Master plan: dossiers for pharma

Dr Rajendra Wable, Sciformix Corporation, describes an innovative approach to repurposing a master dossier

The pharmaceutical industry is highly regulated, with rules enforced by the health agencies to protect the consumer. The number of regulatory requirements has grown exponentially as biopharmaceutical companies enter new and disparate markets, but efforts in global regulatory harmonisation have stalled. To support the global growth imperative, regulatory functions must meet the local needs of a greater number of countries, while supporting an expanding list of products and aggressive project timelines. Differing registration requirements across markets are a burden, however, it is possible for them to use the differences to a certain extent. This can be achieved, for example, by registering products in countries like the US or across the EU that has streamlined regulatory requirements and use these initial registrations to support registration in other countries.

Preparing one core dossier first and adapting it to the regional specificities in a second step (the ‘parallel preparation’ approach) can allow optimising resources and may lead to a faster global registration. Similarly, a sequential approach (preparation of the NDA first and then conversion to an MAA, or vice versa) can allow the applicant to obtain feedback from the first agency and make adjustments to the second dossier prior to its submission, if relevant.

For many biopharmaceuticals, the core or master dossier generally contains the most comprehensive CMC, non-clinical and clinical information available on the product from a regulatory point of view. This master dossier forms the basis of the international master dossier for non-ICH countries. Generally, the master dossier is kept up-to-date with all new information requested by health authorities from the time of initial approval and through the products life cycle. These updated core dossiers are tailored to suit other country specific submission formats and requirements. From this core dossier, the CMC sections are shortened for confidentiality and intellectual property issues. Therefore, in the repurposed dossier, the drug substance section, Module 3, is created containing abbreviated documents. The other documents from Module 2 and the complete Modules 4 and 5 are copied from the core dossier without any redaction. Similarly, the general sections of Module 1 are only reformatted to meet the region specific requirement.

It’s not simple. If an applicant just deletes some sections of the ICH dossier and submits an ‘incomplete’ dossier, there is a risk of refusal to file. Therefore, it is strongly recommended that only the content in some sections (especially in Sections 3.2.S.2 and 3.2.S.3) should be reduced to fulfil the regulatory requirement. One possibility to make these changes within the dossier is the creation of master dossier with a high granularity for documents in order to be able to exchange parts quite easily for the emerging countries (eg for each section and subsection one separate document is available). This approach helps limit the highly confidential information and reduces the workload in the writing and reformatting.

Registration of generic products is similar, but simpler than, the process for new drugs. For a generic, a company develops a dossier that contains data primarily about the pharmaceutical chemistry of the product and some limited clinical data. In some instances, a product can be registered on the basis of chemical and manufacturing data only (eg an injectable formulation for which there is a recognised pharmacopoeial standard, such as the British Pharmacopoeia, or the United States Pharmacopoeia), describing the method of synthesis and quality control for the product. For oral formulations, the application needs to include dissolution testing and limited clinical data in the form of bioequivalence and/or bioavailability studies which show that the generic product is bioequivalent to the innovator. The requirements for generic product registration do vary from country to country, and there are variations in the data required depending on the type of generic product.

For any successful submission creating and managing global submission templates is of paramount importance. Selection of the correct ‘submission template’ for specific country and submission types is a critical step for successful approval. The primary purpose to develop and use the standard template is to ensure compliance with the regulatory norms of that particular region. Regulatory agencies have provided granularity guidelines and these vary based on product, agency and submission type. The template needs to be versatile such that it can be used for submissions in CTD in paper format, Non-eCTD electronic Submissions (NeeS) and for eCTD. Additionally, the template should be user friendly, and ensure that regulatory professionals can perform the reformatting with minimal training.

To achieve simultaneous global approvals, companies need focus on the strategy, capabilities, and processes. By redefining their regulatory operating models now, such companies will be better positioned to achieve near-simultaneous global market approvals and reach populations in need of their products, wherever those patients may be.