What is a Clinical Trial?
A clinical trial is a scientific experiment to understand the risks of a therapy, drug or medical device and to establish whether it has a benefit. Clinical trials test drugs on humans and include controls and monitoring to ensure it is carried out as intended and that any negative risk or issue is identified as soon as possible.
Clinical trials are conducted on new medicines, but also on existing medicines which are being investigated for a new use or in a new type of patient. Clinical trials can be conducted using healthy volunteers or patients, depending on the type of product and its stage of development.
An experiment? Does that mean the people performing it don’t know that it’s going to work?
That is correct. The people who create the trial may expect it will gather enough scientific evidence to support an application to a regulatory body for the approval of the new medicine but they do not know it. Clinical trials often do not achieve the results the clinical trial creators expect, and often do not result in the approval of a new medicine or a new approved use for an existing medicine.
How are Clinical Trials controlled?
Clinical trials are regulated by law. In the U.S. and Europe clinical trials require approval of either an Ethics committee( Europe) or an Institutional Review Board (U.S). These bodies are in place for hospitals conducting research to look after the interests of the potential participants. They will only approve studies with a reasonable expectation
1) That the study design (number of participants and what is being looked for)is appropriate to demonstrate the objective
2) that the benefit bestowed on a participant by use of the drug/therapy or device will outweigh the risks introduced
Before commencing the trial also has to be approved by the local government agency . These are the Food and Drug Administration (FDA) in the US, the Irish Medicines Board (IMB) in Ireland, Medicines and Health Regulatory Agency (MHRA) in U. K. etc..
Who performs Clinical Trials and Why?
Trials are performed to either further understanding or to provide scientific evidence to support an application for a new medicine or a new use for an existing medicine. Understanding who is leading the creation of a trial and why they are doing it is helpful.
Clinical trials involve a number of different parties. Firstly there is the “sponsor” which is the body (usually a company, university or hospital) which takes responsibility for organizing the trial and which often funds the trial. Next there is the “investigator” who is the doctor leading the actual performance of the trial, and who is often a contractor or an employee of the sponsor. Sometimes the sponsor will engage a “CRO”, a contract research organization to help with the logistics of the performance of the trial.
Companies are commercially focused and perform trials so they can use the data they gather to support applications to government agencies that allow them label and promote their products, on the market, for the approved application.
Government funded agencies undertake studies in the best interest of the community and to understand diseases, occasionally they will work with manufacturers or scientists to explore a particular problem, perhaps one that is not of commercial interest but is of interest to the community. For example, the Rare Diseases Centre Research Network is a United States based network of experts that conducts research sponsored by the government, and one of the areas they are committed to performing research for is Angelman Syndrome.
How are Clinical Trials designed?
As any drug or therapy introduces a risk Doctors will want to see that there was a benefit for the user in using the drug and that the drug is safe. The design of each trial depends on what the objective and motivation of the Clinical trial “sponsor” or leader is.
If the trial is designed to secure a regulatory approval to support sale or to expand a licenced indication demonstrating safety and efficacy will be key. Before a clinical trial begins, a full description of the aims and methods of the trial are set out in a protocol which must be approved by the relevant bodies.
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Drug trial phases
New drugs usually undergo 3 phases of clinical trial prior to a sponsor applying to a regulator for approval.
- Phase I involves a small number of participants and test the drug for safety in the general population.
- Phase II involves the intended patient population, tests for safety and asks the question- “Does the drug have some effect?”
- A Phase III study attempts to show scientifically with a statistically valid sample size that the drug has a benefit for the intended application. Data from a phase III study is usually required before a regulator will allow the product to be labelled for use in a specific application or before doctors will prescribe a drug.
If the drug is already available and approved for use in a similar patient group, perhaps for a different application, the safety in the general population is understood and the first phase clinical trial can often be omitted and the drug moves straight into Phase II.
What are prospective ”Single arm” or “Randomised” trials and what is the difference?
Prospective single arm clinical trials:-
A single arm prospective study means everyone enrolled in the clinical trial will be treated the same way.
If a prospective single arm study is focusing on a drug, the data has to show some indication that there is a benefit. In a single arm study everyone in the trial gets the drug or medicine, there are no results from people with a similar condition who don’t get the drug. As a result, there are no data to show that people with the condition have improved compared to those who didn’t get it.
To try to confirm that there was a positive effect scientists can approach the data in two ways:-
1) In a case where no improvement in condition is expected without treatment, measuring and comparing the persons status at the start, and measuring improvements over time, can be used.
2) An alternative approach is to compare the data gathered in the single arm prospective study with scientific data already accepted (usually published) for a comparable group that have not received the therapy. This is difficult, as it is hard to ensure that the data gathered outside of the clinical trial are for a comparable population.
Randomised clinical trials:-
These compare a group exposed to the therapy with a similar group not treated. Data for both groups are gathered side by side in one clinical trial. Usually the sample size has to be statistically significant and the objective measures set out at the start of the study have to be carefully considered so that all potential improvements are captured. This can be difficult in Angelman Syndrome as behaviour measurement scales specifically for people with Angelman Syndrome haven’t been developed. Most clinical trials involving people with Angelman use assessment questionnaires (scales) which were initially developed to measure childhood development behaviours or brain function after stroke.
Randomised clinical trials are well regarded by the scientific community and are usually required to approve and understand an unknown drug.
They can be expensive because of the numbers and follow up required. Phase III studies are usually randomised.
What is a Natural History Study?
A natural history study collects health information in order to understand how the medical condition develops and how to treat it.
What is happening in the United States as regards a large study of Angelman Syndrome?
The National Institute of Health in the U.S. (NIH) are running a single arm prospective study in six United States medical centres with 320 participants to “characterize” Angelman Syndrome.
It is a Natural History Study. This means participants aren’t receiving drugs for the purpose of the trial, but are being assessed and monitored periodically, so that a record is in place to characterize the expected behaviour of a person with Angelman Syndrome over time.
The study will include people of all ages under 60 and will monitor them annually over 5-10 years.
This is an interesting development as it means that future drug studies may able to refer to this data to understand the recorded measures in an untreated population. In undertaking the study the researchers are also checking whether differences in Angelman Syndrome behaviours or progression can be linked back to the genetic type of Angelman Syndrome present.
Are there other trials around Angelman Syndrome going on?
The below link will bring you to those trials underway in the United States.
http://clinicaltrials.gov/ct2/results?term=angelman&Search=Search
