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ОглавлениеBefore Initiation
The scientific quality and validity of a clinical trial is primarily determined by the study design. The design must be planned very carefully, because it is difficult to correct inconsistencies afterward. The academic details of planning is not the only determinant of quality - the financial, organizational, logistical and personnel elements of the clinical trial must also be considered in advance by the sponsor-investigator. Early and painstaking considerations in the study design can also prevent influences (so-called bias) from distorting the results of the pre-planned statistical test procedures.
Regulatory Reference
! ICH GCP Guideline, sections 4.2.1 and 2, 4.7
! EU Directive 2001/20/EC, Art. 2 a, b, c
Responsibilities
Study Types
In principle, two categories of studies exist: the science differentiates between studies of primary and secondary data. This book does not deepen the topic of secondary data studies, because the research with secondary data only looks at studies that have been completed. The research with primary data means the initiation of a trial with recording of primary data. There are also other differences:
The investigator-initiated trial is a clinical trial involving human subjects; it is always a part of interventional clinical research.
Study Population
To make the right conclusions with regards to the general population using statistical test procedures, the sponsor-investigator has to recruit a representative study population. The principle behind this is that the initial starting position or baseline for the clinical trial is, in essence, the definition of the target group for treatment.
Study Design
The primary aim of a study design is an outcome with a high explanatory power. The gold standard of clinical research is the randomized controlled trial or RCT.
The first step is the randomization of the treatment groups, because the experimental units are never identical. By using a random mechanism, the subjects are allocated to the treatment groups. The known and unknown influencing factors on the study results will be equally distributed between study and control group. This method avoids possible bias.
The study is considered controlled when the results of the study population (the active study drug/investigational intervention or verum group) are compared with the results of the non-interventional or control interventional (e.g. placebo, which is considered the most effective measurement) group.
Consider, for example, the so-called crossover design. In this design, the study population and the control group will switch treatments in the middle of the study. This implies that all the participants of the study will get the control intervention and the investigational intervention over two defined periods.
It is advisable to ‘blind’ (also called ‘masking’) the study. This type of design means the participants do not know if they are part of the intervention or control group. The influence of expectations and individual behaviour is considered to be minimized in a blinded/masked study.
• Single-blind: the participants do not know if they are a part of the intervention or control group.
• Double-blind: the participants and the medical staff do not know the allocation.
• Triple-blind: neither the participants nor the medical staff, even those that make the statistical evaluation, do not know who is in the intervention or control group.
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Multicentre Trials
To avoid other influences (e.g. environment) the study can be designed as a multicentre trial.
Steps for a Good Study Design
The starting point of any clinical trial always should be to pose the question or hypothesis that will be answered by the research. The sponsor-investigator must be clear about the subjects and aims of the project. Given this background, the sponsor-investigator must describe the following points accurately in the clinical trial protocol:
• Specification of the primary endpoints and, if applicable, of the secondary endpoints that will be measured during the trial
• Description of the type/design of the study, using a schematic representation of trial design, procedures and stages
• Description of the measurements to minimize bias/distortions, including randomization and blinding
• Description of the trial treatments, the dosage, and dosage regimen of the IMP. This also includes a description of the dosage form, packaging, and labelling of the IMP
• The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if applicable
• Description of the ‘stopping rules’ or discontinuation criteria for individual subjects, parts of trial and entire trial
• Accountability procedures for the IMP, including the placebo(s) and the comparative product, if applicable
• Maintenance of trial treatment randomization codes and procedures for breaking codes
• The identification of any data to be recorded directly on the Case Report Forms (CRFs) (i.e. when no prior written or electronic record of data exists) and to be considered as source data
Advice - Hints and Tips
A schematic overview, e.g. in form of a chart or table of the study design, is highly desirable because it is not only the sponsor-investigator who works with this information. The medical staff, the responsible authorities and the ethic committee(s) must be able to understand and follow the considerations of the sponsor-investigator’s plan.
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Study Protocol
During Study
In the framework of the design and development of masked studies (especially the double-blind), it is necessary to make a randomization plan. This plan is typically made by the biometricians and is the ‘top secret’ of the trial.
In emergency cases, it may be necessary that the sponsor-investigator must decode the randomization and unblind or unmask the trial.
Regulatory Reference
! ICH GCP Guideline, sections 4.7, 4.11
! EU Directive 2001/20/EC, Art. 16
! ICH Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use
! ICH Guideline for clinical safety data management: definitions and standard expedited reporting
Responsibilities
Breaking the Blind
If complications or serious adverse events (SAEs) occur, the sponsor-investigator must report them immediately to the health authorities and also to the Ethics Committee, if they are unexpected (suspected unexpected serious adverse reaction or SUSAR). A SUSAR must be reported if the complication/SAE is not mentioned in the study protocol as a known side effect or a known event that could occur.
To report a SUSAR, the sponsor-investigator must know the allocation of the treatment group and the all details of the patient. However, in a double-blind trial, not even the sponsor-investigator would know this information because the randomization codes are made by the biometricians. In this case, the sponsor-investigator is allowed and required to break the blind.
Emergency Envelopes
In masked trials, for every participant there exists a sealed ‘emergency envelope’. If the sponsor-investigator can no longer ensure the patient’s safety without knowing to which treatment group the patient belongs, he must decide whether to open the envelope.
On the envelope is the subject number of the study patient. After opening, the sponsor-investigator learns the allocation of the patient to the treatment group and is only then able to identify any possible correlations to the substances (verum, placebo, comparator, etc.) and the SAE.
After opening the envelopes the sponsor-investigator must document the incident with:
• Name and date
• Kind of emergency
Required Changes in Study Design
If it is necessary to make amendments to the study design, the sponsor- investigator must contact the Ethics Committee.
Advice - Hints and Tips
The sponsor-investigator must be aware of the consequences when unblinding the study. An unnecessary unblinding could affect the objectivity of the trial. It is justified only to unblind or unmask the treatment allocation when a patient experiences a SUSAR or is in any kind of medical emergency. The sponsor-investigator must further ensure that only authorized people know the data of the participant.
In the chapter ‘Pharmacovigilance’, SUSAR handling is described in detail.
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Pharmacovigilance
