25 th Oct The Path to Easier Product Lifecycle Maintenance
How to maximise long-term benefits and stay abreast of legislation
The pharmaceuticals’ golden era saw the route from bench to clinical trial to authorisation; a well-travelled path with blockbusters numerous and companies’ headcount and profits large. However, by the end of the 1990s, the completion rate of this journey was becoming much rarer. Increasing regulations and associated complexities, combined with the loss of many big patents, mean that healthcare companies must scrutinise every aspect of the development lifecycle for efficiency, cost and commercial risk. The constant throughout product development, registration, marketing and surveillance is regulatory affairs; where an informed approach increases the chances of success at every stage.
Regulatory affairs are often seen as the stumbling block, raising issues, wanting more information and causing delays. But by keeping track of changes in legislation and requirements, they ensure each aspect of the lifecycle is conducted correctly and presented appropriately to the assessors; reducing time to market and improving commercial opportunity. One such change includes the
implementation of the 2016 Clinical Trial Regulations, where to misunderstand the importance of regulatory affairs support will be costly in more ways than one.
Putting the role of regulatory affairs into perspective, we look at the case of a virtual biopharmaceutical company who engaged regulatory expertise 12 months prior to a planned first-in-man (FIM) study. Familiar with FIM studies, they understood the benefits in actively engaging the regulatory function at an early stage. As a result, few questions were received from the Agency, approval was gained quicker than anticipated and a good relationship was able to develop between the applicant and assessor.
A Single Version of the Truth
It may seem trivial in the grand scheme of things, but the importance of starting with good document management is often undervalued. Many companies undertaking FIM studies do not have an electronic document management system (EDMS) and, with many functions contributing to single documents, version control can quickly be lost in the virtual business environment. At best, this can be time-consuming and frustrating to resolve; at worst, this can lead to incorrect documents being submitted or used in the clinical setting. Fast forward 15 years with the product on the market and thousands of associated documents, and you can see how chaos ensues if structure is not in place from day one.
In addition, the Identification of Medicinal Products (IDMP) – officially implemented in July 2016 – will eventually incorporate investigational medicinal products, and so it is now more pressing than ever to build and maintain a ‘single version of the truth’ through good document management.
The main purpose of IDMP is to standardise the way the pharmaceutical industry refers to medicinal products, providing a universal identification for drugs. The EU regulators see the importance of continuity of information throughout the lifecycle of a medicine; from clinical trials through to marketing and, eventually, discontinuation. Although no definitive implementation dates for the use of IDMP in support of investigational products have been set, it is highly advisable to work to this standard for longer term efficiency. From a clinical trial application (CTA) perspective, it has been confirmed that the practical application of IDMP will be aligned with the EU Clinical Trial Regulation No. 536/2014. Some key aspects of this are the deployment of a clinical trial portal and database to be used for the submission, authorisation and supervision of trials, and the implementation of a new EU CTA form will be specifically designed to facilitate IDMP data submission.
If investment in an EDMS is not a priority, there are simple solutions easily implemented at kick-off by your regulatory team. These could include anything from the implementation of a formal numbering system – for when documents are signed off for submission or approval to distinguish versions – to the adoption of share sites that manipulate a master document.
As the product passes through the clinical phases, it is important to understand how the documentation will accumulate, which function will be the owner of certain documents and how these different functions will communicate to ensure consistency in both management and language. To avoid inconsistencies and achieve a licence, all of this documentation will need to come together to demonstrate you have a product of satisfactory safety, efficacy and quality.
Getting it Right First Time
When authoring quality documents, think about the level of detail you are including to prevent unnecessary applications for amendments further down the line and reduce the potential for questions from the Agency. From FIM to manufacturing authorisation the guidance is clear, and providing superfluous information is neither beneficial nor appropriate for the assessor or applicant.
There can be a fine line between providing enough information to adequately demonstrate the quality of the product is consistently controlled, and tying your company down to unmanageable restrictions.
However, broad guidance dictates that information should be related to the medicinal product or active ingredient in question, and regurgitation of general elements of Good Clinical Practice, Good Manufacturing Practice or quality assurance is neither required nor advisable.
The quality requirements for a dossier for a clinical trial and those for a marketing authorisation dossier are markedly different. Bearing in mind the fact that levels of control will also differ during the individual phases of clinical trials as you build knowledge and experience is important. While some differences in the lifecycle expectations are highlighted by the EMA, due to so many
contributing elements, a very detailed set of requirements to cover all scenarios is not provided by authorities.
Information to be provided for investigational medicinal products should focus on the risk aspects. At Phase 1, the start of building your quality case, overall manufacturing and product experience is limited. Stability of the product is not significantly tested and exposure is low, so quality elements such as well-defined specification limits and shelf life are not expected by assessors.
As manufacturing processes become more clearly defined and you work through Phase 2 and Phase 3, your breadth of data increases. With larger and longer exposure of patients, the expectation is that your processes and limits are refined based on this experience, and your quality documentation should reflect this. Specifications and acceptance criteria set for previous Phase 1 or Phase 2 trials should be reviewed by the applicants and adjusted as necessary to the stage of development.
In order to author appropriate documents, it is down to an experienced Chemical Manufacturing Controls professional to consider the nature of the product, the state of development, patient population, nature and severity of the illness, as well as type and duration of the clinical trial itself. There is always going to be some agency and assessor variability, but getting the right regulatory
support will put you on the path to easier product lifecycle maintenance.
Learning from Our Virtual Biopharmaceutical Company
The practical lessons we learnt are that it is never too early to engage regulatory support and to keep the ‘end goal’ in mind at all stages of your clinical development journey. When there is collaboration from the beginning, good regulatory support will:
-Provide strategic advice to highlight particular challenges or changes to regulations early and offer viable solutions, which can be worked towards prior to submission rather than getting unexpected questions during assessment
-Understand how to author dossiers, which provide adequate information but ensure the company is not signed up to a lifetime of submitting changes with the smallest alterations in processes at site
-Help to build and control consistent information during the product lifecycle to avoid inconsistencies and errors.
As with our virtual biopharma company, early stage regulatory support inevitably provides the added value of building a solid relationship between yourselves and the competent authority assessors. Those foundations will benefit you long into the future, with the assessor’s direction and cooperation throughout the lifecycle reducing the risk of unexpected costs and delays, and optimise the chances of your success.
This article is taken from European Pharmaceutical Contractor November 2016, pages 12-13. © Samedan Ltd