GOOD CLINICAL PRACTICE (GCP)
By Dato Dr Ismail Merican
The Ministry of Health (MOH) together with the WHO Special Programme for Research and Training in Tropical diseases (WHO-TDR) recently organised a hands-on 7-day workshop on Good Clinical Practice (GCP). The workshop was officiated by Y. Bhg. Tan Sri Dato' Dr Abu Bakar Suleiman, the Director-General of Health.
At the ceremony, Tan Sri Dr Abu Bakar also launched the Malaysian Guidelines for Good Clinical Practice (GCP) and Guidelines for Application to Conduct Drug-Related Clinical Trials in Malaysia. Both books are available for all those interested in doing clinical research in Malaysia and tunding agencies, sponsors or pharmaceutical companies who wish to conduct drug-related clinical trials in any of the research institutions in this country. There have been a number of concerns regarding timelines and procedures related to clinical research and the Steering Committee on Clinical Trials in Malaysia hopes that the availability of these 2 useful documents will help to facilitate clinical research in the country.
It is important for all clinicians to be aware of GCP before embarking on any clinical research.
What is GCP?
Good Clinical practice (GCP) is a standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial subjects are protected.
GCP ensures that subjects are properly protected in clinical studies. Such studies should be based on good science, are well designed and properly analysed and adhere to procedures that are properly undertaken and documented. Adherence to GCP is vital otherwise, subjects participating in the trials may be put at risk or the clinical trial data submitted may be rejected by health authorities and the scientific committee, if found to be unreliable. Also, the research credibility of the researcher and the research institution may be damaged. Only investigators with GCP training and certification should therefore be chosen by pharmaceutical or healthcare companies to ensure that the studies conducted conform to regulatory requirements.
GCP was born in the USA in the mid 1970s when the Food and Drug Administration (FDA) implemented guidelines for clinical investigators. Subsequently rigorous investigational new drug (IND) procedures were enforced and regularly updated over the years to the version that is in force today. Because of the strict implementation of the new regulations in the USA, the FDA found it necessary to reject data from other countries which it considered of substandard quality. This development left the other countries with little choice but to review their own procedures resulting in the birth of various national GCPs. Eventually, a set of European GCP Guidelines followed and was implemented in 1990. Japan, the 3rd largest pharmaceutical market developed their own GCP Guidelines in 1991. Unfortunately the development of the various GCPs did not solve the problem of acceptability of data as there were, not surprisingly, differences in GCP procedures in Europe, USA and Japan. So data collected in one region would not be automatically accepted by another region despite the data being generated from studies conducted in accordance with local GCP requirements.
A series of meetings held between the regulatory authorities and representatives of the pharmaceutical industry companies in the USA, Europe and Japan, together with observers from Scandinavia, Australia, Canada and the WHO (collectively known as ICH) gave birth to a set of GCP guidelines that would be universally accepted. In May 1996, the ICH GCPs came into being and is now the standard by which all clinical trials have to be performed in order to achieve universal recognition. In 1997, the European Union accepted the ICH GCP as a legal requirement and since May 1997, the FDA expect all trials conducted outside the USA and used to support an application for marketing authorisation (NDA, new drug application) to be conducted in accordance with the ICH GCP Guidelines. Japan implemented the ICH GCP Guidelines in April 1997.
In Malaysia, clinical trials conducted before 1996 were usually Phase IV trials. The last 2 years have seen an increase in Phase III and some Phase II clinical trials. In the 7th NIP, only 19% of research in the Health Sector was attributed to clinical research. This of course did not include clinical research sponsored directly by pharmaceutical companies and those performed within the operating budget.
We are now seeing an increasing number of clinical research projects conducted in both MOH and the Universities. This is due to the increasing confidence the pharmaceutical industry has in the ability of our local researchers to conduct clinical trials efficiently and diligently and to efforts by the Ministry of Health to improve and shorten the waiting time for research applications to be processed.
The principles of GCP recommended by the ICH Harmonized Tripartite Guidelines for GCP can be discussed under the following headings:
1. Rights and protection of Subjects
2. The Trial
3. The Protocol
4. Roles, Responsibilities, Qualifications & Experience
6. The Investigational Products
1. Rights and Protection of Subjects
To protect the rights of subjects, all clinical trials should be conducted in accordance with the ethical principles based on the Declaration of Helsinki and are consistent with the applicable regulatory requirements. The clinical trials taken should also weigh foreseeable risks and inconveniences against the anticipated benefits for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety and well being of the trial subjects are the most important considerations and should prevail over interests of science and society and any trial taken must include freely-given consent to take part in a clinical study. In addition, trial subjects can withdraw from studies at any time without giving a reason and such withdrawal does not prejudice any future medical treatment.
Freely given informed consent should be obtained from every subject prior to clinical trial participation. Written informed consent should be obtained from each patient in accordance with regulatory requirements and the Declaration of Helsinki. Both the person taking the consent and the patients should personally sign (or thumb print) and date the consent form in the presence of a witness present during the whole consent procedure. The witness too will be required to sign.
We always insist that at least 3 languages (English, Bahasa Melayu and Mandarin) be used, in simple terms, to enable the subjects to frilly understand the purpose of the study, how it affects them and what the responsibilities of the sponsor, the investigators and their own responsibilities are. The subject should be given this information both verbally and in writing and an information sheet should be provided for each subject. A 20-point check list for obtaining informed consent in accordance with ICH GCPs is available.
The subjects must also be made aware of any compensation in the event of injury or death and that the sponsor provides indemnity insurance to cover the liability of the investigator and the sponsor in the event of any untoward event that may occur in subjects taking part in the study.
The confidentiality of records that could identify subjects must be maintained, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements.
The proposed clinical trial should be supported by adequate non-clinical and clinical information on the investigational product under study. It should also be scientifically sound and described in a clear detailed protocol.
The protocol is the formal record of how the trials must be conducted and must be clear and detailed. The protocol must have the prior approval of the Institutional Research Review Committee and its Ethics Committee. No modification should be made without prior consultation with the sponsor, unless it poses immediate danger to subjects under the study. All agreed protocol amendments must be documented and approved by the Ethics committee (unless purely administrative in nature) prior to implementation.
The composition of the Ethics committee must fulfill the ICH-GCP requirements. The Ethics Committee should safeguard the rights, safety and well-being of all trial subjects.
Throughout the trial, the medical care given to and medical decisions made on behalf of subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. All investigators involved in the trial should be qualified by education, training and experience to perform his/her respective tasks.
The investigator must have the time and the discipline to do the study. He or she must also provide the sponsors with an up-to date, signed and dated CV as evidence of his or her qualifications. In addition, he or she must provide evidence of suitable post-graduate experience in the specialty under study, backed by relevant publications. He or she must be frilly aware of the proper use of the investigational product, be thoroughly familiar with the study protocol and, at all times, comply with his or her GCP responsibilities. A common problem is the inability to meet study recruitment targets and this issue needs to be given special consideration.
All trial procedures should be consistent with GCP/applicable regulatory requirements. All clinical trial information should be recorded, handled and stored in a way that allows for accurate reporting, interpretation and verification. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
The case report form (CRF) is usually prepared by the sponsor of the study. The investigator should ensure that the pages in the CRF are completed, frilly and legibly, at every visit and that all data recorded in the CRF must be properly done to allow verification during the process of source data verification. There are strict rules for amending data in CRFs. Recording of data, done in accordance with GCP requirements, can be very tedious but necessary to ensure integrity of data. The investigator must cooperate frilly with the study monitor in this somewhat demanding exercise. ICH GCP requires the study monitor to have direct access to all subject files to ensure that all data that have been recorded is correct. An important part of GCP is the collection and maintenance of documents in the trial that demonstrate adherence to all the GCP requirements.
All adverse events must be properly recorded. The investigator must obtain information from the subjects about any adverse events that may have occurred as this information may not be readily offered by the subject unless specifically asked for. An adverse event is any untoward medical occurrence in a trial subject who has been administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. So all adverse events need to be recorded. Of course serious adverse events (as defined by study protocol) must be reported immediately to the sponsor. The Ethics committee must also be informed of serious, unexpected adverse events that are product related.
Investigational products should be manufactured, handled and stored in accordance with applicable Good Manufacturing Practice (GMP) and used in accordance with the approved protocol.
The responsibilities of the sponsor, the monitor and the investigator must be frilly understood by all parties involved in the study. The cost of individual clinical trials has escalated substantially since the implementation of GCP. Clinicians who undertake clinical trials must be frilly aware of the importance of conducting the study efficiently and in the shortest time possible. Therefore before agreeing to do the study, the investigator must read the protocol carefully and decide whether he or she is able to recruit subjects based on the inclusion and exclusion criteria and whether the study procedures fit into his or her usual clinical practice. He or she must regularly check the performance against the agreed recruitment rate and identify problems as they occur and not hibernate then until it is too late.
For successful implementation of the study, the investigator will need a good team including a good research assistant and efficient co-investigators, all of whom are very familiar with GCP and the study protocol. Enough time must be devoted for the study with regular meetings being held to discuss progress and problems pertaining to the study. Proper and accurate documentation is crucial.
From the year 2000, all clinicians who wish to conduct clinical trials are required to have approved GCP training. The Ministry of Health has so far trained at least 60 clinicians throughout the country in GCP and those trained have been requested to conduct echo training sessions in their respective hospitals or institutions. The stage is therefore set for us to march into the new millennium with renewed vigour and determination to make Malaysia the hub of quality clinical research in this region.
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