Rare diseases are by their very nature, uncommon. Approximately 90% of rare diseases still have no effective treatments. Disease-specific barriers to therapeutic success include small populations, disease sub-types, and diagnosis challenges. These barriers can result in an incomplete understanding of disease pathophysiology even when there are approved treatments available. Because of this, critical clinical trials in rare diseases can be difficult to run due to a lack of patients, complicated study designs and challenging logistics; all of the above imply involvement of numerous countries, many sites and lengthy timelines to completion.
These challenges in conducting Rare Disease clinical trials are misconceptions when you have the required expertise; studies in rare diseases are collaborative, innovative and perhaps some of the most rewarding for those of us having the chance to contribute to this research. It’s clear that what is essential to success is ensuring there is the right clinical team in place. Cmed has an established rare and orphan disease portfolio and has successfully delivered 128 studies over the last 18 years; 11 of these products now have approval which is critically important for the over 300 million people living with a rare disease.
As part of #Rarediseaseday 2021, Cmed has interviewed team members who have worked directly on these studies to understand the vital ingredients for successful delivery. What became clear is that, aside from well qualified people and direct experience in the field, the most important consideration to ensure success is to understand the patient journey.
At Cmed we know it’s common for a patient diagnosed with a rare disease to have never met another person with their diagnosis let alone another person directly able to share their experience – so how can they expect to participate in a research study that will work to accommodate their needs when they feel no one can understand? This is where the Cmed team can help. With our on the ground operational experience of rare disease studies, we have shown that to make these studies work, direct involvement of the patients is critical so the study requirements and processes fit in with the needs of the people who will be directly benefiting from the treatment and contributing to the growing understanding of disease and its management.
Facilitating recruitment and retention – what has Cmed learned from experience?
Rare Disease trials require the ability to recruit in a wide–spread population. Patients are often scattered around the world, requiring numerous sites in numerous countries in order to find small numbers of patients. As a result, these trials are expensive and logistically challenging; Cmed can help to manage the impact.
In a study in Primary Biliary Cholangitis, knowing that rare disease studies often recruit slower than anticipated, Cmed overcame the challenges of patients’ recruitment by implementing a multi-step approach to recruitment. Firstly, by suggesting changes to inclusion criteria, the Cmed team worked cross-functionally to broaden the inclusion criteria easing some of the unnecessary restrictive parameters which opened the study up to a wider pool of patients. In parallel, Cmed recommended combined motivational site visits where the Sponsor visited study sites to ensure their protocol was highly visible, and to provide an in-person update on current study and product status which helped to build on existing relationships with the study site teams and Investigators. When enrollment is slow, we often find the investigators and site staff need additional support in understanding the eligibility and visit requirements as enrollment and study visits are not as routine as a typical medium to high enrolling trial. We stand ready to support our sites; keeping investigators and study coordinators engaged.
In a current gene therapy study running in Wilson’s Disease, the Cmed team recommended to add visit windows to assessment timepoints and flexibility into the screening assessments to accommodate patients who have jobs, families and other commitments. Not allowing for this flexibility would otherwise deter patients from study participation.
Building strong trusting relationships with site teams is the key to making studies work, especially in rare diseases where patients, clinicians and research nurses have built up close enduring relationships over the course of treatment. It is important to recognise these trusted connections and deliver patient-centric support when patients agree to the extra effort of a clinical trial. Cmed adopts this patient centricity in all their studies by understanding the patient journey, listening to the site’s perspective, and providing assistance e.g. prefilled study start-up packets, fair reimbursement for work completed and clear, open communication lines with knowledgeable CRO team members.
Cmed further supports the patient journey by linking directly with patient advocacy groups, support networks and charities at the very early stages to get input into the protocol, informed consent form and study documentation. This tangible link into the development of the study and engaging wider stakeholders mean that there is a wider awareness of the study which is crucial to recruitment and participation. Working in the rare disease arena for nearly two decades we have learned that while diseases are rare and often geographically widespread, their community is small. This can be leveraged by working with prominent researchers in the field to spread the message and to raise awareness for the study and boost engagement ensuring patients are informed and ready to participate as soon as the study is activated. This approach was evident in the start–up phase of a current phase II study involving pediatric patients with selected inherited metabolic disorders undergoing stem cell transplantation.
Finally, in a COVID-19 world, offering decentralized Clinical Trials remains a priority for Cmed. Patients need the reassurance to avoid site visits and sites need to be supported for remote SDV and SDR. Cmed provides its encapsia technology to overcome these challenges.
Facing regulatory challenges
There are no documented differences in approval criteria for orphan drugs and drugs for common indications, and sponsors must still provide substantial evidence of the effectiveness of the drug using adequate and well-controlled investigations. Although orphan drugs may qualify for fast-track regulatory review and smaller safety data set requirements, regulatory approval may also come with laborious Risk Evaluation and Mitigation Strategies (REMS) requirements. The regulatory complexity in determining what evidence is sufficient to support approval of orphan drugs is due, in part, to lack of clinical trial precedents and limited scientific understanding of rare disease processes. Both the EMA and FDA, as well as many other national competent authorities provide guidance on procedures for the granting of marketing authorization under exceptional circumstances, including indications which are encountered so rarely that comprehensive evidence cannot be provided, and orphan drugs may meet the criteria to be considered for approval under exceptional circumstances.
Often, rare disease therapies are based on gene therapies and fall under very complex trial designs, for example by involving radiopharmaceuticals It is therefore essential to understand the implications of such trials, such as how the extensive regulatory pathway may throw unforeseen complications into study start–up.
To combat this, our teams ensure fast start-ups by talking to regulatory bodies, working closely with Ethics Committees/HRA coordinators and initiating clinical contracts early. We do not wait for our Sponsors to tell us what to do – we move ahead and we move fast.
Managing recurrent data deliveries and data visibility
As a trusted partner in the management of data, Cmed can advise on selecting appropriate endpoints and outcome measures. Small patient populations limit study variation and the genetic basis or associated co-morbidities of many rare diseases can be confounding factors in study predictability. Smart designs are essential to identify the key questions to be answered as well as the critical timepoints.
The EDC technology used in our studies enables an effective way to collect complex data alongside adaptive or sophisticated study designs. With few patients enrolled in rare disease trials, the focus on quality is primordial. In addition, with data generated from multiple sources, our data management team ensures clarity and integrity of data flow supporting ongoing data visibility and review for the whole study team.
Making this data available immediately to both the study team and trial committees allows instantaneous analysis of emerging data and real-time trend review. At Cmed we understand the upmost importance of delivering early and high quality data outputs that a study review committee can rely on quickly especially in early phase rare disease studies.
Corporate Social responsibility
At Cmed, we go beyond this. We are all personally engaged in supporting rare diseases clinical trials. For some of us, with friends and/or family directly impacted by some of these illnesses, we know that although these patients live with a diagnosis it doesn’t define them and as a team, we work relentlessly to make the impossible possible. We are also engaged in charity initiatives raising funds and participating in various associations.
Long diagnosis, misdiagnosis, or no diagnosis – rare diseases go under the radar. At Cmed, we will do everything we can to help 300 millions of you.
For more information on Cmed experience with rare diseases: https://cmedresearch.com/clinical-services/rare-diseases/
We’re here to help.