Outside support — supporting marketing authorisation applications with non-clinical overviews
Dr Rajendra Wable, subject matter expert-medical writing and regulatory affairs at Sciformix Corporation, discusses how marketing authorisation applications across Europe, Australia and other countries can be supported with non-clinical overviews.
The origin of the non-clinical overview (NCO) is from the twin directives 75/318/EEC and 75/319/EEC issued on 20 May 1975. Directive 75/319 article 2 indicates that the marketing authorization application should provide an assessment of the pharmacotoxicological data and annex 1 of directive 75/318 refers to such assessment as an ‘expert report’.
Today much care and resource must be applied to non-clinical data to ensure that the three elements of overview, written summary and tabular summary tell the same story and give the same interpretation, especially if the authors of each part are not the same.1 As such, the complexity of regulatory writing is at an all time high, and the intensity and skill level required is constantly expanding.
Furthermore, over the past decade regulatory submission requirements have grown substantially, in part due to the increased product registrations in the EU, Australia and other countries. Many organizations from small to the top pharmaceutical companies struggle to fulfil their non-clinical regulatory writing and submissions in a timely manner and therefore require assistance from external sources.
As companies’ internal teams do not have the capacity to sustain their clinical regulatory writing and submission work, outsourcing these processes to an external provider can be a cost effective and flexible option to author NCOs as part of the CTD dossier submission (CTD Module 2.4). NCOs look primarily to provide integrated and critical assessments of the pharmacologic, pharmacokinetic and toxicologic evolution of the active ingredients.
The evolving regulatory landscape
For any generic applications in the EU it is necessary to show that the finished product in application is essentially similar to the innovator finished product, as required by directive 2003/63/EC annex part II(2)(b).2 This is so that all pharmacotoxicological information and clinical experience data can be transferred from the innovator product to the generic product for this application, provided through submitting NCOs.
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. NCOs are also required to demonstrate a well-established use for a medicinal product, with acceptable efficacy and safety levels, as prescribed in Directive 2001/83/EC.3
Challenges for pharmaceutical organisations
When authoring NCOs, the literature search and selection of publications, to be included in the integrated assessment, can be a sticking point for many pharmaceutical companies.
A literature search is often a lengthy process due to the sheer amount of safety and efficacy data available for well-established generic molecules. However, by using a functional service provider (FSP) to undertake these activities a pool of highly-skilled and knowledgeable resources is readily available. Additionally, FSPs generally have access to widely acceptable literature search tools like Embase, Medline as well as some specific toxicological databases like Registry of Toxic Effects of Chemical Substances (RTECS), the Hazardous Substances Data Bank (HSDB), Developmental and Reproductive Toxicology Database (DART), and Chemical Carcinogenesis Research Information System (CCRIS), etc.
After the NCOs are authored they need to be reviewed by an external independent non-clinical expert who provides the declarations (CTD module 1.4.2) which is to be submitted alongside the CTD dossier.
Additionally, external vendors can spend more time analysing relevant regulations and recommendations of products for particular therapeutic areas by international societies when authoring NCOs. For example, in the area of antibacterial molecules, when authoring NCOs, recommendations from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are highly relevant to consider in addition to EMEA regulations.
With their additional resources FSPs are able to maintain high quality reporting within agreed timelines for volume surges of up to 200%. Finally, additional time can also be spent assisting in drafting responses to questions from health authorities, such as requests for supplementary details about specific non-clinical testing issues, or biological characterisation of impurities.
Supporting client needs
FSPs can quickly establish teams of expert regulatory writers in toxicology and pharmacology, along with medical reviewers to support client needs. Once the vendor is familiarised with the organisations preferred processes for NCOs a standard practice can be implemented and a template created, that will be accepted across all regulatory regions.
These templates should look to 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 various animal species like rats, mice, dogs, rabbits and cynomolgus monkeys.
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.
In summary
For pharmaceutical companies to achieve 100% compliance with NCO requirements for their entire generic product portfolio utilising an external provider can be a cost-effective approach.
With the ever-changing regulatory landscape, by choosing to invest more resources to discrete non-core competence activities, a strong partnership can be built with a vendor that is able to assist through the whole authoring and submission process, using a flexible approach to adapt to individual companies’ needs.
References
- International Pharmaceutical Product Registration, Second Edition. Edited by Anthony C. Cartwright and Brian R. Matthews CRC Press 2009
- 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]
- 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]