Quality Risk Management and Data Integrity in R&D Laboratories Supporting CMC Lifecycle of Biological Products.

The development of pharmaceutical products is the critical bridge that moves a potential new medicine from academic discovery to applied treatment of patients. It translates an idea for a new drug to bench-level research on how it can be manufactured, formulated, characterized and controlled for use in non-clinical and early clinical trials. From pre-clinical R&D discovery work through the commercial launch, substantial R&D CMC data is generated to develop and optimize cGMP manufacturing and testing operations, while also supporting product comparability, elucidating product / impurity structures, assessing critical quality attributes, developing the drug delivery mode, and developing the product formulation for long-term stability. Significant R&D CMC work continues post-approval to support continuous improvement and market expansion of the commercial product. These activities are crucial elements of Product Lifecycle Management, and taken together, they comprise Pharmaceutical Quality or Chemistry, Manufacturing and Controls (CMC). The objective of this paper is to mitigate the regulatory ambiguity of R&D quality systems with practical, risk-based examples and recommendations when conducting supportive CMC studies for biological products. Making sound strategic CMC decisions under any circumstances assumes data from R&D studies are reliable, traceable, and complete. While there are specific regulatory guidelines on phase-appropriate cGMP activities, none exist for quality practices in R&D CMC laboratories conducting non-cGMP studies. Hindsight is not the time to discover that R&D studies lack key elements that would otherwise have allowed the data to be directly presented to regulators, if needed. There is a strong prospective business interest in protecting considerable investments made for CMC R&D studies. Therefore, establishment of a robust and stage-appropriate R&D laboratory quality system is essential for companies seeking to capitalize on prior knowledge, protect investments, and be prepared for accelerated approval pathways.

A Risk-Based Assessment for Determining the Pharmacokinetic Comparability Requirements of Biologic-Device Combination Products Administered by Subcutaneous Injection.

The development of new large molecule drug therapies along with the innovation of biologic-device combination products such as prefilled syringes, autoinjectors and pen injectors have significantly impacted the treatment of new diseases and has improved the process of administering parenteral medicines. To support the regulatory approval of a new biologic-device combination products or subsequent chemistry, manufacturing and control changes impacting a combination product, sponsor companies must thoroughly assess the potential impact to product quality, safety and efficacy. In this report, a risk-based process to determine the potential impact to product quality, safety, and efficacy as well as corresponding regulatory actions supporting a chemistry, manufacturing and control change is presented. The risk assessment includes the standardized assessment of a) chemistry, manufacturing and control risk factors, potential responses and appropriately weighted scoring; b) pharmacokinetic risk factors, potential responses and appropriately weighted scoring; and c) the use of a 2-dimensional risk grid to combine the chemistry, manufacturing and control risks and pharmacokinetic risks to provide a regulatory recommendation. Three case studies (two clinical case studies and a post-approval case study) are provided to demonstrate the assessment process and capabilities.

A Bayesian approach for evaluating equivalence over multiple groups, and comparison with frequentist tost.

Manufacturing and testing of pharmaceutical products frequently occur in multiple facilities within a company's network. It is of interest to demonstrate equivalence among the alternative testing/manufacturing facilities to ensure product consistency and quality regardless of the facility where it was manufactured/tested. In the Frequentist framework, equivalence testing is well established when comparing two labs or manufacturing facilities; however, when considering more than two labs or production sites, the Frequentist approach may not always offer appropriate or interpretable estimates for demonstrating equivalence among all of them simultaneously. This paper demonstrates the utility of Bayesian methods to the equivalence assessment of multiple groups means, with a comparison against traditional Frequentist methods. We conclude that a Bayesian strategy is very useful for addressing the problem of multi-group equivalence. While it is not our intention to argue that Bayesian methods should always replace Frequentist ones, we show that among the advantages of a Bayesian analysis is that it provides a more nuanced understanding of the degree of similarity among sites than the hypothesis testing underpinning the Frequentist approach.

Assessing Similarity in Production from Organizational and Department-Level Financial Accounting Statements.

Hospitals are complex organizations which provide a wide array of health care services. This complexity creates challenges for stakeholders who wish to use financial accounting statements to make inferences about the productive choices made by a hospital's management. These challenges are especially salient when using data reported at the department (or cost center) level, or where the provision of care is coordinated across hospital departments. This study applies information entropy-based comparability analysis techniques to overall and department-level hospital financial data to identify hospital peer groups. Hospitals peer groups not only exhibit similar financial positions overall, but are also likely to exhibit operational similarities at the department level. Data for this analysis are drawn from the financial statements of Washington State critical access hospitals in the fiscal year 2019. The medical laboratory and pharmacy departments were specifically assessed because their services impact or support virtually every other revenue-producing department in the hospital. Findings suggest both departments significantly impact the formation of peer groups, with the pharmacy department contributing the largest impact.

Planning Split-Apheresis Designs for Demonstrating Comparability of Cellular and Gene Therapy Products.

A recent FDA draft guidance discusses statistical considerations for demonstrating comparability of cell and gene therapy products and processes. One experimental study described in the guidance is the split-apheresis design. The FDA draft guidance recommends a paired data analysis for such a design. This paper demonstrates that the paired analysis is under powered for some quality attributes for practical sample sizes of three to five donors unless a significant portion of variability is attributed to donor. Addition of historic lots from the pre-change process can increase the power for these attributes. This paper provides appropriate statistical methods for including this information.

Imlifidase: Is it the Magic Wand in Renal Transplantation?

Potential kidney transplant patients with HLA-specific antibodies have reduced access to transplantation. Their harmful effects are mediated by the Fc portion of IgG, including activation of the complement system and Fc receptor-initiated cytotoxic processes by circulating leucocytes. Avoiding antibody incompatibility is the conventional approach, but for some patients this can mean extended waiting times, or even no chance of a transplant if there are no alternative, compatible donors. For these cases, pretransplant antibody removal may provide access to transplantation. Plasmapheresis is currently used to achieve this, with acceptable outcome results, but the process can take days to reduce the antibody levels to a safe level, so has limited use for deceased donors. There is now an alternative, in the form of an IgG-digesting enzyme, Imlifidase, which can be administered for in vivo IgG inactivation. Imlifidase cleaves human IgG, separating the antigen-binding part, F(ab')2 from Fc. Typically, within six hours of dosing, most, if not all, of the circulating IgG has been inactivated, allowing safe transplantation from a previously incompatible donor. For deceased donor transplantation, where minimizing cold ischaemia is critical, this six-hour delay before implantation should be manageable, with the compatibility testing processes adjusted to accommodate the treatment. This agent has been used successfully in phase 2 clinical trials, with good short to medium term outcomes. While a donation rate that matches demand may be one essential answer to providing universal access to kidney transplantation, this is currently unrealistic. IgG inactivation, using Imlifidase, is, however, a realistic and proven alternative.

Constructing comparable intimate partner violence indicators across the DHS, MICS, and PMA health surveys.

We construct comparable indicators that measure the prevalence of recent intimate partner violence (IPV) using publicly available, integrated microdata within the IPUMS data collections across many countries. The objective of this work is to increase opportunities for comparative research by leveraging vast quantities of harmonized data. We use consistent and comparable variables that measure domestic violence in international health surveys. The most consistent indicators of domestic violence measure physical, psychological, and sexual IPV in the last 12 months. We imposed a consistent reference period and restricted to a comparable subpopulation where these differed across surveys. Aggregating IPV variables across surveys, without careful attention to question wording and subpopulations, may produce inconsistent measures leading to bias, over- or under-estimation of IPV prevalence, or spurious trends and associations. Using comparable indicators in microdata and studying the level, distribution, and covariates of IPV in multiple settings over time, we can better understand these phenomena and identify effective policy interventions.

Three steps towards comparability and standardization among molecular methods for characterizing insect communities.

Molecular methods are currently some of the best-suited technologies for implementation in insect monitoring. However, the field is developing rapidly and lacks agreement on methodology or community standards. To apply DNA-based methods in large-scale monitoring, and to gain insight across commensurate data, we need easy-to-implement standards that improve data comparability. Here, we provide three recommendations for how to improve and harmonize efforts in biodiversity assessment and monitoring via metabarcoding: (i) we should adopt the use of synthetic spike-ins, which will act as positive controls and internal standards; (ii) we should consider using several markers through a multiplex polymerase chain reaction (PCR) approach; and (iii) we should commit to the publication and transparency of all protocol-associated metadata in a standardized fashion. For (i), we provide a ready-to-use recipe for synthetic cytochrome c oxidase spike-ins, which enable between-sample comparisons. For (ii), we propose two gene regions for the implementation of multiplex PCR approaches, thereby achieving a more comprehensive community description. For (iii), we offer guidelines for transparent and unified reporting of field, wet-laboratory and dry-laboratory procedures, as a key to making comparisons between studies. Together, we feel that these three advances will result in joint quality and calibration standards rather than the current laboratory-specific proof of concepts. This article is part of the theme issue 'Towards a toolkit for global insect biodiversity monitoring'.

The National Cancer Database Conforms to the Standardized Framework for Registry and Data Quality.

BACKGROUND: Standardization of procedures for data abstraction by cancer registries is fundamental for cancer surveillance, clinical and policy decision-making, hospital benchmarking, and research efforts. The objective of the current study was to evaluate adherence to the four components (completeness, comparability, timeliness, and validity) defined by Bray and Parkin that determine registries' ability to carry out these activities to the hospital-based National Cancer Database (NCDB). METHODS: Tbis study used data from U.S. Cancer Statistics, the official federal cancer statistics and joint effort between the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI), which includes data from National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) to evaluate NCDB completeness between 2016 and 2020. The study evaluated comparability of case identification and coding procedures. It used Commission on Cancer (CoC) standards from 2022 to assess timeliness and validity. RESULTS: Completeness was demonstrated with a total of 6,828,507 cases identified within the NCDB, representing 73.7% of all cancer cases nationwide. Comparability was followed using standardized and international guidelines on coding and classification procedures. For timeliness, hospital compliance with timely data submission was 92.7%. Validity criteria for re-abstracting, recording, and reliability procedures across hospitals demonstrated 94.2% compliance. Additionally, data validity was shown by a 99.1% compliance with histologic verification standards, a 93.6% assessment of pathologic synoptic reporting, and a 99.1% internal consistency of staff credentials. CONCLUSION: The NCDB is characterized by a high level of case completeness and comparability with uniform standards for data collection, and by hospitals with high compliance, timely data submission, and high rates of compliance with validity standards for registry and data quality evaluation.

Antenatal care coverage and early childhood mortality in Zimbabwe: new interpretations from nationally representative household surveys.

Zimbabwe has implemented universal antenatal care (ANC) policies since 1980 that have significantly contributed to improvements in ANC access and early childhood mortality rates. However, Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS), two of Zimbabwe's main sources of health data and evidence, often provide seemingly different estimates of ANC coverage and under-five mortality rates. This creates confusion that can result in disparate policies and practices, with potential negative impacts on mother and child health in Zimbabwe. We conducted a comparability analysis of multiple DHS and MICS datasets to enhance the understanding of point estimates, temporal changes, rural-urban differences and reliability of estimates of ANC coverage and neonatal, infant and under-five mortality rates (NMR, IMR and U5MR, separately) from 2009 to 2019 in Zimbabwe. Our two samples z-tests revealed that both DHS and MICS indicated significant increases in ANC coverage and declines in IMR and U5MR but only from 2009 to 2015. NMR neither increased nor declined from 2009 to 2019. Rural-urban differences were significant for ANC coverage (2009-15 only) but not for NMR, IMR and U5MR. We found that there is a need for more precise DHS and MICS estimates of urban ANC coverage and all estimates of NMR, IMR and U5MR, and that shorter recall periods provide more reliable estimates of ANC coverage in Zimbabwe. Our findings represent new interpretations and clearer insights into progress and gaps around ANC coverage and under-five mortality rates that can inform the development, implementation, monitoring and evaluation of policy and practice responses and further research in Zimbabwe.

Implementation of a Three-Way Comparability Assessment for a Bioanalytical Anti-Drug Antibody Method.

Immunogenicity evaluation is a critical part of drug development. Regulatory guidelines from multiple health agencies provide recommendations for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity in clinical trials. These recommendations primarily describe an ADA method run in one bioanalytical laboratory supporting a biotherapeutic molecule; however, there are increasing instances that may necessitate the support of the ADA method being run in more than one laboratory. A program can rapidly expand into multiple clinical studies within one or multiple countries, where the most appropriate way to support the program is by having multiple laboratories perform ADA sample analysis. In addition, there may be certain country-specific challenges that may make it infeasible to transport samples outside of the country for analysis. China for example has a lengthy sample exportation process that has potential to negatively impact study timelines. If multiple laboratories analyze samples using the same ADA method, comparable method performance should be established. Here, we describe a three-way assessment of ADA assay comparability between two US-based bioanalytical laboratories and one based in China.

Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study.

Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double-blind, 2-sequence crossover, sequential 2-stage study (ISRCTN59409907), single intravenous (IV) doses of 1st- and 2nd-generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd- compared to the 1st-generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st- and 2nd-generation drug products, and antidrug antibody (ADA) was not observed in this study.

Quality assessment of a rural population-based cancer registry (PBCR) at Ratnagiri, Maharashtra, India for the years 2017-18.

Background: Cancer registries are valuable resources for cancer control and research. To justify their purpose, their data should be of satisfactory quality by being comparable internationally, complete in their coverage, valid in their values and timely in reporting. This study aimed to assess the quality of the Ratnagiri Population Based Cancer Registry's data for the years 2017-18 across the four dimensions of data quality. Methods: Regarding comparability, the registry procedure was reviewed vis-à-vis the rules they follow for cancer registry operation. We have used four methods for validity: re-abstraction and re-coding, diagnostic criteria methods- like the percentage of microscopically verified (MV%) and of death certificate only (DCO%) cases, missing information like proportion of cases of primary site unknown (PSU%) and internal validity. Semi-quantitative methods were employed for assessing completeness. Timeliness for all years of registry functioning was assessed qualitatively. Results: The overall accuracy rate of the registry was found to be 91.1% (94.7% for demographic and 88% for tumour details). Mortality to incidence ratios were found to be 0.50 for females and 0.59 for males. MV% was found to be 90.8% for males and 91.5% for females. The average number of sources per case was found to be 1.5. DCO% was found to be 2.7%. PSU% was 7.4%. Conclusion: We have positive results regarding the data's validity and comparability, but there is scope for improvement concerning completeness. Continuous training of the registry personnel and monitoring of the registry is recommended.

Painful differences between different pain scale assessments: The outcome of assessed pain is a matter of the choices of scale and statistics.

OBJECTIVES: Perceived pain is a multi-factorial subjective variable, commonly measured by numeric rating scales, verbal descriptive scales (VDS), or by a position on an analogue line (VAS). A major question is whether an individual's VAS and VDS pain assessments, on the same occasion, could be comparable. The aim was to compare continuous and discretized VAS pain data with verbal descriptive pain datasets from the Oswestry Disability Index (ODI) and the European Quality of Life Scale (EQ-5D) in paired pain datasets. METHODS: The measurement level of data from any type of scale assessments is ordinal, having rank-invariant properties only. Non-parametric statistical methods were used. Two ways of discretizing the VAS-line to VAS-intervals to fit the number of the comparing VDS-categories were used: the commonly used (equidistant VAS,VDS)-pairs and the (unbiased VAS,VDS)-pairs of pain data. The comparability of the (VAS,VDS)-pairs of data of perceived pain was studied by the bivariate ranking approach. Hence, each pair will be regarded as ordered, disordered, or tied with respect to the other pairs of data. The percentage agreement, PA, the measures of disorder, D, and of order consistency, MA, were calculated. Total interchangeability requires PA = 1 and MA = 1. RESULTS: The wide range of overlapping of (VAS,VDS)-pairs indicated that the continuous VAS data were not comparable to any of the VDS pain datasets. The percentage of agreement, PA; in the (equidistant VAS,ODI) and (equidistant VAS, EQ-5D) pairs were 38 and 49%, and the order consistency, MA, was 0.70 and 0.80, respectively. Corresponding results for the (unbiased VAS,VDS)-pairs of pain data were PA: 54 and 100%, and MA: 0.77 and 1.0. CONCLUSION: Our results confirmed that perceived pain is the individual's subjective experience, and possible scale-interchangeability is only study-specific. The pain experience is not possible to be measured univocally, but is possible for the individual to rate on a scale.

Cognitive Science From the Perspective of Linguistic Diversity.

This letter addresses two issues in language research that are important to cognitive science: the comparability of word meanings across languages and the neglect of an integrated approach to writing systems. The first issue challenges generativist claims by emphasizing the importance of comparability of data, drawing on typologists' findings about different languages. The second issue addresses the exclusion of diverse writing systems from linguistic investigation and argues for a more extensive study of their effects on language and cognition. We argue for a refocusing of cognitive science research on linguistic diversity in all modalities to develop the most robust understanding of language and its role in human cognition more broadly.

Patient-centric Comparability Assessment of Biopharmaceuticals.

The comparability assessment of a biological product after implementing a manufacturing process change should involve a risk-based approach. Process changes may occur at any stage of the product lifecycle: early development, clinical manufacture for pivotal trials, or post-approval. The risk of the change to impact product quality varies. The design of the comparability assessment should be adapted accordingly. A working group reviewed and consolidated industry approaches to assess comparability of traditional protein-based biological products during clinical development and post-approval. The insights compiled in this review article encompass topics such as a risk-evaluation strategy, the design of comparability studies, definition of assessment criteria for comparability, holistic evaluation of data, and the regulatory submission strategy. These practices can be leveraged across the industry to help companies in design and execution of comparability assessments, and to inform discussions with global regulators.

The comparability tales: A phase-appropriate roadmap for CGT drug product development.

Cell and gene therapies (CGTs) have revolutionized patient outcomes and provided care options for previously untreatable conditions. The clinical and commercial progress of CGT therapies is hindered by chemistry, manufacturing, and control (CMC) challenges. This article summarizes recommendations from the 2023 Annual Meeting CMC sessions wherein speakers advocated for science-driven comparability strategies, proactive risk assessments, clearer regulatory guidance, and a shift from retrospective to prospective studies. Planning for manufacturing changes, statistical approaches, and consideration of multiple product versions also emerged as crucial elements to help sponsors navigate CMC hurdles for successful CGT clinical and commercial development.

Best Practices for the Electronic Implementation and Migration of Patient-Reported Outcome Measures.

While the use of electronic methods to collect patient-reported outcome data in clinical trials continues to increase, it remains the case that many patient-reported outcome measures (PROMs) have originally been developed and validated on paper. Careful consideration during the move from paper PROMs to electronic format is required to preserve the integrity of the measure and ensure a "faithful migration." Relevant literature has long called out the importance of following migration best practices during this process; nevertheless, such best practices are distributed across multiple documents. This article consolidates and builds upon existing electronic PROM implementation best practice recommendations to provide a comprehensive, up-to-date, single point of reference. It reflects the current consensus based on the significant advances in technology capabilities and knowledge gleaned from the growing evidence base on electronic migration and implementation, to balance the need for maintaining the integrity of the measure while optimizing respondent usability. It also specifies whether the practice is rooted in evidence or expert consensus, to enable those using these best practices to make informed and considered decisions when conducting migration.

A survey of FDA Approved Monoclonal Antibodies and Fc-fusion Proteins for Manufacturing Changes and Comparability Assessment.

OBJECTIVE: Manufacturing changes occur commonly throughout stages of biologics development and may result in product quality attribute changes. As changes in critical quality attributes have the potential to affect clinical safety and efficacy of products, it is imperative to ensure the quality and clinical performance before introducing the after-change products. Thus, we embarked on this project to understand what data have supported the manufacturing changes for licensed products with pre- and post-approval changes. METHODS: We surveyed the manufacturing changes of 85 monoclonal antibodies and 10 Fc fusion proteins approved by the Food and Drug Administration as of December 25, 2021. After collecting the type and timing of changes for these products, we investigated the approaches that provided supporting data for the changes. The source documents included reports submitted by applicants and FDA's regulatory reviews. RESULTS: Analytical comparability was assessed to support all identified manufacturing changes. Supporting clinical data were available in 92% of these manufacturing changes; including data from pharmacokinetic comparability studies alone (3%), other studies on efficacy or safety (70%) and a combination of both (19%). Clinical pharmacokinetic comparability data contributed to supporting substantial changes, such as host cell type or master cell bank changes, concentration or formulation changes, and changes from pre-filled syringes to autoinjectors, especially when introduced after completing pivotal studies. CONCLUSION: Our comprehensive retrospective analysis provides an understanding of the regulatory experience and industry practice, which could facilitate developing appropriate comparability approaches to support manufacturing changes in the future.