Successful regulatory agency interaction - A nonclinical regulatory strategist's perspective.

Regulatory agency interaction occurs from before a candidate drug enters clinical development and all the way to marketing approval and beyond. This paper presents ways to enable successful interaction by avoiding issues, with an emphasis on nonclinical testing aspects. Strategic thinking as to whether an early regulatory agency meeting should occur is discussed and if yes, how to make it a success by generating relevant questions with proper preparation including a robust Briefing Document. Examples of unfavourable regulatory agency feedback during meetings is given which may have been avoided. Similarly, ways for successful regulatory submission in the form of a Clinical Trials Application (CTA) in Europe or an Investigational New Drug (IND) application in the US are considered with examples of comments that can be received from regulatory agencies. At marketing application stage with submission of a Marketing Authorisation Application (MAA) in Europe and a New Drug Application (NDA) or a Biologic License Application (BLA) in the US, a key document is the Nonclinical Overview and suggested content and potential deficiencies are presented to allow avoidance of adverse regulatory agency responses and time delay. Successful regulatory agency interaction involves robust scientific thinking, proper planning and well-written documentation.

Correlates of time to approval and other clinical development periods.

The drug development cycle is classically divided into a clinical phase and review phase, with the clinical phase typically being further partitioned based on the planning and conduct of adequate and well controlled trials. Factors affecting the duration of the development intervals have not previously been systematically investigated. Here, we analyze a large population (N=825) of New Drug Applications (NDAs) approved between 2008 and 2017 to characterize the typical duration of these intervals and the development factors associated with their duration. These data and analyses will help those involved in pharmaceutical development by enabling data-driven planning and by providing insight into the effect of certain factors on the duration of drug development programs.

Phage Therapy Regulation: From Night to Dawn.

After decades of disregard in the Western world, phage therapy is witnessing a return of interest. However, the pharmaceutical legislation that has since been implemented is basically designed for regulating industrially-made pharmaceuticals, devoid of any patient customization and intended for large-scale distribution. Accordingly, the resulting regulatory framework is hardly reconcilable with the concept of sustainable phage therapy, involving tailor-made medicinal products in the global perspective of both evolutionary and personalized medicine. The repeated appeal for a dedicated regulatory framework has not been heard by the European legislature, which, in this matter, features a strong resistance to change despite the precedent of the unhindered implementation of advanced therapy medicinal product (ATMPs) regulation. It is acknowledged that in many aspects, phage therapy medicinal products are quite unconventional pharmaceuticals and likely this lack of conformity to the canonical model hampered the development of a suitable regulatory pathway. However, the regulatory approaches of countries where phage therapy traditions and practice have never been abandoned are now being revisited by some Western countries, opening new avenues for phage therapy regulation. As a next step, supranational and international organizations are urged to take over the initiatives originally launched by national regulatory authorities.

Development and Evaluation of a New Technological Way of Engaging Patients and Enhancing Understanding of Drug Tolerability in Early Clinical Development: PROACT.

INTRODUCTION: During early clinical testing of a new medication, it is critical to understand and characterise patient tolerability. However, in early clinical studies, it is difficult for patients to contribute directly to the sponsors' understanding of a new compound. Patient reported opinions about clinical tolerability (PROACT) provides a new, simple and innovative way in which patients can collaborate using an application downloaded to a mobile computer or smartphone. METHODS: PROACT was designed with special consideration given to patient confidentiality, patient engagement and data security. A pilot study was conducted to investigate patient uptake of PROACT and to characterize clinical trial information it captured. Patients recruited to Phase I oncology trials at a UK center were eligible to participate but were required to have a tablet computer or smartphone. Patients used PROACT to upload audio/video messages that became available instantly to their clinical team, who were able to reply to the patient within PROACT. The patient's message was also analyzed, personally-identifiable information removed and anonymized information then made available to the sponsor in an analytics module for decision-making. In parallel, a patient focus group was engaged to provide feedback on communication needs during early clinical trials and the PROACT concept. RESULTS: Of the 16 patients informed of PROACT, 8 had a smart device and consented to take part. Use of PROACT varied and all messages volunteered were relevant and informative for drug development. Topics disclosed included tolerability impacts, study design, and drug formulation. Alignment with the clinical study data provided a richer understanding of tolerability and treatment consequences. This information was available to be shared among the clinical team and the sponsor, to improve patient support and experience. Patient forum feedback endorsed the concept and provided further information to enhance the application. CONCLUSION: Overall, PROACT achieved proof of concept in this small pilot study and delivered a secure end-to-end system that protected patient privacy and provided preliminary insight into patient experiences beyond the usual clinical trial data set. The use of mobile devices to interact actively with participants in clinical trials may be a new way of engaging and empowering patients. Further validation of this technology in larger patient cohorts is ongoing. FUNDING: AstraZeneca.

Guidance on preparing an investigational new drug application for fecal microbiota transplantation studies.

Fecal microbiota transplantation (FMT) is an effective treatment for Clostridium difficile infections that are refractory to antibiotic therapy. Because of the important roles of the microbiota in the function of the gastrointestinal tract and other aspects of human physiology, there is a growing interest in studying FMT for other clinical indications. The US Food and Drug Administration regulates clinical studies to evaluate the safety and efficacy of FMT. Studies of FMT for recurrent Clostridium difficile infection or other indications could require submission of an investigational new drug application. Most academic physicians and investigators do not have the regulatory experience necessary to undertake this process. We provide guidance to researchers on the preparation and submission of investigational new drug applications to study FMT.

Biosimilares: situación regulatoria para su autorización / Biosimilars: regulatory status for approval

Los medicamentos biotecnológicos representan el futuro en la medicina. Al expirar la patente de algunos de ellos, aparecen las primeras “copias” de los mismos, que son conocidos como biosimilares. Éstos son producidos por otro fabricante, utilizando nuevas líneas celulares, nuevos procesos y diferentes métodos analíticos. Por ello, su regulación queda a cargo de la Agencia Europea del Medicamento (EMEA) a través del procedimiento centralizado, la cual ha desarrollado unas guías perfectamente establecidas que definen el proceso de autorización que deben seguir los mismos, donde son necesarios estudios preclínicos y clínicos destinados a establecer su perfil de calidad, eficacia clínica y seguridad. Respecto a su denominación, la Organización Mundial de la Salud (OMS) ha determinado que los biosimilares tengan el mismo International Nonpropietary Name (INN) que su medicamento de referencia (AU)

Biotecnological drugs represents the future treatment in medicine. Since the expiry of the patent of the first approved biotech drug, “copying” and marketing of them can be offered by any other biotech company, these new medicines are known as biosimilar medicines. They are approved by the EMEA (European Medicines Evaluation Agency) through the European centralised procedure, the EMEA issued several stringent guidelines to approve a biosimilar drug on the European market, preclinical and clinical studies are necessary to assess the highest standards in quality, efficacy and patient safety. The World Health Organization has determined that biosimilar have the same INN than the original product (AU)

No longer "if," but "when": the coming abbreviated approval pathway for follow-on biologics.

Abbreviated approval of follow-on biologics involves answering complex scientific, legal, and policy questions. The Food and Drug Administration (FDA or the Agency) asserts that it lacks the statutory authority to approve follow-on versions of biologics licensed under Section 351 of the Public Health Service Act (PHSA). Despite persuasive arguments to the contrary the one hundred and tenth Congress entertained four legislative proposals to give FDA this authority, each markedly different. It is no longer a question of "if," but "when" FDA will receive authority to review and license abbreviated applications for follow-on biologics. Any legislation in the one hundred and eleventh Congress must determine: (1) if FDA should be granted authority to develop an abbreviated pathway through rulemaking or guidance; (2) if human clinical trials should be mandatory or discretionary; (3) the feasibility of interchangeability determinations in light of patient safety concerns; (4) the duration of marketing exclusivity for associated products; (5) which products are eligible for follow-on approval; and (6) the degree to which uniformity is achievable between the FD&C Act and the PHSA. This paper recommends the one hundred and eleventh Congress strike a balance between patient safety, incentives for product innovation, price competition, and the need for a flexible, transparent process that capitalizes on FDA's growing expertise with follow-on biologics approvals under Section 505(b)(2) of the FD&C Act.

Delayed access to generic medicine: a comment on the Hatch-Waxman Act and the "approval bottleneck".

Prescription drug costs can be astronomical. The advent of generic drugs, which sell at substantially lower prices than their brand-name counterparts, can save consumers billions of dollars per year. The Hatch-Waxman Act, which governs the introduction of generic pharmaceuticals into the marketplace, produces an undesired side effect-the "approval bottleneck." This Comment examines the "approval bottleneck"-a potential roadblock to the generic drug approval process, and comments on attempts to alleviate the problem.This Comment suggests that developments in statutes and case law have made leaps in attempting to alleviate the "approval bottleneck" problem.The Comment evaluates these developments, which include (1) the ability of a subsequent Abbreviated New Drug Application (ANDA) filer to trigger the generic exclusivity period of the first ANDA filer; (2) the forfeiture provisions; (3) declaratory judgments and the relaxed declaratory judgment test; and (4) the rulings on covenants not to sue. Despite these attempts, however, the potential harm to consumers resulting from delayed access to generic medicines remains.

Challenges Encountered in Dermatologic Drug Development / Los desafíos que se encuentran en el desarrollo de fármacos dermatológicos

Few truly new drugs are developed primarily for the treatment of dermatologic diseases. We discuss challenges and special considerations of dermatology drug development which contribute to this relative absence of novel drugs in dermatology. The issues considered are: a) the economic potential of dermatologic drugs including the potential return on investment (ROI); b) the benefit-to-risk ratio for treatments of skin disease; e) the relative absence of surrogate end points for topically applied drugs; d) drug penetration and vehicles; e) shelf life, stability, emulsifiers, preservatives; f) contact irritancy, contact allergy, contact photoallergy and photocarcinogenicity; g) drugs with more than one active; h) semi-quantitative or soft primary end points; i) inadequate basic knowledge of pathophysiology of skin diseases. Of the many challenges, we conclude it is the low economic potential or ROI available with skin disease treatments which inhibits the creation of novel therapies for dermatologic disease (AU)

Para el tratamiento de enfermedades cutáneas se desarrollan muy pocos fármacos verdaderamente novedosos. En esta revisión discutimos los desafíos y las consideraciones especiales del desarrollo de fármacos dermatológicos que contribuyen a esta relativa falta de fármacos novedosos en dermatología. Las cuestiones que se consideran son: a) el potencial económico de los fármacos dermatológicos, incluyendo la rentabilidad potencial de la inversión; b) el cociente beneficio-riesgo para los tratamientos de las enfermedades cutáneas¡ c) la relativa falta de criterios indirectos de valoración; d) la penetración de los fármacos y los vehículos; e) el periodo de validez, la estabilidad, los emulsionantes y los conservantes; f) la irritación de contacto, la alergia de contacto, la fotoalergia de contacto y la fotocarcinogenia; g) los fármacos con más de un principio activo; h) los criterios de valoración semicuantitativos o cualitativos; e i) el conocimiento básico inadecuado sobre la fisiopatología de las enfermedades cutáneas. De todos los retos, el que más dificulta la creación de terapias novedosas para las enfermedades cutáneas es el bajo potencial económico o la rentabilidad de la inversión disponible con los tratamientos para enfermedades cutáneas (AU)

Understanding FDA regulatory requirements for investigational new drug applications for sponsor-investigators.

Clinical investigators invoke a number of specific regulatory requirements if their study includes use of a pharmaceutical agent. Studies using a drug that has not been approved by the Food and Drug Administration (FDA) or for indications not in the approved labeling may require filing an Investigational New Drug (IND) application with the FDA. If a study meets specific regulatory exemption criteria, then an IND may not be needed. Individual investigators may meet the FDA definition of a sponsor-investigator, in which case the application process is generally less complicated than for commercial sponsors, and this review addresses only this circumstance. Filing an IND requires completion of 3 sets of forms: 1 detailing the study (FDA Form 1571), 1 providing information about the investigator and study site (FDA Form 1572), and 1 certifying that the study is registered in the national database of clinical trials (FDA Form 3674). If the IND is approved, the study may begin 30 days after the FDA acknowledges receipt and assigns an IND. If the FDA requires additional information or if the study is placed on a "clinical hold," the study must not proceed. While the IND is active, the investigator must also continue to meet a set of regulations for monitoring the study and reporting to the FDA.

Biosimilars: opinion of an expert panel in the Middle East.

BACKGROUND: Several biotechnology-derived drugs are reaching the end of their patent lives. As a result, so-called biosimilar products are in development, and a few have already gained approval in Europe and other countries such as the USA. Biosimilars, unlike generic versions of conventional drugs, are not identical to their reference product, and their production is complex and sensitive to even slight changes in the manufacturing and storage process. Therefore, the registration of these products requires more stringent evaluation than that for conventional generics. METHODS AND SCOPE: A consensus group of experts from the Near and Middle East discussed the currently available guidelines for registration of biosimilars--including those produced by the European Medicines Agency (EMEA)--and their application in this region. To inform this report, a literature search was also conducted on PubMed in January 2008, using the search terms 'biosimilar' and 'follow-on biologic'. This paper provides an overview of the issues in the development and registration of biosimilars, a description of the EMEA guidelines and the recommendations of the consensus group for the registration of biosimilars in the Middle East. FINDINGS: Because of the complex nature of biosimilars and their potential immunogenicity, these products cannot undergo the abbreviated approval process used for generic agents. Instead demonstration of their quality, safety and efficacy, in comparison with their reference biological product, is required. CONCLUSIONS: The consensus group recommended the implementation of the EMEA guidelines as the basis of Regional guidelines for the registration of biosimilars in the Near and Middle East. Registration would, therefore, require demonstration of the robustness of the manufacturing process and quality-control methods, the comparability of pharmacokinetics, pharmacodynamics, efficacy and safety between the biosimilar and reference product and plans for post-marketing surveillance of the long-term risks and immunogenicity of new biosimilars.

Velocidad de incorporación de nuevos medicamentos en la práctica clínica / Time required to introduce new drugs into clinical practive

Objetivo: Analizar la velocidad de incorporación de nuevos medicamentos en la práctica clínica. Diseño: Estudio descriptivo retrospectivo. Unidad de estudio: Principios activos comercializados entre enero de 2003 y junio de 2004, excluidos los de uso estacional y los que no tienen establecida la dosis diaria definida (DDD). Emplazamiento: Primeros 2 años de comercialización de cada fármaco en atención primaria y atención especializada, en Aragón. Unidad de medida: Facultativos distintos que prescriben mensualmente cada fármaco y consumo mensual (DDD y gasto). Se utilizan las medias móviles de 3 meses. Se analizan también las categorías de aportación terapéutica. Resultados: En el cuarto mes se han incorporado el 33% de los facultativos que realizan alguna prescripción durante el primer año (35,6% intervalo de confianza (IC) del 95% 25,5-45,8), en el cuarto mes en atención primaria (31,5%, IC del 95% 21,4-41,5) y el primer mes en atención especializada (22,5%, IC del 95% 11,2-33,7). El 33% del consumo mensual máximo en DDD se alcanza en el cuarto mes durante el primer año (31,3% IC del 95% 22,2-40,5), en el quinto mes en atención primaria (25,4$%, IC del 95%: 10,7-40,2) y el primer mes en atención especializada (34,0%, IC del 95% 25,9-42,2). Los resultados en el segundo años son similares y el consumo máximo de DDD se produce un mes más tarde. No se aprecian diferencias según las categorías de aportación terapéutica. Conclusiones. La atención especializada se incorpora más rápidamente que la atención primaria. La velocidad de incorporación no parece relacionada con la aportación terapéutica. Para que los profesionales tengan la información sobre la utilización de nuevos medicamentos en un tiempo útil es necesario que dispongan de evaluaciones objetivas sobre su aportación terapéutica, como mínimo, antes del cuarto mes tras su comercialización (AU)

Objective: To analyze the time it takes for new medications to be introduced into clinical practice. Design: A retrospective, descriptive study focusing on the active ingredients commercialized between January 2003 and June 2004, with the exception of those of seasonal use and those for which the defined daily dose (DDD) had not yet been established. Study period and site: the first two years of commercialization of each drug employed in Primary Care and Specialized Care in Aragon, a region in northeastern Spain. Unit of measurement: The different physicians who prescribed each drug on a monthly basis and the monthly use (DDD and cost9. Moving averages of here months were utilized. Categories of therapeutic contribution were also analyzed. Results. By the fourth month, 33% of the physicians who made any prescriptions during the first year had become incorporated (35,6%, 95% CI:25,5%-45,8%) (4º month in Primary Care (31,5%, 95% CI; 21,4%-41,5%) and 1st month in Specialized Care (22,5%, 95% CI: 11.2%-33.7%). Thirty-three percent of the maximum monthly consumption in DDD was reached by the fourth month during the first year (31.3%, 95% CI: 22.2%-40,5%) (5th month in Primary Car (25,4%, 95% CI: 10,7%-40,2%) and 1st month in Specialized Care (34,0%, 95% CI: 25,9%-42,2%)). The results in the second year were similar, with the maximum consumption in terms of DDD occurring one month later. No differences were observed according to the category mary Care. The time required for incorporation does not appear to be related to the therapeutic contribution. In order for health care professionals to receive information on the utilization of new medications within a useful time frame, the must be provided with objective evaluations of the therapeutic contribution of these drugs within no more than four months of their commercialization (AU)

Principios activos autorizados en España en 2006 (I. ª parte) / No disponible

Cada año la Agencia Española de Medicamentos evalúa la documentación correspondiente a los fármacos que le son presentados con propuesta para su registro y aprobación. Otros fármacos lo hacen a través de la Agencia Europea. En nuestro país se han autorizado veinticuatro principios activos durante el pasado año 2006. Se presentan y comentan los datos correspondientes a aquellos considerados por los autores de mayor interés. Tres principios son considerados como «Innovación excepcional», y uno más es considerado «Innovación importante ». El resto presentan mejoras menores aunque en determinadas circunstancias o en pacientes específicos pueden llegar a ser la alternativa de mayor interés (AU)

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High Throughput Screening in drug discovery

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Drug discovery is a highly complex and multidisciplinaryprocess which goal is to identify newantitumoral drugs. The screening attrition rate inthe current drug discovery protocols suggests thatone marketable drug emerges from approximatelyone million screened compounds. This leads topressure to screen larger libraries in order to continuethe pipeline and to the development of HighThroughput Screening. HTS is only a name forspecific developments in laboratory automation tocollect a large amount of experimental data in arelatively short time. HTS can test hundreds ofthousands of compounds per day, however, if fewercompounds could be tested without compromisingthe probability of success, the cost and time wouldbe greatly reduced. To that end, new developmentsin large-scale cell biology and compound librarydesign in silico have evolved to obtain data withhigher predictability of clinical efficacy

Lessons from gefitinib-induced interstitial lung disease in Japan: problems in approval, pharmacovigilance, and regulatory decision-making procedures

Objective: The objective of this study was to identify problems in the approval, pharmacovigilance, and post-approval regulatory decision-making procedures involving gefitinib and to propose countermeasures to prevent further drug-induced suffering in Japan in the future. Methods: We comprehensively reviewed reports regarding gefitinib published during the period from 2000 to 2006 by regulatory agencies, the manufacturer of the gefitinib-containing drug, cancer clinical study groups, and a scientific society. Results: We identified the following major problems in the approval, pharmacovigilance, and regulatory decision-making procedures: 1) the results of animal experiments and pre-marketing clinical trials, and reports of adverse drug reactions from other countries were not properly reflected in the label; 2) indications for the drug were expanded without strict evaluation of the external validity of pre-marketing clinical trials; and 3) despite many serious cases of interstitial lung disease (ILD) being spontaneously reported, well-designed post-marketing surveillance was not immediately performed. Conclusions: We propose a mandatory total registry of all drug users and surveillance (i.e. a prospective outcome study) as one of the rational solutions for preventing further drug-induced suffering in Japan (AU)

Objetivo: Identificar los problemas en el registro, farmacovigilancia y toma de decisiones post-registro relativas al gefitinib y proponer contramedidas para prevenir futuros problemas producidos por medicamentos en Japón. Métodos: Revisamos intensamente los informes sobre gefitinib publicados durante el periodo 2000 a 2006 por las agencias reguladoras, el fabricante de medicamentos que contenían gefitinib, grupos de ensayos clínicos sobre medicamentos anti-cáncer, y una sociedad científica. Resultados: Identificamos los siguientes problemas principales en la aprobación, farmacovigilancia y proceso de toma de decisiones reguladoras: 1) los resultados de los estudios en animales y los ensayos clínicos pre-comercialización y los informes de reacciones adversas de otros países no se reflejaron correctamente en las fichas técnicas; 2) se expandieron las indicaciones del medicamento sin una estricta evaluación de la validez externa de los ensayos clínicos pre-comercialización; y 3) a pesar de que se comunicaron espontáneamente reacciones adversas graves de ILD, no se realizó inmediatamente una vigilancia post-comercialización bien diseñada. Conclusiones: Proponemos un registro obligatorio de todos los usuarios de medicamentos y vigilancia (p.e. un estudio retrospectivo de resultados) como una de las soluciones racionales para evitar futuros sufrimientos producidos por medicamentos en Japón (AU)

Trials and tribulations: a primer on successfully navigating the waters of the Food and Drug Administration.

Conducting clinical trials in a regulated environment constitutes unfamiliar territory for most physicians. There exists no formal training in this subject, so many clinicians lack even a basic understanding of the procedures required by the Federal Food, Drug, and Cosmetic Act and their implications vis-à-vis clinical practice. The authors distill drug regulation to relevant applications and elucidate the rationale and procedures for submitting an Investigational New Drug application by providing a user-friendly road map of the process.