Last week we introduced 5 key challenges that, based on interviews at various biotech congresses, appear to be at the forefront of Biotech executives’ thinking:

  1. Finding patients
  2. Challenges with clinical trial design and recruitment
  3. Regulatory requirements
  4. Long term revenue stream
  5. Reimagining commercialisation

In the first post in this blog series we explored the challenges that Biotech companies face in finding patients and the overall low levels of awareness with rare and orphan diseases and advanced, novel therapies.

This week we focus on the specific challenges with clinical trial design and recruitment arising in rare and orphan diseases, especially in advanced, novel therapies.

Across the industry and especially for Biotechs with limited resources it is becoming ever harder to recruit patients for clinical trials. For example, fewer than 5% of cancer patients participate in clinical trials, making it challenging to test new therapies or interventions.[1] Lack of awareness or understanding about clinical trials can be an issue, but patients are often concerned about safety and are worried about being on the placebo/control arm.  Furthermore, many rare and orphan diseases affect children. Parents are often reluctant to enrol their child in a trial where he or she may receive a placebo rather than the active drug. Once identified, patients often need to travel significant distances to reach a limited number of trial sites. This can be particularly problematic for patients with mobility issues or for trials involving small, sick children.

In recent years the number of trials focused on defined populations has exploded. This has added to the pressure of recruiting patients; as more trialists struggle to recruit patients from the same pool. Since 2012, there has been a steady increase in drugs that have received orphan drug designation with 2017 seeing the most (462). There were 1,695 clinical trials for those drugs’ indications in that time period.[2] Although fewer patients are generally recruited for rare disease trials the scarcity of patients and boom in trial numbers has put additional pressure on recruitment. In the 12 years up to 2018 the average number of patients in a clinical trial for a rare disease was 336 vs. 1406 for non rare diseases.[3]Considering that to classify as a rare disease the prevalence in the EU must be less than 1 in 2,000 patients and in the US must have a prevalence of less than 200,000 it is clear that recruiting the necessary number of patients is challenging.

Immuno-oncology (IO) therapies have experienced a similar pattern to orphan drugs. Within IO, clinical trial numbers have rapidly increased. In 2013 there were only 13 new clinical trials involving IO agents yet in 2017 there were 469 new trials. In patient numbers this is a change between planned enrolments of 4867 to 52,539 patients.[4]

When speaking to Biotech executives, they also seemed significantly challenged around trial design which is not surprising. There are a significant number of issues that need to be considered, some we reflect on here:

Rare and orphan disease patients, by nature are extremely difficult to find, and finding enough patients to generate sufficient data can be extremely challenging. Not only are sample sizes small by necessity but there is huge variability patient to patient, which diminishes a study’s power. Use of controls obviously strengthens a trial design by addressing concerns regarding clinical variability. However, in rare and orphan diseases, many of which cause a reduced lifespan, there are ethical concerns about placebo-controlled trials. In many situations, clinical trials have to be designed for rare diseases where there are limited prior data. There is often little or no information about disease mechanism, progression, and symptoms. Researchers are faced with designing one of the first clinical trials conducted in a specific patient population and the research teams will need to design new efficacy measures based on endpoints, surrogates or biomarkers that have never been used or fully validated.

Due to these challenges there is a growing need to rethink study design, identifying alternative approaches and statistical techniques. Researchers need to maximise data from small and heterogeneous groups, they need to expand their knowledge - study by study, look for efficiencies and creativity, including crossover arms and using adaptive approaches where possible.

It is worth highlighting that changes are taking place (although our original survey highlighted that these changes are not happening fast enough to keep up with innovation in the industry). There are a growing number of orphan designation drug approvals, based on smaller trial sizes and pivotal studies that are not randomized, placebo-controlled, or double-blind. And in recognition of the challenges in developing therapies for rare diseases, the FDA introduced the Safety and Innovation Act (FDASIA) of 2012 and the 21st Century Cures Act of 2016, both of which include provisions that recognize the need for new levels of flexibility in the regulatory review process for many of these diseases. 

There are slowly becoming more innovative trial designs, including sightless trials; but the barriers to implementing these, especially those in complex areas such as oncology are high. Take for example Duchenne muscular dystrophy (DMD). DMD is a rare neuromuscular disease caused by a lack of functional dystrophin protein that results in progressive muscle weakness. The disease almost always affects boys, and symptoms usually begin early in life. Patients eventually lose the ability to walk in their early teens and typical life expectancy is mid-20s, frequently due to life-threatening lung and heart complications. As symptoms and severity of disease can vary, it is difficult for researchers to establish appropriate criteria to demonstrate clinical benefit in studies. There are several Biotech companies developing DMD therapies (e.g. PTC Therapeutics and Santhera) but it is clear that planning and executing an appropriate clinical research program requires entirely new levels of innovation and flexibility from both clinical researchers and regulators. For example Summit Therapeutics Ezutromid  was discontinued after Phase 2 results did not meet primary endpoints[5]

Throughout the industry there is a move toward Real World Evidence (RWE) and Patient (and Physician) ‘relevant’ outcomes, it is critical that Biotechs engage with patients and Patient Advocacy Groups (PAGs) as early as possible. Listening to the ‘patient voice’ can provide companies with significant early insights into the condition and its impact on lives and also provides invaluable wisdom for researchers and regulators to better understand the relationship between clinical trial results and the impact of treatment on a broader range of factors in patient health and quality of life. This is critically important given that the use of innovative and often first-used endpoints, ensuing they are meaningful to patients and relevant in clinical practice.

For Biotech companies competing in the Immuno-oncology (IO) space there is similar difficulties in trial design. Keytruda’s pan-tumour FDA approval in May 2017 was the first where a product was approved based on biomarker expression rather than tumour location and added another layer of complexity to future trial designs and opening the door for others in the industry to follow suit. 

The term “histology agnostic trials” has been proposed when referring to trials aiming at including various tumor types with only the molecular aberration or target as a common denominator. Although there is a lack of consensus around the optimal design for this type of trial; ESMO suggests that a ‘basket trial’ may well be a preferred option for many[6]

There are long term benefits of looking at “druggable” targets related to a specific molecular profile across different histological tumour‐types as it might result in making rare molecular subtypes less rare. Patients with extremely rare histological tumour types for which no standard treatment exists may benefit from molecular profile tailored treatments. So although there may well be some way to go before the industry unites around the ideal histology agnostic trial design; further approvals are likely to have positive impacts on the lives of patients living with rare diseases.

In the IO space there is added pressure on clinical trial design caused by a trend towards combination therapy in particular using checkpoint inhibitors as a backbone. Unfortunately for Biotech companies wanting to develop IO combinations the only approved checkpoint inhibitors are owned by Pharma companies, giving them control over the clinical trials and their design.

It is clear that successfully designing clinical trials for rare and orphan diseases and advanced, novel therapies is complex and an area where best practice is rapidly evolving. Patient numbers, disease awareness, prior experience, therapy area infrastructure, geographical diversity and access constraints are in themselves substantial barriers to overcome for a Biotech. There is a need for new and innovative approaches to clinical research, in particular where a disease is progressive and life-threatening with no approved therapies available. Without change, it is possible that many much-needed therapies might be delayed or worse, not be approved, leaving patients without new treatment options and the significant clinical benefits promised.


Clinical trial design is not an area that I particularly specialise in, however, in dealing with multiple biopharmaceutical companies facing these challenges I have observed several trends:

Those who appear to do well take an open-minded, collaborative and inquisitive approach. They engage with other organisations in the space to help navigate the clinical trial recruitment and design challenge in particular when designing one of the first clinical trials conducted in a specific patient population. They will work with organisations such as NORD and those specialised in rare disease clinical trials design such as  IDEAL and ASterix. They work with companies like Cello Health to understand the patient journey, scientific platform or Target Product Profile to help define the design requirements. They work to investigate what other Biotech and Pharma companies have delivered to address these challenges.  As rare disease day approaches it is a good reminder that there are many passionate and interested patient groups and corporations to share with and learn from

It is also important to utilise technology to improve likelihood of success. Social media can be critically important in building relationships where patients and caregivers communicate and engage. Even in the early stages of development platforms such as Pulsar can ensure meaningful endpoints are built into trial design. It is also possible to reduce the risks involved with clinical trials using mathematical models and Quantitative Systems Pharmacology (QSP). Using QSP it is possible to clarify the connection of complex drug and disease mechanisms to material preclinical and clinical outcomes. Exciting companies like Rosa & Co with their Physio PD approach use diverse information sources to produce unique insights that increase the confidence in key program decisions and reduce the risk of ambiguous studies in early development and failed trials in late development. We also heard excitement from Biotech executives around siteless clinical trials. With a focus on remote monitoring and patient engagement, ‘siteless’ or direct-to-patient clinical trials have the potential to impact the most perennial of problems – patient recruitment and retention. In addition to the sheer convenience for patients, siteless trials tear down geographic barriers, opening up trials to a much wider – and potentially more diverse and representative patient population. By harnessing wearable technologies and mobile health, such trials offer the allure of not just enhanced data quality but better data volume through continuous monitoring.

Next week we will focus related topic and explore the 3rd big challenged posed by Biotech executives around the Regulatory requirements with rare and orphan diseases and advanced, novel therapies