Supporting Marketing Authorization Applications with Non-Clinical Overviews

The development of a pharmaceutical product is a step-by-step process involving an evaluation of both animal and human efficacy and safety information. The goals of the nonclinical safety evaluation generally include a characterization of toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility. Overall, the pharmacology, pharmacokinetics, and toxicology result supports the safe use of the pharmaceutical product in humans.

Over the past decade, regulatory submission requirements have grown substantially, in part due to the increased product registrations in the EU and other countries. Drafting Marketing Authorization Applications can be a resource-intensive task, as care needs to be taken to ensure the non-clinical data parts - the overview, the written summary and the tabular summary - all tell one story, particularly if written by different authors (1).

Within this, the non-clinical overviews (NCOs) look primarily to provide integrated and critical assessments of the pharmacologic, pharmacokinetic, and toxicologic evolution of the active ingredients. The NCO provides an assessment of the pharmaco-toxicological data, as prescribed by Directive 75/319 Article 2. Furthermore, Annex 1 of Directive 75/318 directs that the NCO should be an ‘expert report’.

In the EU, generic applications must demonstrate pharmaceutical/clinical equivalence to the finished innovator product, as required by Directive 2003/63/EC annex Part II(2)(b) (2). This allows transfer of all the innovator product’s pharmaco-toxicological information and clinical experience data to the generic product.  Many other health authorities have similar requirements including, TGA (Australia), MCC (South Africa), and LATAM countries (Brazil, Mexico, etc.), to fulfil the criteria for generic marketing applications. Directive 2001/83/EC (3) indicates that NCOs are also required to demonstrate well-established use for a medicinal product, with acceptable efficacy and safety levels.

Due to the time and expertise it requires, as well as challenges in a company’s internal capacity to complete these requirements, many pharmaceutical companies struggle to fulfil their non-clinical regulatory writing and submissions in a timely manner. Drafting NCOs for generic molecules can be a challenge, due to the sheer volume of safety and efficacy data available for well-established molecules for the literature search and selection of publications. Outsourcing the authoring of NCOs, as part of the CTD dossier submission (CTD Module 2.4), to an external provider can be a cost-effective and flexible option.

NCOs should also include critical information on the safety of excipients and the impurities in the product. Additionally, a summary with important safety topics, including information that supports safe use of the products as per the proposed product label or the Summary of Product Characteristics (SmPC) should be incorporated.

NCOs look to include important information for the reviewer on the safety of excipients and the impurities in the product. Additionally, a summary highlighting important safety topics and how the information supports safe use of the products as per the proposed product label or the Summary of Product Characteristics (SmPC) should also be included.

An Example of an Effective Solution

One consideration is to effectively utilize a functional service provider (FSP) to undertake these activities as it can be a cost-effective approach, enabling access to a pool of highly-skilled and knowledgeable experts and authors. Additionally, FSPs have access to widely accepted literature search tools like Embase and Medline, as well as toxicological databases like Registry of Toxic Effects of Chemical Substances (RTECS), the Hazardous Substances Data Bank (HSDB), and the Developmental and Reproductive Toxicology Database (DART), etc. FSPs can also manage the review of the NCO by an external independent non-clinical expert who provides the declarations (CTD Module 1.4.2), which are required to be submitted alongside the CTD dossier.

FSPs can quickly establish teams of expert regulatory writers, along with medical reviewers to support client needs. Standard operating practices for drafting NCOs can then be developed for the partnership and a template created, that will be accepted across all regulatory regions. These templates should follow the requirements set out by the EU directives and the ICH, particularly for the overview of in-vitro and in-vivo non-clinical testing strategies, primary and secondary pharmacodynamics, safety pharmacology, pharmacokinetics and toxicity data.

In Summary

With the ever changing regulatory landscape, outsourcing non-core activities is a flexible approach to managing resources and remaining compliant with NCO requirements for the entire generic portfolio.

References

1.     International Pharmaceutical Product Registration, Second Edition. Edited by  Anthony C. Cartwright  and Brian R. Matthews CRC Press 2009.

2.     Official Journal of the European Union – commission directive 2003/63/EC. 2003 (Internet) available at: http://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2003_63/dir_2003_63_en.pdf  [accessed 23/05/2017]

3.     Official Journal of the European Union – Directive 2001/83/EC of the EU Parliament and of the council of 6 November 2001 on the community code relating to medicinal products for human use.  (Internet) Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf [accessed 23/05/2017]

ENDS

About the Author

Dr. Rajendra Wable, Subject Matter Expert-Medical Writing and Regulatory Affairs, is a post graduate in Veterinary Science [M.V. Sc (Veterinary Pathology)]. He is currently managing several regulatory writing projects (Preclinical and Clinical) and providing support to the global pharmaceuticals for product registration in international markets. He has hands-on experience in authoring variety of regulatory submission documents including protocols, clinical study reports, investigator’s brochure, CTD Summaries and Overviews required for marketing applications.  He is also experienced in developing strategies for regulatory submission, responding to health authority queries, bio-waiver applications, and biological characterization of pharmaceutical impurities. He has worked as a Study Director/Study pathologist for various regulatory toxicity studies and managed several PK, PD and toxicology projects.

Email: Rajendra.Wable@Sciformix.com

About Sciformix

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