PHARMACEUTICAL GLOBALIZATION - Navigating Opportunities & Obstacles

INTRODUCTION

There are many reasons to celebrate the globalization of the pharmaceutical industry. It brings with it access to medicinal prod­ucts for far more patients, as well as greater commercial oppor­tunities for pharmaceutical companies.

At the same time, globalization adds complexity. Companies must navigate ever-changing regulations and government poli­cies that differ across jurisdictions. They must consider cost con­straints or expectations at the local and regional levels that can affect market access. And they must consider heightened con­sumer demands.

This environment means companies must plan strategically, drawing on good regulatory intelligence, before launching their products. This need is further accentuated by the fact that drug development, particularly for innovative products, can span 8 to 15 years, meaning it’s a significant challenge for companies to predict the global regulatory landscape at the time of submission or even being granted marketing authorization.

Companies should consider early market access strategies, carefully selecting which markets to pursue first and how to re­purpose a regulatory submission to best effect, taking into con­sideration economic factors, in particular the relationship between expected profitability and investment in research and develop­ment. They should seek to gain insights into the market and reg­ulatory dynamics in each region and have on-the-ground expertise in all markets they plan to target. And they must ensure they understand the patient population and medical need in each market.

MAKING THE MOST OF HARMONIZATION

The most notable regulatory harmonization initiative is that of the International Council for Harmonisation of Technical Re­quirements for Pharmaceuticals for Human Use (ICH), which works collaboratively across regulators and industry to develop uniform guidelines and technical requirements. ICH members adopt those guidelines, helping to:

• create greater uniformity around quality, safety, and efficacy criteria
• support the electronic transfer of regulatory information
• adopt a common format for information sharing
• use standardized medical terms to enable regulatory informa­tion to be shared internationally

Certainly, COVID-19 helped to accelerate the level of col­laboration between regulators. As highlighted in a Lancet paper, there was unprecedented convergence in regulatory requirements to support vaccines and therapeutics for COVID-19, enabling de­velopers to set development plans without significant hurdles.¹

Propelled, in part, by the urgent need for more agile regu­latory processes during the pandemic, a number of harmoniza­tion initiatives have developed between regulatory authorities. Most notable are the Access Consortium and Project Orbis.

The Access Consortium was established to promote collab­oration among regulators across different geographic regions, as well as better alignment of requirements for assessment and approval of medicinal products. Its members include the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA), Health Canada, Australian Therapeutic Goods Administration (TGA), Swissmedic, and Singapore’s Health Sciences Authority (HSA). The goal is to work toward a goal of improving cooperation, reduce regula­tory duplication, and increase each agency’s capacity to ensure consumers have timely access to safe and effective medicinal products.

In its strategic plan overview, the con­sortium noted “Greater regulatory agility and international alignment by sharing of scientific resources and expertise, while at the same time maintaining independent regulatory decision-making within each authority, will reduce a product’s time to a wider market. Exploring collaboration with national health technology assessment or­ganizations (and similar) by Access coun­tries also serves to improve patient access to safe and effective health products.”²

Project Orbis, meanwhile, was estab­lished in 2019 as a collaboration between the US FDA, the TGA, and Health Canada. Since its initial launch, several other regu­latory authorities have joined: Brazil’s Health Regulatory Agency (ANVISA), Is­rael’s Ministry of Health Pharmaceutical Division, HAS, and the MHRA. The aim of Project Orbis is to cut cancer drugs’ review time across country borders, facilitating concurrent submissions by sponsors and collaborative reviews between agencies.

Project Orbis is a model for regulatory collaboration that is taking shape around the world and a reminder that collabora­tion is the key to improving the review process and access to life-changing med­icines.

For its part, the UK’s MHRA has been taking broad steps to streamline and har­monize processes, recently announcing plans for a new international recognition framework.³ The MHRA adopted the Euro­pean Commission Decision Reliance Pro­cedure (ECDRP) after Brexit, extended to the end of 2023, which allowed the UK agency to fast track any products man­aged by the European Medicines Agency (EMA) and granted marketing authoriza­tion by the EC. From the start of 2024, MHRA will introduce the new framework, which will consider decisions by EMA and some other regulators, enabling a simpli­fied, more harmonized route to market in the UK.

There are also initiatives to improve regulatory harmonization to enable better access to medicines in the developing world. Led by the World Health Organiza­tion (WHO) and the International Federa­tion of Pharmaceutical Manufacturers and Associations (IFPMA), efforts have focused on a drug classification system, Interna­tional Pharmacopoeia and standards for pharmacovigilance through the WHO Pro­gram for International Monitoring, and a medicines prequalification program to fa­cilitate the distribution of drugs to devel­oping nations.

EARLY ACCESS HARMONIZATION

Important early access initiatives in the EU, UK, and US are also starting to see greater harmonization. Recently, the EMA introduced several important changes to its PRIority Medicines (PRIME) scheme, which seeks to speed the development of life-changing medicines.

Changes to the scheme include a roadmap to assist innovator companies when compiling information, expedited scientific advice, and submission readiness meetings a year ahead of submitting a marketing authorization application.

These changes bring PRIME into closer alignment with the UK’s Innovation Licensing and Access Pathway (ILAP) pro­gram, which provides tools to support companies through the development process. ILAP is similar to the FDA Fast Track process, which enables rolling re­views and allows applicants to submit completed sections for review rather than waiting until the entire application is com­plete.

With the PRIME changes, developers of innovative products can take advantage of greater harmonization between the three regions with regard to scientific ad­vice and regulatory support.

Early access or accelerated access programs, such as for orphan drug products, can guide market decisions. If navigated effectively, making use of scien­tific advice offered by many regulators, companies may be able to design strate­gically considered dossiers that might then be leveraged for easier transfer to other markets.

NAVIGATING DIFFERENCES

While there is fairly seamless harmo­nization between some authorities, for ex­ample, the FDA and Health Canada, that is not always the case. Some emerging markets have not only tightened their reg­ulatory requirements but also have some region-specific expectations. For example, in some Asia-Pacific markets, high-level knowledge of the regulation is not suffi­cient. Rather, companies must have access to the local health authorities through face-to-face interactions to understand and interpret what they want and expect.

It is important to understand regula­tors in many developing countries must balance public health requirements with cost, while responding to rapid change as these markets open up and expand. After all, there are currently 300,000 manufac­turing facilities in 150 countries – countries that are not only producing products but also seeing increased demand for medical goods and services.⁴

Different approaches to the regula­tion of medicines can also occur in regions where there is, ostensibly, full harmoniza­tion. In the EU, despite efforts by the EMA to ensure consistency across member states, there are varying requirements and expectations in various countries when it comes to specific tasks that must be car­ried out at the national level.

One notable example is advertising of prescription medicines. The principles that underpin responsible advertising and pro­motion often get fleshed out in detail on a national level through self-regulation and adherence to industry codes of practice, reflecting the norms, lifestyles, and societal preferences of those local markets.

The supply chain is another market difference that is often poorly understood. When seeking global launches, compa­nies need to know whether the product or active pharmaceutical ingredients and ex­cipients can be imported from the country of origin. If not, they must ask themselves some critical questions, such as: What are the logistical challenges with building a manufacturing site in the target markets? Is there potential to partner with third-party manufacturers? What are the regulatory requirements to register those sites? Can increased demand in a certain country/re­gion be managed by importation?

LOCAL & GLOBAL REGULATORY INTELLIGENCE

Local regulatory intelligence and on-the-ground expertise in all the markets a company operates in are imperative for that adherence to local requirements and for interacting effectively with health au­thorities. As an example, in the area of pharmacovigilance, most regulators re­quire a local contact person who is a citi­zen of and physically located in that country.

Good regulatory intelligence is also important if companies are to streamline their submission processes, such as lever­aging a submission with a reference coun­try – in other words, countries or regions with trusted regulatory authorities, such as the US or EU or a comparable health au­thority – when seeking to bring those in­novations to other markets.

Regulations and legislation are con­stantly evolving, and companies must de­ploy regulatory intelligence – internally or externally – to stay on top of these. As an example, the European Commission re­cently submitted a proposal for a new Di­rective and a new Regulation to the European Parliament and Council for con­sideration.

The new legislation seeks to drive in­novation, to ensure the safety, quality, and efficacy of medicinal products for EU pa­tients, and to harmonize the supervision and control of such products. In particular, the legislation will repeal and replace gen­eral and specific legislation, such as the Orphan Regulation and the Paediatric Regulation, with legislation that applies to all other products. The new EU legislation incorporates specific requirements that apply to these products in the new regula­tion and the directive “in order to ensure clarity and coherence of all the measures applicable to these products.”⁵

This puts everything in a consolidated legal document that provides more precise guidance, enabling more strategic plan­ning for companies, ensuring they have clear guidance in one place to support them from early development and to un­derstand what regulators expect.

PREPARING FOR REIMBURSEMENT

As complex as the regulatory land­scape is, an even greater source of uncer­tainty for the industry is market access and reimbursement. To gain market access, developers must be able to demonstrate clinical and economic evidence to providers, healthcare decision-makers, and payers – be these insurers, govern­ment programs, or health technology as­sessment bodies (HTAs).

They must not only show the efficacy and safety of their product, but also its ef­fects on healthcare outcomes and resource utilization. To effectively demonstrate their product’s value to payers, developers must be able to show how their product im­proves patient outcomes or reduces the burden on the patient and the healthcare system. That means having good real-world evidence to provide a better value proposition to decision-makers.

Too often, given the time span for de­velopment and not always knowing the in­tended markets early on, this process only begins later in product development, by which time it is too late to determine if the clinical trial and clinical data fits the needs of the HTA.

Early phase modelling, which evalu­ates costs and expected outcomes of new and current treatments using assumptions and extensive sensitivity analysis, should be performed as soon as possible in the product development process when there is a need to understand opportunities and challenges from a health economic per­spective.

The importance of early discussion, particularly for novel therapies, is again underscored with the UK’s ILAP program, which is a collaboration between the MHRA, the National Institute for Health and Care Excellence (NICE), the Scottish Medicines Consortium (SMC), and the All Wales Medicines Strategy Group (AWMSG).

As Daniel O’Connor, Deputy Director of Innovation Accelerator and Regulatory Science in the Scientific Research and In­novation Group at the MHRA, has noted “If a company wants to do something novel or if it wants to try to push the boundaries on the acceptability of the data or think about different managed access approaches, then having those early dis­cussions with both the medicines regulator and the HTA bodies is key.”⁶

CAUTIOUS PROGRESS

Globalization has brought with it nu­merous issues to consider at every stage of the journey – whether bringing an innova­tive product to market or planning expan­sion initiatives. Yet, it has also created new opportunities to bring products to more people in more markets.

From important cooperative pro­grams, such as the Access Consortium and Project Orbis, to efforts by global organi­zations, such as ICH, WHO, and IFPMA, there are growing opportunities to stream­line global regulatory processes. Differ­ences remain – and likely will continue, due to the needs and expectations of each market – but by taking advantage of im­portant programs and staying on top of market dynamics through regulatory intel­ligence, companies can enjoy greater suc­cess globally. Most importantly, increasing numbers of patients in developed, emerg­ing, and developing countries that will enjoy access to these medicines.

The contents of this article are solely the opinion of the author and do not rep­resent the opinions of PharmaLex GmbH or its parent AmerisourceBergen Corpora­tion. PharmaLex and AmerisourceBergen strongly encourage readers/listeners to re­view available information related to the topics mentioned herein and to rely on their own experience and expertise in mak­ing decisions related thereto.

REFERENCES

1. Shaping EU medicines regulation in the post COVID-19 era, Cavaleri, M. et al, Oct 2021, The Lancet. https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00169-1/fulltext.
2. Access Consortium, Strategic Plan 2021-2024. https://assets.publish­ing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/995111/Access_Strategic_Plan_2021-2024_Final__with_graphic_.pdf.
3. European Commission Decision Reliance Procedure (ECDRP) extension, MHRA, Jan 2023. https://www.gov.uk/government/news/european-commission-decision-reliance-procedure-ecdrp-extension.
4. Current Challenges (and Solutions) in Global Regulatory Harmoniza­tion, https://premier-research.com/blog-global-regulatory-harmoniza­tion-current-challenges/.
5. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:52023PC0193.
6. Science Huddle – Small Data, Big Outcomes, Biopharma Excellence. https://www.biopharma-excellence.com/insights/whitepapers/strate­gies-for-achieving-statistical-significance/.

Dr. Jürgen Hönig is Senior Director, Regulatory Business Intelligence at PharmaLex. He has played a significant role in the design of the regulatory intelligence strategy at PharmaLex and provides analysis on trends in the pharmaceutical and medical device industries. He is a pharmacist by training and earned his PhD from Johann-Wolfgang-Goethe University, Germany.