Preparing a good regulatory strategy document

Hey friends, in today’s blog I am sharing some key elements, which in my opinion are important and hence needs to be captured in a regulatory strategy document. Regulatory strategy is very specific to a firm as it is closely aligned with the business strategy/goals of that firm. Having said that there are certain common elements which forms the basis of a regulatory strategy and I am making a humble attempt to cover those in my blog.

Let me begin by sharing my view of a regulatory strategy document (it can also be called as a regulatory plan). It is a simple road map of activities and resources needed to take any product from development to approval. It is a live document which would undergo revisions as we proceed with development and reach to a stage of getting the final approval. I believe such a document can also act as a means of written communication with different functions at different stages such as drug development, technology transfers, manufacturing of exhibit batches at sites, conducting stability studies, during validations, and marketing of drug after approval. Some firms may extend the scope of this document up to post approval stages and life cycle management of the product. 

Before I delve into how to prepare a document I want to emphasize the need for such a document. A strategy document ensures proactive planning, identification and mitigation of risk, well in advance by thorough research of the market and the product, so that there are no major surprises or pitfalls during later stages of development, manufacturing, registration and approval of the drug. It is akin to doing a thorough homework before going for the final step.

The earlier you get into regulatory planning, and preparing of this document the better. Ideal timing would be pre IND (Investigational New Drug) phase if you are into new chemical entity (NCE) development or pre product development phase for a new drug or generic development. In fact this document proves to be extremely useful in case we have to opt for official meetings with any health authorities during the development or clinical stages of the drug.

As a good practice a RA professional/Group lead/HOD should have a kick-off meeting before starting to prepare this document. The kick-off should be a cross functional meeting held with key functions by preparing a fixed agenda to discuss key elements. Regulatory can prepare a working draft wherein they can share their own research and come to the table for larger cross functional team discussions. Generally, at the start of project, most interactions would involve functions such as R&D, BD, Strategy, Project management team. As the development progresses to a stage of validation and manufacturing of batches at manufacturing facility the RA interactions would involve more functions such as validation, analytical, manufacturing and quality assurance teams. Regular meetings to discuss the strategy document ensures that all possible issues, gaps, assumptions are thoroughly discussed by subject matter experts and unanimous decision is taken on the way forward thus making it more relevant and useful to the end user. 

A meaningful strategy document would include the information listed below. For ease of understanding, I have also provided few examples.

Target market information - A regulatory strategy document will be aligned with the business strategy of the product. So, it should discuss about target markets where the product would be registered to get marketing approval. If it is considered for global submission all target markets should be mentioned.

Executive Summary - An executive summary should be included which provides a brief and crisp information about the basis of submission mentioning the type of application and details about the relevant health authorities. For e.g. if the target market is US and the strategy document is for a generic drug development, typically the information shared would be the type of application which in this case is ANDA (Abbreviated New Drug Application) and the reviewing and approving authority is Office of Generic Drugs (OGD) within FDA and the submission would be done electronically as per eCTD requirements of FDA.

Basis of submission – A regulatory strategy should explain why a particular type of application or regulatory pathway/route is most suitable for a particular market. Again taking an example of the US market, if the product under consideration is  entirely a new molecule and it is being introduced in the market , it would fall under category of New Chemical Entity (NCE) and Phase I, II, III and IV Clinical trial applications is done before it is provided as a full-fledged New Drug Application (NDA) for granting marketing approval. If the product is such that brand product is already in the market and it is a copycat drug then it will fall under generic application called ANDA, wherein marketing approval will be granted after proving only the bioequivalence (BE) of the drug with the innovator drug available in the market. In this case clinical trail involved would be bioequivalence study alone and approval granted without going through the conventional pathway of clinical trial approvals as mentioned above. To explain further, if the focus of a firm is developing a product in a specialized therapeutic area, then there would be additional considerations while deciding the basis of submission and regulatory pathway. A cancer drug which falls under a niche category for which there is an unmet medical need may classify under an orphan drug category and a fast track application or accelerated application pathway may apply. Identifying the type and basis of application ensures that the relevant studies are planned and conducted as per requirements for that particular type/ route of application.

Project summary –Under this section essential elements about a product can be captured. It is like creating a Target Product Profile (TPP). For new drug the TPP of the product would be considering aspects such as Intended use or indication, unique features or design characteristics, the proposed claims / proposed labeling.

Considering another example of generic submission, this section would include critical information about the reference listed drug or reference product, information about the innovator firm, the strengths approved and available in the market, the patent scenario of both - the active ingredients and the product, indications, dosage form, therapeutic category, brand names and other generics, if approved and available in the market.

All available information such as the drug approval package for same or similar drug can be shared. For example in the case of US submissions the link from Drugs@FDA , i.e. https://www.accessdata.fda.gov/scripts/cder/daf/ has a lot of information about various approved drugs and their reviews including the chemistry, medical, pharmacology, statistical, microbiology, clinical pharmacology, biopharmaceutics, labeling covering the quality, safety and efficacy aspects of any new drug . Similarly in case of Europe (EU) the following link : https://www.ema.europa.eu/en/medicines/download-medicine-data can be referred for EPAR reports. This information proves quite handy and helps in designing the development strategy and relevant study. It is like learning from regulatory precedence. Competitor website can also act as a very good source of information and should be explored and studied well.

Country/market specific requirements – If the product is being considered for different markets, then specific requirements for each market can be listed under this section. For example if a generic product is considered for marketing in three countries viz, US, EU and Brazil, information about the specific BE requirements for each market needs to be mentioned upfront which will include selection of right reference product, study requirements in terms of design (Fed/Fast, number of subjects, etc). The development study design may involve quality by design concept for few markets as mandated while it may not be so for others. Few other market specific requirements are - US requires IID (inactive ingredients database) checks for excipients, EU requests for specific tests as per EP monograph and Brazil requires BE at labs accredited by Brazilian authority (ANVIZA). These are just few examples and differences, or similarity may exist w.r.t the number of exhibit/pivotal batches which will be required for each market, requirements of official monographs, minimum stability data requirements and specific stability requirements depending on the temperature zone they fall into. Audit/inspection conducted by health authorities before granting any approval should be another important aspect as it has impact on approval timelines as well as budget. A tabulated information about all markets with its similarities and differences would be a good way of presenting the requirements.

Risks and assumptions – It is extremely essential to identify potential risks, be it during development, clinical studies or regulatory reviews and approvals. Identifying risk and documenting it in a strategy document ensures that a mitigation plan or remedial actions are discussed and implemented at right time saving loss of time, effort and money. For example, while developing a complex highly variable generic drug getting a comparable dissolution and BE results is a perceived risk as the probability of failure is high. So this risk should be highlighted as it may need reconsideration of product development design and probably a repeat BE study as well.

Similarly, preparing a list of assumptions considered during planning or costing helps to keep a track on it. As more and more information become available during development, there may be changes to these assumptions which may need course correction due to its impact on the successful outcome. For example during generic development, based on earlier information on similar product or reference listed drug it was assumed that a pivotal BE trial with ’n’ number of subjects may be required. Later, based on the developed products pilot study BE results there may be a need to increase the number of subjects for a pivotal study from whatever was assumed earlier.

Another risky assumption would be w.r.t audits and inspection of all sites involved be it for an Active Pharmaceutical Ingredient (API), Finished Formulation (FP), clinical site or any contract testing labs site. It may so happen that all or some of these may come under the purview of inspection while the review is on and depending upon the audit outcome the approval timelines may get impacted. So, there should be a provision to capture such risks and assumptions in a regulatory strategy document.

Meeting with health authorities - As mentioned earlier, meeting with health authorities may also be required for certain complex or novel product development especially when a need arises to do investments in new studies.  Such needs should be captured in strategy documents as regulatory plays an extremely important role in preparing the data package for such pre-submission meetings asking very specific and relevant questions to get meaningful answers from agency.

Timelines/budget/resource requirements– This is one of the most critical section of the strategy document as everything boils down to returns and how early we can achieve that with optimal investment or expenses. Regulatory needs to achieve the objective of getting approvals in time with submission of a high-quality dossier. The submission timelines should be proactively planned so that both the above objectives can be met. Checklist of all documents with suggested timelines should be shared mentioning the names of key function and stakeholders. Regulatory budget for doing the submissions, applicable fees depending on submission timelines and the consultant charges, if required, should be identified and mentioned upfront. Any additional resource requirement, if applicable should also be highlighted.

References – I strongly recommend providing links of all important guidance, regulations and policy documents for each country/target market. For eg for US before starting any new clinical trial, FDA website clinicaltrial.gov (follow link : https://clinicaltrials.gov/)  can be referred to as it helps to identify products in clinical investigation and also provide good information on clinical trial design and study results. For generic development reference drug labeling information is critical. For US, latest labelling information can be referred to on the daily med website (follow link : https://dailymed.nlm.nih.gov/dailymed/index.cfm), for EU the Summary of Product Characteristics (SPC) (follow link : https://www.ema.europa.eu/en/glossary/summary-product-characteristics ) can be referred to for labelling information. Similarly for BE US provides specific BE requirements at link : https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development . Similarly for EU follow link : https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/clinical-pharmacology-pharmacokinetics/product-specific-bioequivalence-guidance. The EPAR also provides the BE summary and can be referred to in case product specific information is not available. This section may regularly undergo revisions whenever any reference guidance is updated or revised. This will ensure change in development plan is implemented immediately for compliance to new requirements. As mentioned earlier this is live document and is expected to change due to changes in regulations, changing expectations of agencies, new information on similar products in markets. 

I would like to conclude this blog by saying that even though every firm may have their own business goals and a regulatory strategy must be aligned to that goal but the four key aspects which every strategic document should try to answer is what has to be done, when it has to be done, how much is required to be done, and who will be responsible and accountable to do it.

In my next few blogs I will cover aspects of quality by design and how it leads to faster approval with a case study on US market. See you soon!!