ICH-GCP = International Conference on Harmonization – Good Clinical Practice.

GCP is defined in the ICH guideline as an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. This standard ensures the public that the rights and safety of the trial subjects are protected and that the trial results are credible.

Organisation of a Trial

With the historical aspects of ICH-GCP discussed in part 1 and the general description of Clinical Research plus the four Phases discussed in part 2, this article takes a look at how a Clinical Trial (i.e. a study during a certain Phase of C.R.) is organised: data flow and the parties involved.

1. Data Flow

The flow of data can be divided into two parts: data retrieval, during which data about the subject and its progress in the study is collected and data processing, with the cleaning and analysis of the collected data and writing of the final report.

Data Retrieval


Before a person can become enrolled in a clinical trial, he or she goes through an extensive screening period, during which it is determined whether the subject is eligible to enter the study or not. This is done by using a list of inclusion and exclusion criteria. Such a list can be quite extensive, depending on the protocol*, but certain criteria return in every study. e.g. The subject must be 18 years or older (except when it is a study concerning children’s medication), female subjects can’t be pregnant and should use contraceptives during the study, the subject should have signed the Informed Consent Form, the subject is in good clinical health…

Besides this list, other assessments are also preformed, such as basic demographic data collection (initials, gender, date of birth…), vitals signs* can be assessed, sometimes a blood and/or urine sample is taken and sent to the central laboratory. A urine pregnancy test is standard issue during screening, for female subjects. All these tests and assessments are done in order to ensure that the subject is eligible to enter the study with a minimum of risk for the patient and to ensure the investigator that the study is conducted in controlled circumstances.

The tests and assessments that are done, further in the study, depend on the study medication and vary from trial to trial. Blood samples and vitals signs are common to occur.


All this data is collected on what is called the source document. This is verified by the CRA* and then copied onto the CRF, or the Case Report Form. This document and the data it contains are used during the data processing stage.

Data Processing


When the CRF arrives at either the sponsor or the CRO*, the data is entered in the clinical database. This electronic data is than checked for consistency and correctness. Consistency is needed within the clinical database and between the clinical database and external data, e.g. data collected from the central laboratory about blood samples.

Consistency within the clinical database is needed for instance between any adverse event* and a medication that was started because of this event: if the start date of the therapy falls before the start date of the event, this is deemed inconsistent. The consistency checks between the clinical database and external data can e.g. be that when a lab value (e.g. white blood cell count) is outside the reference range, that this is recorded in the clinical database as an adverse event.

When the clinical database is considered ‘clean’, it can be analyzed statistically.

With the results from the statistical analysis and reports about any unresolved and outstanding inconsistencies, generated during data cleaning, the final report can be written.

2. Parties involved

Three major groups can be defined amongst the several parties involved with a Clinical Trial: internal parties, external parties and the IEC/IEB*

Internal


The first and most important player in the development of a new drug is of course the company that wants to market the drug and issues the clinical studies. This company is called the sponsor. The sponsor can decide to conduct the trial all by itself, or to employ a Contract Research Organisation to do all, or part, of the work. All of the tasks, mentioned below, can either be done by the sponsor or one or more CRO’s.

First of all, a clinical trial protocol needs to be written, in which the study design, previous studies on the same or related drugs and the ethical aspects of the study are described. Based on this document, other documents are prepared. Such as: the CRF, used for data capture, the Data Management Plan and Data Review Guidelines*, Investigator’s brochure* and others.

A clinical trial team is coordinated by the medical leader. The biometrics team, in charge of data processing, is run by the PM-BIOM: Project Manager-Biometrics. For monitoring and checking up on the data capture/retrieval on the site, a team of CRAs* is assembled and run by the Project Manager-Clinical Research (PM-CR). Besides these two components of the clinical trial team, other departments are also active in an indirect manner. For example: Quality Assurance makes sure that everything is done according to regulations, Management Assistants aid the Project Managers in coordinating communication between the different parties. Especially between the internal and external parties.

External


External parties involved in the organisation and execution of a clinical study consist of companies and people, not part of either the sponsor or the CRO. First in line are of course the sites and their staff: trial nurses and investigators. Sites can be hospitals, general practices and other medical institutions. Blood samples and urine samples are sent to either a central lab or a local lab. When every sample of every site goes to one lab, this is called the central lab. When each site sends the samples to a different laboratory, these are called local labs. It can be that a central lab as well as local labs are being used for a study, depending on the type of tests that need to be done on the samples taken.

Besides these two important actors, some minor ones are also active on the external field. A company is responsible for the packaging, shipment and dispensation of the drug. When a blind study is conducted, an Interactive Voice Response System* can be used to randomize patients to a certain treatment group. This is mostly done by phone. The investigator dials a certain number, he is then asked to provide certain data about the subject in question and afterwards receives a randomization number and treatment group for that patient.

IEC/IRB


The Independent Ethics Committee/Institutional Review Board is responsible to safeguard the safety, the rights and general well-being of subjects participating in clinical trials. It reviews certain documents such as the protocol, the informed consent form, investigator’s brochure, information about recruiting subjects and financial agreements. An IEC consists of at least five persons and one of those members’ primary interest field should be non-scientific.
The IEC/IRB should be kept up to date by the sponsor, CRO and investigators on any changes or adaptations to the trial in general, in order to fulfil it’s responsibilities. Communication with the Ethics Committee is very important, especially when submission to the regulatory authority is being considered.

This article concludes the factual and descriptive part of the series of ICH-GCP. The fourth and final part will take a more critical approach to ICH-GCP and Clinical Research. Safety and efficacy will be discussed, with a look at the ethical aspects. The pro’s and con’s of generic drugs, the problems that these bring with them to the patenting of new drugs and the cost of developing new drugs will be covered. Other issues, like subject recruiting, drugs in the Third World and publishing in medical journals will also be treated.