Regulators across the globe have hailed collaboration, and in particular regulatory reliance and worksharing initiatives, as the future of drug regulation. Schemes such as Project Orbis, the ACCESS Consortium, and the UK’s new International Recognition Procedure (IRP) promise not only to improve cross-border harmonization, but also to speed up patient access to drugs in countries outside of the US and EU.
While many longstanding regulatory reliance (RR) pathways were introduced to improve access to medicines in lower-income countries, there has been a rise in international collaboration between higher-income nations, such as the UK, Switzerland and Canada, over the last year.(Also see "International Regulators Say Collaboration Is Key To Tackling Pharma Globalization Challenges" - Pink Sheet, 25 October, 2023.).
The EU, meanwhile, has begun to implement its new OPEN initiative, three years after an initial pilot of the scheme began, which will allow partnering agencies to contribute to scientific evaluations while retaining autonomy in their decision-making.
However, while the trend towards regulatory globalization looks set to continue in 2024 and beyond, some experts and industry representatives have raised concerns around the challenges of regulatory reliance and the limitations that must be addressed.
Alison Dennis, partner and co-head of the international life sciences team at law firm Taylor Wessing, told the Pink Sheet that the challenge for any country using a reliance pathway is “balancing having some control over the products entering their market, where that might be necessary, and having a system which facilitates placing new products on the market.”
She also explained that some pathways, such as Project Orbis, are not pure reliance routes but rather “a collaborative regulatory pathway” between different agencies.
“A reliance route is where one country accepts or ‘relies upon’ the decisions of another country,” Dennis observed, adding that there may be instances where countries have different requirements that medicines must meet to be approved “because their perception of the risks and benefits of particular types of pharmaceuticals is different.”
“In that situation, harmonization would only be achieved if regulators in all countries were to combine their thinking and agree to harmonize their approach. This would be a collaborative way of working rather than a reliance route,” she said.
While Project Orbis and the ACCESS Consortium might not fall within the technical definition of pure reliance pathways, the use of these collaborative frameworks does signify a shift towards regulators implementing more harmonized, flexible and faster ways of working.
“Globally, we see many positive trends in using and implementing reliance pathways both by the industry and the regulators as a way to use resources wisely to approve medicines more effectively to expedite the review process,” a spokesperson from EFPIA, the trade association for Europe’s R&D-based pharmaceutical industry, told the Pink Sheet.
While the spokesperson said that EFPIA “believes that reliance should also be used during all stages of a product’s life-cycle, including handling of post-approval changes since this represents the majority of regulatory filings,” they outlined “a number of challenges to be addressed to bring reliance into action around the world.”
“One of the main challenges in using reliance as a standard regulatory tool by regulators is that its use needs to be encoded in the respective drug regulations/legislations of many international countries,” the spokesperson said.
Without such an explicit legal provision, authorities “might not feel empowered” to use the decisions from reference regulators to inform their own decisions, but would be “obliged to perform the entire operation in a redundant manner leading to inefficient use of scarce available resources.”
2023: A Busy Year For The UK
Of all the international medicines agencies, the UK’s MHRA was perhaps the busiest in terms of regulatory reliance in 2023, as the organization continued to traverse its new role as a free-standing regulator following the country’s departure from the EU.
Most notably, the UK firmed up the terms of its new IRP, the framework under which it will take into account approval decisions made by seven other world regulators during its own review process.(Also see "UK’s New International Recognition Procedure A ‘Win-Win’ For Stakeholders" - Pink Sheet, 2 January, 2024.).
A spokesperson for the MHRA told the Pink Sheet that the IRP would allow the agency to “make the most of the expertise and decision-making of trusted regulatory partners to streamline assessments of specific products.”
“As a result, cutting-edge medicines that have been approved in other countries will get to UK patients without delay, resulting in a more rapid, efficient, and cost-effective process for applicants.”
Launched officially on 1 January, the IRP replaced the European Commission Decision Reliance Procedure (ECDRP), under which the MHRA could use centralized EU approval decisions in its assessments.
The IRP is also intended to speed up MHRA reviews, with two choices of pathway within the framework: the type A route, which offers a 60-day timeframe for authorization decisions, and the type B route, which has a 110-day timetable with one clock stop at day 70, giving the applicant up to 60 days to respond to any issues identified.(Also see "UK Regulator On Using The New International Reliance Procedure To Encourage Filings" - Pink Sheet, 9 October, 2023.).
The seven reference regulators for the IRP are: the EU (the European Medicines Agency and national regulatory agencies), Australia, Canada, Japan, Switzerland, Singapore and the US.
Dennis noted that the UK “clearly” trusts the decision-making of the reference countries, or it would not have chosen them, something that is important for any country when entering a reliance pathway.
“However, there are products for example which are authorized in the US which have never been authorized in the UK,” she said, adding that there are also “different classification decisions,” such as some UK pharmacy-only products being more freely available in the US, or available in larger pack sizes, such as analgesics.
“Where the UK has a more restrictive approach, applicants might find that the UK decision does not precisely match their RR authorization, or that it is rejected,” she said.
Daniel O’Connor, director of regulatory and early access policy at the Association of the British Pharmaceutical Industry (ABPI), told the Pink Sheet that having various routes to market “helps to align the product launch and timely access to innovative medicines.”
“Options like the IRP give companies more choice, based on the decisions of another trusted regulator,” he continued, although he said there was a “need for more positioning information on the MHRA’s regulatory flexibilities and the impact of the IRP.”
“Better understanding of these regulatory options will help companies allocate their resources efficiently, making sure they can choose the most suitable regulatory path at the right time,” he added.
Route A offers companies a 60-day, fast-track timeframe, but most innovative products will fall within the slower route B pathway. In an ABPI blog post last September, O’Connor described route B as “not particularly competitive versus the national procedure”, and said that most innovative products would fall within this category due to the eligibility criteria for each route.
The UK also continued its participation in Project Orbis and the ACCESS Consortium, two separate but similar drug review schemes that aim to harmonize and streamline regulatory submission and review processes across jurisdictions.(Also see "How Does The ACCESS Consortium Compare To Project Orbis?" - Pink Sheet, 31 October, 2023.).
Fast-Track Routes: Is The Bar Too Low?
Despite enthusiasm from the MHRA around its participation in new regulatory reliance pathways, some academics have voiced concerns about whether fast-track pathways are fit for purpose.
Richard Sullivan, professor of cancer policy and global health at Kings College London and director of the Kings Institute of Cancer Policy, told the Pink Sheet that the MHRA was “effectively waving through any drug that is filed through pretty much any route.”
“The bar is really low. Far too low,” he said, adding that fast-to-market pathways were “dumping ineffective drugs on the market and also creating price negotiation pressures that simply should not be there.”
Sullivan was one of eight high-level academics to co-author a paper entitled ‘From the European Medicines Agency to Project Orbis’, published in April 2023 in The Lancet, a world-leading peer-reviewed medical journal. The paper outlined the MHRA’s activities in oncology regulation post-Brexit, and stressed the need for stringent regulation and alignment with health technology assessment (HTA) processes.
The paper’s authors warned that “enthusiasm” for expedited drug development and approval needed to be “tempered with the reality that fast-tracking cancer drugs might simply add more medicines into the market that might not necessarily deliver clinically meaningful benefit or value.”
Sullivan further explained that in terms of market access, there were two issues posed by fast-track pathways such as Orbis, which focuses on oncology drugs. The first was that some marketing authorizations were being granted to cancer medicines “which do not deliver clinically meaningful benefit” – something that would not be “fixed” by any HTA process as these drugs “are just unfit for clinical use”.
The second issue presented by fast-track approval pathways, according to Sullivan, was the approval of medicines which, although clinically beneficial, were launched at a “premium price,” beyond the willingness-to-pay thresholds of HTA organizations such as England’s NICE.
“Regulatory approval these days does not mean either a) an effective cancer drug that delivers clinically meaningful benefit, or b) one that is then fairly priced,” Sullivan contended.
In October last year, an analysis of drug approval and HTA data by the Pink Sheet found that, at the time of publication, fewer than half of drugs licensed under the Orbis pathway had been approved for National Health Service (NHS) reimbursement in England.(Also see "Project Orbis: More Cancer Drugs Available In Scotland Than England" - Pink Sheet, 24 October, 2023.).
Although more cancer medicines authorized through the pathway were available in Scotland, the analysis revealed a lag between the approval of a medicine and its availability on the NHS in both regions.
Meanwhile, a subsequent Pink Sheet analysis of the regulatory decisions made by all Project Orbis partners found that most partnering countries did not keep pace with decisions made by the FDA, even when those countries participated in the review process.(Also see "Project Orbis 2023: FDA Approves Six New Cancer Drugs, But Partner Nations Lag Behind" - Pink Sheet, 5 December, 2023.).
However, several regulatory agencies, including Swissmedic, Health Canada, and Australia’s TGA, praised the Project Orbis pathway and claimed that it had led to faster drug approvals in their jurisdictions.(Also see "Swissmedic On Project Orbis: Faster Access To Drugs, Valuable Scientific Discussions" - Pink Sheet, 5 October, 2023.).
ACCESS Consortium Expansion
Another regulatory reliance initiative that expanded during 2023 was the ACCESS Consortium, a work-sharing coalition made up of the regulatory agencies for Australia, Canada, Singapore, Switzerland and the UK.
In December, the regulators announced the launch of a pilot scheme dubbed the “promise pathway”, a framework within the ACCESS Consortium’s existing new active substance work-sharing procedure that offers a priority review to medicines that meet certain criteria, such as those being developed to treat life-threatening or severely debilitating conditions.(Also see "How The ACCESS Consortium’s New ‘Promise Pathway’ Can Benefit Drugmakers" - Pink Sheet, 18 December, 2023.).
The ACCESS Consortium has also set its sights on advanced therapy medicinal products (ATMPs). In November, the organization announced that it had established a new working group to focus on these products, but little information was revealed following a request from Pink Sheet about whether any cell and gene therapies were undergoing an assessment by the ATMP working group.
The introduction of the promise pathway pilot and the ATMP working group within the ACCESS Consortium framework suggests that use of this reliance pathway will become more prevalent during 2024.
ACCESS has not proved a resounding success, though, at least according to EFPIA, which says the industry experience with the consortium so far “has been mixed”, with advantages of shorter approval times in some cases “but no clear time saving in other cases.”
“Although the work-sharing mechanism results in more robust regulatory decisions, different national requirements and regulatory processes could prolong the time for national approval as the industry has experienced with some submissions,” EFPIA added.
EMA: Collaboration To Continue
The EMA participates in three main regulatory reliance pathways, which are primarily focused on enabling non-EU countries to benefit from EMA assessments: the EUMedicines4all procedure, the WHO collaborative registration procedure and the recently introduced OPEN initiative. These are presented in the table below.
In addition to these three procedures, the EMA has also joined Project Orbis as an informal observer, meaning it is not a Project Orbis partner but it will begin to watch the process more closely.([A# PS149579]).
Implementing the new OPEN (Opening our Procedures at EMA to Non-EU authorities) initiative, a pilot version of which was launched in December 2020, will be a key focus of the EMA in the year ahead, a spokesperson for the agency told the Pink Sheet.
The OPEN pathway involves the medicines regulators in Australia, Canada, Japan and Switzerland, as well as the EMA and the World Health Organization. It allows these regulators to exchange information with the EMA and participate in scientific evaluations, but the different agencies remain independent throughout.
The EMA spokesperson said that the agency expects international collaboration to “play a bigger role in the future,” and noted that the proposals to overhaul the EU pharmaceutical legislation set out by the European Commission “explicitly foresee this.”
“International collaboration was already a firm fixture on the pharmaceutical regulatory scene before COVID-19, but the pandemic cemented the importance for all regulators – no matter how big or small,” the spokesperson added.
“Collaboration and convergence are in the interests of regulators and the pharmaceutical industry, and ultimately in the interest of public and animal health.”
The commission adopted its proposals for the revision of the EU pharmaceutical legislation on 26 April, but the package is still being debated by the European Parliament and the Council of the EU.(Also see "EU Pharma Reform Proposes Cuts In Regulatory Protections & Faster Drug Approval Times" - Pink Sheet, 26 April, 2023.).
The EMA also said it supports and encourages national regulatory authorities to implement the WHO’s Good Reliance Practices, which were published in April 2021 with the aim of helping regulators make the best use of the available resources and expertise and improve access to quality-assured, safe and effective medicines.
“Reliance needs to be seen as a modern 21st century way of doing our regulatory business,” the EMA’s spokesperson said, adding that the agency would “continue to contribute to WHO efforts to help regulators understand and implement reliance.”
