Transformative trends with real-world data from early access programmes

The complex and changing needs of patients with life-threatening conditions has led many health authorities to introduce early access programmes. These pathways offer patients who have severe conditions with high unmet medical needs to access investigational medicines outside of clinical trials.¹

Two programmes in particular that have gained momentum in many countries are named patient programmes and cohort programmes. Named patient programmes are aimed at a specific patient suffering from a rare, ultra-rare, or life-threatening disease, while cohort programmes involve patients identified with the same disease, possibly across countries.

France led the way with early access programmes, introducing its Temporary Authorization Program in 1992 and introducing a major reform in 2021 to simplify the schemes and accelerate patient access.² The emphasis on visibility with its assessment methods and consistency with decisions around early access will be a growing trend in the years ahead.

Other countries globally have introduced similar programmes under slightly different names, such as expanded access in the US or, in some circumstances, compassionate use programmes.³

Generating real-world evidence

In addition to bringing treatment and hope to patients without alternatives, such programmes provide further information on a product’s safety and efficacy data in real-world conditions. While these programmes can’t replace data collected in a randomised clinical trial setting, the real-world data (RWD) gathered can then be added to a company’s regulatory dossier as supporting information in the approval process.

A cross-sectional study of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regulatory approval documentation found data from early access programmes was used to inform clinical efficacy in 39 approvals, and, in 13 cases, early access data was the central evidence for approval. Of those 13 products, 12 were granted orphan drug designation. Most notably, the study points to four treatments that won approval based entirely on early access efficacy data.⁴ These included treatments for hyperammonaemia in patients with urea cycle disorders, a treatment for patients after 5-fluoruoacil or capecitabine overdose, treatment for bile acid synthesis disorders, and a treatment for hereditary tyrosinemia type 1.

Separate analysis uncovers approvals for several products that address rare diseases with significant unmet need where data from both clinical trials and early access or compassionate use studies have played a role in the regulatory assessment and approval process.

One recent example is the FDA accelerated approval of Vijoice® (alpelisib) for adults and paediatric patients over the age of two with severe manifestations of PIK3CA-related overgrowth spectrum (PROS). Efficacy was assessed in patients who were enrolled in an expanded access programme for compassionate use.⁵ The application was granted priority review, breakthrough designation, and orphan drug designation in April 2022.

Another example is Zolgensma® (onasemnogene abeparvovec) for the treatment of spinal muscular atrophy (SMA). In 2019, the FDA approved the product for paediatric patients under the age of 2 with a specific type of SMA. Data shared by the company, AveXis (now Novartis Gene Therapies), included results from a phase 3 trial and information from an expanded access programme.⁶ Currently Novartis’ Managed Access Program – which covers all early programmes – makes Zolgensma available to eligible patients in countries where the product has not received regulatory approval.⁷

The orphan drug product Lutathera® (lutetium ((177Lu)) oxodotreotide) to treat adults with somatostatin receptor (SSTR) positive gastroentero-pancreatic neuroendocrine tumours (GEP-NETs) received approval from the FDA based on both a randomised controlled trial and a single-arm study based on an expanded access programme that “provided supportive data on safety” and “support for the indication for the treatment of patients with GEP-NETs other than those arising in the midgut.”⁸

While these examples illustrate the use of RWD collected from expanded access programmes for granting approval from regulatory bodies, such data could also be used for granting line extensions.⁹ An example is Keytruda® (pembrolizumab), where data collected from an expanded access programme helped to support clinical efficacy for an FDA supplementary indication approval in May 2017.¹⁰

Embedding RWD and RWE in decision-making

In the near future, use of RWD gathered from early access programmes is likely to gain momentum, amid growing efforts by health authorities to integrate data from these programmes into regulatory decision making.

The FDA has long used RWD and RWE in its monitoring and evaluation of post-market safety of approved products and in a more limited way in evaluating effectiveness.¹¹ In 2022, the agency announced an Advancing RWE Program to support new intended labelling claims. Companies selected for the programme can discuss with the agency proposed use of RWE in product development. One objective is to identify ways in which RWE can support regulatory decision making.¹²

In Europe, the EMA and the European Medicines Regulatory Network (EMRN) are working towards that objective and are seeking to achieve those goals by 2025.¹³ The two authorities have been working on a RWD study framework to support various committees, national competent authorities, and external stakeholders with scientific assessments.

The International Conference of Harmonization (ICH) published a reflection paper in June 2023, which was open for public consultation until the end of September, on the role of RWD and RWE to support the evaluation of medicines across different stages of development. A key goal is the standardisation of RWD/RWE terminology and formats, the heterogeneity of data quality and study designs used based on disease, medicine, and regulatory context.¹⁴

Some companies are developing strategies to guide their use of RWD gathered from early access programmes. For example, Novartis has guidance for the collection of baseline patient data and follow up information at product resupply for its compassionate use and managed access programmes. The company has highlighted the importance of a clear regulatory framework to support the collection and use of data from compassionate use programmes, but notes that the collection of some efficacy data at product resupply for certain products can be seen as complementary to clinical trials for related products and indications.¹⁵

There are a growing number of innovators of products for rare diseases or products with unmet medical needs that are conducting early access programmes with the hope of using data from these programmes to complement safety and efficacy information coming from clinical trials. PharmaLex is working with two clients taking advantage of these programmes. One is developing a product for a (rare) enzyme deficiency disorder that is going through the named patient programme. A second is developing an antimicrobial for a condition that can affect patients undergoing chemotherapy, which has been authorised for a cohort program in a number of countries.

Proving payer value through early access

In addition, generally, early access programmes can be a valuable source of data in the health technology assessment (HTA) process to support reimbursement discussions.

While a 2017 comparative study of six health technology assessment (HTA) agencies (Sweden, UK, Germany, France, Italy, and the Netherlands) found differences in how RWD is used for effectiveness assessments,¹⁶ there is a move toward harmonisation. The Joint Clinical Assessment (JCA), which is central to the EU’s Health Technology Assessment Regulation (HTAR), will seek to harmonise the clinical assessment process, starting from January 2025.¹⁷

The UK’s National Institute for Health and Care Excellence (NICE) does use data from early access programmes to inform safety, efficacy, or resource use, a study found. In fact, more than one in five NICE appraisals make use of early access data.¹⁸

Future of early access programmes

As regulators and other authorities establish and strengthen their RWD and RWE frameworks, a key trend in the near future is likely to be increased focus on leveraging data from early access programmes to support regulatory submissions and reimbursement efforts.

For rare diseases and conditions with unmet medical needs, including cancer patients who do not respond or stop responding to existing treatments, these early access programmes can prove life changing. Data and evidence from these programmes could, therefore, potentially be integral in supporting decision-making by regulators, as well as HTA bodies.

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