Introduction to Clinical Trials

With advances in medicine and the development of new drugs, there are still diseases for which no cure is available. Clinical studies are the foundation of medicine development because they allow to test the new drug or device and the assessment of the safety of new products and if they meet the conditions set by the law.

Clinical trials are aimed at determining whether the investigational substance is not only effective, but above all, safe in the fight against a particular disease. For this purpose patients are enrolled into the study and pharmacological and pharmacodynamic activity of IMP is monitored (investigational medicinal product), adverse reactions occurring during the administration of the drug report are prepared and the absorption distribution, metabolism and excretion of the drug is monitored.

Investigational Product is a pharmaceutical form of active ingredient or placebo, which is tested in a clinical trial. This term also applies to authorized medicines, but the study is testing a new indication of the product. (ICH GCP 1.33)

Clinical trials must be correct scientifically and ethically justified. several phases of clinical trials of a new medicinal product can be distinguished. Preclinical studies rely on the use of animals and tissue culture and are conducted in a laboratory. After successful completion of the preclinical studies, it is possible to start clinical trials in humans.

Research can de distinguished on the basis of:

Single-blind study, where one party (the patient) does not know whether a given product is the study

Double-blind study, in which the researcher, patient or research team member does not know which treatment the participant receives.

The allocation of study participants to one of the treatment groups (treatment or control) occurs at the time of randomization using random sampling, which reduces the possibility of bias.

The effectiveness of IMP is compared to commonly available treatment because during the study placebo administration has been criticized because of the deprivation of participants of the standard treatment. The use of placebo is possible if there is no known method of pharmacotherapy.

The role of Investigator

Researcher is the person responsible for the conduct of a clinical trial at the site, which has the appropriate education (doctor or dentist). If the study is conducted by the research team, the investigator is the leader of the team and called a Principal Investigator (PI). The Principal Investigator is responsible for the whole team and the study conducted at the site.

Sub-investigator shall be appointed by the Principal Investigator among the members of the research team and through delegating tasks he is a competent person to make important decisions related to the study.

The Sponsor of the study may be a natural person, company, institution or organization taking full responsibility for the initiation, management and financing of a clinical trial.

The task of each investigator is to provide to the sponsor, prior to the start of the project, all the necessary information concerning the qualifications for the role of investigator and the ability of the site to perform the study.

The investigator as responsible person for the conduct of the clinical trial at a given facility must demonstrate that he has sufficient time to conduct and complete the trial.

In order the study could take place at the given site investigator should demonstrate the ability to enroll the expected amount of patients by the sponsor. In addition, he must demonstrate that he has a sufficient number of qualified staff.

Research site should be equipped with necessary equipment and rooms that will be needed during the study (eg. laboratories, a pharmacy, a place to store the drug at low temperature, equipment, space for storage of clinical trial materials: IMP and confidential data of study participants). Equipment used in the study should be efficient, properly serviced and calibrated.

The investigator / center should sign a contract with the sponsor which will take into account the financial aspects of the study.

Informed Consent Form (ICF)

Informed consent form to participate in the study is a document that contains all the necessary information for the patient having to take part in the study. This document explains how is the study conducted and how it will be carried out. ICF should contain all the information that is needed to make an informed consent to participate in the study and should be written in plain, intelligible language for the patient.

Research teams use this document during the informing and translating to potential participants principles of research. The potential participant can not be enrolled into the study before signing the ICF, which was accepted by EC. (ICH GCP 1.28)

Monitoring of the clinical trial

Monitoring consist on supervising the progress of the clinical trial, as well as ensuring that it is conducted, recorded and reported in accordance with the protocol, standard operating procedures (SOP), the principles of GCP and regulatory requirements of referent country.

Auditing is based on an independent analysis of the documents related to the study, which confirm that the study was conducted in accordance with the protocol, standard operating procedures (SOP), the principles of GCP and regulatory requirements of referent country.

The inspection is carried out by the regulatory body. It is based on the official review of the documentation and institutions deemed to be related to the audit. The inspection may be carried out at the site, at the sponsor or CRO headquaters.

Sponsor determines the frequency of monitoring visits, taking into account the research project, its complexity, goals and the number of participating sites and patients involved in the study. Medical monitor (CRA – Clinical Research Associate) normally performs site visits prior to, during and after the study.

CRA is appointed by the sponsor in order to ensure that the sites in which research is conducted clinical study protocol, the requirements specified by the sponsor and by law are respected.

CRA during visits at sites applies to the Standard Operating Procedures – SOPs of Sponsor or CRO (which should be indicated in the contract).

The purpose of the monitor is to ensure that:

• A clinical study at the site is carried out in accordance with GCP, regulations and the study protocol
• The site has appropriate housing conditions, equipment and other capabilities needed to conduct the study,
• The researcher has an appropriate number of (potential) participants in the study,
• The composition of the research team is updated,
• Staff involved in the study is trained in terms of GCP,
• Study documentation  is checked by the investigator,
• IMP is properly stored and dispensing of the drug is documented,
• Participants and investigators signatures on Informed Consent Forms are properly dated,
• Recruitment is proceeding according to trial schedule,
• Study data are reliable and identical with the source documents,
• The site archives all documents related to the study to the audit, according to the research institution rules and with the requirements of the law.

Each CRA visit must be preceded by a Confirmation letter (CL) informing investigators about the planned monitoring visit, ended by Follow–up Letter (FU) informing the Investigator about procedures performed at the visit. Sponsor receives report from the visit, which contains a list of all documents that have been reviewed by the CRA and all explained inaccuracies. The report also contains a newly discovered problems.

CRA as an intermediate between the sponsor and the investigator should be familiar with the reports from previously conducted visits and during next visit unsolved problems should be explained.
 

End of study:

On the study close-out visit, CRA ensures that documents remaining in the facility (ISF) and the sponsor files (Trial Master File - TMF) are complete.

Medical monitor confirms the amount of drug remaining at the site, the drug returned and destroyed (on the basis of appropriate documentation). CRA also confirms that the relevant reports during the study were written and submitted by the investigator in a timely manner, and that they meet adequate quality standards.