INSIGHT BLOG
A Regulatory Examination of Managed Access Trends
Introduction
Around the world, many patients with serious illnesses have exhausted all available treatment options, or in some cases, no treatments even exist. Alongside this, new treatment options can take years to come to market. Unlicensed supply mechanisms can bridge this crucial gap outside of access through clinical trials or commercially available reimbursed products in a given territory.
And whilst unlicensed drug supply is not a new concept, demand for such supply, particularly for post-trial access and additional indications, is on the rise. Growing knowledge among empowered patients, advocacy groups and healthcare professionals, and across emerging and low-and-middle income countries (LMICs), means a rapidly changing regulatory geography for unlicensed access.
In this article, we will explore some of the trends Clinigen Regulatory Affairs are seeing in this environment, review what works well and where there are suggested improvements.
Post-trial access
Post-trial access (PTA) programs now represent almost half of all access programs run by Clinigen, in stark contrast to the 10% this made up 10 years ago.
This is due to increasing clinical trial costs, further delays to access, increased awareness of such access programs and Clinigen have recently seen EMA requesting Sponsors to put post-trial access programs in place beyond a trial.
The vast majority of unlicensed access routes were not initially designed or established with post-trial patient access in mind and are therefore not always fit for purpose. Consequently, working with a partner with practical experience of navigating this space compliantly and successfully is critical. Clinigen anticipates seeing more countries establish regulatory pathways specifically designed for post-trial access and aligning this to the Declaration of Helsinki 2020 and the post-trial obligations and ethical considerations therein.
PTA programs are arguably a more sustainable, cost-effective alternative to provide long term access, particularly in territories where a Sponsor may not have immediate plans to commercialise, so Clinigen expects growth in this area to continue.
Additional indications
The concept of a “pipeline in a product” has become increasingly prominent, particularly in areas like oncology, immunology, and rare diseases. This approach refers to the strategic development of a single therapeutic product across multiple indications, effectively treating it as a pipeline of opportunities within one product. This is especially viable when the product targets fundamental biological pathways that are implicated in various diseases. In parallel, Clinigen has observed a sharp rise in additional or off-label indications being considered for access programs. According to the BMJ, “in Europe, 48% (42/88) of drugs had one supplemental indication, 23% (20/88) had two supplemental indications, 13% (11/88) had three supplemental indications, and 17% (15/88) had four or more supplemental indications”1, with similar figures observed in the US.
All these further indications result in post-trial supply obligations to patients that have derived clinical benefit from the product through trials, plus an increased awareness of the product’s use in the additional indication amongst healthcare professionals, patients and advocacy groups.
It is far from straight forward to supply off-label indications into countries through an unlicensed supply mechanism once a product has become commercially available in another indication. Many countries would view this as “parallel importation” and not encourage this, rather preferring the less burdensome approach of healthcare professionals prescribing local commercial products on an off-label basis. But this is not always ethical due to lack of funding or reimbursement for such off-label prescriptions, and does not provide a structured program through which to supply access supported by protocols, and removes the possibility of collecting further real-world data within the program. Clinigen would therefore encourage development of access mechanisms designed for additional indications, and for Sponsors to use such access mechanisms for further real-world data collection to support Marketing Authorisation Applications, pricing negotiations and reimbursement discussions. This is shown to work well in countries that have access mechanisms for additional indication supplies like Belgium and Italy. However, there are alternative mechanisms which utilise the local commercial packs for these kinds of programs whilst the regulations catch up.
LMICs
There is a trend towards the globalisation of clinical trials and increasing appeal of some LMIC regions as clinical trial sites, based on their lower costs, which is estimated at 40-60% less than in developed countries. With more clinical trials in LMICs, comes post-trial supply obligations, ethical considerations around expanding that access, and the increase in awareness and healthcare professional experience with a product on the global stage.
This brings considerable complexity to access because there is little to no harmonisation across the approximately 195 countries in the world in relation to mechanisms for unlicensed supply. The 2024 Access to Medicine Index, conducted by the Access to Medicine Foundation (AMF), which ranks 20 of the world’s largest pharmaceutical companies on their efforts to improve access to essential medicines in low- and middle-income countries (LMICs), finds that the current pace of progress is falling short of growing healthcare needs in under-served countries2.
The AMF suggest the following measures for improving access equity globally:
- Pharmaceutical companies should adopt “inclusive business models [IBMs] that prioritise low-income and least-developed countries.
- Transparent reporting should be made available on patient access across LMICs and data on which products are being delivered to what territories, enabling more effective, scalable solutions in such under-served regions.
- Stronger focus on R&D within LMICs – only 43% of trials take place across LMICs3.
- Industry should commit to voluntary licensing and technology transfers to local manufacturers to improve long-term, sustainable access in LMIC regions.
A key challenge across the world is the lack of harmonisation in regulatory pathways, access routes, and reimbursement policies. Some experts suggest harmonising unlicensed access programs on France’s model to improve efficiency and data collection, but that might not be reasonable or scalable for all countries. For this reason, Clinigen recommends that Sponsors consider the potential for unlicensed supply in any LMICs included in their overall clinical development programme as early as possible , to ensure effective and equitable access across all regions.
Conclusion
Currently, regulatory frameworks for unlicensed medicine access vary greatly, leading to inefficiencies, delays and disparities in access.
But varying national healthcare policies and processes does allow for a certain level of regulatory autonomy. Governments may hesitate to align with international standards due to concerns of local control and liability. Global regulatory bodies, such as ICH (International Council for Harmonisation) and WHO, are working towards greater alignment, but practical implementation remains complex. Increased data sharing and cross-border collaboration could help bridge gaps.
Harmonising global regulations for unlicensed medicine access is arguably crucial to ensuring equitable patient treatment, streamlined approvals, and consistent safety standards across countries, whilst also facilitating cross-border collaboration and improving transparency.
For now, the good news is that Clinigen’s Regulatory Intelligence database houses 118 specific access mechanisms or patients to gain access to unlicensed medicines, with practical experience to back that up, and research showing more countries adopting similar guidelines every year.
If you have any questions, please reach out to Regulatory@clinigengroup.com or Elizabeth.Taylor@clinigengroup.com .