Regulatory Expectations Research Articles

Proceedings of the 2017 Viral Clearance Symposium, Session 2.1: DSP Unit Operations-Virus Filtration/Inactivation.

The manufacturing processes of biological medicinal products are expected to be capable of removing and/or inactivating viruses, to primarily provide for adequate safety margins to patients and to thus satisfy the corresponding regulatory expectations. To achieve this goal, process segments specifically dedicated to the task of virus removal or inactivation are designed into manufacturing flows. The state of the art now includes virus removal by nanofiltration, and the more traditional low pH or (solvent-) detergent treatments are used widely, often to provide for two complementary and mechanically different means of virus clearance. Reflective of these process preferences, the virus-filtration/-inactivation session included seven case studies on virus filtration, and one each for a detergent and a low pH treatment.LAY ABSTRACT: To enhance virus clearance capacity, manufacturing processes of therapeutic proteins include process steps dedicated to virus clearance, especially virus-retentive filtration and virus inactivation. This article summarizes the current understanding of process preferences for the said process steps.

Overcoming Challenges Associated with The Bioanalysis of an Ester Prodrug and its Active Acid Metabolite

Bioanalysis of ester prodrugs represents a great analytical challenge due to poor matrix stability in the presence of esterases. Materials& methods: An approach that includes pH control, temperature and the use of an inhibitor (sodium fluoride, NaF) was employed for complete stabilization of an ester prodrug and its corresponding acid metabolite. Stability information was used to design a methodology with negligible ex vivo hydrolysis of the ester to the corresponding acid analyte during all critical parts of bioanalysis. Results&conclusion: The assay was fully validated to regulatory expectations and employed to support a preclinical Good Laboratory Practice study in rats. Incurred sample reanalysis was also conducted and the percent difference between repeat and original results were within±20%, thus confirming the repeatability of the assay.

Regulatory Expectations of Offended Audiences: The Citizen Interest in Audience Discourse

In this article we analyze fieldwork with 90 people in the UK and Germany, exploring the expectations audiences articulate about regulatory processes behind television content they find offensive. First, mapping people’s responses on to the conceptual pairing of citizens and consumers, we find audiences aligning themselves with citizen interests, even when, often on the surface, they respond to media regulation and institutions with suspicion. Second, we find that complaints that make it to media regulators are just the tip of iceberg. Third, in investigating people’s expectations of actors and institutions in their responses to television content that startles, upsets, or just offends them, we note that it is crucial to treat a conversation on free speech and censorship with caution.

Assessing the satisfaction and burden within an academic animal care and use program.

Although animal research requires adherence to various regulations and standards, the manner in which compliance is maintained and the degree of additional constraints varies between institutions. Regulatory burden, particularly if institutionally imposed, has become a concern for institutions as increased regulatory expectations result in decreased resources available for research efforts. Faculty, research staff, and support staff engaged in animal research were surveyed to determine what institutional animal care and use committee (IACUC) processes were considered burdensome, the perceived value of some suggested modifications, and satisfaction with the IACUC administrative office and the animal resource unit. Although the results revealed overwhelming satisfaction with the IACUC administrative office and the animal resource unit, several IACUC processes were deemed burdensome, and therefore there would be value in modifying IACUC processes. When comparing the value of modifying IACUC processes, different groups within the animal care and use program (ACUP) tended to have different responses on many of the topics. This survey identified several perceived burdensome IACUC processes that would likely benefit individuals if modified. In today's environment of shrinking budgets for biomedical research, minimizing regulatory burden-particularly unnecessary, self-imposed burden-in the ACUP is particularly important to ensure that costs, time, and effort are appropriate to achieve animal welfare and quality of research endeavors.-Norton, J. N., Reynolds, R. P., Chan, C., Valdivia, R. H., Staats, H. F. Assessing the satisfaction and burden within an academic animal care and use program.

Dealing with politically exposed persons: Navigating the changing regulatory environment

The increased risk posed by dealings with politically exposed persons (PEPs) will already be well known to regulated firms. Although regulators have been keen to emphasise the need to manage this risk, clear and detailed guidance on exactly how firms must do so has been harder to come by. New regulatory requirements will bring the practical challenges involved in dealing with PEPs into sharper focus. This paper provides an overview of the current PEPs regime and highlights forthcoming changes at both the EU and UK level. We examine, in particular, the proposed changes to the UK PEP regime, aimed at promoting a risk-based approach to this category of customers. We also provide an overview of the practical compliance steps that firms should consider taking in relation to PEPs in order to ensure that they are meeting regulatory expectations.

Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals

Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufacturing. The fate of this emerging technology will rely, in large part, on the regulatory implementation of this novel technology. This paper, which is based on the 2nd International Symposium on the Continuous Manufacturing of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufacturing of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufacturing. Collaborative efforts, among academia, industry, and regulatory agencies, are the optimal solution for ensuring a solid future for this promising manufacturing technology.

Recommendations of the Oligonucleotide Safety Working Group's Formulated Oligonucleotide Subcommittee for the Safety Assessment of Formulated Oligonucleotide-Based Therapeutics.

The use of lipid formulations has greatly improved the ability to effectively deliver oligonucleotides and has been instrumental in the rapid expansion of therapeutic development programs using oligonucleotide drugs. However, the development of such complex multicomponent therapeutics requires the implementation of unique, scientifically sound approaches to the nonclinical development of these drugs, based upon a hybrid of knowledge and experiences drawn from small molecule, protein, and oligonucleotide therapeutic drug development. The relative paucity of directly applicable regulatory guidance documents for oligonucleotide therapeutics in general has resulted in the generation of multiple white papers from oligonucleotide drug development experts and members of the Oligonucleotide Safety Working Group (OSWG). The members of the Formulated Oligonucleotide Subcommittee of the OSWG have utilized their collective experience working with a variety of formulations and their associated oligonucleotide payloads, as well as their insights into regulatory considerations and expectations, to generate a series of consensus recommendations for the pharmacokinetic characterization and nonclinical safety assessment of this unique class of therapeutics. It should be noted that the focus of Subcommittee discussions was on lipid nanoparticle and other types of particulate formulations of therapeutic oligonucleotides and not on conjugates or other types of modifications of oligonucleotide structure intended to facilitate delivery.

OIL SPILL PREPAREDNESS ASSURANCE IN A POST MACONDO WORLD

ABSTRACT The increased public awareness of oil spills and their impacts following the 2010 Macondo oil spill incident along with the changing global landscape of regulatory requirements and stakeholder expectations present numerous challenges to operators. Many of these challenges, as well as incorporation of lessons learned from Macondo, can be addressed through robust preparedness. Oil spill preparedness programs generally include a combination of response plans, incident management and response teams, response equipment and personnel (resources), training and exercises. However, what constitutes a robust preparedness program is often open to interpretation. While acknowledging the availability of a few preparedness assessment/audit tools, such as RETOS, it was felt a fit for purpose assurance program that facilitated open communication, free exchange of ideas and sharing of best practices would result in a greater overall improvement to the company’s global level of preparedness. Consequently, ConocoPhillips retained Oil Spill Response Ltd. (OSRL) to assist in developing a process and methodology for evaluating ConocoPhillips’ existing oil spill preparedness programs. The evaluations were conducted at nine business units (BUs) in various countries whose operations ranged from deepwater exploration and production to onshore production to tanker operations. The main objective of this project was to achieve a high and consistent level of global preparedness through the identification of potential gaps in each BU’s preparedness program and implementation of associated improvement plans. The preparedness assurance process consisted of several components including:Detailed review of the oil spill/emergency response plans to evaluate contents and identify improvement opportunities and best practices.Evaluation of each BU’s Incident Management and Emergency Response Team size, structure, competency and lines of communication and coordinationEvaluation and validation of training and exercise programsEvaluation of Tiers 1, 2 and 3 response resource availability including dispersant stockpiles The results of the evaluations were shared with the BU emergency response leads and management and an improvement plan developed to address any identified gaps. Upon completion of the program, a report was prepared summarizing the preparedness evaluation results for each BU, highlighting best practices identified during the evaluations and providing a general assessment of what “good” looks like. This report was then shared with all BUs to, along with the individual improvement plans, enhance consistency and the level of spill preparedness across the company. The primary objective of this paper is to explain the assurance process that was developed, share key lessons learned during the implementation and provide a summary of the general findings such that it can provide a blue-print for use by other companies to inform the development of similar oil spill preparedness assurance programs.

Multivariate Analysis and Statistics in Pharmaceutical Process Research and Development.

The application of statistics in pharmaceutical process research and development has evolved significantly over the past decades, motivated in part by the introduction of the Quality by Design paradigm, a landmark change in regulatory expectations for the level of scientific understanding associated with the manufacturing process. Today, statistical methods are increasingly applied to accelerate the characterization and optimization of new drugs created via numerous unit operations well known to the chemical engineering discipline. We offer here a review of the maturity in the implementation of design of experiment techniques, the increased incorporation of latent variable methods in process and material characterization, and the adoption of Bayesian methodology for process risk assessment.

Organizational strategies in the context of legitimacy loss: Radical versus gradual responses to disclosed corruption

How do organizations respond to the loss of legitimacy in the context of disclosed corruption, and what drives the particular responses adopted? In this article, we study the organizational strategies of three multinational companies before, during, and after legitimacy loss due to disclosed organizational corruption. We explore why some multinational companies exceed regulatory expectations and choose radical strategies that substantially influence their environment by defining a new benchmark of anti-corruption practices, while others follow a more gradual approach. We build on the concept of legitimacy in institutional theory and focus on three strategies that organizations tend to adopt to regain legitimacy: isomorphic adaptation, moral reasoning, and strategic manipulation. Based on our empirical study, we suggest that when a transgression is accompanied by a strong legitimacy shock, transgressors are likely to see no alternative but to react both radically and instantly. We identify two distinct extremes of strategic manipulation: decoupling and substantial influence.

Opportunities to Apply the 3Rs in Safety Assessment Programs.

Before a potential new medicine can be administered to humans it is essential that its safety is adequately assessed. Safety assessment in animals forms an integral part of this process, from early drug discovery and initial candidate selection to the program of recommended regulatory tests in animals. The 3Rs (replacement, reduction, and refinement of animals in research) are integrated in the current regulatory requirements and expectations and, in the EU, provide a legal and ethical framework for in vivo research to ensure the scientific objectives are met whilst minimizing animal use and maintaining high animal welfare standards. Though the regulations are designed to uncover potential risks, they are intended to be flexible, so that the most appropriate approach can be taken for an individual product. This article outlines current and future opportunities to apply the 3Rs in safety assessment programs for pharmaceuticals, and the potential (scientific, financial, and ethical) benefits to the industry, across the drug discovery and development process. For example, improvements to, or the development of, novel, early screens (e.g., in vitro, in silico, or nonmammalian screens) designed to identify compounds with undesirable characteristics earlier in development have the potential to reduce late-stage attrition by improving the selection of compounds that require regulatory testing in animals. Opportunities also exist within the current regulatory framework to simultaneously reduce and/or refine animal use and improve scientific outcomes through improvements to technical procedures and/or adjustments to study designs. It is important that approaches to safety assessment are continuously reviewed and challenged to ensure they are science-driven and predictive of relevant effects in humans.

The Promise of New Technologies to Reduce, Refine, or Replace Animal Use while Reducing Risks of Drug Induced Liver Injury in Pharmaceutical Development.

Drug induced liver injury (DILI) has contributed more to marketed pharmaceutical withdrawals and clinical development failures than any other human organ toxicity. DILI seen in animal studies also frequently leads to the discontinuation of promising drug candidates very early in the pipeline. This manuscript reviews and critically assesses the current regulatory expectations; the current drug development approaches, strategies, and gaps; and the numerous exciting opportunities becoming available to address these gaps through technological advances. Emerging integrated pharmaceutical development strategies, while far from uniform, have generally evolved to currently inform early DILI risk potential using supplemental assays for reactive metabolite formation, mitochondrial toxicity, inhibition of bile salt transport, and cellular imaging endpoints including cytotoxicity. Despite these approaches and robust animal testing, significant gaps in addressing human DILI remain. Increasingly sophisticated in vitro humanized test systems, new animal models, emerging computational models, and novel translational biomarkers are being introduced to improve our ability to more accurately predict DILI. Expectations are high for a future state with more predictive tools and problem solving strategies that will improve pharmaceutical discovery and development in relation to understanding human DILI risk potential and make it less dependent on animal studies for successfully developing safer drug candidates.

Precision Medicine, Diabetes, and the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration (FDA) has long sought to achieve the broader use of personalized medicine, which is better targeting of FDA-approved therapies through incorporating precise knowledge of a patient's underlying condition to therapies optimally chosen to match those needs. While some strides have been made in precision medicine-particularly in oncology and rare genetic diseases-most of the standard general medicine indications have yet to realize the benefits of precision-guided therapies. This includes those for diabetes mellitus (DM), both type 1 and type 2. Although the scientific and regulatory considerations needed to move to a more "precise" future of DM prevention and treatment differ between the two disease subsets, scientific advances in both must occur before the FDA can incorporate precision medicine into its oversight of DM drug development and approval. This article provides an overview of the regulatory expectations and challenges in realizing a future where the therapeutics for DM are informed by precise knowledge of a patient's genetics and specific phenotype.

Design of a strong cation exchange methodology for the evaluation of charge heterogeneity in glatiramer acetate

Complex pharmaceuticals are in demand of competent analytical methods able to analyze charge heterogeneity as a critical quality attribute (CQA), in compliance with current regulatory expectations. A notorious example is glatiramer acetate (GA), a complex polypeptide mixture useful for the treatment of relapsing-remitting multiple sclerosis. This pharmaceutical challenges the current state of analytical technology in terms of the capacity to study their constituent species. Thus, a strong cation exchange methodology was designed under the lifecycle approach to support the establishment of GA identity, trough the evaluation of its chromatographic profile, which acts as a charge heterogeneity fingerprint. In this regard, a maximum relative margin of error of 5% for relative retention time and symmetry factor were proposed for the analytical target profile. The methodology met the proposed requirements after precision and specificity tests results, the former comprised of sensitivity and selectivity. Subsequently, method validation was conducted and showed that the method is able to differentiate between intact GA and heterogeneity profiles coming from stressed, fractioned or process-modified samples. In summary, these results provide evidence that the method is adequate to assess charge heterogeneity as a CQA of this complex pharmaceutical.

Regulatory Forum Opinion Piece: Review-Toxicological Pathology Profile and Regulatory Expectations for Nonclinical Development of Insulins and Insulin Analogues.

The toxicological profile of insulins is exclusively due to exaggerated pharmacology resulting in hypoglycemic findings. Insulin analogues displaying modifications and aimed at improving pharmacokinetics do not induce different toxicity. The main target is the brain displaying neuronal necrosis. Wallerian degeneration of nerves occurs rarely after severe hypoglycemia. These findings are of potential human relevance; nevertheless, these changes are induced in normoglycemic animals whereas diabetic patients suffer from hyperglycemia. Therefore, it is usually not difficult to achieve a therapeutic window for subsequent use in patients. Based upon this and in the absence of classical toxicity, there has been no scientific need for diabetic animal models. A greater challenge is the mitogenicity already inherent with regular insulin. Thus, the focus for preclinical safety evaluation of analogues is to demonstrate that modifications in regular insulin do not result in enhanced mitogenicity. The approaches used to assess the mitogenic potential of insulin analogues have changed over time driven by scientific progression and changes within the regulatory environment. Therefore, in vitro and in vivo evaluation of cell proliferation has become common practice, and to date there has been no evidence that the mitogenic potential of insulin analogues may be increased compared to regular insulin.

Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency

Good Clinical Practice (GCP) is an international standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials. The goal of GCP is to ensure the protection of the rights, integrity, and confidentiality of clinical trial participants and to ensure the credibility and accuracy of data and reported results. In the United States, trial sponsors generally require investigators to complete GCP training prior to participating in each clinical trial to foster GCP and as a method to meet regulatory expectations (ie, sponsor’s responsibility to select qualified investigators per 21 CFR 312.50 and 312.53(a) for drugs and biologics and 21 CFR 812.40 and 812.43(a) for medical devices). This training requirement is often extended to investigative site staff, as deemed relevant by the sponsor, institution, or investigator. Those who participate in multiple clinical trials are often required by sponsors to complete repeated GCP training, which is unnecessarily burdensome. The Clinical Trials Transformation Initiative convened a multidisciplinary project team involving partners from academia, industry, other researchers and research staff, and government to develop recommendations for streamlining current GCP training practices. Recommendations drafted by the project team, including the minimum key training elements, frequency, format, and evidence of training completion, were presented to a broad group of experts to foster discussion of the current issues and to seek consensus on proposed solutions.

Information Frictions in Uncertain Regulatory Environments: Evidence from U.S. Commercial Banks

AbstractInformation frictions between firms and regulators are typically seen as a means by which firms evade enforcement. In contrast, we argue that information frictions between firms and regulators can reduce the efficiency of firms’ compliance efforts when the interpretation of regulatory standards is uncertain. We exploit plausibly exogenous variation in distance between firms and their regulators to demonstrate this for a panel of community banks in the US. We find that banks located at greater distance from regulatory field offices face significantly higher administrative costs, at a rate of 20% of administrative costs per hour of travel time. These differences do not come with reduced compliance, are not driven by endogenous regulator choice, and are stable over time. Further, the costs borne by distant firms are negatively related to the scale of the jurisdiction in which they operate, suggesting that information spillovers between firms limit uncertainty about regulatory expectations.

Payment Reform: Unprecedented and Evolving Impact on Gynecologic Oncology

With the signing of the Medicare Access and CHIP Reauthorization Act in April 2015, the Centers for Medicare and Medicaid Services (CMS) is now positioned to drive the development and implementation of sweeping changes to how physicians and hospitals are paid for the provision of oncology-related services. These changes will have a long-lasting impact on the sub-specialty of gynecologic oncology, regardless of practice structure, physician employment and compensation model, or local insurance market. Recently, commercial payers have piloted various models of payment reform via oncology-specific clinical pathways, oncology medical homes, episode payment arrangements, and accountable care organizations. Despite the positive results of some pilot programs, adoption remains limited. The goals are to eliminate unnecessary variation in cancer treatment, provide coordinated patient-centered care, while controlling costs. Yet, meaningful payment reform in oncology remains elusive. As the largest payer for oncology services in the United States, CMS has the leverage to make cancer services more value based. Thus far, the focus has been around pricing of physician-administered drugs with recent work in the area of the Oncology Medical Home. Gynecologic oncology is a unique sub-specialty that blends surgical and medical oncology, with treatment that often involves radiation therapy. This forward-thinking, multidisciplinary model works to keep the patient at the center of the care continuum and emphasizes care coordination. Because of the breadth and depth of gynecologic oncology, this sub-specialty has both the potential to be disrupted by payment reform as well as potentially benefit from the aspects of reform that can align incentives appropriately to improve coordination. Although the precise future payment models are unknown at this time, focused engagement of gynecologic oncologists and the full care team is imperative to assure that the practice remains patient centered, embodies the highest quality in research and education, yet transforms into a sustainable and agile sub-specialty to pro-actively and effectively manage the immense and relentless financial pressures and regulatory expectations that will be faced over the next decade.

Assessing Asthma Symptoms in Adolescents and Adults: Qualitative Research Supporting Development of the Asthma Daily Symptom Diary

BackgroundDespite the widespread availability of patient-reported asthma questionnaires, instruments developed in accordance with present regulatory expectations are lacking. To address this gap, the Patient-Reported Outcome (PRO) Consortium’s Asthma Working Group has developed a patient-reported asthma daily symptom diary (ADSD) for use in clinical research to assess outcomes and support medical product labeling claims in adults and adolescents with asthma. ObjectivesTo summarize the qualitative research conducted to inform the initial development of the ADSD and to provide evidence for content validity of the instrument in accordance with the Food and Drug Administration’s PRO Guidance. MethodsResearch informing the initial development and confirming the content validity of the ADSD is summarized. This comprised a review of published qualitative research, semi-structured concept elicitation interviews (n = 55), and cognitive interviews (n = 65) with a diverse and representative sample of adults and adolescents with a clinician-confirmed diagnosis of asthma in the United States to understand the asthma symptom experience and to assess the relevance and understanding of the newly developed ADSD. ResultsFrom the qualitative literature review and concept elicitation interviews, eight core asthma symptoms emerged. These were broadly categorized as breathing symptoms (difficulty breathing, shortness of breath, and wheezing), chest symptoms (chest tightness, chest pain, and pressure/weight on chest), and cough symptoms (cough and the presence of mucus/phlegm). Conceptual saturation was achieved and differences in the experience of participants according to socio-demographic or clinical characteristics were not observed. Subsequent testing of the ADSD confirmed participant relevance and understanding. ConclusionsThe ADSD is a new patient-reported asthma symptom diary developed in accordance with the Food and Drug Administration’s PRO Guidance. Evidence to date supports the content validity of the instrument. Item performance, reliability, and construct validity will be assessed in future quantitative research.

Development of a Symptom-Based Patient-Reported Outcome Instrument for Functional Dyspepsia: A Preliminary Conceptual Model and an Evaluation of the Adequacy of Existing Instruments.

ObjectivesThe aim was to document, from the perspective of the empirical literature, the primary symptoms of functional dyspepsia (FD), evaluate the extent to which existing questionnaires target those symptoms, and, finally, identify any missing evidence that would impact the questionnaires’ use in regulated clinical trials to assess treatment efficacy claims intended for product labeling.MethodsA literature review was conducted to identify the primary symptoms of FD and existing symptom-based FD patient-reported outcome (PRO) instruments. Following a database search, abstracts were screened and articles were retrieved for review. The primary symptoms of FD were organized into a conceptual model and the PRO instruments were evaluated for conceptual coverage as well as compared against evidentiary requirements presented in the FDA’s PRO Guidance for Industry.ResultsFifty-six articles and 16 instruments assessing FD symptoms were reviewed. Concepts listed in the Rome III criteria for FD (n = 7), those assessed by existing FD instruments (n = 34), and symptoms reported by patients in published qualitative research (n = 6) were summarized in the FD conceptual model. Except for vomiting, all of the identified symptoms from the published qualitative research reports were also specified in the Rome III criteria. Only three of the 16 instruments, the Dyspepsia Symptom Severity Index (DSSI), Nepean Dyspepsia Index (NDI), and Short-Form Nepean Dyspepsia Index (SF-NDI), measure all seven FD symptoms defined by the Rome III criteria. Among these three, each utilizes a 2-week recall period and 5-point Likert-type scale, and had evidence of patient involvement in development. Despite their coverage, when these instruments were evaluated in light of regulatory expectations, several issues jeopardized their potential qualification for substantiation of a labeling claim.ConclusionsNo existing PRO instruments that measured all seven symptoms adhered to the regulatory principles necessary to support product labeling. As such, the development of a new FD symptom PRO instrument is supported.