Participants who wish to take part in a clinical trial should be able to do so with the knowledge that their rights and well being are treated as a priority and that everything has been done to provide the best possible care available. In order to do this we need to understand the history of Good Clinical Practice and the reasons why this special code should be adhered to at all times.
What is a Clinical Trial?
A clinical trial is a research study designed to test the safety and /or efficacy of new drugs, devices or treatments that are to be used in human subjects. These clinical trials are carried out in different stages known as phases:
Phase I trials look at a new drug or treatments safety as well as the pharmacokinetics and pharmacodynamics. Phase I studies usually only enrol a small number of patients (20-100).
Phase II trials look further into the safety and efficacy of the new drug or treatment. A larger group of people (20-300) are recruited to this particular phase.
Phase III trials are when the experimental drug or treatment is given to a much larger group of people, usually to treat the disease or medical condition for which it is intended. In this phase the new treatment can be compared with the standard therapy and is often done so in a randomised trial. The safety and efficacy studied very closely.
Phase IV trials are the long term follow up studies on the new drug or treatment after approval has been achieved. The purpose of these trials is to evaluate the long term effects in larger number of subjects over a longer period of time.
Why should clinical trials be regulated?
When carrying out these clinical trials is it important that all applicable regulations are adhered to. The advantages of following the correct regulations ensure that the research is scientifically sound and that the results are credible. It also provides reassurance that the rights and safety of the trial participants are protected.
Historically there have been a number of medical events or disasters that raised the question of safety, such as the Elixir Sulphanilamide disaster in 1937 or the Thalidomide incident of the 1960’s. These discussions ultimately led to the development of certain regulations and guidelines which evolved into the code of practice by which all those involved in clinical research now work. This code is known as International Conference on Harmonisation of Good Clinical Practice (ICH – GCP)
What is Good Clinical Practice (GCP)?
GCP is an internationally recognised ethical and scientific quality standard for the design, conduct, recording and reporting of clinical trials that involve the participation of human subjects.
The development of GCP began at the end of WW2 following the Nuremberg Trials. During these trials Nazi Doctor’s were prosecuted for performing inhumane experiments on human beings in the name of medical science. However, at trial they argued that there was in fact no law in place or even an informal statement suggesting that this experimenting should not be carried out.
After these trials, and in order to protect the rights of the individual taking part in research, two American Doctors, who had been present in Nuremberg, devised a list of 10 points defining how valid and legitimate research should be conducted.
This was known as the “Nuremberg Code” and it was from these instructions that the foundations of GCP were formed. The key points of this code indentified and prioritised the rights of the individual and included, for the first time in an international document, such principles as voluntary participation, informed consent and allowing the participant to withdraw from the experiment at any time. It also suggested that measures should be taken in order minimise any risk to the participant, and that the benefits of the research should outweigh the potential risks.
In 1964 the World Medical Association, which had formed in 1945 to address in particular the non clinical issues that Physicians might be faced with, enhanced the points highlighted in the Nuremberg Code and created a more formal statement of ethical principles. Its purpose was to provide specific guidance to physicians, and any other interested participants, who work in any medical research that involves human subjects. This statement was known as the “Declaration of Helsinki”, and in its introduction contained a binding statement for physicians: “The health of my patient will be my first consideration”. The Declaration of Helsinki has itself been updated and revised several times over the past 47 years, the latest being in 2008.
From this the basis of GCP was formed.
What about Harmonisation?
During 1970’s and 1980’s Japan, UK and other European committees had each developed their own set of GCP guidelines, this inevitably created a difference in the standards of practice throughout the world as well as the repetition of clinical trials in different countries. This in turn led to delays in getting the product to market and created an increase in the costs to the pharmaceutical industry.
The solution to this problem came about in 1996 when a series of conferences were held in order to unify the differing codes of practice. These meetings became known as the “International Conference on Harmonisation of Good Clinical Practice” ICH – GCP. All parties from various countries agreed to follow the same code of good practice, leading to an internationally recognised, uniform standard to which all countries could commit.
ICH – GCP covers all member states within Europe as well as North America, Japan and Australasia. It provides guidance on such issues as
- The principles of good clinical practice
- Research ethics
- Being an investigator or sponsor
- Trial protocol and amendments
- All trial documentation
European Regulation on GCP
The European Commission control the legislation on pharmaceuticals throughout the European Union. In 2001 it published a directive that would make GCP a legal requirement across all member states. This was known as 2001/20/EC and provided the legal framework and core requirements for each member state to adhere to. It also stated that this legislation must be transposed into the laws of each member state by May 2004 and is applicable to all clinical trials on human subjects that involve medicinal products.
In addition to this the European Commission required that each member state appoint a “Competent Authority” to oversee this implementation and ensure that the directive was completed correctly. In the UK this competent authority is known as The Medicines and Healthcare products Regulatory Agency (MHRA).
The implementation of the 2001/20/EC directive in the UK was in the form of the UK Medicines for Human Use (clinical trials) regulations 2004. This became law on 1st May 2004 under the statutory instrument 2004/1031.
2001/20/EC directive changed the way in which clinical trials were conducted in the UK. It had made GCP a legal requirement and all trials involving investigational medicinal products must now be conducted to the same GCP standard, there would also be mandatory inspections by the MHRA.
Informed consent was a particular issue in this directive and it provided added protection to vulnerable groups of people unable to give legal informed consent for themselves. Among many other specifications it also encouraged the development of national ethics committees operating within a legal framework and suggested firm deadlines for the approval of research projects and protocols.
A second directive, 2005/28/EC, was published in April 2005 by the European Commission and was transposed unto UK law on 29th August 2006 under statutory instrument 2006/1928.
This directive is described as amendment No 1 and acts as a supporting document to 2001/20/EC. It confirms the importance of ICH – GCP and states that all clinical trials should be conducted in accordance with the 1996 version of the Declaration of Helsinki. It also states that sponsors retain responsibility even if they delegate functions, and specifies the sponsor responsibilities in relation to reporting Serious Breaches in GCP.
A second amendment was implemented under statutory instrument 2006/2984 and became law on 12th December 2006.
Having achieved prior ethical approval to do so this amendment allows incapacitated adults in certain emergency situations to participate in research trials without the consent of a legal representative. However, this only applies when the treatment is required urgently and when it is not reasonably practical to meet the conditions of obtaining informed consent.
In conclusion, the EU Directives 2001/20/EC, 2005/28/EC as well as the amendments provide the public with the assurance that the rights, safety and well being of the trial subject is protected and that any breach of this legislation is now considered to be a criminal offence.
We can now understand the rationale behind the development of Good Clinical Practice and that it is a set of interwoven laws and guidelines that together provide the foundation for high quality processes in clinical research. We as research professionals must understand these documents and work with them to the best of our ability in order to provide the high standard of care that our patients so deserve.