rights for Ayurveda: An Outlook for the Future

Ayurveda is getting its due recognition at worldwide forums due to its ancient philosophy even though the medical and scientific fraternity around the globe has a very strong opinion regarding the safety and efficacy of Ayurvedic medicines. The provisions of Intellectual Property Rights under the World Intellectual Property Organization and patents have drawn interest from many individuals and organizations seeking commercial benefits from Ayurvedic traditional knowledge. However there are numerous challenges related to protecting traditional medical knowledge with unclear explanations. Efforts to safeguard traditional medicine face a complex array of national and international policies and governance systems primarily designed to address therapeutic efficacy safety concerns and challenges to rights held by traditional knowledge holders. Traditional knowledge has been categorized into three classes 1. Traditional medical knowledge 2. Traditional agricultural knowledge 3. Traditional ecological knowledge. This text is an attempt to assist traditional medical knowledge holders government representatives and third-party collaborators considering intellectual property law issues specifically related to traditional medical knowledge. Whether traditional healing knowledge is documented can significantly impact intellectual property protection commercialization promotion of traditional medicine regulatory submissions and collaborations. Its crucial for traditional knowledge holders to be well-informed to protect their reputations and interests when engaging with third parties. This understanding can empower them to navigate the complexities of traditional medicine and intellectual property enabling informed decisions on how best to utilize their knowledge.

Liquid Chromatographic Peak Purity Assessments in Forced Degradation Studies: An Industry Perspective

This review article discusses scientific rationales and current best practices in the pharmaceutical industry for performing chromatographic peak purity assessments (PPA). These activities are associated with the development and validation of liquid chromatographic (LC) stability-indicating analytical methods applicable to regulatory submissions of small-molecule drug candidates. The discussion includes a comprehensive overview of the PPA-related regulatory and scientific landscape and common industry approaches to obtain PPA results, as well as the strengths and weaknesses of PDA-facilitated ultraviolet (UV) PPA and other PPA techniques.