We welcome Sue Allen, Senior Regulatory Affairs Consultant, to discuss the practical considerations of international expansion and the questions that should be asked during the planning and execution stages of licencing your pharmaceutical products globally.
As developed markets continue to stagnate, emerging markets are becoming even more important as a source of revenue growth for pharmaceutical companies. Whilst international expansion is critical to ensuring the greatest reach of products to patients across the globe, there are challenges as companies move away from the large established EU and US markets. Many companies find that they are not readily equipped for gaining access into these markets and there is a need to upgrade commercial, regulatory and technical capability, either within the company’s resources or with external support.
Defining the geographic reach
Defining the company’s strategy for global expansion as early as possible is the key for success. The expansion plan will likely include products that are already licenced in the other large markets (EU, US etc.) and those which are currently in development. One of the first questions to ask when looking at potential markets is ‘Is the market ready for the product?’ Whilst a company may have a great product, the market may not be ready for it. Externally a company may need to build relationships with policy makers, policy shapers and other medical and non-medical stakeholders, to get that market to a stage where it is ready. There is also a need to hold discussions that go beyond products to include health systems, disease pathways and other policy topics. Marketing Authorisation (MA) approval times can be long so a company could well embark on an application knowing that in 12/18/24 months etc they can prepare the market, but this will depend on how confident the company is in being able to develop that market. The other option is to wait until the market is ready before the MA submission takes place, but of course in this instance valuable time is lost in being able to commercialise the product.
For products under development the company has an advantage of being able to define its expansion strategy from the start, and to ensure that data is available to meet the regulatory submission milestones down the line.
For those that are already licenced in other markets the focus is on gap analysis – what data is available, what can be repurposed and what additional justifications are needed. To make the expansion model as efficient as possible the company should primarily look at re-evaluation of data rather than generating new data and to understand what is really being requested by the Health Authorities and be able to use the data to satisfy those requirements.
Companies need to ascertain the data requirements for MA applications as soon as possible. In most cases each country has its own national regulatory legislation, although there may be regional legislation (Middle East) or cross country collaborations such as Project Orbis and the Access Consortium. Understanding the details of what is actually required can be difficult and this can be exacerbated by guidance and communication being in the local (non-English) language.
Partner/Third party engagement
In many cases a local presence is needed in the international country, either to represent the company or to actually hold the MA. For the larger multinationals, who have affiliates in international markets this is a much easier task. However for small companies who do not have local presence they will need to engage with a local or regional partner. This is essential to acquire local knowledge of what is needed to support MA applications, to be able to communicate to the local HA in local language and to bring along expertise as to how in practice the regulatory process works. Often how things operate ‘on the ground’ is different to what is provided in guidance and legal text.
Depending on the company’s expansion plans it may be more prudent to engage with a local partner directly in the market, or if the company is expanding into a region it may make more sense to work with a regional partner who will manage their local agents in the countries. This avoids having to have multiple agreements with a number of partners and can offer some consistency of communication and approach.
It is vital to fully assess the partner you intend to work with. Not just from a regulatory standpoint but to assess what other services they can offer to support the registration and commercialisation of the product. Does the partner need to fulfil all the necessary obligations or does the company want to work with multiple third parties who have different specialities. Engage with a Quality Expert to ensure that a robust assessment is carried out of the partner. Looking at how they operate, do they have a Quality Management System in place, do they have accreditations etc. Companies need to be very clear on what they want the partner to do and who will be responsible for each task, and ultimately who will be accountable for the information provided to the Health Authority.
Key areas that should be focused on include the following:
- Does a MA alone allow the company to commercialise the product, or are other approvals also required, such as a post marketing study? If so what are the requirements, does the company have the expertise in market to carry out such a study, how many patients need to be enrolled and what is the cost?
- Is the demographic for the available study data appropriate for the international market? Are further clinical studies needed?
- What are the market access requirements – what are the pricing requirements? Does pricing form part of the MA application or does it need to be agreed post MA approval? Is pricing based on prices in reference countries? If so, is the product still viable at that price? What impact does a price in an expansion country have on your other markets?
- Is the dosage form of the product acceptable in that market? Some markets are more likely to accept a certain dosage form over another. Something being developed for the US market may not be suitable for Japan for example. Is further product development required and what additional data is needed to support the MA application. Can data already available in another dosage form be extrapolated?
- What patent protection is available for the drug? Are there potential issues in the international market around data security?
- Is the country of the manufacturer recognised by the country where the company intends to make the MA submission, or does it restrict MA pathways available.
- Timing can be crucial in expediting MA assessments in some markets.
- There is an advantage in submitting international MA applications within a certain timeframe of receiving approval from the reference country, such as potential for an expedited assessment.
- Is the company ready to commercialise the product after MA approval? In some markets the inability to commercialise the product within a certain timeframe can lead to loss of the MA or a negotiation with the Health Authority to retain it. The Sunset Clause in the EU is an example of this.
- What are the pharmacovigilance requirements: Is a local Pharmacovigilance System Master File needed? Does a local PV person need to be registered with the authorities? Can the partner respond to Healthcare Professional and patient enquiries, can they process Adverse Events? If not who will do this?
- Is local quality support needed? Does there need to be a local complaint handling procedure in place? Who will manage recalls? Does the MA application require formal documentation of the process being in operation?
- How will the product be distributed to the market? Does the application require shipping validation? Who will provide this information end to end? Is the partner going to be involved or will product be shipped directly from the company to the local wholesalers?
- Does the product require redress? In some instances it may be possible to provide an English labelled pack but sometimes over-labelling or replacement of the Patient Information Leaflet may be required. Does this product have to be re-released? Who will do this?
Managing the regulatory information
As mentioned previously the majority of international expansions are at a national level. For companies who are used to dealing only with EU centralised licences, geographic expansion brings in new complexities of having to manage many more dossiers and additional local requirements.
Some markets require an exact copy of the information supplied say in an EU submission, however for some markets a slightly reduced Module 3 may be submitted. This may benefit the company for some countries where data security may be an issue, or the company may see value in reducing detail to reduce the number of future variations during life cycle maintenance. However the more variants of the dossier there are, the more work is required to manage them. So a reduction in detail may ultimately lead to a reduced number of variations and reduced cost, however it adds to the need for impact assessments to be carried out on an individual dossier basis and further administrative burden, something that can be avoided if a ‘global dossier’ is used.
In conclusion, international expansion offers the advantage of a much larger product reach. However, companies need to recognise that the international region is simply not an ‘add on’ to key markets and the key for success is the need for a clear defined strategy and an understanding of the complexities that expansion brings.