What is a clinical trial?
The term "clinical trial" refers to the set of studies that aims to establish weather a new medicine or medicinal treatment route is suitable to be tested/used on a wide number of patients. Clinical trials are necessary to test new medicines but can also discover new possible uses for existing medicinal treatments.
The entire cycle of clinical trial includes:
Pre-clinical studies: researchers test the medicine on animals and decide if it's suitable to be tested on people.
Clinical studies, which are divided in IV phases:
- Phase I - includes investigations on the product's safety and on it's optimal dosage.
- Phase II - researchers investigate the efficacy and side effects of the medicine.
- Phase III – at this stage the study focuses on the clinical efficacy of the medicine in terms of benefits to a specific population and possible long-term side effects.
- Phase IV – after the medicine's approval, further studies aim to provide more details on its safety and possible side effects.
What are "arms" in clinical trials?
The term "arm" refers to the group of people that take part in the study as volunteers. Normally, the protocol sets a minimum of two arms for each clinical trial:
- Investigated arm (or studied arm) includes sick patients who are being treated with the medicine on which the study focuses.
- Reference arm (or control arm) includes patients (who might be affected by the disease or not) who receive, respectively, a placebo during Phase III or the medicine during Phase I.
Patients are assigned to one or the other arm using a procedure called "randomisation
" which works completely by chance.
Double arm clinical trials are crucial to determine weather patients can really benefit from a medicine. For years researchers, clinicians, regulators and patients' representatives have been discussing the simplification of clinical studies' rules for rare diseases – and rare cancers. The number of rare cancer patients is often limited and it's difficult to reach the minimum obligatory number of volunteers to start double arm clinical studies, including a studied arm and a control arm. In such cases, special protocols allow single-arm clinical studies: every patient in the studied arm receives the experimental therapy and his/her response to the treatment is observed and valued over time. Single-arm clinical studies are normally used to collect data about the benefits and safety of the treatment but not to confirm its efficacy. This method is useful when the available patient pool is very limited thus randomizing many volunteers in a control arm is not an optimal solution (1).
Why and when can single-arm clinical trials be useful?
In June 2016, the European Medicines Agency (EMA) and the European Society for Medicinal Oncology (ESMO) organized a workshop on single arm trials in oncology, involving researchers, representatives of the EMA, the pharma industry, HTAs and cancer patients' community (ECPC and EuropaUomo). The workshop was focused on finding medicines with significant anti-cancer proprieties, that could be used in cases when patients have no options of treatment or when it is particularly difficult to conduct a standard double-arm clinical trial. The workshop's participants discussed the different experiences they had with marketing authorisation based on single-trial data, the strengths and weaknesses of different approaches and the utility of sharing data. The workshop was also a great opportunity to explore stakeholders' ideas and to affirm the need for regulatory guidance in developing new cancer treatments.
Both multi-arm and single-arm clinical studies have advantages and disadvantages. The treatment of cancer patients depends on the histopathologic analysis of the tumour sample for identifying and differentiating cancers at cellular (microscopic) level. During the last thirty years, great advancements in technology and science discovered new ways to diagnose cancer, not only at a cellular level but also at a molecular-genetic level. Nowadays, genetic identification is successfully applied in cancer diagnosis and in the choice of the proper therapy. This means that modern medicines work with specific mutations in cancer cells' genes. This also helps to limit the medicine's effect on healthy cells, hence the side effects of the therapy.
E.g. Lung Cancer
Histopathologic analysis is useful to find out weather the lung cancer is a NSCLC (non small-cell lung carcinoma) or a SCLC (small-cell lung carcinoma). In case of NSCLC Fifteen, characteristic genetic mutations in cancer cells were described. However, some genetic mutations show in smaller groups of patients. This strongly affects clinical trials' management according to applicable rules. The so called "ALK+ gene reorganisation" is present in less than 1% of patients with NSCLC. "MEK mutation in the gene" is present in less than 1% of patients with NSCLC (2). From a genetic perspective, this proves that there is no such thing as one disease called lung cancer, but there are many different types of genetic cancers that affect the lungs. This determines a complication in clinical trials' procedures: new medicines cannot be tested using large groups of patients, they must be studied in small groups. In these case researchers apply single-arm clinical trials to gather as much data as possible about the safety and clinical efficacy of the medicines. This genetic differentiation is already applied in different types of cancer, including bladder, stomach, breast, skin, and kidney.
Nowadays it seems manageable to use clinical trials with small groups of patients and researchers can define multiple small subsets where some specific medicines can achieve high levels of efficacy. However, there are regulatory issues which need to be addressed, such as improvement of single-arm clinical studies' reliability. Small control groups for clinical trials may be difficult to define, nonetheless they are necessary for comparison and should be available. A possible solution could be using historical groups (or concurrent groups): keeping registries with all historical data about each specific disease. For such purpose, sharing clinical data shall be recognized as a necessary procedure. Evidences can be based on different families of data sources and methodologies, which aim to complement randomized clinical trials and not to replace them.
To provide single-arm clinical trials, researchers agree that some prerequisites are necessary:
- Knowledge about the medicine's action mechanism, supported by strong scientific rationale and/or pre-clinical data.
- Knowledge if the medicine is intended for a defined population of patients.
- The benefits are more than the risks.
- It is a good alternative when randomization is considered unethical or unfeasible.
Anyway, the inclusion of non-randomized studies requires huge efforts to national regulators (mainly HTA bodies), and should involve prior considerations about advantages and disadvantages. The possible inclusion of single-arm clinical trials shall not lead to the false belief that randomized clinical trials are not worth being performed. Thus, HTA might act as an obstacle in trying to define the impact of intervention such as the inclusion of single-arm clinical trials (3).
In conclusion it is important to stress that patients need new therapies. Researchers and regulators' support the efforts to simplify clinical trials' procedure, but stakeholders' activity have to be very prudent in the field of clinical trial studies: it is fundamental to maintain high standards in research and data credibility.
1. Scott R. Evans, "Clinical Trial Structures", J Exp Stroke Transl Med. 2010 Feb 9; 3(1); 8-18.
2. Lovly CM, Horn L, Pao W, "Molecular Profiling of Lung Cancer", www, mycancergenome.org, updated in February 2015.
3. EUnetHTA Guideline, "Internal Validity of Non-Randomized Studies (NRS) on Interventions".