The Early Preclinical Development Program for Locally Administered Investigational Medicinal Products in Ophthalmology: Preclinical Data Required for Starting a First-in-Human Clinical Trial in Europe-Basic Considerations and 2 Case Studies.

BACKGROUND: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-in-human clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse. METHODS: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated. RESULTS AND CONCLUSION: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance.

U.S. Regulatory Considerations for Development of Live Biotherapeutic Products as Drugs.

Interest in the use of bacteria-containing products for the treatment or prevention of disease has increased in recent years. Bacterial preparations for human consumption are commercially available in the form of dietary supplements and typically contain strains with a history of use in food fermentation. Advances in our understanding of the role of the microbiota in health and disease are likely to lead to development of products containing more novel bacterial species, along with genetic modification of strains to provide specific functions. By law, any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans meets the definition of a drug, and an Investigational New Drug (IND) application for clinical investigation must be filed with the FDA. This article is meant to provide information about the IND submission process and additional considerations with regard to chemistry, manufacturing, and controls information for live biotherapeutic products.

Experience of an academic institute in importing a novel preclinical drug into India.

The article throws light on the process of importing a novel preclinical drug into India based on the real-life experience from one of our studies. A novel drug "X" acting through a new mechanism of action was hypothesized by us to function as a neuroprotectant. It was decided to import this novel drug from a university located in Brazil. An official collaboration pact was exchanged between both the sides. In accordance with the Indian Drug and Cosmetics Act 1940, unauthorized import of drug into India is not permitted. Hence, we decided to apply for the import license from Government of India. During the process of registration, we realized that the CDSCO SUGAM portal did not have facilities for the application from academic institute. We further faced challenges in different steps of import such as registration of the institute, individual drug application, fee transaction through the bank for Form 12, and customs duty clearance in the New Delhi airport. The process of import of drug for the purpose of testing by academic institutes has not been regularized by the CDSCO, and we suggest the apex organization to make separate provision for the academic institutes. This will encourage more academic institutes in India to opt for global collaborative works. This narration will further help them in following the same footsteps without facing significant hurdles. If more research on novel chemical entities is carried out in various academic institutes of India, it would not be far that we discover a blockbuster drug making the whole world turn toward us.

Regulation of Clinical Trials with Advanced Therapy Medicinal Products in Germany.

In the European Union, clinical trials for Advanced Therapy Medicinal Products are regulated at the national level, in contrast to the situation for a Marketing Authorisation Application, in which a centralised procedure is foreseen for these medicinal products. Although based on a common understanding regarding the regulatory requirement to be fulfilled before conduct of a clinical trial with an Advanced Therapy Investigational Medicinal Product, the procedures and partly the scientific requirements for approval of a clinical trial application differ between the European Union Member States. This chapter will thus give an overview about the path to be followed for a clinical trial application and the subsequent approval process for an Advanced Therapy Investigational Medicinal Product in Germany and will describe the role of the stakeholders that are involved. In addition, important aspects of manufacturing, quality control and non-clinical testing of Advanced Therapy Medicinal Products in the clinical development phase are discussed. Finally, current and future approaches for harmonisation of clinical trial authorisation between European Union Member States are summarised.

Marketing Regulatory Oversight of Advanced Therapy Medicinal Products (ATMPs) in Europe: The EMA/CAT Perspective.

With the release of Regulation 1394/2007, a new framework for gene and cell therapy medicinal products and tissue-engineered products was established in the European Union. For all three product classes, called advanced therapy medicinal products, a centralised marketing authorisation became mandatory. The European Medicines Agency (EMA) together with its Committee for Advanced Therapies, Committee for Human Medicinal Products and the network of national agencies is responsible for scientific evaluation of the marketing authorisation applications. For a new application, data and information relating to manufacturing processes and quality control of the active substance and the final product have to be submitted for evaluation together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMPs are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines. Due to the diversity of ATMPs, a tailored approach for regulating these products is considered necessary. Thus, a risk-based approach has been introduced for ATMPs allowing flexibility for the regulatory requirements. Since the regulatory framework for ATMPs was established, five products have been licenced in the European Union. However, the pipeline of new ATMPs is much bigger, as seen from the significant numbers of different products discussed by the CAT in scientific advice and classification procedures. In 2013, a public consultation on the ATMP Regulation was conducted by the European Commission, and the results were published in 2014. The report proposes several improvements for the current framework and established procedures for the regulation of ATMPs.

Requirements for Clinical Trials with Gene Therapy and Transplant Products in Switzerland.

This chapter aims to describe and summarize the regulation of gene and cell therapy products in Switzerland and its legal basis. Product types are briefly described, as are Swiss-specific terminologies such as the term "transplant product," which means products manufactured from cells, tissues, or even whole organs. Although some parts of this chapter may show a guideline character, they are not legally binding, but represent the current thinking of Swissmedic, the Swiss Agency for Therapeutic Products. As so far the experience with marketing approval of gene therapy and cell therapy products in Switzerland is limited, this chapter focuses on the regulation of clinical trials conducted with these products. Quality, nonclinical, and clinical aspects are summarized separately for gene therapy products and transplant products.

Regulation of Cell and Gene Therapy Medicinal Products in Taiwan.

Owing to the rapid and mature development of emerging biotechnology in the fields of cell culture, cell preservation, and recombinant DNA technology, more and more cell or gene medicinal therapy products have been approved for marketing, to treat serious diseases which have been challenging to treat with current medical practice or medicine. This chapter will briefly introduce the Taiwan Food and Drug Administration (TFDA) and elaborate regulation of cell and gene therapy medicinal products in Taiwan, including regulatory history evolution, current regulatory framework, application and review procedures, and relevant jurisdictional issues. Under the promise of quality, safety, and efficacy of medicinal products, it is expected the regulation and environment will be more flexible, streamlining the process of the marketing approval of new emerging cell or gene therapy medicinal products and providing diverse treatment options for physicians and patients.

Regulatory Oversight of Cell- and Tissue-Based Therapeutic Products and Gene Therapy Products in Singapore.

The regulatory environment for cell- and tissue-based therapeutic products and gene therapy products is rapidly evolving and drug regulatory agencies are working towards establishing a risk-based system in the regulatory framework. Similarly in Singapore, a risk-based tiered approach has been applied whereby clinical trials and product licence of high-risk cell- and tissue-based therapeutic products (substantially manipulated products, products intended for nonhomologous use or combined products) and gene therapy products are regulated as medicinal products under the Medicines Act. There is no legal definition for cell- and tissue-based therapeutic and gene therapy products. The current working definition for a cell- and tissue-based therapeutic product is an article containing or consisting of an autologous or allogeneic human cell or tissue that are used for or administered to, or intended to be used for or administered to, human beings for the diagnosis, treatment, or prevention of human diseases or conditions. Gene therapy products are included under the current biological medicinal product definition.

Regulation of research: is it a drug trial or a supplement trial?

Investigators and sponsors of dietary supplement research need to know the relevant regulatory requirements and how to comply with them. This brief review describes how research on dietary supplements is regulated by FDA. In general, whether an FDA sanctioned Investigational New Drug (IND) application is required for a human research project on dietary supplement depends on the intended use and clinical setting of the clinical study, and not on the supplement's physical or chemical properties. Even if the study product is already available on the market as a dietary supplement, an IND will be required for products that will be used as a drug to treat, mitigate or prevent a disease or its related conditions in the proposed clinical study. On the other hand, for studies on structure and function endpoints, and not on drug use, no IND will be required. The paper also discusses the principles FDA uses to determine whether an IND is needed for clinical studies of surrogate endpoints that do not lead to approvable drug claims. Useful FDA contact information is also provided.

The IND application.

Translational biomedical research is often directed to the introduction of a new drug or biologic intended to treat unmet medical need in humans. This unit describes the timing and content of the investigational new drug (IND) application, the primary document required by the U.S. FDA for the initiation of clinical trials in humans with any new chemical entity (NCE) or biologic. The IND application contains all the information necessary for the FDA to make an assessment of the risks and benefits of the proposed clinical trials for the NCE/biologic, containing a detailed but succinct description of the biology, safety, toxicology, chemistry and manufacturing process, and the proposed clinical plan. This unit is geared for those with little or no experience with the IND process and is intended as a global introduction to this, the initial stage of the drug development process for drugs used in humans.

Calidad de los estudios postautorización de tipo observacional registrados en España antes de su regulación / Quality of observational post-authorization studies registered in Spain before their regulation

Fundamento y objetivo: En julio de 2002, los estudios postautorización de tipo observacional quedaron definitivamente regulados en España. La justificación de dicha regulación ha sido cuestionada. El objetivo de este trabajo es evaluar la calidad científica y ética de los estudios registrados el año previo a la entrada en vigor de la normativa, así como el valor social de sus resultados utilizando su publicación como indicador. Material y método: Se ha recogido los datos de carácter administrativo, metodológico, ético y de seguimiento de los estudios postautorización presentados en la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) durante el año 2001. Resultados: En 2001 se presentó en la AEMPS un total de 162 estudios postautorización que pretendían incluir un total de 306.539 pacientes. El diseño más habitual fue el de «seguimiento prospectivo no controlado» (122 estudios [75%]) y prácticamente en su totalidad (99%) el médico fue la única fuente de información. En un 43% no se especifica el tamaño muestral o no se justifica. La duración de los estudios fue inferior a 12 meses en el 83%. Sólo en el 13% de los estudios se solicitó la revisión por un comité ético de investigación clínica y sólo en el 44% se preveía algún procedimiento de información a los sujetos de investigación. Once estudios se publicaron como originales en revistas (el 10% de los finalizados), 1 de ellos en una revista internacional, y 13 (el 12% de los finalizados) en forma de comunicaciones a congresos, 2 de ellos internacionales. Conclusiones: Los estudios postautorización presentados en la AEMPS durante el año 2001 tuvieron escasa calidad metodológica y ética. La mayoría de ellos no se publicó, lo cual pone en cuestión el valor de esas investigaciones al tiempo que alimenta las dudas sobre su verdadera finalidad. La regulación de esos estudios parecía, pues, justificada

Background and objective: In July, 2002, observational post-authorization studies were subjected to regulation in Spain, giving rise to an uproar among sponsors and investigators. The aim of the present report was to assess the scientific and ethical quality of the studies presented during the year before the regulation came into force. In addition, we explored how many of them reached publication. Material and method: We extracted information relative to administrative procedures, methods, follow-up and ethical issues from the protocol of the studies presented to the Spanish Agency for Medicines and Healthcare Products (AEMPS) during 2001. Results: A total of 162 studies intended to recruit 306,539 patients were registered as post-authorization studies in 2001. The most widely used design was the «non-controlled prospective follow-up study» (122 studies; 75%). Physicians were the only source of information in 99% of the studies. In 43% of them, the sample size was neither specified nor justified. In 83% of the studies the observation period per patient was less than 12 months. An ethical review was requested for only 13% of the studies while a procedure to inform patients was planned in 44%. Eleven studies (10% of those finalized) had been published in scientific journals (1 of them international) and 13 (12% of those finalized) were reported as a communication to a national (11) or international (2) congress. Conclusions: Most post-authorization studies presented to the AEMPS in 2001 had poor methodological and ethical quality. Only a few became published, raising doubts about their scientific aims. These results give empirical support to the regulation adopted

GW-1000. GW Pharmaceuticals.

GW Pharmaceuticals is developing GW-1000 (Sativex), a narrow ratio delta9-tetrahydrocannabinol:cannabidiol product for the potential treatment of multiple sclerosis, spinal cord injury, neurogenic pain and peripheral neuropathy. In March 2003, the company filed for approval for the treatment of MS with the UK Medicines Control Agency, and in May 2004, filed for new drug submission with Health Canada.

Off-label or out of bounds? Prescriber and marketer liability for unapproved uses of FDA-approved drugs.

Professor O'Reilly's study of recent drug review legislation applies a historical and holistic view of promotion practices for unapproved uses of prescription drugs. He faults Congress for moving public health protections away from a strictly protective mode and toward assistance to drug marketers. He argues that the adverse health consequences of "off-label" promotion of drugs are not well understood, and that the 1997 amendments deserved the public health interest while expanding pharmaceutical company profits.