By John Lagus, founder of Bluestem Pharma Consulting, LLC

Nearly a decade ago while working for an early access service provider, I oversaw the team facilitating a global Early Access Programme (EAP) in the United States (US), Europe, and other countries for a medicine to treat a rare genetic condition that significantly impacted young children. This new and innovative therapy would be the first medicine approved by any regulatory agency in the world to treat this disease.

Given the critical nature of the disease, the pharmaceutical company developing the medicine put the EAP in place to allow patients to start treatment with this new therapy before regulatory approval. They focused on patients who did not qualify for the pivotal clinical trial or who were diagnosed in the time between the end of the clinical trial and expected US Food and Drug Administration (FDA) approval.

I had an opportunity to help set up one of the last hospitals in the US to join the EAP before FDA approval. We got the medicine to the hospital and treatment began for several waiting patients. Looking back, it was wonderful to help make such a timely and profound difference in these families’ lives. The pharmaceutical company went on to supply this medicine via a global EAP for hundreds of patients around the world.

While reflecting on the programme during a public presentation several years later, representatives from the pharmaceutical company stated they were elated to have helped so many patients. The team disclosed that more patients were treated in their global EAP than had been treated in the clinical trials used to obtain regulatory approvals in the US and Europe. While data about the safety and adverse effects of a medicine must be captured in an EAP, the company’s one regret was that they did not capture any data about the effectiveness of this new medicine in this relatively large group of patients.

In clinical trials, pharmaceutical companies often want to enroll patients that are as similar as possible. Companies do this to have the best chance to show observations in the trial are due to effects of the investigative medicine. This is done by using certain eligibility criteria such as the patient’s age, stage of disease, previous use of specific medications, fitness level, results of certain laboratory tests, tobacco use, etc. For this reason, the eligibility criteria used in clinical trials may seem restrictive to patients who do not qualify. Ultimately tight control best ensures the medicine can get regulatory approval so the greatest number of patients can access the investigative medicine in the long run. Evidence coming from controlled clinical trials may not represent the patient population that will have access to the medicine after regulatory approvals and commercial launches. The company developing the medicine for the rare genetic condition realized too late that collecting effectiveness data in the EAP was a missed opportunity to gain experience about the disease and how the medicine behaved in patients who did not meet the tight clinical trial requirements. In the rare disease space where some diseases affect very few patients, any and every data point can be useful in better understanding disease progression, clinical outcomes, and ultimately how therapeutics may benefit patients.

Real-world data and real-world evidence

Data collected from sources beyond the controlled environment of clinical trials are often referred to as real-world data. Among other things, real-world data may include information from electronic health records, health insurance claims, patient registries, or data from wearable devices like fitness trackers, etc.

Another important source of real-world data is from global EAPs. Pharmaceutical companies in the past were sometimes reluctant to capture data in this setting because they felt the core spirit of an EAP is to help patients with unmet medical needs, not to collect data. That thinking has changed over the past 10 years, especially for companies developing medicines for rare diseases. The general rule is that companies can ask but not oblige physicians to collect these data. In my experience, physicians treating patients with a rare disease understand the importance of these data and are often willing to participate.

Collecting data is helpful, but the key is to demonstrate how real-world data can be used to accelerate access to medicine for more patients. Real-world evidence means the real-world data is analysed to provide insights that influence healthcare decisions for patients. With respect to EAPs, companies have utilised real-world evidence to provide actionable insights that influence and support regulatory and payor decisions with the intent to help accelerate access for more patients.

Supporting regulatory decisions

Data coming from controlled clinical trials are the gold standard for providing evidence of a medicine’s safety and efficacy for regulatory bodies like the FDA and European Medicine Agency (EMA). However, companies have been successful using real-world data sourced from EAPs to support regulatory approvals, both from the FDA and EMA. This is particularly true for medicines that have an orphan designation and a high unmet medical need.

A paper from Polak, et. al.¹ assessed whether evidence supports the premise that real-world data from EAPs may lead to regulatory approvals. The authors employed machine learning techniques to review regulatory approvals by FDA (years 1955 to 2018) and EMA (years 1995 to 2018). They searched for terms related to early access and found data from EAPs were used to help support the clinical efficacy for 39 approvals. In 13 cases, data from these programmes formed the main evidence for approval. For these 13 approvals, six (6) were approved just by the FDA, two (2) were approved just by EMA, and five (5) were approved by both regulatory authorities.

The authors concluded that EAPs can generate real-world evidence prior to approval of the medicine, and that both FDA and EMA increasingly use real-world data from EAPs in regulatory decision making for orphan designations with high unmet medical need. Pharmaceutical companies developing a new therapeutic for a rare disease should consider having discussions early in development with FDA and EMA about how the company approaches and incorporates data captured in an EAP into the regulatory submission.

Support of Payor Decisions

In European countries when the intention is to commercialise a medicine after receiving regulatory approval from EMA or UK Medicines and Healthcare products Regulatory Agency, the next step to consider is a health technology assessment. This means that the company must provide data demonstrating the cost effectiveness of the new medicine. In the rare disease space, real-world evidence can play an important role in supplementing data from controlled clinical trials. Again, EAPs are one source of real-world data that companies often consider.

In the UK, the National Institute for Health and Care Excellence (NICE) is responsible for conducting reviews of cost effectiveness. In a review of NICE technology appraisals, Polak, et.al.² wanted to see if real-world data from EAPs were being used in reviews by NICE. The authors screened 380 technology appraisal records submitted 2010-2020 and found that 206 of the 380 (54%) appraisals included terms related to expanded/early access. Further, in 80 of the 380 (21%) appraisals, real-world data from EAPs were used to support safety (n=43), efficacy (n=47), and resource use (n=52). The authors conclude that when combined with data from well-controlled regulatory clinical trials, data collected from EAPs may meaningfully inform NICE decision-making. I assert this is also true for health technology appraisal processes in other countries.

Final Thoughts

In the rare disease space, the primary benefit of an EAP is to allow one or more patients with significant unmet medical needs get access to medicines before commercial availability in the country where the patient lives. EAPs play a significant role providing hope for patients with serious or life-threatening diseases.

A secondary benefit of EAPs is to use real-world data gathered to strengthen the amount of information provided to regulators and entities like NICE in determining cost effectiveness of new medicines to treat rare diseases. Collecting these data in an EAP can ultimately accelerate access for more patients who could not join the EAP.

It’s incumbent on pharmaceutical companies to make the most of EAPs related to data capture. 

While not necessarily easy or straightforward to implement this in practice, coordinating with physicians, patient groups, and sometimes patients themselves can make all the difference.

About John Lagus

About John Lagus

John is the founder of Bluestem Pharma Consulting, LLC, helping patients around the world access medicines to treat serious or life-threatening diseases. John works with pharma and biotech companies to better understand and implement best practices for global early access and expanded access programmes that meet a patient’s unique medical needs.

Early in his career, John was introduced to the orphan drug and rare disease space, when he joined Orphan Medical. Early access strategies were utilised to supply several of the company’s FDA-approved medicines to patients outside the US.

Over the years, John has had extensive experience with the design, set-up and implementation of more than 200 global early access programmes. John also provides help to patient groups and those they serve. Supporting the rare disease community continues to be his passion.

Contact John at john@bluestempc.com, visit his website bluestempc.com, or connect with him on LinkedIn.

References

[1] Polak TB, van Rosmalen J, Uyl-de Groot CA. Expanded Access as a source of real-world data: An overview of FDA and EMA approval. Br J Clin Pharmacol. 2020;86:1819-1826 https://doi.org/10.1111/bcp.14284

[2] Polak TB, Cucchi DGJ, van Rosmalen J, et al. Real-world data from expanded access programmes in health technology assessments: a review of NICE technology appraisals. BMJ Open 2022;12:e052186. doi:10.1136/bmjopen-2021-052186

---