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Once a candidate drug has been selected and preclinical tests in disease models have been conducted, it is necessary to perform rigorous tests in clinical trials to build an evidence base for off-label use or to achieve marketing authorisation. This section details important considerations when establishing clinical trials in a repurposed drug, highlighting some of the roadblocks and challenges that could be faced outside of standard clinical practice. 

To learn more about the process of delivering clinical trials, please see Findacure’s “Developing and conducting clinical trials” course on our E-learning portal.

To exemplify some of the important considerations when undertaking clinical trials for repurposed drugs, information from the MCDS-Therapy Project is included throughout this section. 

In this lesson we will cover: 

  • MCDS Therapy
  • Clinical trials testing, contracting and protocol development 
  • Funding, sponsorship and insurance 
  • Recruitment, data collection and storage
  • Ethical approval and transfer of biological samples 

MCDS Therapy 

Once a candidate drug has been selected and preclinical tests in disease models have been conducted, it is necessary to perform rigorous tests in clinical trials to build an evidence base for off-label use or to achieve marketing authorisation. This section details important considerations when undertaking clinical trials in a repurposed drug. For more information on clinical trials, please see Findacure’s “Developing and conducting clinical trials” course on our E-learning portal.

This MCDS case study outlines an academic-led approach to repurposing the generic drug, carbamazepine, for metaphyseal chondrodysplasia type Schmid (MCDS); a rare condition that leads to short stature, short limbs, bowed legs and joint pain. Having established through research that endoplasmic reticulum (ER) stress is a primary cause of MCDS, academic researchers screened several drugs that act to reduce this process, to identify a candidate that could be repurposed to treat MCDS.

 Carbamazepine demonstrated the largest reduction in ER stress and so was taken forward to be tested in an MCDS mouse model. Mice with MCDS are generally shorter in length and have a distorted pelvis, with analysis of the growth plate of the long bones under a microscope demonstrating that collagen X is abnormally retained in the cells. Carbamazepine treatment was shown to improve growth and reduce pelvic distortion, with less collagen X retained in the cells. 

These results are now being taken forward into a clinical trial which is being organised by 11 international partners and funded by the European Union’s Horizon 2020 research and innovation programme, to test if carbamazepine could ultimately be used as a MCDS treatment. Whilst MCDS-Therapy is an academic-led project, where researchers have independently taken a repurposed drug from bench to bedside, the learnings for testing in clinical trials described below are applicable to any repurposing project, including ones driven primarily by patient groups.

You can see Professor Michael Briggs discussing repurposing at our 2018 Drug Repurposing conference below.

Clinical trials testing, contracting and protocol 

Once a candidate drug has been selected and preclinical tests in disease models have been conducted, it is necessary to perform rigorous tests in clinical trials to build an evidence base for off-label use or to achieve marketing authorisation. This section details important considerations when undertaking clinical trials in a repurposed drug. For more information on clinical trials, please see Findacure’s “Developing and conducting clinical trials” course on our E-learning portal.

To exemplify some of the important considerations when undertaking clinical trials for repurposed drugs, information from the MCDS-Therapy Project is included throughout this section. This case study outlines an academic-led approach to repurposing the generic drug, carbamazepine, for metaphyseal chondrodysplasia type Schmid (MCDS); a rare condition that leads to short stature, short limbs, bowed legs and joint pain. Having established through research that endoplasmic reticulum (ER) stress is a primary cause of MCDS, academic researchers screened several drugs that act to reduce this process, to identify a candidate that could be repurposed to treat MCDS. Carbamazepine demonstrated the largest reduction in ER stress and so was taken forward to be tested in an MCDS mouse model. Mice with MCDS are generally shorter in length and have a distorted pelvis, with analysis of the growth plate of the long bones under a microscope demonstrating that collagen X is abnormally retained in the cells. Carbamazepine treatment was shown to improve growth and reduce pelvic distortion, with less collagen X retained in the cells. These results are now being taken forward into a clinical trial which is being organised by 11 international partners and funded by the European Union’s Horizon 2020 research and innovation programme, to test if carbamazepine could ultimately be used as a MCDS treatment. Whilst MCDS-Therapy is an academic-led project, where researchers have independently taken a repurposed drug from bench to bedside, the learnings for testing in clinical trials described below are applicable to any repurposing project, including ones driven primarily by patient groups.

The MCDS therapy logo

Contracting

If the clinical trial research for your repurposed drug is being conducted by a separate organisation, it is important to remember that contract negotiations can take a substantial amount of time and resources. Close follow-up with the contracted organisation at each stage of the project is also necessary, to ensure the research is being conducted as expected and to evaluate successes and challenges periodically.

Protocol development

Prior to commencing clinical studies, it is necessary to write a protocol that establishes all details of the tests that will be performed during the trials. This should include how the drug(s) will be administered (frequency, dosage etc.) and the clinical endpoints that will be measured to determine the efficacy/safety of the treatment. It is important to get in touch with regulatory/reimbursement bodies such as the EMA and National Institute for Health and Care Excellence (NICE) as early as possible, to understand what clinical endpoints they would need to be met in the trials, in order to be granted regulatory/reimbursement approval.

Funding, sponsorship and insurance

Funding

It is important to consider how your clinical trials will be funded early on in the project (preferably at least one year in advance of when they will go ahead), as the process of applying for funding can be lengthy. It may be worth considering partnering with a grant-writing company when completing applications to ensure both the academic and lay sections of the application are accurately completed.

The MCDS-Therapy Project received funding from the European Union’s Horizon 2020 Research and Innovation Programme after applying to the Horizon 2020: personalised medicine call 2016–2017. Any group can apply to these calls, with the prerequisites that the drug must have been given orphan drug designation by the EMA and that the trial proposal takes into account recommendations given by the EMA during a protocol assistance meeting.

Clinical trial sponsorship and insurance

When planning for clinical trials, it is necessary to consider sponsorship and insurance as early as possible in the process to avoid delays.

Sponsorship and insurance for the MCDS-Therapy Project was provided by the Newcastle-upon-Tyne Hospitals NHS Foundation Trust. Obtaining this involved a lengthy process as the providers had limited familiarity with obtaining insurance for international trials.

Recruitment, data collection and storage 

Recruitment

Patient recruitment for clinical trials can be a very challenging aspect of trial design, especially for rare diseases with small and fragmented patient populations. This should therefore be considered early on, and patient sources identified as soon as possible so that collaborations can be set up with those clinical sites with prospective patients. Patient groups are often able to offer an invaluable source of potential recruits for clinical trials through their extensive patient networks.

For the MCDS-Therapy Project, the first patients will be recruited in the UK by Newcastle-upon-Tyne Hospitals NHS Foundation Trust and the Evalina London Children’s Hospital. After a year, recruitment will be expanded to the international sites in the partnership (MCDS therapy partners). For MCDS, as with many rare paediatric diseases, recruitment can be challenging as patients are often misdiagnosed. In addition, there is only a small age window in which patients can be recruited as they must not have reached skeletal maturity. This highlights the importance of international collaboration in drug repurposing projects.

Data collection and storage

Under the new General Data Protection Regulation (GDPR) laws in the EU, health data is considered ‘sensitive data’, which may only be processed with explicit consent or based on medical care need. Patients’ data should be stored in a secure online system and shared only in the contexts that are permitted in the clinical study. For further information on GDPR, click here.

Ethical approval and transfer of biological samples

Ethical approval

Full, informed consent is a legal requirement for clinical trials or studies involving human subjects. Within this category, assent forms are documents that pertain to people who are too young or are unable to provide knowing consent. It typically requires oversight/signature from a parent or guardian. Consent mechanisms must be fully GDPR compliant, involving a clear affirmative action (an opt-in), with a clearly communicated right to withdraw consent. Consent can be gathered through paper forms or electronically.

Transfer of biological samples

International transfer of biological samples can be logistically challenging due to a variety of factors including temperature, contamination etc. It is therefore often preferable for analysis to take place in the centre at which samples are taken. In the case of the MCDS-Therapy Project, in the event that samples were required for the development of clinical endpoint biomarkers, these were taken from UK sites only to limit extensive transfer.