Celebrating World Clinical Trials Day!

A clinical trial is the best way we have of finding out which treatment works for a particular condition, and participation in this research is the driving force for the licensing of new treatments which can help to best manage the symptoms and effects of Scleroderma and Raynaud’s.

Thursday 20 May 2021 marks World Clinical Trials Day, to honour participants and research professionals across the globe who offer not only their time and expertise, but themselves too, to the clinical trials process.  Since 2005 this day has been celebrated in commemoration of the first clinical trial, run by physician James Lind in 1747, as he tried to cure 12 patients with scurvy on the boat ‘Sailsbury at Sea’. Following on from his pioneering work, clinical trials have become essential in the development of therapies and treatments for all conditions. All the medications you take, the dosages in which they are given and how they are administered, will have been established through a multi-phase clinical trial process.

This year, the staggering half-a-million people worldwide who have taken part in pioneering COVID-19 research alone deserve a special mention, in addition to the incredible involvement of all those who have supported other conditions. Research into COVID-19 has been an obvious and necessary priority, however it has caused a shift in the clinical trials landscape, putting many studies into chronic conditions like scleroderma on hold.

Clinical trials – what you need to know

1. What are clinical trials?

Medical devices and drugs are tested for safety and efficacy through clinical trials in order to gain the evidence needed for regulatory approval and to be used in practice. There are many types of clinical studies but the ‘gold standard’ is a randomised control trial, where the new device or medicine is tested against either a ‘placebo,’ (a sugar pill or saline injection, or the current standard of care). These are often ‘double-blinded’ so that neither the treating clinician nor the patient know what treatment they are receiving.

The clinical trial process is outlined below. Phases are completed in a linear manner and the time taken to complete all phases usually takes eight years; with just under 10% of candidate drugs making it through to successful outcomes. Therapies for chronic diseases have a lower likelihood of approval than average. The massive investment made by governments across the world to de-risk vaccine development has meant that COVID vaccine research could be accelerated.  Each phase has its own purpose, and its own patient group to reflect that.

• Pre-clinical stage – toxicity and mechanism of action

Prior to testing in humans, the treatment's toxicity and efficacy is established in model systems, these can be either animals or human cell/tissue samples.

• Phase 1 – safety studies
  These are usually conducted on very small groups of healthy volunteers, to examine how the treatment interacts with the body, and whether there are any severe side effects. This stage is largely for testing safety, and for establishing an effective dosage.
•  Phase 2 – efficacy testing
  All participants will have the condition for which the treatment is being designed with the efficacy and side effects of the drug monitored.
• Phase 3 – multi-site randomised control trial
  Up to 3,000 people (depending on the rarity of the condition) take part in the final phase before the drug is released to the market so that the effects of different dosages and combinations can be examined in a diverse selection of people, ages, and ethnicities. At this point, the treatment is compared to either a placebo or to the current treatment methods that are already available.

This process varies in how long it can take; as seen with COVID-19 it is possible to bring a vaccine to market in under a year, however often the process is much longer.

2. What happens before a clinical trial?
The short answer is: a lot of research! As mentioned above, there is a pre-clinical stage to each clinical trial, where the treatment is developed and refined as much as possible before it is tried by people. In this stage there is also a vast amount of time spent establishing how phases 1-3 can be conducted to minimise the risk to participants and ensure that they receive the best standard of care possible.

During some clinical trials, participants are split into groups, where half of the cohort receive the treatment being investigated, and the other half receive a placebo treatment. For many conditions however, it would be unethical to provide half the group with an intervention that offered no benefit, rather than an actual treatment, as stopping their current regime could result in a decline in health. In these cases, the trial must be designed carefully, to ensure that all the participants are offered care. Usually in these examples, the half of the group who do not receive the new treatment being examined will be given an alternative treatment instead. Regardless of what is offered, the standard of care for participants is very high, and they are likely to have increased monitoring of their condition from medical professionals, which is beneficial regardless of which arm of the study a person is in.

Increasingly, as part of the pre-trial work, companies work in collaboration with expert patients to gain input on the trial methodology and the metrics collected, as well as to review the information and consent forms to be provided to patients being recruited onto the trial. These expert patients also have an input into the variables which the clinical trials measure to establish whether the treatment has resulted in a positive change. SRUK is supporting two projects that are currently working with patients to develop a series of criteria against which new treatments can be measured in both limited and diffuse cutaneous systemic sclerosis – CRISTAL and CRISS respectively. These are anticipated to benefit future clinical trials of new treatments.  These factors are all judged by an independent ethics committee before being reviewed and authorised by a government agency called the Medicines and Healthcare products Regulatory Agency, that protects the interests of patients within health research.

3. What is it like for participants in a clinical trial?
The experience will vary depending upon which phase you participate in and what the treatment is for. You will usually be assigned to either the treatment group or the control group, meaning that you will be offered the treatment being assessed or an alternative, which could be a placebo, or the existing standard treatment. This will be randomly decided, and in almost all trials, you will not be told initially which treatment you are receiving. To read more about the different types of clinical trials, take a look at this summary from SRUK.

For the duration of the trial, you will receive treatment in-line with the group you are in, and will undergo tests to assess how the treatment is working. The nature of these tests, and the time they will take up vary significantly depending on the trial as well as what the treatment is used for. Blood tests may be used if the clinical trial is investigating a new drug, or questionnaires could be employed if the trial focuses on a new method of therapy for example.

Even if you do not receive the new treatment being trialled and are instead given a placebo, by participating in a clinical trial you will usually receive additional clinical care and monitoring to your usual standard of care. This can therefore still be beneficial to your health, despite the fact that the treatment you receive has no physiological effect.

4.  What happens after a clinical trial?
After the three phases of a clinical trial, provided that each stage is successful and the treatment is proved both safe and effective, there is a fourth stage: post-market surveillance. This takes place once the treatment has been licenced and is done in order to monitor the effects of long-term use in a global population.

A fantastic example of how a clinical trial has made a positive impact within the SRUK community is Dame Carol Black’s lifesaving algorithm, which enables rapid and accurate diagnosis of lung fibrosis in scleroderma. Fibrosis in the lungs affects up to half of people with scleroderma and can have a significant impact upon daily life. Before Dame Black’s pioneering research was conducted, the technique by which lung function was assessed was variable and complex, and therefore inaccessible to all but the most experienced doctors. Dame Black’s new approach used cross-sectional X-rays to classify a patient’s degree of lung disease severity, which was tested in a clinical trial with over 200 patients with scleroderma. The result: doctors with less than two years’ experience were able to classify the severity of disease to the same standard as an experienced radiologist after only 10 minutes of training. Prior to the clinical trial which began in 2006, there were several years of pre-clinical research which solidified the foundation upon which the trial was conducted. Following the initial publishing of the trial results in 2008, it was several years before the methodology developed by Dame Black and her team was accepted as the international standard of assessment. All told, a process of around seven years, which shows just how long high-quality research can take!

Making clinical trials more efficient

Raising the efficiency and therefore reducing the timescale of the clinical trials process is essential to ensure that pioneering new treatments are accessible to the patients they can benefit. In 2014, the Clinical Trial Regulation came into operation, which aimed to do just this by harmonising the assessment and supervision process for clinical trials across the EU. This was to be done via a Clinical Trials Information System, which in April 2021 was declared fully functional and on track to go live in January 2022. This system will speed up the registration, conduct, and supervision of clinical trials within the EU, ensuring a more transparent system for the public and enabling lifesaving, beneficial research to reach each patient group as quickly as possible. 

How do I get involved?
If reading this has inspired you to support the work of scientists around the globe by taking part in a clinical trial, then we have a list of resources below!

To find a clinical trial for Raynaud’s or Scleroderma:

• Be Part of Research (nihr.ac.uk)
• Home - ClinicalTrials.gov
• Ask your consultant if they know of any trials that are recruiting and for which you might be suitable.

Anyone can take part in a clinical trial, however it is important to check that you meet the inclusion / eligibility criteria before applying to join a trial. This information will be available within the description of the clinical trial, and you can usually assess for yourself whether you fit the criteria. Talking to your doctor or healthcare provider prior to applying is additionally recommended.