3 Rare Disease Challenges Overcome From A Recent Phase 3 Pivotal Study

Allucent specializes in the conduct of complex global rare disease clinical trials. Because Phase 3 trials are designed to assess the efficacy, effectiveness, as well as safety of a new drug, this is typically a difficult, costly and time-intensive process. The difficulty of Phase 3 trials rachets up even more when it is conducted in a rare disease population.

Since Allucent has completed over 100 rare disease trials, this post will discuss how we leveraged our expertise to successfully conclude a pivotal study in acquired thrombocytopenic purpura (aTTP) for Ablynx (a Sanofi company).   

The completion of this trial led to the successful approvals of their drug, Cablivi® (caplacizumab), for aTTP in both the US (FDA) and European (EMA) markets. aTTP is a rare, life-threatening genetic blood disorder characterized by anemia, thrombocytopenia (decreased platelet count), purpura (bleeding under the skin) and generalized blood clots (thrombi). 

The goal of this discussion is to shine a spotlight on some of the challenges that needed to be addressed, several of which could be transferrable to your own studies in rare disease: 

  • Drug Administration – Easing the Burden on Patient Participation
  • Mapping Site-Patient Landscape – Creating a Supportive Patient Funnel
  • Managing Informed Consent – Securing Consent in an Acute Setting



For the effectiveness, efficacy, and safety of a drug to be properly ascertained, it must be administered using the recommended routes of administration, at the recommended dosage and at the recommended frequency; it must also be stored, as well as transported, using the prescribed drug protocol.

We all know this (above statement) is the expectation in clinical trial conduct, but where Sponsors and CROs often fall short is thinking through the above information and how the clinical trial truly impacts the site and patient from a time commitment or complexity standpoint in relation to drug administration.   


At Allucent, we pride ourselves on working with our Sponsors to think about all the angles and requirements of every trial, and what the burden is on our sites and patients.  In the Ablynx Phase 3 trial, the route of drug administration was by injection. This route of administration introduced some measure of complexity into the clinical trial, namely how to ensure adherence and compliance to the prescribed drug protocol. Study participants had to be properly and thoroughly trained on the techniques and considerations for self-injections. Sites were provided with dummy drug kits to use in training participants.

Additionally, a professional booklet and training video were produced with clear instructions for injections. The booklet also included an easy-to-use diary for recording every dose along with notes/comments from the study participant.

For our study participants who were unwilling or unable to self-inject, plans were made to involve other people, such as family members or professional nurses to provide the required injections.  Where additional members (family or nurses), they too were trained.  Accounting for the patient’s perspective in drug administration so it does not become an impediment to recruitment or retention is a must, especially in rare disease where every single patient matters to your study’s success or failure. 


When we discuss the dynamics of site and patient landscape, we are really talking about how and where these patients present (seek treatment) and how our clinical trial strategy accounts for and supports/engages that ecosystem (sites and patients). 

This is not unique to rare diseases, but it can take on different compounding complexities depending on the rare disease being researched. In the case of aTTP in adults, we had to account for patients presenting at the clinic (with already-established care by a treating physician) as well as acute onsets of the disease where the patients would present at hospitals near or far from research sites.

This particular clinical trial required the engagement of private clinics (hematologists) and local emergency rooms within hospitals that would need to handoff the patients to participating sites (hematologists). Doing this on a global scale can make your study even more daunting/complex during the site activation and enrollment stage, requiring advanced and timely logistical support of sites and patients. 


Finding study participants for our Ablynx Phase 3 trial was quite challenging. With aTTP, ~28% of our patients presented in an acute setting by going to hospital emergency rooms.

In rare disease, every patient matters when thinking about patient participation and, therefore, we had to create a supportive patient funnel in partnership with local emergency rooms spanning 17 countries and 94 sites. They had to be trained, be kept aware of the clinical trial and know who their patients should be referred to for participation in the trial.

This required extended hours of CRO staff as well as tightly coordinated communication with participating investigative sites that would later receive these patient referrals. 

In addition, we needed to consent the patients while in the hospital and often while in a critical medical state. Consenting is discussed in the next challenge below. We worked closely with the emergency room staff in identifying potential qualifying study participants and were able to enroll 145 study participants from a total of 56 patient-recruiting sites.

Due to Allucent and Ablynx establishing a supportive patient funnel with the appropriate study staff availability, we were able to complete enrollment early and over-enroll the study by 53 patients, thus providing the sponsor even more critically valuable data to support their successful approvals with the FDA and EMA. 


For most Phase 3 clinical trials, the issue of securing and documenting informed legal consent is not of particular significance; prospective study participants are typically aware of the nature of the study and able to sign the required documents that let them participate in the trial.

For some studies, however, where the study participants present acutely or with an altered mental state, obtaining the requisite legal consent can prove to be a challenge.


In our Ablynx study, obtaining the consent needed for patients to participate in our clinical trial sometimes proved challenging; the patients typically presented at hospital emergency rooms in a critical medical state, with an altered mental status, or even totally unconscious.

This, therefore, made it difficult to obtain the needed consent that would allow the patient to participate in the clinical trial. Legally Authorized Representatives (LARs) and the associated regulatory and ethical approvals for such use were absolutely essential to the success of recruitment in the trial and also in allowing patients’ access to the clinical trial while in a very vulnerable state of health. 

Pharm-Olam and Ablynx had to develop a repeatable and consistent process for sites to follow that would support the consenting and/or reconsenting of patients pending their situation (level of consciousness) and the potential involvement of a legal guardian/LAR.

The consenting process also had to account for country-specific regulatory and ethical requirements (spanning 16 countries), which adds another level of complexity when working with patients across so many countries and sites. This required research and excellent teamwork by Pharm-Olam’s regulatory department and local staff to achieve.


In rare disease, all the trials conducted are truly unique, but many of the lessons here in regards to ensuring easing patient/site burden (patient/site centricity) as well as mapping the landscape and having appropriate plans in place to support a complex consent process are all relatable and transferrable in their application to planning your next clinical trial.  

At Allucent, we pride ourselves on being nimble and responsive to your clinical trial needs and bring solutions to the table to successfully deliver them. Working with a CRO experienced in rare disease is important to your company’s success.

We look forward to speaking with you about your next clinical trial in rare disease. We are here to help you create a healthier world for everyone. 

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