Search

Abstract: Aims: Patient-reported outcomes (PROs) have recently gained greater credibility with regulatory bodies aiming to standardise their use and interpretation in RCTs, thereby supporting medicinal product submissions. For this reason, the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have released guidelines. This review paper provides an overview of the current perspectives and views on these guidelines. Method: To evaluate the FDA and EMEA PRO guidelines, 47 expert responses to the FDA guidance were qualitatively reviewed. Two reviewers independently extracted data from these letters and checked these responses to warrant consistency and agreement in the evaluation process. A PubMed literature review was systematically examined to obtain supporting evidence or related articles for both the guidance documents. Results: Generally, there is agreement between regulatory authorities and the research community on the contents of the FDA and EMEA PRO draft guidance. However, disagreements exist on significant philosophical topics (e.g. the FDA focuses more on conceptual models and symptoms than the EMEA) and design topics (e.g. the FDA is more restrictive on issues of recall bias, blinding of oncology trials and degrees of psychometric validation than researchers and the EMEA). This could influence the approval of PRO claims. Conclusion: PRO guidance from the EMEA and FDA has been valuable, and has raised the profile and active debate of PROs in oncology. However, our review of the current opinion shows that there are controversial aspects of the guidance. Consequently, greater latitude should be given to how the guidance is interpreted and applied. [Copyright &y& Elsevier]

This paper reviews the main tools for communicating benefit-risk medicines information to patients that are used, or could be used, by pharmaceutical regulators. One highly successful tool from the food safety sector (front-of-package traffic-light labelling) and the mental models approach (which provides a framework for developing new tools) are also reviewed as they show great promise for being usefully adapted to the pharmaceutical context. The evolution of benefit-risk medicines communication is first contextualised within the broader risk communication literature. Three distinct goals are then made explicit before critically examining the evidence for and against tools developed in the US (e.g. at the Food and Drug Administration [FDA]) and Europe (e.g. at the European Medicines Agency [EMA]). These goals are (i) sharing information (e.g. publishing clinical trial and adverse event data online); (ii) changing patients' beliefs by conveying factual knowledge (e.g. patient information leaflets and the drugs facts box); and (iii) changing behaviour (e.g. patient alert cards and warning labels). The mental models approach and traffic-light labelling, developed outside the pharmaceutical context, are then examined. Ultimately, the paper provides a helicopter view of the variety of benefit-risk communication tools that are used, or could be used, by pharmaceutical regulators in the US and Europe. [ABSTRACT FROM AUTHOR]

This special issue of Social Studies of Science centers on the topic of regulation in medicine and, in particular, on the notion of regulatory objectivity, defined as a new form of objectivity in biomedicine that generates conventions and norms through concerted programs of action based on the use of a variety of systems for the collective production of evidence. The papers in the special issue suggest ways in which the notion of regulatory objectivity can be tested, extended, revised, or superseded by more appropriate notions. They insist on the need to examine more closely clinical-therapeutic (and not just clinical-research) activities, and to pay more attention to the activities of regulatory agencies such as the US Food and Drug Administration and to standard-setting organizations. They call attention to the professional and organizational activities surrounding the mobilization of conventions for regulating clinical practices. Finally, they provide material that can help us to think about how analytical notions such as regulatory objectivity may or may not inform interventionist research projects. [ABSTRACT FROM AUTHOR]

Over the past 10 years, European pharmaceutical regulators (especially the European Medicines Agency [EMA]) have enacted a wave of transparency policies. Since 2010, the overwhelming majority have focused on releasing more scientific medicines information online and providing open access to regulatory data. Amongst other benefits, EMA expects its policies to build public trust and provide outsiders with a better understanding of regulatory decision-making. Yet, few studies have empirically examined the EMA’s transparency policies, especially on the end users of ‘transparent’ information (e.g. medical doctors or patients). This paper presents standout findings from a November 2014 survey conducted in Spain, Germany, France and the United Kingdom with a sample of 1005 general practitioners and medical specialists treating either multiple sclerosis, rheumatoid arthritis, osteoporosis, idiopathic pulmonary fibrosis or HIV/AIDS. The study found that 76% of respondents think it is a bad idea to release information into the public domain before possible safety issues have been investigated by the regulators and (relevant) pharmaceutical company. The results also suggested that medical doctors in Europe have a poor understanding of pharmaceutical regulatory activities. In particular, the majority were largely unaware of the current activities of the EMA, did not have good knowledge of how the regulators assess the safety of medicines (e.g. only 17% said they had good knowledge of how EMA assess the safety of medicines) and were unfamiliar with regulatory documents frequently used by regulators and industry to discuss the safety of medicines (e.g. in approving a medicine). [ABSTRACT FROM PUBLISHER]

Therapeutic use of an unauthorised drug (or of an authorised drug for an unauthorised indication) for patients with a life-threating disease is permitted outside a clinical trial as an Expanded Access Programme (EAP).The regulations regarding EAPs is not the same all over the world. For example, the recommendation of the European Medicines Agency (EMA) in EU countries also includes within EAPs patients who have been treated in a clinical trial and who wish to continue the treatment. Nevertheless, the patients treated in a clinical trial could have the option of continuing treatment for an extended period in an Open-label Extension study, aimed to generate long-term data on efficacy, safety, tolerability and administration.The aims of this paper - based on the difficulties and incoherence encountered by an Italian Ethic Committee (EC) during the authorisation process of EAPs - are: understanding the origin of this misclassification by analysing differences and similarities among USA, European and Italian regulations concerning EAPs; and showing difficulties in classifying international study protocols as a consequence of the lack of harmonisation of definitions.We performed a critical review of the current USA, European and Italian regulations and we analysed some practical cases by retrieving protocols from Clinicaltrials.gov and the Italian Clinical Trials Registry (OsSC) containing in the title the keywords 'Expanded Access Programme', "'Expanded Access', 'Open-label Extension study' or 'Early Access'.We observed that the Food and Drug Administration ( FDA) definition of EAP is very clear while the EMA definition is similar to that of an Open-label Extension study. This lack of a clear definition generates misclassification and it is possible to find an EAP with an efficacy or safety endpoint; or an EAP managed as a clinical trial; or an EAP classified in Clinical Trials Registries as a phase II, III or IV clinical trial.The internationalisation of the studies requires a harmonisation on a global level of legislation and definitions to eliminate misclassification of protocols. For this reason, the authors suggest that: a) the EMA definition should be harmonised with the FDA definition of EAPs, b) European regulation, even if optional, should be adopted in a compulsory way by national regulations. Moreover, separate registries for both EAPs and clinical trials should be organised. [ABSTRACT FROM AUTHOR]

Non-inferiority trials test whether a new product is not unacceptably worse than a product already in use. This paper introduces concepts related to non-inferiority, and discusses the regulatory views of both the European Medicines Agency and the United States Food and Drug Administration. [ABSTRACT FROM AUTHOR]

The European Medicines Agency (EMEA) leads in providing regulatory guidelines to this emerging industry. While biosimilars are not yet available in the United States, as the legal and regulatory pathway is being developed there, biosimilars and other such products are marketed in other regions of the world. We reviewed the European assessment reports of biosimilars to gain insights into the current practices pertaining to the pharmacokinetic (PK) and pharmacodynamic (PD) similarity evaluations because we believe that they might help to shape the future global regulatory landscape. This paper illustrates the molecular complexity of therapeutic proteins, challenges associated with PK and PD evaluations, limitations of similarity assessment using PK and PD endpoints, and design considerations for PK and PD studies. The scope of biotechnology-derived products will be limited to therapeutic protein products, including recombinant human proteins, fusion proteins, and monoclonal antibodies. The challenges to demonstrate similarity are complex and appear to be unique to each therapeutic agent; therefore, the requirements for regulatory approval will most likely continue to be handled at a product-specific level as stipulated in current EMEA guidelines. [ABSTRACT FROM AUTHOR]

Biosimilars are defined as biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components. Biosimilars show no clinically meaningful differences in safety, purity, and potency of the product in comparison to the reference product. With the ever looming patent expiry of some major high cost biologics, biosimilar production is becoming ever more lucrative to companies. Europe (EU) set the precedent, followed by the United States (US) in early 2012, for the approval process for biosimilars. Therefore, the purpose of this paper is to explore the nature of the regulatory processes in the US and EU and to determine the requirements of each in the approval process of a biosimilar. The current Food and Drug Administration (FDA) and European Medicines Agency's (EMA) guidance documents for biosimilars were reviewed revealing a need for further clarifications, as well as specifically addressing Celltrion's and Sandoz's application for approval for the biosimilars infliximab and filgrastim, respectively. Currently, the FDA and EMA focus on comparability in terms of the clinical, pharmacokinetic (PK)/pharmacodynamic (PD), preclinical, biological activity, and physiochemical characterization results, as well as requiring a robust and consistent manufacturing process. Both the EU and US have prepared guidance documents for biosimilars that will result in biotherapeutics that are as safe and efficacious as the innovator product but the necessity exists to globally harmonize international nonproprietary naming nomenclature and clarify how the concept of pharmacovigilance, extrapolation, and interchangeability will be handled and regulated in the future. [ABSTRACT FROM AUTHOR]

The amount and type of data in regulatory submissions increases dramatically from the first-in-human clinical trials application through to the extensive dossier that is required for marketing authorization. The Pharmaceuticals and Biotechnology industries are very familiar with the requirements and expectations of Health Authorities for small molecule and biologics, but have limited experience for cell-based therapies. Fortunately, the United States Food and Drug Administration (FDA) and European Medicines agency (EMA) Committee for Advanced Therapies (CAT) have considerable experience in regulating cell therapies and have provided extensive Guidance documents for developers. The Agencies offers advice to Sponsors through a variety of meetings. However, it is incumbent on the Sponsor to understand the regulations, interpret the Guidance documents and formulate clear company positions to enable the Agency to provide clear feedback. It is important for Sponsors to understand the factors that are critical for the safety and efficacy of their product and to demonstrate to the Health Authorities that they have a control strategy that ensures safety and efficacy during all stages of development. The focus of this paper is to describe some of the challenges for the chemistry manufacturing and controls (CMC) for cell therapies being development internationally. [ABSTRACT FROM AUTHOR]

Abstract: With the introduction of specific pediatric legislation in the United States (US) and the European Union (EU) requiring the development of medicines for children the interest in juvenile animal studies (JAS) increased, but also the discussion about the value and necessity of such studies. Regulatory guidance regarding JAS is available from The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) M3(R2) guideline and from more specific guidance documents issued by the Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA). This paper summarizes and discusses the regulatory requirements regarding the need for JAS, their design and timing as well as the current experience with such studies. The relevant guidance documents as well as several authors support a case-by-case approach regarding the need for and design of JAS. JAS should be considered, especially in cases when organ systems undergoing postnatal development, like the kidney, the skeleton or the central nervous system (CNS), have been identified as toxicity target organs, as developing organ systems usually are more sensitive to toxicity than mature organs. The relevance of the findings from JAS for human use will essentially depend on an appropriate study design, especially on the choice of species as well as the age of the juvenile animal at the start of study. As the available data from JAS show, the design of JAS seems to have improved since the introduction of specific guidance documents. However, so far, there is not enough experience to finally answer the question if JAS are useful. Interpretation of the results from JAS and their extrapolation to the pediatric population is hampered by the incomplete understanding of the animal models used in these studies as well as the lack of access to existing JAS data. Further data will be necessary to ultimately clarify the need for such studies. [Copyright &y& Elsevier]

Abstract: The administration of biological therapeutics may result in the development of anti-drug antibodies (ADAs) in treated subjects. In some cases, ADA responses may result in the loss of therapeutic efficacy due to the formation of neutralizing ADAs (NAbs). An important characteristic of anti-drug NAbs is their direct inhibitory effect on the pharmacological activity of the therapeutic. Neutralizing antibody responses are of particular concern for biologic products with an endogenous homolog whose activity can be potentially dampened or completely inhibited by the NAbs leading to an autoimmune-type deficiency syndrome. Therefore, it is important that ADAs are detected and characterized appropriately using sensitive and reliable methods. The design, development and optimization of cell-based assays used for detection of NAbs have been published previously by Gupta et al. 2007 . This paper provides recommendations on best practices for the validation of cell-based NAb assay and suggested validation parameters based on the experience of the authors. [Copyright &y& Elsevier]

The article focuses on the draft guidance released by the U.S. Food and Drug Administration (FDA) for adaptive designs. According to the draft guidance, adaptive designs refer to research that contains a planned opportunity for modification of specified aspects of the field. The European Medicines Agency (EMEA) defines adaptive design as adaptive if statistical methodology permits the design element modification. It adds that the guidance provides useful framework for the types of adaptations.

Abstract: To identify key challenges and propose technical considerations in designing electronic case report form (eCRF) for post-marketing studies, the author undertakes a comprehensive literature review of peer reviewed and grey literature to assess the key aspects, processes, standards, recommendations, and best practices in designing eCRFs based on industry experience in designing and supporting electronic data capture (EDC) studies. Literature search using strings on MEDLINE and PUBMED returned few papers directly related to CRF design. Health informatics and general practice journals were searched and results reviewed. Many conference, government commission, health professional and special interests group websites provide relevant information from practical experience — summarization of this information is presented. Further, we presented a list of concrete technical considerations in dealing with EDC technology/system limitations based on literature assessment and industry implementation experience. It is recognized that cross-functional teams be involved in eCRF design process and decision making. To summarize the keys in designing eCRFs to address post-market study safety and pharmacovigilance needs, the first is to identify required data elements from the study protocol supporting data analyses and reporting requirements. Secondly, accepted best practices, CDASH & CDISC guidelines, and company internal or therapeutic unit standard should be considered and applied. Coding (MedDRA & WHODD) mapping should be managed and implemented as well when possible. Finally, we need to be on top of the EDC technologies, challenge the technologies, drive EDC improvement via working with vendors, and utilize the technologies to drive clinical effectiveness. [Copyright &y& Elsevier]

Maraviroc (Pfizers UK-427857, Selzentry or Celsentri outside the USA) is the first agent in the new class of oral HIV-1 entry inhibitors to acquire approval by the US Food and Drug Administration and the European Medicine Agency. Considering the mechanism of action, it is expected that this drug will be effective only in a subpopulation of HIV-1-infected people, namely those harbouring the R5 virus. The favourable toxicity profile of the drug has been demonstrated in Phase III clinical trials in treatment-naive (MERIT) and treatment-experienced (MOTIVATE) patients. In the latter population, maraviroc showed a superior antiviral efficacy and immunological activity compared with optimized backbone therapy placebo. However, in MERIT, a prospective double-blind, randomized trial in treatment-naive patients, maraviroc zidovudine/lamivudine failed to prove non-inferiority to efavirenz zidovudine/lamivudine as standard of care regimen in the 48 week intention-to-treat analysis. Using an assay with higher sensitivity for minority CXCR4-using (X4) HIV variants (the enhanced Trofile™ assay—Monogram), non-inferiority was reached for the maraviroc- versus efavirenz-based combination. These data indicate the important impact of the sensitivity of tropism testing on treatment outcome of maraviroc-containing regimens. This paper discusses both the prospective and retrospective analyses of the MERIT data and highlights the impact of these results on daily practice in HIV care. [ABSTRACT FROM AUTHOR]

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics. [ABSTRACT FROM AUTHOR]

Background and Purpose: Therapeutic area guidelines (TAGs) published by the EMA and the FDA offer guidance in planning the launch of a trial in a certain indication. We assessed and compared the guidance on preclinical efficacy of all available TAGs from EMA and FDA.Experimental Approach: EMA and FDA websites and databases were searched for all TAGs. A mixed deductive and inductive approach was applied to analyse and cluster content for preclinical efficacy.Key Results: A total of 114 EMA and 120 FDA TAGs were identified, covering 126 indications. Our core finding is that 75% of EMA TAGs and 58% from the FDA TAGs do not offer any guidance on preclinical efficacy. TAGs varied widely on the extent, nature and detail of guidance.Conclusions and Implications: Guidance on preclinical efficacy in a consistent, comprehensive and explicit way that still allows for justified deviations is an important but neglected aspect of transparency for drug development. This transparency would help sponsors in designing preclinical studies and in negotiating more efficiently with regulators. [ABSTRACT FROM AUTHOR]

Background: Relenza represents the first neuraminidase inhibitor (NI), a class of drugs that also includes the drug Tamiflu. Although heralded as breakthrough treatments in influenza, NI efficacy has remained highly controversial. A key unsettled question is why the United States Food and Drug Administration (FDA) has approved more cautious efficacy statements in labelling than European regulators for both drugs.Methods: We conducted a qualitative analysis of United States and European Union regulatory appraisals for Relenza to investigate the reasons for divergent regulatory interpretations, pertaining to Relenza's capacity to alleviate symptoms and reduce frequency of complications of influenza.Results: In Europe, Relenza was evaluated via the so-called national procedure with Sweden as the reference country. We show that FDA reviewers, unlike their European (i.e. Swedish) counterpart, (1) rejected the manufacturer's insistence on pooling efficacy data, (2) remained wary of subgroup analyses, and (3) insisted on stringent statistical analyses. These differences meant that the FDA was less likely to depart from prevailing regulatory and scientific standards in interpreting trial results. We argue that the differences are explained largely by divergent institutionalised review methodologies, i.e. the European regulator's reliance on manufacturer-compiled summaries compared to the FDA's examination of original data and documentation from trials.Conclusions: The FDA's more probing and meticulous evaluative methodology allowed its reviewers to develop 'deep' knowledge concerning the clinical and statistical facets of trials, and more informed opinions regarding suitable methods for analysing trial results. These findings challenge the current emphasis on evaluating regulatory performance mainly in terms of speed of review. We propose that persistent uncertainty and knowledge deficits regarding NIs could have been ameliorated had regulators engaged in the public debates over the drugs' efficacy and explained their contrasting methodologies and judgments. Regulators use major resources to evaluate drugs, but if regulators' assessments are not effectively disseminated and used, resources are used inefficiently. [ABSTRACT FROM AUTHOR]

Scientific knowledge and our understanding of the human body and diseases have limited any possible treatment tailoring to each patient. The technological advances enabling the integration of various data sets (e.g. '-omics', microbiome, epigenetics and environmental exposure) have facilitated a greater understanding of the human body, the molecular basis of disease and all the factors influencing disease onset, progression and response to treatment, thereby ushering in the era of personalized medicine. We evaluate the regulatory approaches available to facilitate early patient access to efficacious and safe compounds in the EU and the USA in order to make more informed recommendations in the future as to the gaps in regulations for early patient access. An in-depth analysis of conditional approvals (EU) and accelerated approvals (USA) is performed based on the publicly available information (European public assessment reports and a summary review of products approved under both programmes). The types of product, indications, time to approval and type of evidence submitted were analysed. Between 2007 and early 2015, 17 products were conditionally approved in the EU and 25 in the USA, most of them in the area of oncology and based on evidence from phase II clinical trial data. Early approval of promising products based on data from early phases of development is already possible in the EU and the USA. Some of the improvements could entail implementing a rolling assessment of evidence in Europe and extending the scope of early dialogues. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Metastatic castration-resistant prostate cancer (mCRPC) and its treatment significantly affect health-related quality of life (HRQOL). Our objectives were to evaluate and compare patientreported outcome (PRO) claims granted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for 5 recently approved mCRPC treatments and to examine key characteristics, development, and measurement properties of the PRO measures supporting these claims against current regulatory standards. Methods Five products approved for treatment of mCRPC by the FDA and the EMA (2010-2013) were examined: enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and radium Ra 223 dichloride. United States (US) drug approval packages and European Public Assessment Reports were reviewed. PRO claims in the US labels and European Summaries of Product Characteristics and supporting measures were identified. For PRO measures supporting claims, a targeted literature review was conducted to identify information on key characteristics and measurement properties; this information was compared against FDA PRO guidance criteria. Results Nine PRO "claims" were granted across 4 of 5 products reviewed. The EMA granted more claims (7 claims–4 for pain, 3 for HRQOL) than the FDA (2 claims, both for pain). The Brief Pain Inventory-Short Form (BPI-SF) worst pain item supported most pain claims and was the only measure supporting US claims. EMA pain claims were supported by BPI-SF worst pain (n = 2) and average pain (n = 1) items and the McGill Pain Questionnaire Present Pain Intensity component (n = 1). EMA HRQOL claims were supported by the Functional Assessment of Cancer Therapy-Prostate Module (n = 2) and the EuroQol 5 Dimensions with visual analogue scale (n = 1). Pain and prostate cancer-specific HRQOL measures supporting claims met US regulatory standards for construct validity, reliability, and responsiveness; these properties were strongest for the BPI-SF worst pain item. Only the BPI-SF worst pain item has documented content validity in mCRPC. Conclusions PRO label claims were commonly granted across the mCRPC products reviewed. Among the measures reviewed, only the BPI-SF worst pain item supported US label claims. The BPI-SF worst pain item is recommended for pain assessment for the evaluation of new mCRPC treatments. [ABSTRACT FROM AUTHOR]

Rothmann et al. (2003) proposed a method for the statistical inference of fraction retention noninferiority (NI) hypothesis. A fraction retention hypothesis is defined as a ratio of the new treatment effect verse the control effect in the context of a time to event endpoint. One of the major concerns using this method in the design of an NI trial is that with a limited sample size, the power of the study is usually very low. This makes an NI trial not applicable particularly when using time to event endpoint. To improve power, Wang et al. (2006) proposed a ratio test based on asymptotic normality theory. Under a strong assumption (equal variance of the NI test statistic under null and alternative hypotheses), the sample size using Wang's test was much smaller than that using Rothmann's test. However, in practice, the assumption of equal variance is generally questionable for an NI trial design. This assumption is removed in the ratio test proposed in this article, which is derived directly from a Cauchy-like ratio distribution. In addition, using this method, the fundamental assumption used in Rothmann's test, that the observed control effect is always positive, that is, the observed hazard ratio for placebo over the control is greater than 1, is no longer necessary. Without assuming equal variance under null and alternative hypotheses, the sample size required for an NI trial can be significantly reduced if using the proposed ratio test for a fraction retention NI hypothesis. [ABSTRACT FROM AUTHOR]

In the US, the Biologies Price Competition and Innovation Act (BPCI Act, 2009) provided the pathway to create an abbreviated licensure procedure for biologic products that are demonstrated to be biosimilar to or interchangeable with a Food and Drug Administration (FDA) licensed biologic product. In February 2012, the FDA issued three guidelines that list the requirements for biosimilar registration. The topics covered include scientific and quality considerations to demonstrate biosimilarity to a reference product and a guidance that clarifies the BPCI Act implementation. The sponsor application for the biosimilar approval must contain biosimilarity information based on data derived from analytical, animal, and clinical studies. Clinical studies should include an assessment of immunogenicity, pharmacokinetics, pharmacodynamics, and address one or more indications licensed for the reference product. To demonstrate biosimilarity the applicant is allowed to use comparative animal or clinical data with a non-US-licensed product. According to these guidelines, the FDA will consider different aspects when evaluating biosimilarity, such as product formulation, complexity, and stability which will have a risk-based approach and will depend on the degree of knowledge of the product characteristics, as well as clinical experience with the reference one. The FDA intends to use a risk-based and facts-focused approach for review of applications of biosimilars, although it faces several challenges. Once a biologic medicine has been demonstrated to be biosimilar to the reference product, an abridged development program for the biosimilar medicine can be carried out in a similar way to that established by the European Medicines Agency (EMA). In addition, FDA legislation goes a step further than the EMA, offering the possibility to adopt full interchangeability for biosimilars. [ABSTRACT FROM AUTHOR]

Oral tissue engineering aims to treat and fill tissue deficits caused by congenital defects, facial trauma, or malignant lesion surgery, as well as to study the biology of oral mucosa. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require a large animal model to evaluate cell-based devices, including tissue-engineered oral mucosa, prior to initiating human clinical studies. Porcine oral mucosa is non-keratinized and resembles that of humans more closely than any other animal in terms of structure and composition; however, there have not been any reports on the reconstruction of a porcine oral mucosa equivalent, probably due to the difficulty to culture porcine fibroblasts. In this study, we demonstrate the feasibility of a 3D porcine oral mucosa equivalent based on a collagen-GAG-chitosan scaffold, as well as reconstructed porcine epithelium by using an amniotic membrane as support, or without any support in form of epithelial cell sheets by using thermoresponsive culture plates. Explants technique was used for the isolation of the porcine fibroblasts and a modified fibroblast medium containing 20% fetal calf serum was used for their culture. The histological and transmission electron microscopic analyses of the resulting porcine oral mucosa models showed the presence of non-keratinized epithelia expressing keratin 13, the major differentiation marker of non-keratinized oral mucosa, in all models, and the presence of newly synthesized collagen fibers in the lamina propria equivalent of the full-thickness model, indicating the functionality of porcine fibroblasts. [ABSTRACT FROM AUTHOR]

Purpose: To explore the comparative performance of the recently proposed bioequivalence (BE) approaches, FDA and EMA, by the FDA working group on highly variable drugs and the EMA, respectively; to compare the impact of the GMR-constraint on the two approaches; and to provide representative plots of % BE acceptance as a function of geometric mean ratio, sample size and variability. Methods: Simulated BE studies and extreme GMR versus CV plots were used. Three sequence, three period crossover studies with two treatments were simulated using four levels of within-subject variability. Results: The FDA and EMA approaches were identical when variability was <30%. In all other cases, the FDA method was more permissive than EMA. The major discrepancy was observed for variability values >50%. The GMR-constraint was necessary for FDA, especially for drugs with high variabilities. For EMA, the GMR-constraint only became effective when sample size was large and variability was close to 50%. Conclusions: A significant discrepancy in the performances of FDA and EMA was observed for high variability values. The GMR-constraint was essential for FDA, but it was of minor importance in case of the EMA. [ABSTRACT FROM AUTHOR]

The assessment of endometrial safety is one of the key requirements for the clinical development of new products for hormone therapy (HT) to treat menopausal symptoms in women who have a uterus. Both the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) provide detailed guidance on the requirements for the evaluation of biopsies to prove endometrial safety. However, there are some discrepancies between the European and the US requirements, making it difficult to fulfil both guidelines simultaneously. In order to facilitate multinational clinical trials performed within clinical programs to develop novel HT products, we developed an approach considering both guidance documents as far as possible and proposed solutions for issues that are inconsistently described in these guidelines. A table with the required sample sizes is given. Our recommendation for a unified approach for the estimation of the hyperplasia rate for hormone therapies fulfils the intent of the recommendations of both the FDA and the EMA and thus leads to a globally harmonized drug development for hormone therapies. [ABSTRACT FROM AUTHOR]

Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme - which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency - are discussed, and general lessons are highlighted. [ABSTRACT FROM AUTHOR]

The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts. [ABSTRACT FROM AUTHOR]

This section offers news briefs concerning the pharmaceutical industry. A U.S. Food and Drug Administration (FDA) study revealed that drug providers seem to be fulfilling their regulatory obligations and completing postmarketing surveillance (PMS) studies. Marie Lindquist has been selected as the director of the Uppsala Monitoring Centre (UMC). The European Medicines Agency (EMEA) has released reports on the priority areas for European Union (EU)-funded research into adverse drug reactions (ADRs) under the 7th Framework Programme.

The Food and Drug Administration (FDA) and European Medicines Agency (EMEA) are willing to consider including information on patient reported outcomes (PROs) in product labeling and advertising. Pharmaceutical industry researchers must provide sufficient evidence supporting PRO benefit before an approval may be granted. This report describes the purpose and content of a PRO Evidence Dossier, which consists of important information supporting PRO claims. The dossier should be completed by pharmaceutical industry or other researchers to document the planning of the PRO assessment strategy, psychometric evidence, desired target labeling statements, and the clinical trial evidence of PRO benefits. The systematic reporting and documentation of information on the rationale for including PROs, rationale for the selection of specific PRO instruments, evidence on the psychometric qualities of the PRO measures, and guidelines for interpreting PRO findings will facilitate achieving a PRO labeling or promotional claim. Combining all the relevant information into a single document will facilitate the review and evaluation process for clinical and regulatory reviewers. The PRO Evidence Dossier may also be helpful to industry and academic researchers in identifying further information that will need to be developed to support the clinical development program and the PRO endpoints. [ABSTRACT FROM AUTHOR]

The authors highlight the importance of streamlining the qualification process for biomarkers in helping coordinated protocols facilitate progress and drive novel biomarker discovery and validation. They stress the need for dedicated qualification procedures implemented by the U.S. Food and Drug Administration and European Medicines Agency to be tested with submissions for qualification of biomarkers from various platforms, nonclinical and clinical areas, biotechnology and pharmaceutical companies, diagnostic companies and academic institutions.

New regulatory guidance documents from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently been finalized or are in draft format outlining new pathways for preclinical safety testing. The US and the European Union appear to be moving in a similar direction focussing and refining preclinical safety data requirements for both radiodiagnostics and radiotherapeutics. We here summarize these recent documents from both the US and European perspective. [ABSTRACT FROM AUTHOR]

The author addresses the promotion of transparency in the drug regulatory process. He claims that the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) are conducting consultations on transparency. He explains how the mechanical aspects of the regulatory processs be well defined. He looks at the transparency measures made by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain.

The article offers information about the activities of the European Medicine Agency (EMA) in the year 2012. It states that EMA's executive director Guido Rasi has appointed liaison officer at the U.S. Food and Drug Association (FDA) for promoting EMA-FDA interaction on issues related to medicines, clinical trials and drug development. It highlights that EMA has received 42 good clinical practice (GCP) requests for clinical and non clinical compliance.

The article discusses the aspects of the utilization of health products founded by biotechnology that are expected to penetrate the healthcare industry by 2012 to 2015. These products, which have undergone industrial processes, are cited including biopharmaceuticals, medical equipment, and bioinformatics which encompass deoxyribonucleic acid (DNA) sequencing and pharmacogenetics. It is also noted that the information discussed was gathered from sources including the Organisation for Economic Cooperation and Development (OECD), the U.S. Food and Drug Administration (FDA), and the European Agency for the Evaluation of Medicinal Products (EMEA).