Preclinical and Clinical Drug Research and Development …sis.vfu.cz/links/strnadovav-preclinical-and-clinical-drug.pdf · 1 VETERINÁRNÍ A FARMACEUTICKÁ UNIVERZITA BRNO FARMACEUTICKÁ

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VETERINÁRNÍ A FARMACEUTICKÁ UNIVERZITA BRNO

FARMACEUTICKÁ FAKULTA Ústav humánní farmakologie a toxikologie

Preclinical and Clinical Drug Research and Development

Věra Strnadová, MD, PhD

BRNO 2014

Tato výuková opora vznikla v rámci řešení projektu: „Zvyšování pedagogických, manažerských a odborných dovedností pracovníků VFU“

s registračním číslem CZ.1.07/2.2.00/28.0110. Tento projekt je spolufinancován Evropským sociálním fondem

a státním rozpočtem České republiky.

VETERINÁRNÍ A FARMACEUTICKÁ UNIVERZITA BRNO

FARMACEUTICKÁ FAKULTA Ústav humánní farmakologie a toxikologie

Preclinical and Clinical Drug Research and Development

Věra Strnadová, MD, PhD

BRNO 2014

I would like to express my thanks to PhDr. Magdalena Karelová for her invaluable help with translation of this manuscript.

CONTENTS

1. DRUG DEVELOPMENT .......................................................................................................... 5

1.1. PRECLINICAL TESTING OF DRUGS ..................................................................................... 6

1.2. CLINICAL EVALUATION ....................................................................................................... 10

1.3. THE COURSE OF CLINICAL EVALUATION OF A NEW DRUG ......................................... 12

1.3.1. ARRANGEMENT AND SPECIFICS OF THE PHASES OF CLINICAL TRIALS OF A NEW DRUG ........................................................................................................................ 12

2. HISTORY AND DEVELOPMENT OF METHODS IMPLEMENTED IN THE CLINICAL EVALUATION OF MEDICINAL PRODUCTS ....................................................................... 15

2.1. GOOD CLINICAL PRACTICE ................................................................................................ 17

2.2. CLINICAL EVALUATION OF DRUGS IN COMPLIANCE WITH GOOD CLINICAL PRACTICE ............................................................................................................................. 21

2.3. ETHICAL ASPECTS OF CLINICAL EVALUATION ............................................................... 23

3. ORGANIZING CLINICAL TRIALS IN COMPLIANCE WITH GOOD CLINICAL PRACTICE (GCP) .................................................................................................................. 27

3.1. STATE AND EUROPEAN REGULATORY AUTHORITIES (SÚKL, EMA) ............................ 27

3.2. INDEPENDENT ETHICS COMMITEES (EC, REC, IREC, IRB) .......................................... 27

4. DOCUMENTS AND CT PRACTICE ...................................................................................... 31

4.1. PREPARING DOCUMENTS (PROTOCOL, CRF, IB, TS) .................................................... 31

4.1.1. THE PROTOCOL ................................................................................................................... 32

4.1.2. CRF – CASE REPORT FORM .............................................................................................. 36

4.1.3. IB – INVESTIGATOR´S BROCHURE .................................................................................... 37

4.1.4. INFORMATION AND INFORMED CONSENT (IC, PATIENT INFORMATION) .................... 40

4.1.5. INVESTIGATIONAL PRODUCT AND PHARMACEUTICAL DATA ON INVESTIGATIONAL PRODUCTS .......................................................................................... 42

4.2. REQUEST FOR AUTHORIZATION OF A CLINICAL TRIAL ................................................. 44

4.3. SUPERVISION OVER CLINICAL TRIAL ............................................................................... 44

4.4. INTERIM REPORTS AND REPORT ON CLINICAL TRIAL TERMINATION ........................ 45

4.5. CLINICAL TRIAL FINAL REPORT ........................................................................................ 46

5. SUBJECTS ACTIVELY PARTICIPATING IN THE CLINICAL TRIAL, AND THEIR SCOPE OF RESPONSIBILITY .............................................................................................. 47

5.1. SPONSOR ............................................................................................................................. 47

5.2. MONITOR .............................................................................................................................. 49

5.3. INVESTIGATOR .................................................................................................................... 50

5.4. TRIAL SUBJECT, SUBJECT, HEALTHY VOLUNTEER, PATIENT ...................................... 55

5.5. CLINICAL / CONTRACT RESEARCH ORGANISATION – CRO .......................................... 56

5.6. LEGAL REQUIREMENTS PRIOR TO THE CT COMMENCEMENT .................................... 56

6. GLOSSARY ........................................................................................................................... 57

7. USED ABBREVIATIONS ....................................................................................................... 67

8. LITERATURE ......................................................................................................................... 68

DRUG DEVELOPMENT

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1. DRUG DEVELOPMENT

Before a drug reaches the patient, it must undergo an extremely complex evaluation

process, which can be divided into several stages according to the drug’s purpose. In one

stage, the tested drug is administered to relatively homogeneous groups of people. This stage

is called “clinical evaluation of drugs,” (clinical trials) and constitutes the greatest part of

clinical research.

Fig.1 Development of a new drug

The development of a drug has several stages. During the clinical evaluation stage, the

tested drug is administered to a human subject in order to assess its conformity. This stage

represents the final step in pharmaceutical and medicinal research, and constitutes an inherent

part of the registration process for each drug. Registration precedes the introduction of a drug

into the market and its distribution to patients. Knowledge of pharmacology is very useful

during the preclinical trial and clinical evaluation stages.

1

DRUG DEVELOPMENT

Basic research Development of substance

Technology Development of drug form

Preclinical research Safety

Registration Legal aspects

Market Clinical use

Clinical research Efficiency and safety

DRUG DEVELOPMENT

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A drug can be experimentally administered to a human in cases where the substances

were found to be sufficiently effective and safe during the preclinical testing on animals, and

where their clinical use can be expected. Clinical evaluation is therefore preceded by basic

chemical, biological and pharmacological research, including the use of laboratory animals.

It is stated that out of approximately 50,000 synthesized substances only 5 reach the

stage of clinical evaluation and just one, on average, proves to be sufficiently safe and

effective in order to be used in human medicine.

Why are new drugs developed? There are several reasons: 1) to be responsive to the

general need combined with a search for new therapeutic methods; 2) to shorten therapy

time; 3) to optimize the characteristics of a drug, including the limitations of the risks and

adverse effects.

1.1. PRECLINICAL TESTING OF DRUGS

Preclinical testing uses laboratory animals, which are kept in a special environment

solely for this purpose. Wild animals are never used. Preclinical testing has a logic structure

with exact, defined, interconnected stages. The obtained results are used to stipulate

hypotheses for clinical research.

Stages of preclinical testing:

1. Pharmacodynamics: the effect and its mechanism.

Screening monitors the impact on the nervous (NS) cardiovascular (CVS), respiratory,

endocrine and immune systems, the gastrointestinal tract (GI tract), the liver, kidneys

and also monitors the antibacterial effect as well.

2. Pharmacokinetics: monitors the passage of an administered drug through the

body.

Pharmacokinetics looks for answers to questions connected with the path and behavior

of a tested substance within a living organism – how it gets absorbed, distributed and

altered due to the effects of biotransforming systems, and how it is excreted from the

body. Pharmacokinetics works within the pharmacokinetic parameters.

PRECLINICAL TESTING

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3. Acute, chronic and targeted toxicity

Safety is assessed according to the wide range of adverse effects observed in a living

organism.

Both acute and chronic changes of functions are monitored as well as the possibility of long-

term damage to subsequent generations (mutagenicity, cancerogenicity, etc.).

4. Experimental pharmacotherapy

Should some physiological functions prove to be altered, further research focuses on

model pathological conditions, i.e. the pathological condition is developed in laboratory

animals. For example, laboratory animals are bred to have genetically fixed pathological

conditions, such as hypertension.

5. Experimental pharmacokinetics.

A very important part of preclinical research is the determination of pharmacokinetic

parameters in various species of healthy laboratory animals and in animals with symptoms of

specific conditions.

6. Comparative pharmacokinetics

Even though no pharmacokinetic parameters of any animal can be transferred to

humans, long-term experience allows the modeling of the probable behavior of a tested

substance in humans. Therefore, it is important to understand inter-species differences from

the perspective of pharmacokinetics, which is the aim of comparative pharmacokinetics.

Pharmacodynamic screening

Prior to the experiments using animal subjects, new substances must be tested on

specific models, e.g. in vitro (in a laboratory vessel), which often includes experiments on

cell or tissue cultures. It is also possible to carry out key experiments on isolated organs, i.e.

in situ, which is often tissue from veins, intestines, kidneys or the liver. Due to the fact that

living organisms work as perfectly coordinated units, the next step is necessary to confirm in

vitro and in situ results on live, healthy animals, i.e. to carry out in vivo experiments.

The following tests should focus on the pharmacokinetics and pharmacodynamics of

deliberately induced pathological conditions.

Preclinical trials provide the initial information on the safety of the tested substance,

which can be expressed as a therapeutic index. A therapeutic index is the ratio between

a toxic, lethal dose (the amount that causes death), and an effective therapeutic dose (marked

LD/ED). The higher the therapeutic index is, the safer the substance.

PRECLINICAL TESTING

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Generics

Pharmacokinetic testing in laboratory animals is also important when introducing new

generic medicinal products where there are required bioequivalence studies comparing

pharmacokinetic parameters such as bioavailability, Cmax, Tmax, T1/2, etc., to the original MP

(Medicinal Product) and generics. A generic drug form is a drug that contains the same active

ingredient as the original registered MP (or its acceptable equivalent), whose predefined

parameters cannot substantially differ (given by the prescription). Various older sources call

generics the “me-too drugs”. Except for the bioequivalence, it is also desirable to prove its

therapeutic compliance by demonstrating its clinical equivalence, i.e. the compliance between

therapeutic effects. Presently however, this is often not required after the registration of

a generic drug.

During the process of preclinical testing for new drugs, a large emphasis is placed on the

toxicity limits determination:

1) Determination of acute toxicity and of the lowest dose causing toxic symptoms;

2) Subchronic and chronic toxicity is monitored during a repeated administration of the

tested substance;

3) Targeted toxicity such as mutagenicity, teratogenicity, embryotoxicity,

cancerogenicity, local irritability and metabolic disorders are studied based on the

character of the tested substance.

The administered dose plays a significant role in drug toxicity. Paracelsus said as

early as the 16th century that “it is only the dose which makes a thing poison.” (Dosis sola

facit venenum)

In the preclinical testing of new drugs, toxicology tests focus primarily on toxic

effect manifestations: behavioral, neurotoxic, cardiovascular, respiratory, dermatotoxic,

metabolic, hepatotoxic, gastrotoxic, endocrine, hematotoxic, influence on the immune system

and specific tests regarding the structure of a tested substance.

At present, there are many methods to test toxicity; in Decree No. 449/2005 Coll. we

can find 43 validated methods as well as general and special testing methods.

Testing toxicity is also influenced by the expected length of application. There is

a difference if it is a single-dose administration or chronic application lasting several months or

even years.

PRECLINICAL TESTING

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Testing according to the expected application length

1×...................1 week

1 week............1 month

1 month..........3 months

> months......12 months

To evaluate the effect on a living organism, the following parameters are monitored in

laboratory animals – animal behavior (e.g. sociable/aggressive), water and food intake, changes in

weight, the appearance of the animal subjects, motility, and periodically (at least once in 3

months) the hematological and biochemical markers are checked. Targeted tests usually focus on

cancerogenicity, reproductive toxicity, teratogenicity, mutagenicity and local irritation.

There are several methods to determine drug safety. In pharmacology, there is the

therapeutic index (see above), but there are also other scales (fig. 2).

LD50 Category

> 15 g/kg practically non-toxic

5 – 10 slightly toxic

0.5 – 5 moderately toxic

0.05 – 0.5 highly toxic

5 – 50 mg/kg extremely toxic

< 5 super toxic

Table 1. Toxicity categories

Even in the phase of preclinical testing it is necessary to adhere to ethical norms,

which were adopted for experiments on laboratory animals and which must be observed by

everybody participating in such experiments. There are regulations (Act No 359/2012 Coll. on

the protection of animals against abuse) which address this area. Furthermore, all workplaces

where preclinical testing takes place must establish a committee, whose responsibility would

be to assess and approve or reject research projects.

PRECLINICAL TESTING

10

The philosophy of ethics during preclinical testing can be summarized with the

concept of the 3R’s: Replacement, Reduction and Refinement.

Replacement – in practice means to replace in vivo experiments with model tests in vitro and

in situ, where applicable.

Reduction is the effort to minimize the number of animal subjects used for the tests,

providing that the group will be large enough to obtain a statistical analysis.

Refinement means that animal’s distress and discomfort is minimized before, during and

after the test.

In summary, the preclinical testing of drugs is a research activity with an aim to

demonstrate the drug’s biological effect, describe basic pharmacokinetic and

pharmacodynamic characteristics of the tested substance in a higher living organism, the

drug’s relative safety, the therapeutic effect targeted to a certain disease, and finally, the

quality of the tested drug as a prerequisite for its use in humans. In other cases, the aim may

be to verify the anticipated characteristics of an investigational drug and/or to compare the

characteristics of various drugs for the same indication. Preclinical testing is a prerequisite for

the administration of the tested substance in humans; the decision making process regarding

the approval of the clinical evaluation in humans is based on preclinical results.

To date, there is no sufficiently perfect model that would replace preclinical testing in

animals. At the same time, tests on animal subjects cannot fully simulate the complex and

integrated human body controlled by the brain with its unique ability for volitional reactions.

1.2. CLINICAL EVALUATION

The clinical evaluation of a new drug aims to demonstrate and specify its therapeutic

effect and tolerance in particular indications and dosages, as well as to determine the

contraindications and the possible interactions and adverse effects in humans. In the case of

generics created according to the original drugs, it is something similar to an identity card

(bioequivalence) from the perspective of its pharmacokinetic and pharmacodynamic

characteristics as well as its therapeutic equivalency compared to the same drug form from

a reference preparation. However, this is not required for the registration of all generic drugs.

CLINICAL EVALUATION

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Clinical evaluation is required even when introducing a new indication or change in the

dosage or the drug form.

Clinical evaluation is subjected to the same strict requirements as any other scientific

experiment, i.e. it must be transparent and repeatable. There are also imposed special ethical

requirements.

These controls and the gradual introduction of rules under which clinical research can

be conducted resulted not only from new biotechnological advances, but from unsound

practices during the introduction of new drugs into the market, which consequently harmed

patients. And because they were adopted analogically, like other regulated activities in the

area of drug research and development, they were analogically marked and are called Good

Clinical Practice (GCP). Carrying out the studies in compliance with GCP should ensure the

sufficient quality, transparency and predictive value of the obtained results, and at the same

time protect people from dangerous and unnecessary risk.

A basic principle of the modern medicine is to always provide a therapy for patients

that has a favorable ratio between benefit and risk. In humans, the extent of risk should

always be provably lower than the extent of benefits. Supervision over the safety of

administered drugs – pharmacovigilance – constitutes an inherent part of contemporary drug

policy in all developed countries. In the Czech Republic, it has been legally supported for

many years.

The cooperation of various specialists, including pharmacists and doctors, on the

development of drugs resulted in the foundation of a new multidisciplinary science –

pharmaceutical medicine. The aim of pharmaceutical medicine is to educate specialists who

participate in the individual stages of the drug development.

Pharmaceutical medicine deals with drug development from its chemical beginnings

via the drug form development and the experimental testing of desirable and undesirable

effects on laboratory animals, to the clinical evaluation of drugs, completed with the

development of a new drug prior to (and occasionally subsequent to) its introduction into

clinical practice. It also focuses on the ethical and legal aspects of the development and use of

drugs, and on the activities of pharmaceutical companies.

Pharmaceutical medicine is a postgraduate study of medicine, and has had the longest

tradition in Great Britain, where the first diplomas were awarded in 1976 (Cardiff, Wales).

PHASES OF CT

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1.3. THE COURSE OF CLINICAL EVALUATION OF A NEW DRUG

1.3.1. ARRANGEMENT AND SPECIFICS OF THE PHASES OF CLINICAL TRIALS OF A NEW DRUG

Time schedule

Clinical trial of the tested drugs, in compliance with GCP, is implemented in several

consequent logical phases. The stage of clinical trial of a new drug can be divided according

to various criteria. The division according to time phases from preclinical to clinical

evaluation has had a long tradition; clinical trial is divided into four stages.

During Phase I, the drug is administered for the first time to a human subject with an

aim to determine its basic pharmacological parameters, to answer questions regarding human

pharmacology from the perspective of safety and tolerance, and to determine

pharmacokinetics in humans and the suggested tolerable dosage range. A therapeutic target is

not always the goal; it can sometimes be a secondary evaluation parameter. The drug is

usually administered to several (often 12–24) healthy volunteers, and only in some cases to

a small group of patients (cytostatics). The initial phase of clinical trial cannot include

vulnerable individuals, nor groups of individuals, e.g. children and youth under 18 years of

age, pregnant women and people over 70.

Phase II is already targeted toward therapeutic effects. Sometimes it is further

subdivided into stages 2a – pilot trials and 2b – pivotal trials. The aim of the pilot trial is to

determine the drug’s efficacy and safety within a carefully selected group of patients having

the condition for which the particular drug is being developed. In stage 2b, there is expected

verification and specification or the completion of assumptions from stage 2a. The patients,

usually numbering from 100 – 300, are thoroughly monitored and they are usually

hospitalized. The results of phase 2 should bring about the verification of the assumptions,

confirm the dependence between the dose and effect, specify the dosage regimen and confirm

the therapeutic range. Based on the drug’s characteristics, the secondary goal may also be to

determine the effects in a specific group of people, e.g. children or the elderly.

Phase III is an extended clinical trial, which verifies, and often with the help of

comparable drugs, compares, checks and further specifies the results of previous studies with

an aim to prove the safety and efficiency of the drug in humans, under conditions similar to

PHASES OF CT

13

usual practice. Inclusion criteria are more liberal than in previous phases. Large numbers of

patients (hundreds to thousands of subjects) are enrolled in the trials. Results of Phase III of

clinical evaluation should be evaluated by professionals using biostatistical analysis and they

play a key role in the drug registration and launching in the market. This phase is sometimes

followed by phase 3b conducted after the regulatory submission, but before the drug’s

approval and launched into the market. Its aim is to gather more knowledge with more

information, e.g. to determine its influence on life quality, or to further specify previous

results.

Phase IV is the post registration phase of the clinical trials, in case there is a need to

further specify the drug effects in light of new scientific discoveries, or to use more exact

methods of measurement, a different dose and schedule administration or to re-evaluate

interactions. During the post registration period, any possible ADRs are usually of the greatest

interest. This is especially important in new original drugs and in the case of rare ADRs.

Division of clinical trials according to their aim

Presently, in these times of rapid and technically advanced pharmaceutical and

medicinal research, the traditional schematic division into four phases has become

insufficient. Therefore, the division is often used according to the designed primary aim. This

way we can distinguish between the pharmacological, exploratory, confirmatory and

therapeutic studies.

Pharmacologically – focused studies spread through the entire range of clinical trials

from phase I to VI. The aim is to determine and verify drug tolerance and the basic

parameters of pharmacokinetics and pharmacodynamics.

Exploratory studies are more important during the second traditional phase of the

clinical trials, but they also integrate into other phases. The purpose is to determine

pharmacodynamics and the therapeutic effect of a drug in a given indication as well as its

dose dependency.

Confirmatory studies are implemented partially in the second phase, but mostly in the

third traditional phase of clinical trials. Their aim is to verify the therapeutic effect on large

groups of patients and to confirm recommended dosage schedules, as well as to compare the

effect influenced by various doses. Also during this studies, particularly in the 3rd phase of

PHASES OF CT

14

clinical trials, the drug’s safety is verified, and its character and frequency of ADRs are

further specified. These studies constitute a basis for the regulatory submission.

Large-scale studies focusing on therapeutic use without any restrictive entrance criteria

(according to registered data) are traditionally carried out in the fourth phase, i.e. after the drug’s

registration. These studies generate information confirming the effects and confirming or

discovering less frequent and new ADRs and interactions, along with the real therapeutic value

of a new MP. This category also includes pharmacoepidemiologic and pharmacoeconomic studies

as well as the long-term monitoring of the impact on mortality and morbidity.

Fig. 2 Phases of clinical evaluation of a new drug

Investigational medicinal product (IMP) has to meet applicable requirements of

Good Manufacturing Practice (GMP), i.e. it must only be produced by a manufacturer

who has the certificate of GMP. The IMP must be also coded and labeled in a manner that

protects the blinding, if applicable. The labeling should comply with applicable regulatory

requirements. The GMP stipulates requirements (Annex 13) on information that must be

provided on the external label (package) as well as on the internal label (ampoule, blister,

tube, etc). Unlike in registered products, in the IMP must be kept all and detailed records

regarding administered drugs as well as returned empty packages or remaining IMPs. 100

% medication reconciliation is required. The IMP records form must contain at least the

date, batch, expiration date and recipient’s name or code.

VERIFICATION

RESEARCH

HUMAN PHARMACOLOGY

I. II. III. IV.

THERAPEUTIC USE

GCP HISTORY

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2. HISTORY AND DEVELOPMENT OF METHODS IMPLEMENTED IN THE CLINICAL EVALUATION OF MEDICINAL PRODUCTS

Everything that happens with a new drug, from the research and development to its

production and distribution into pharmacies, is subjected to obligatory legislation known as

“good practice.” Good clinical practice was introduced in the 1990s in order to protect

patients and healthy volunteers participating in clinical trials, and to facilitate the publishing

of transparent, i.e. correct, credible and reproducible data. The greatest emphasis is placed on

the ethics of clinical trials and taking responsibility for the correctness of the results.

America, Europe and Asia (especially Japan) represented the three largest territories in

the 20th century having an important pharmaceutical industry, including research and

development. However, there were substantial differences between these territories in the

applied methods of drug development. Historically, the first state-controlled organization was

founded in the U.S. In 1930, the U.S. Congress approved the establishment of an organization

to control the quality, effectiveness and the registration of drugs, known as the Food and Drug

Administration (FDA).

The Czech Republic has had a privileged tradition in this area, dating from the

foundation of an independent Czechoslovak Republic in 1918, when “The Drug Investigation

Institute” was established. Initially, it had its laboratories at various workplaces at Charles

University in Prague. Since 1931, laboratories were centralized under the State Health

Institute, out of which several were allocated in 1952 to the State Institute for Drug Control

(SÚKL). At this time, the scope of the institute’s activities was expanded to include the

control of “medical supplies, especially therapeutic and diagnostic tools and disinfecting and

other devices”. An additional expansion occurred in 1992, when the “Drug Control

Laboratories” became affiliated with the Institute. It also took control of the agenda regarding

the approval of health instruments. In 1997 this scope was expanded to include all types of

health issues. However, not all European countries have had such a tradition or institutions

similar to SÚKL. In many countries, control and registration activities fall under the scope of

the officers of the Ministry of Healthcare.

GCP HISTORY

16

The Czechoslovak Republic has also had an enviable position regarding the

monitoring of ADRs. When an international group was established in 1968 to monitor the

adverse effects of drugs, Czechoslovakia was one of the 10 founder members.

After World War II, the entire system of drug administration garnered more

professional attention thanks to the activities of the World Health Organization. A result of

this effort was the approval of the Revised Drug Strategy W.H.O. (1986), which became the

basis for national drug policy projects of individual W.H.O. member states. Groups of

W.H.O. experts arrived at the conclusion that in new drugs, it was not enough just to monitor

their benefits, but that it was also important to monitor their safety and health risks. Based on

these conclusions they recommended a significant expansion of preclinical trials in newly

developed medicinal products, and for the monitoring of adverse drug effects after their

introduction into clinical practice. Following negotiations on quality control and drug safety,

W.H.O. recommended the creation of a new discipline – clinical pharmacology.

The gradual globalization of the world necessitates the effort to unify conditions for

drug development in order to facilitate mutual acceptance of drugs developed in various parts

of the world. This was also a reason for establishing the International Conference on

Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human

Use (ICH-GCP), which has been continually operating since 1991 in order to create uniform

conditions for the development of medicinal products in the modern world. These activities

were implemented in compliance with W.H.O. and the Council for International

Organizations of Medical Sciences (CIOMS), which played a substantial role in the founding

of the Declaration of Helsinki, for example.

ICH GCP has adopted the following objectives:

a) the possibility of mutually accepting of data regarding safety (toxicology), to produce

quality and effective medicinal preparations for humans;

b) the unification of technical requirements regarding the testing of various parameters,

the use of individual standards for methods of obtaining data and for the content of

reports.

Until recently, there has not been an agreement between individual European

countries, much less between continents, regarding the requirements for drug research and

development. The globalization of Europe has necessitated the cooperation for the designing

of individual GCP rules based on ICH work. The resulting document was adopted by

GCP HISTORY

17

European Parliament as “Directive 2001/20/EC of the European Parliament on the

approximation of the laws, regulations and administrative provisions of the Member States

relating to the implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use” (hereinafter Directive 20 EC), and it constitutes a binding

legal regulation for all EU membership states. Candidate countries must also respect this

norm. The Czech Republic and its legislature has fully cooperated with this legal regulation

since 2003.

As explained in the foreword of the ICH GCP guidelines, the principles stipulated

therein should by applied not only during drug research and development, but also in all

clinical research, because it is always necessary to demand safety and the quality of life for

human participants in clinical trials as investigational subjects, and to ensure credible results

from such research.

2.1. GOOD CLINICAL PRACTICE

Good clinical practice is defined as a set of internationally accepted ethical and

scientific requirements, which must be adhered to during the designing, implementing and

recording of clinical evaluations having participating human subjects, and during the

processing of reports on these evaluations.

Good clinical practice was established in order to protect human rights and ensure the

confidentiality, safety, health, well-being and inviolability of all trial subjects in order to

prevent mistakes or even falsifications during the process of obtaining correct and credible

data from clinical trials. GCP is therefore based on the respect of both ethical and scientific

principles.

GOOD CLINICAL PRACTICE

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ICH E6 GCP

The document ICH E6 GCP consists of eight chapters. There is a glossary at the

beginning, which should be familiar to everyone who works in the area of clinical trials. The

second chapter describes the thirteen principles of GCP. The following three chapters

describe in detail the activities and scope of responsibilities of the active participants in

clinical trials. There is a section focused on the role of “opponents” that also include ethics

committees. Furthermore, it describes the scope of activities of an investigator (researcher)

and a sponsor (client), regardless of whether it is a pharmaceutical company or an academic

institution.

Last three chapters address in detail essential documents for the conduct of clinical

trials, e.g. clinical trial protocol and its supplements, and an investigator’s brochure (IB),

which every investigator should use as a summary of the information on the tested substance;

since such knowledge should allow correct interpreting of possible ADRs. The last chapter

describes which documents are essential for the conduct of clinical trials. The documents are

divided according to the stages of a clinical trial. The first group of documents must be

available Before the Clinical Phase of the Trial Commences. It is stipulated what must be

available at the sponsor’s site and at the investigator’s site. The second group defines the

documents necessary During the Clinical Conduct of the Trial and the third includes a list of

documents necessary After Completion or Termination of the Trial.

1. Glossary 2. Principles of ICG GCP 3. IRB/IEC (Institutional Revue Board/Independent Ethics Committee) 4. Investigator 5. Sponsor 6. Clinical Trial Protocol and Protocol Amendment(s) 7. IB (Investigator’s Brochure) 8. Essential Documents for the Conduct of a CT


19

ICH GCP Principles

The thirteen principles begin with the ethical aspects containing requirements

consistent with principles that have their origin in the Declaration of Helsinki* (WMA), where

there are defined requirements regarding the suitable ratio between the risk and the benefit of

the tested drug for a patient. It highlights the principle that the patient’s rights and well-being

must always have priority over scientific interests, i.e. the demands on the scientific aspects

and exactness of the trial protocol. Furthermore, the need to assess the trial protocol is

emphasized from both from the scientific and ethical perspectives.

GCP also contains requirements for the professional and ethical qualities of doctors

participating in clinical trials, and emphasizes the voluntary patient’s decision to take part in

the study, which must be duly recorded. It also stipulates a trial subject’s rights on

confidentiality and finally, there are requirements for the quality of the tested preparations as

well as for the compliance with other directives (GMP, GLP) to ensure the quality of all

aspects of the clinical study.

GCP principles:

1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

2. Before a trial is initiated, all foreseeable risks and inconveniences should be weighed against any anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

3. The rights, safety, and well-being of the trial subjects are of the upmost consideration and should prevail over the interests of science and society.

4. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

6. A trial should be conducted in compliance with the protocol that has received prior

* Ethical Principles for Medical Research Involving Human Subjects were adopted in 1964 and consequently updated and amended by assemblies of World Medical Association (WMA): Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, Oct 1975, 35th WMA General Assembly, Venice, Italy, Oct 1983, 41st WMA General Assembly, Hong Kong, Sept 1989, 48th WMA General Assembly, Somerset West, Republic of South Africa, Oct 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland, Oct 2000, Note of Clarification on Paragraph 29 added by the WMA GA, Washington 2002, Note of Clarification on Paragraph 30 added by the WMA GA, Tokyo 2004, 59th General Assembly, Seoul, South Korea, Oct. 2008, 64th General Assembly, Fortaleza, Brazil, Oct. 2013 in which not only formal changes were made.


20

approval/favorable opinion from an institutional review board (IRB) or an independent ethics committee (IEC)

7. The medical care given to all subjects, and any medical decisions made on their behalf, shall always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

8. Each individual involved in conducting a trial should be qualified by academic degree, training, and experience to perform his or her respective task(s).

9. Freely-given informed consent should be obtained from all subjects prior to their clinical trial participation.

10. All clinical trial information should be recorded, handled, and stored in such a way that will allow for its accurate reporting, interpretation and verification.

11. The confidentiality of records that could possibly identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP), and should also be used in accordance with the approved protocol.

13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

The Czech Republic was among the first countries in Central Europe to adopt ICH-

GCP in 1997 as a regulatory requirement by Act No. 79 on Pharmaceuticals, complemented

by Decree No. 472/2000 Coll., governing good clinical practice and detailing conditions for

the performance of clinical studies.

However, as European legislation keeps developing and cooperating, in the Czech

Republic, Act No. 79 and Decree No. 472 were replaced in 2007 and 2008 by Act No.

378/2007 Coll. and Decree No. 226/2008, which are fully in compliance with Guideline 20

EC and the complementary EC Directive (Directive 2005/28/EC) as of April 8, 2005, laying

down principles and detailed guidelines for good clinical practice as regards to investigational

medicinal products for human use, as well as the requirements for the authorization of the

manufacture or importation of such products.


21

2.2. CLINICAL EVALUATION OF DRUGS IN COMPLIANCE WITH GOOD CLINICAL PRACTICE

During its entire process, clinical evaluation weighs the benefits of a new drug and its

drug forms from the perspective of human use. It is based on the results of preclinical studies,

which provide clinical pharmacologists and specialized doctors with basic information on the

new drug and its drug form. Preclinical data gives information on pharmacokinetics in animal

subjects, which demonstrate the probable, although not definite, behavior of the drug within the

human body. Pharmacokinetic data characterizes pharmacological effect and therefore allows

for the prediction of the indication area as well as for contraindications and possible ADRs.

When scheduling a clinical evaluation, it is necessary to find optimum methods to

prevent overemphasizing the data obtained from animals and their analogical use in humans.

At the same time, it would be a mistake to not use preclinical data or pharmacological

knowledge already confirmed in humans from repeated trials. At this stage, a study of a new

drug can imply that there are conflicts of interests between scientific, pharmacological and

commercial spheres, or even between interests of certain companies that would want to have

an effective and relatively safe drug as quickly as possible.

Clinical evaluation, by definition, is any systematic testing conducted on human

patients to discover or verify clinical, pharmacological, pharmacokinetic and

pharmacodynamic effects, or to determine the adverse effects of the tested drug. In general,

the goal is to discover or verify the safety and efficiency of the investigational drug.

Clinical evaluation is sometimes carried out solely for research reasons, without any

direct benefits to the investigational subject. This mostly concerns the testing of

pharmacokinetics in humans. Such clinical evaluations, when there are not any expected

preventive or therapeutic benefits, cannot be implemented on (vulnerable) subjects who

were deprived of legal capacity, subjects whose consent cannot be obtained because of their

health condition, or foreign citizens and people under 18 years of age. Furthermore, in these

clinical evaluations it is not possible to include pregnant and nursing women and vulnerable

subjects, i.e. individuals kept in detention or that are under arrest, or individuals incapable of

giving their consent for the provided healthcare.

Non-interventional studies, i.e. observational studies or studies using data collected

previously, that have not intervened in the drug administration methods or the examination


22

and therapy processes do not constitute a part of clinical evaluation. Non-interventional

studies are most often organized by manufacturers to monitor a medicinal product after its

introduction into clinical practice. In non-interventional studies, medicinal products are used

in full compliance with the registered conditions and requirements, both from the perspective

of indication and dosage regimen. Non-interventional studies can include, for example,

pharmacoepidemiologic, pharmacoeconomic or pharmacovigilance studies. Non-

interventional studies are often retrospective. Similarly, post-marketing questionnaires from

manufacturers or retrospective evaluations of certain clinical observations cannot be

considered as clinical evaluation.

Clinical evaluation includes not only scientific medical aspects, it also addresses

ethical and specific methodological and legal aspects. There is a legal premise that clinical

evaluation must be implemented in compliance with ethical rules, which are binding for the

Czech Republic because of its membership in the WHO and in the EU.

Scope of responsibility during clinical evaluation

In clinical evaluations, the scope of responsibility is divided between the sponsor, the

research worker or their employer and the investigational subject. Individual types and scopes

of responsibility in individual participants are regulated by civil rights, labor law and moral

and ethical regulations.

In summation, every active participant in the clinical trial has a certain scope of responsibility

that cannot be neglected.

Even though the sponsor can share their responsibilities with contractual partners,

and the research worker can form a large team of collaborators, the investigational subject is

non-substitutable and should be protected, not only by the moral principles of their doctor or

a research worker, but also by the independent judgment of an ethics committee.

Prior to the onset of a clinical evaluation, it is necessary to meet several legal

conditions: to obtain consent from a state regulatory body (State Institute for Drug Control),

to obtain a positive response from a relevant ethics committee, and to obtain a written

informed consent from the investigational subject. These consents are pre-conditioned by

many clearly defined documents and contracts, both insurance contracts and contracts

between individual contractual parties actively participating in the clinical evaluation.

ETHICAL ASPECTS

23

2.3. ETHICAL ASPECTS OF CLINICAL EVALUATION

From an ethical perspective there is no doubt that clinical research, as well as

preclinical experimentation constitute an indispensable part of medical advancement, both in

therapy and diagnostics. It is therefore necessary to understand the complex ethical issues

regarding the testing of anything that is unknown to human subjects. It is necessary to clearly

define the rules that prevent experiments on humans that violate basic human rights, such as

when people are tortured or exposed to the possibility of premature death.

On the other hand, it is necessary to understand that no ethical code can ensure the

safety of everyone. Some things that could be beneficial to one person, could harm someone

else, and some things which are in the best interest of society, may not be in the best interest

of an individual, who may become the tested subject. It is therefore not possible to create one,

absolutely valid and detailed instruction manual on the ethical aspects of clinical trials. It is

necessary to constantly keep in mind the very substance of medical profession and appeal to

the moral behavior of clinical research employees.

The necessity to obtain informed consent (IC) for approved clinical studies has already

become an obvious fact, in research institutions and pharmaceutical companies. An important

note is that the process of obtaining IC must not become a mere formality. It must also be

emphasized that IC does not make an unethical experiment ethical. This means that safety for

human participants in a clinical experiment does not lie in a formal observance of certain rules

but in the responsibility and morality of the research employees. Since 2001, the Czech

Republic has been obligated to respect the Convention on Human Rights and Biomedicine

(6), ratified by a majority of developed countries.

The field of human research includes clinical drug evaluation (Act No. 378/2007 Coll.

on Pharmaceuticals and on Amendments to Some Related Acts), the clinical evaluation of

medical devices (Act No. 123/2000 Coll. on Medical Devices and on Amendments to Some

Related Acts, as amended), and the clinical evaluation of therapeutic and diagnostic methods,

research using human tissue or organs (Act No. 285/2002 Coll. on the Donation, Removal and

Transplants of Tissues and Organs and on Changes to Certain Acts [the Transplantation Act],

as amended). This issue is also addressed by Act No. 372/2011 Coll. on Health Services and

the Terms and Conditions for the Providing of Such Services, as amended by Act No.

167/2012 Coll.

ETHICAL ASPECTS

24

A common denominator for all types of clinical research is the fact that it is carried out

on human subjects, either healthy or ill – trial subjects (TS), is how they are called in

applicable Czech legislation. Another linking factor is that the risk to which the trial subject is

exposed must not be high, and that the risk not exceeds the benefits.

At the time when experiments were carried out just within the scope of natural

sciences, there were not many moral issues. Such problems arose when experiments on

human beings were introduced, and became important in contemporary medical research.

Experiments with human subjects necessarily beg the question regarding the most

precious thing we have, human dignity and sanctity of human life. It is interesting that

questions regarding human dignity usually do not need further explanation, whereas

justification of interfering with the sanctity of life does. It is necessary to justify, why we dare

to infringe upon this inviolability. There is always judgment i.e., whether or not there are

sufficient benefits to counterbalance the risks, or whether such “sacrifice” is proportional to

the benefits.

In this context, there can be a conflict of interests between an individual and society,

i.e., between an individual’s well-being and the common welfare. There is a danger of conflict

between the right of an individual and the rights of the community. At this point, it is

important to realize that an individual is not anonymous; that they are always a real person,

who knows the value of their own well-being. On the other hand, society’s welfare is more of

an abstract notion, and a much more general one.

These days, progress is generally seen as the interest of all society, and since science is

a prerequisite of progress, and research (in this case clinical research) is an inherent tool of

science, then it is obvious that experiments with human subjects have become an interest to

society as well. However, the interest of society is not a tangible right, rather, it is more of

a moral right, and therefore it requires, with respect to GCP, a free decision of the given

subject, (with their consent) to participate in a clinical trial.

A priority of all of biomedicinal research is the human body, usually a patient, less

often a healthy individual. From the perspective of ethics, both the author and sponsor of

a clinical trial should not differ in their attitude towards a research project. When considering

ethical issues, it should not make any difference if the research plan author is a research

institution, clinical worker or a pharmaceutical company.

There is no doubt that health and life are priority values. Doctors work directly with

these every day, researchers more indirectly – while applying their experimental knowledge.

ETHICAL ASPECTS

25

When a decision must be made regarding a clinical trial, the greatest responsibility lies with

the scientist, i.e., a doctor-research worker. These individuals should be relatively advanced,

not only scientifically, but also morally. Usually it is someone who has a personal interest,

who is in internal conflict with their own motivation, seeking a new invention, personal career

or benefits, etc. Even so, there is a thread of “professional blindness.” Furthermore, we all are

imperfect, and there is always a danger of an error, even in the field of medicine. Therefore

there should be an attempt to minimize the human factor, such as inviting other people to the

process of clinical trials assessment, especially members of ethics committees and other

regulatory authorities (e.g. SÚKL).

Scientific correctness is usually guaranteed by the project author and sponsor. In the

case of grant assignments, the project is also assessed by professional opponents, with whom

the agencies cooperate. These opponents should always be specialists in the subject field.

Scientific aspects are, therefore, not the main emphasis to ethics committees. Ethics

committees should only judge whether or not the expected scientific contribution of the

research is legitimate and the project is not autotelic. To make such a judgment, ECs must not

only know the project design, but also the evaluated parameters, the invasiveness of the

examinations, and the expected ADRs, etc.

To make a qualified judgment, ECs must consist of experienced professionals, or have

an opportunity to consult with such professionals. There is evidence confirming the adherence

to ethical issues in medical research since the mid 20th century and there has been discussion

about ethics even before World War II (Act as of 1935 in Germany) Documents having

a significant impact on present policy include the Nuremberg Code, and the most frequently

quoted Declaration of Helsinki, which was amended several times, the last in 2004, in Tokyo.

More recent documents include the Convention on Human Rights and Biomedicine drafted by

the Council of Europe in 1997, and ratified by the Czech Republic in 2001 (Communication

of the Ministry of Healthcare No. 96/2001 Coll., on the acceptance of the Convention for the

Protection of Human Rights and Dignity of the Human Being with regard to the Application

of Biology and Medicine). The Additional Protocol (Strasburg 2001) on the Prohibition of

Cloning Human Beings (Communication of the Ministry of Healthcare No. 97/2001 Coll., on

the Acceptance of Additional Protocol to the Convention for the Protection of Human Rights

and Dignity of the Human Being with regard to the Application of Biology and Medicine and

the Prohibition of Cloning Human Beings, ratified by the Czech Republic in 2001). Also,

International Ethical Guidelines for Biomedical Research Involving Human Subjects –

ETHICAL ASPECTS

26

CIOMS, complied by “Council for International Organisations of Medical Sciences” in

cooperation with the World Health Organization (CIOMS + WHO, 1982, 1993 and 2002).

Having respect for these and other related documents guarantees the right of every

human to make decisions regarding their participation in medical research. However, this

notion can only by fulfilled by making such a decision feasible.

Ethical principles for the clinical evaluation of drugs are therefore based on the respect

for basic human rights. An ethical assessment of clinical trials must regard human dignity,

psychological and physical integrity and the possible benefits for any given person. Again, it

is important to defer to the individual’s interests rather than to scientific and social interests.

The ethical principles of the clinical evaluation of drugs are based on the respect for

the participating subject, i.e. respecting their autonomy (free decision-making) and protecting

individuals with somewhat limited autonomy, i.e., vulnerable subjects. Another issue is to

examine what the benefits are for the investigational subject, usually a patient. An emphasis is

placed on the same principle, which has a supreme law in medicine from Hippocrates: “Nihil

nocere” (Do not harm.). Lately, this credo has been expressed as a ratio between the possible

risk and positive health improvement of the ill person, i.e. “risk vs. benefit”. The third main

ethical principle of the clinical evaluation of drugs is justice. No group of people, nor any

individual, can be discriminated against by being exposed to more high-risk projects than

other subjects, nor can they be forced to participate in a clinical evaluation of drugs

(vulnerable subjects).

REGULATORY AUTHORITIES

27

3. ORGANIZING CLINICAL TRIALS IN COMPLIANCE WITH GOOD CLINICAL PRACTICE (GCP)

3.1. STATE AND EUROPEAN REGULATORY AUTHORITIES (SÚKL, EMA)

In most European countries, the ministries of healthcare represent the supreme state

regulatory authorities, who express their opinion not only on the registration of drugs but also

on the implementation of the clinical evaluation process. In the U.S, this authority is the Food

and Drug Administration (FDA), in Japan, it is the National Institute of Health Science

(NIHS), and in Australia, the Therapeutic Goods Administration (TGA). In the Czech

Republic and in several European countries, institutions were established by their ministries

and delegated to implement the authorization and supervisory procedures in the area of drug

development and use. In the Czech Republic, this institution is the State Institute for Drug

Control (SÚKL), whose rights and duties are embedded in legal regulations, and in the case of

drug evaluation, in Act No. 378/2007 Coll. on Pharmaceuticals. Documents, which must be

presented by SÚKL together with the application, and is uniform for all member countries,

are listed in Decree No. 226/2008 Coll. on good clinical practice and detailed conditions of

clinical trials on medicinal products, as amended.

SÚKL is the institution that represents the Czech Republic within the EU and in other

countries in the area of medicinal preparations. In the EU, the umbrella body for state

regulatory authorities is the European Medicines Agency (EMA), and drug databases are

centralized in EUDRA (European Union Drug Regulation Authorities).

3.2. INDEPENDENT ETHICS COMMITEES (EC, REC, IREC, IRB)

EU Directive No. 2001/20/EC defines an ethics committee as an independent body

consisting of healthcare professionals and non-medical members, whose responsibility it is to

protect the rights, safety and well-being of the human subjects involved in clinical trials.


28

Above all, an ethics committee is protection for the investigational subjects and it can

also be an advisory body for a healthcare institution; however, the impact of its decisions can

be much broader. The committee should also be responsible to the public and should not

permit projects that are high-risk for the given investigational subject, nor projects that are

socially dangerous. An ethics committee should therefore be a social guarantee, publishing its

opinions on clinical evaluation protocol, judging the anticipated goals, the suitability of

investigators, the adequacy of facilities, and the methods and documents prepared to inform

the investigational subjects in order that they may obtain their informed consent. Ethics

committees publish their opinions, much as SÚKL does, prior to the onset of the clinical trial.

Another role of ethics committees lies in the supervision regarding the observance of the

rights of investigational subjects and in expert risk evaluation, i.e., what risks the investigational

subjects may be exposed to, and for which they usually cannot assess for themselves. Very few

subjects are able to evaluate the real risks involved. This “handicap” is not necessarily related to

their achieved education. People that are sick often have decreased judgment ability because of

their condition, and healthy volunteers can have their decision biased by financial motivation.

ECs should therefore play a key role in the decision-making process, as designated by the

applicable legislation for the clinical evaluation of drugs and medical devices.

However, ECs judgments should be equally important in other types of clinical research as well.

If an EC wants to assess the risks for the SO with complete objectivity, it should

regard the entire issue in depth, and assess the justifiability of the research plan and study

design, e.g. and that it does not employ outdated or enormously difficult methods. An EC

should also judge the risk for the SO, e.g. the required period without any therapy (the wash-

out period), the quality of documentation, especially the explicitness of the protocol and

project plan, to ensure that information is up-to-date for the doctors and a sufficient amount of

information about the TS – an emphasis is specifically placed on the burdens and benefits

arising from the participation in the trial. ECs should also focus on the quality and

comprehensibility of the informed consent, the quality of insurance and conditions of any

possible compensation in case the participant’s health is harmed in a clinical trial. Ethics

committees should also assess the method of TS’s recruitment, and finally, the qualifications

of the research employees (investigators) and whether their workplace provides a sufficient

base for a quality implementation of the research plan. ECs should also determine that all

financial compensations are guaranteed. This does not mean that a committee should control

financial aspects in detail; it should judge the compensation from the perspective of standard

practices and good manners. ECs should also be informed whether the clinical trial is

sufficiently covered by an insurance and TSs are insured through the investigator’s and


29

sponsor’s insurance, and how the TS will be paid, especially in cases where no therapeutic

effect from the clinical trial is expected (e.g. healthy volunteers, evaluation of

pharmacokinetics, etc.).

It is generally accepted that ECs are independent, but it is also necessary to raise the

question about who and what is independent. The answer is that the EC is independent in its

decision-making and it should address and decide all clinical-trial-associated issues

independent from the sponsor, investigator and also the EC founder.

The role of the EC does not end with the approval of a clinical trial; the EC should

supervise the entire process and results of the clinical trial, with special respect to ADRs, the

amount of risk, to respect the rights of the TS during the entire trial, and to publish all results,

i.e., both the expected and unexpected positive results as well as the results which might

signal a danger for the user. In the case of trials focusing on new drugs, the EC should

continuously supervise the entire clinical trial at least one a year, and in the case of minors

(children), once every six months. In the Czech Republic, this supervision usually comes in

a written form, whereas the sponsor informs the EC on the progress of the clinical trial with

an emphasis on the amount of risk taken and about any new facts, should they occur.

Ethics committees in all of the EU countries have different systems of operations. In

some, there is one central EC and several regional or local ECs, in others, there are ethics

committees located according to the country regions. In the Czech Republic, there is a network

of ethics committees for multicentre evaluations and local ethics committees of a ratio approx.

1:10. All ethics committees are established by the management of medical institutions.

ECs can be established legally by the Ministry of Healthcare or by a medical

institution. The status of an ethics committee for multicentre clinical evaluations is always

provided by the Ministry of Healthcare.

The ethics committee acts as an independent body that should protect the rights, safety

and health of trial subjects, i.e., an EC should supervise the ethical aspects of clinical trials.

An EC consists of healthcare professionals and non-medical members. In compliance with

GCP, an EC is quorate when the meeting is attended by at least 5 its members.

When a person is not capable of giving their consent prior to their acceptance in the

clinical trial, the EC shall decide how and when the issuance of a substituted informed

consent and the acceptance of the particular trial subject shall be stipulated. The EC shall also

assess whether this will affect the acceptance of every individual TS by such an approval.

In the Czech Republic, it is the sponsor who submits the application to an authorized EC.

However, according to GCP, it is the investigator who usually negotiates with the EC. The EC is

entitled to require all documentation in a language that can be understood by all the committee


30

members. Considering the legal requirement that states that the EC must also include non-medical

members, it is expected that all pertinent data will be translated into Czech.

Directive 2001/20/EC of the European Parliament and Czech regulations obligate

ethics committees to give their opinion before a clinical trial commences, especially on:

1. the relevance of the clinical trial and the trial design;

2. whether the evaluation of anticipated benefits and risks is satisfactory and whether the

conclusions are justified;

3. the protocol;

4. the suitability of the investigator and supporting staff;

5. the investigator’s brochure;

6. the quality of the facilities;

7. the adequacy and completeness of the written information to be given and the

procedure to be followed for the purpose of obtaining informed consent, including the

justification for any research on persons incapable of giving informed consent;

8. provisions for indemnity or compensation in the event of injury or death attributable

to a clinical trial;

9. any insurance or indemnity covering the liability of the investigator and sponsor;

10. the amounts and, where appropriate, the arrangements for rewarding or compensating

investigators and trial subjects, and the relevant aspects of any agreement between the

sponsor and the site;

11. the arrangements for the recruitment of subjects.

Ethics committee must have the following documents submitted to them; however, EC is

entitled to require additional documents:

a) Protocol

b) Informed consent and S and information on TS

c) Recruitment procedures and methods, especially advertising

d) Sets of information (IB or SPC)

e) Detailed information on the compensation of costs and TS remuneration

(remuneration in cases, where there is not any direct therapeutic benefit for TS)

f) Investigator’s CV and qualification certificates (for clinical evaluation of drugs)

g) Insurance policy (investigator, sponsor)

h) additional materials requested by EC

DOCUMENTS AND CT PRACTICE

31

4. DOCUMENTS AND CT PRACTICE

From a practical point of view, activities connected with clinical trials can be,

according to GCP, divided into three basic stages: preparatory, implementation and the final

stage. In the preparatory phase, which is carried out by the sponsor or investigator, the overall

objective is discussed, basic documents are prepared, approvals are obtained and contracts are

concluded. During the CT implementation phase, activities focus on supervision and the

monitoring of events that may have an impact on the CT, e.g. the quality of results, an

unexpectedly high occurrence of complications, not only with the evaluated drug but also

because of insufficient compliance or cooperation in adhering to the CT schedule. When the

clinical results are obtained, the final stage then follows. This stage is carried out at the

investigator’s site and consists of the evaluation of results and a written final report, after

which the activities connected with CT are returned back to the sponsor.

4.1. PREPARING DOCUMENTS (PROTOCOL, CRF, IB, TS)

Basic documents used during clinical trials include a protocol, a case report form

(CRF), an investigator’s brochure (IB), an informed consent, which includes information for

the trial subject (TS) and pharmaceutical data on the evaluated preparations.

ICH GCP provides a list of necessary documents, which proves the CT’s adherence to GCP

and legislation. These documents are divided into three groups and are required prior to the

clinical trial: 1) 20 documents, including information for investigators, information for the

trial subject, ethics committee consent from its members, certificates of the evaluated drugs

and a clinical trial initiation report; 2) documents that are created during the implementation

phase, e.g. amendments and changes to the protocol, certificates for new labels of drugs, etc.;

3) documents that are filed after the CT termination. These include all previously listed

documents as well as documents certifying the registration of the evaluated drug, audit or

inspection protocol, along with the monitor’s final report and the CT final report. ICH rules of

GCP also state which documents must be held at the sponsor’s site and which must be at the

investigator’s site (see Decree No. 226/2008 Coll.).

PROTOCOL

32

4.1.1. THE PROTOCOL

The protocol is a detailed schedule of the CT. It describes its objective, design,

methods, evaluated parameters, statistics and CT arrangement. The protocol is a basic

document that is reviewed during the CT approval process both by state authorities and ethics

committees. The protocol is a key document of the CT, and it must be adhered to by all of the

subjects that are actively participating in the implementation of the CT, especially the

investigators. The protocol must contain all of the information that allows the investigator to

select suitable trial subjects, define the exact use of the evaluated drug and acquire credible

data on the effect and safety of the evaluated drug. The content of the protocol is also

stipulated in the decree on GCP.

The protocol includes not only the approved protocol but also all updated versions and

amendments thereof. The protocol is compiled by a team consisting of the sponsor’s

specialist, clinical consultant, statistician and other specialists according to the type of study.

It is also a good idea to invite the person who will be carrying out the monitoring to

participate in the protocol finalization.

Basic GCP requirements regarding the protocol content has developed gradually. At

present, the basic structure of the protocol constitutes a section of Decree 226/2008 Coll.,

from the Act on Medical Devices.

Title Page

The content of the title page is governed by legislation. It should contain the

identification number of the protocol or CT, and the date, along with the name and address of

the sponsor and of the monitor, the name of the person authorized to sign the protocol on

behalf of the sponsor, the name, address and telephone number of the qualified advisor

appointed by the sponsor for consultation regarding health issues and issues arising in

association with the CT. The names of the investigators should also be included as well as the

addresses and telephone numbers of trial sites, the name, address and telephone number of the

doctor responsible for medical decisions at the CT site and the names and addresses of the

laboratories or other facilities participating in the CT.

PROTOCOL

33

Basic Information

The protocol content starts with a review of the basic information containing the name

and description of the evaluated drug, an overview of the findings from preclinical and

clinical studies that may be of clinical significance, findings from clinical trials connected

with the study in question, and the clinical trial justification. Known and potential risks and

benefits, and administration and dosage forms and schemes shall be summarized. The

characteristics of suitable trial subjects and references to scientific literature shall be provided.

This introductory section shall also contain a declaration that the clinical trial shall be

conducted in compliance with the protocol, GCP principles and legal regulations.

Objectives of the Clinical Trial

The second chapter describes the objectives and rationale of the clinical trial; the

primary and, if applicable, secondary objectives shall be specified herein.

The Clinical Trial Plan

The clinical trial plan describes the type and the particular design of the conducted CT.

It states whether it is an open, blind, placebo-controlled, parallel-group, or other type of study,

etc. The individual steps are described, the treatment of the trial subject, the description,

packaging and labeling of investigational medicinal products, the expected duration of the

trial subject’s participation in the trial, the criteria for termination and for the discontinuation

of participation, the follow-up, where applicable, and procedures of handling randomization

codes and decoding. There is also specific data that will be entered directly into the CRFs

without previous written or electronic recording, as well as information that shall be

considered to be the source data.

Criteria for the Selection and Exclusion of Trial Subjects and Withdrawal Parameters

The protocol must detail the criteria used for the selection of the TS, and also for the

inclusion, exclusion and withdrawal parameters for the participation of the TS in the clinical

trial. The withdrawal procedure shall include data about when and how a subject is to be

withdrawn from the clinical trial, which data from these subjects will be used and how, and

whether and how such a subject will be replaced along with their follow-up data.

PROTOCOL

34

Treatment of Trial Subjects

The section describing the treatment of trial subject is very detailed. It must specify all

medicinal products that are planning to be administered; their dosage, dosage schedule, and

duration of the treatment including follow-up of subjects. Acceptable treatment and treatment

that is not acceptable during the CT shall also be specified herein, including rescue therapy.

This section should also specify the procedures and activities that are not recommended

during the CT or even those that are banned.

Evaluation of Efficacy and Safety

This section focuses on the efficacy of the evaluated medicinal product, its desired

effect, tolerance and undesired effects from the perspective of therapeutic safety. Efficacy

parameters and methods are described, along with the timing of the assessment and the

evaluation of the efficacy parameters.

Similarly, the chapter on safety describes the observed safety parameters and analysis

methods, as well as the methods for identifying, recording and reporting adverse events and

intercurrent diseases. Also, the type and duration of the follow-up on the trial subject is stated

in the case of an adverse event occurrence.

Statistics

Statistical analysis of the data constitutes an inherent part of the protocol. In this

chapter, the applied statistical methods are described, as well as the timing of individual steps,

especially when there are scheduled interim analyses. The selection of the set size, the number

of trial subjects scheduled to participate in the CT and the number of subjects planned for the

individual trial sites shall be noted herein. There should also be specific criteria for the

calculation of the CT’s statistical cogency, the applied level of significance, missing methods

of processing, unused or false data, criteria for the termination of the CT, measures adopted in

the case of any noncompliance, procedures for reporting of any deviations from the original

statistical plan, and criteria for the selection of trial subjects for the evaluation. This section

should be processed by a specialized statistician.

Ensuring Confidentiality

Unless direct access to the source data and documents is safeguarded by a separate

written agreement, it should be stipulated in the protocol just who shall be authorized to

access the source data and documents. This information is also provided to the trial subject in

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the informed consent. Authorized personnel would include the investigator and healthcare

personnel of the healthcare facility implementing the CT, the ethics committee responsible for

the supervision, inspection and control, the sponsor during the monitoring, audit and

inspections and the regulatory authority (SÚKL), which is authorized to carry out the

preliminary assessment as well as inspections.

Quality Assurance and Supervision

The sponsor is obliged, in compliance with GCP, to ensure the necessary quality of the

CT, and the following section of the protocol focuses on this topic. A prerequisite for the

sufficient quality of data is the adherence to GCP and applicable legislation. In compliance

with GCP, it is necessary that the employees meet all relevant qualifications, to provide

healthcare facilities of appropriate quality, to adhere to the approved protocol and standard

operating procedures, to properly handle the evaluated medicinal products, to provide

exhaustive and reproducible records and last, but not least, to provide for the quality care of

the trial subject. The sponsor is responsible for the quality of the CT by using monitoring and

evaluating the reports from the monitor, by controlling data from independent or internal

audits, and, in the case of problems, by inspection.

Ethical Issues and Data Storage

The ethical principles of a clinical trial constitute another chapter of the protocol. They

summarize the main ethical principles in regards to the Declaration of Helsinki, which may

also constitute an attachment to the protocol. Also, the handling of personal data, the storage

of records and source data and the guarantee of confidentiality is described.

Funding and Insurance

In Europe, information on the funding of the CT does not constitute a part of the

protocol. In most cases, this is specified by separate agreements, therefore, the protocol

usually contains only a reference to the insurance agreements.

Principles of Publication

Unless specified in a separate agreement, the principles of publication shall be stated

herein. The principles should specify how the CT results will be made public in order to

prevent the situation where unfavorable results would not be published. This part of the

protocol should be assessed by the ethics committee. Specialists, as well as the patients, i.e.

the trial subjects, should be entitled to know the results.

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4.1.2. CRF – CASE REPORT FORM

The CRF documents the clinical trial. It can be a document in paper form, in picture or

an electronic format intended for the recording of any information on the trial subject that is

pursuant to the CT protocol. Usually, it is in the form of an NCR carbonless paper with

preprinted boxes and questions, where the investigator enters the obtained values and data.

Individual sheets are generally filed in a folder and form a brochure. At the end of the CT, the

CRF, which is under the control of the monitor, is given to the sponsor; the original and the

first copy for the statistician is received by the sponsor and the second copy is kept by the

investigator at the CT site.

As in every official document, the content and formal arrangement of CRF is

regulated. The CRF content is governed by the requirements stated in the protocol. It is

original for every CT and should be created gradually, along with the protocol. Unlike other

approved documents, there are no detailed legal requirements in regards to its content and

form. However, a well-organized CRF contains only the relevant data in a sufficient amount

to prevent situations where, at the end of the CT, some of the data that was unobtainable

would be missing. On the other hand, there is no point in filing excessive data for evaluation

since it may have no real value and would only occupy the time of the investigator, monitor

and data manager, thereby increasing the cost of the CT.

As for the formal arrangement of the CRF, there are guidelines and requirements for

the investigators and essential personnel to follow.

When preparing the CRF, unambiguous wording must be used and only a minimum

amount of undefined data should remain to prevent it from being misunderstood by data

managers, which in turn, may require that there be further editing and corrections. The most

suitable solution is to encode the complete set of findings or to redefine them and only tick the

appropriate answers in the CRF. It is also convenient to enter numbers into the preprinted

boxes, including the date, and not on the lines,.

The investigator is responsible for the data in the CRF, therefore only the investigator

or a person authorized in writing to do so can complete the form. It must never be the

monitor, who is in fact the first person that checks the correctness of the data. The CRF

should contain exact, exhaustive and legible data, and should be filled out without any delay,

i.e. immediately after the required values are obtained. If an error occurs, it must be corrected

CRF

37

in the proper manner, i.e. cross it out so that the original data remains legible, and enter the

correct data next to it, plus the date of the correction and the investigator’s signature. In the

case where the error is not formal or technical, it is recommended that an explanatory

comment be added.

An adverse events and undesired effects reporting form is usually part of

the CRF, as well as various scales evaluating physiological functions.

4.1.3. IB – INVESTIGATOR´S BROCHURE

The IB, or Investigator’s Brochure, is a document summarizing information for the

investigator. It contains all of the important data on the investigational medicinal products

from the preclinical and clinical studies. This document should at least be updated on a yearly

basis or sooner, if there is any new important data relevant to the study.

This information should be provided in an abbreviated form, well-arranged,

objectively worded, and should be unambiguous, without any promotional intentions.

Should a registered drug be used in a CT as the evaluated medicinal product, the IB

can be replaced with a Summary of Product Characteristics (SPC), possibly complemented by

separate, up-to-date articles on the product in question.

In the case of unregistered evaluated medicinal products, the IB must contain chapters

required by GCP and the Decree on GCP.

The IB has a Title Page, which contains the sponsor’s name, the identity of the

evaluated medicinal product or its identification code and the release date for the version of

the information for the investigator. The following chapters should follow as such:

1. Table of Contents

2. Summary A brief summary highlighting significant physical, chemical, pharmaceutical,

pharmacological, toxicological, pharmacokinetic, metabolic and clinical information about the

investigational product.

3. Introduction This section contains all of the identification data for the investigational

product, especially its chemical name, or possibly its international generic or trade name, all

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active ingredients, its pharmacological class and its expected position within this class, along

with the rationale for performing the research and the expected use and indication.

4. Physical, Chemical, and Pharmaceutical Properties and Formulation A description should

be provided about the investigational product substance(s), including the chemical and/or

structural formula, and a brief summary of its physical, chemical and pharmaceutical

properties. The drug form and content should then be described, including excipients, and

instructions for the appropriate storage and handling of the evaluated medicinal product. Any

structural similarities to other known compounds should be mentioned as well.

5. Nonclinical Studies are provided in the introduction in summary form, often in tables

summarizing the results of relevant nonclinical pharmacology, toxicology, pharmacokinetic

and metabolic studies. This summary should mention the methodology used, the results and

discussion of the relevance of the findings to the investigational product, and its possible

unfavorable and undesired effects in humans. If appropriate, the information may include any

animal species used in the nonclinical evaluation, the number and sex of animals in each

group, unit dose, dose intervals, route of administration, duration of dosing, information on

systemic distribution and the duration of the post-exposure follow-up. Results include: the

nature, frequency, severity and intensity of pharmacological or toxic effects, the onset of any

effects, the reversibility and duration of the effect and dose response.

This section provides the most important findings from the nonclinical studies and

their expected relevance to the human subjects. Effective and nontoxic doses in the same

animal species (therapeutic index) are compared, as well as the correlation between the

dosages proposed for humans.

5.1. The chapter Preclinical Pharmacology summarizes the pharmacological characteristics of

the investigational medicinal product and its significant metabolites studied in animals. Such

a summary should incorporate studies that assess potential therapeutic activity, e.g. an

efficacy model, receptor binding and specificity, and studies assessing safety, i.e. special

studies assessing pharmacological actions other than for their intended therapeutic effect.

5.2. The chapter Pharmacokinetics and Product Metabolism in Animals summarizes data for

pharmacokinetic, biological transformation and distribution of the investigational product in

all studied species. The discussion of the findings should address the absorption, the local and

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39

systemic bioavailability of the investigational medicinal product and its metabolites, and their

relationship to pharmacological and toxicological findings in animal species.

5.3. Toxicology provides a summary of toxicological effects in different animal species found

in the relevant toxicity studies monitoring single dose, repeated dose and carcinogenicity,

along with special studies of irritancy and sensitization, reproductive toxicity, genotoxicity

and mutagenicity.

6. Effects in Humans provides an evaluation of the known effects of the investigational

product in humans, including pharmacokinetics, metabolism, pharmacodynamics, dose

response, safety, efficacy and other pharmacological activities. If applicable, it should also

provide a summary of each completed clinical trial and any experience regarding the practical

use of the investigational product. This section is usually the most lengthy and each area is

addressed in a separate chapter.

6.1. The first summarized information addresses Pharmacokinetics and Product Metabolism

in Humans. This chapter provides information on metabolism, absorption, plasma protein

binding, distribution and elimination, the bioavailability when using a reference dosage form

(absolute and/or relative), population groups in which the data were obtained (e.g. gender, age

and impaired organ functions), and interactions (both product-product interactions and effect

of food). Other pharmacokinetic data relevant to the study can also be stated, according to the

substance’s character.

6.2. Safety and Efficacy is a summary of information on safety, pharmacodynamics, efficacy

and dose response for the investigational product or its metabolites, which was obtained from

previous clinical trials in healthy volunteers and patients. In cases where a number of clinical

trials have been completed, the use of summaries for safety and efficacy across multiple trials

with indications in population subgroups may provide a clear presentation of the data.

A summary of adverse drug reactions (ADRs) for all the clinical trials would be very useful.

Important differences in the character and occurrence of ADRs across indications or

population subgroups, the possible risks and ADRs to be anticipated on the basis of prior

experiences with the investigational product or with related products should also be discussed

herein. A description should also be provided regarding the precautions and/or special

monitoring to be done as a part of the investigational use of the product.

IB

40

6.3. Marketing Experience should identify the countries where the investigational medicinal

product has been registered or has not received approval for marketing, or was withdrawn

from registration. This chapter should also provide any significant information arising from

the marketing use (including drug form, dosage, administration route and ADRs).

7. The IB Summary provides an overall evaluation of nonclinical and clinical data on the

investigational drug obtained from various sources to provide the investigator with the most

informative interpretation of the available data, including implications for future clinical

trials. Furthermore, published reports on related products should be discussed to help the

investigator anticipate the ADRs of the investigational product or any other problems with the

clinical trials.

4.1.4. INFORMATION AND INFORMED CONSENT (IC, PATIENT INFORMATION)

Informed consent represents a voluntary expression of the free will of the trial subject,

or their legally-acceptable representative, to participate in a CT. Informed consent can only be

signed after prior information on the objectives, risks, benefits and other conditions of the CT

is made available.

Informed consent should only be signed after informing the subject on all of the

important and substantial aspects of the CT. This information is usually provided to the

subject by the doctor-investigator. In case of more demanding studies or chronic diseases, the

trial subject is usually given a longer time to make their decision regarding their participation

in the CT so that they can consult their relatives at home, etc. However, when conducting

a CT for registered medicinal products, a subject usually needs a much shorter time.

A specific situation therefore arises in cases of patients in acute states who are unable to

comprehend or provide their IC, and is discussed in detail in the Act on Pharmaceuticals.

A formal arrangement and the contents of the IC are stipulated by GCP and pertinent

legislation.

Informed consent must be provided in writing and contain the date and signature of the

person authorized to provide it; also, it must be in a language that is understandable to the

respective person. IC must be signed voluntarily after thoroughly informing the subject by the

IC

41

investigator, and all these facts must be duly documented. For example, it must be proven as to

who obtained the informed consent, when it was obtained and on what information it is based.

Where a CT involves minors, informed consent should be obtained from both the

parents and minors themselves. However, only IC signed by the child’s parents is considered

to be legally valid. Children have a right to receive information on the CT, therefore they

should be provided information in an understandable manner to be able to give or withhold

their consent, which must be respected by the investigator. For children, informed consent

/assent must be in a form that corresponds with their age group, and there are various

recommendations how to divide the age groups for this purpose. Usually, they are divided

into groups of <6 years-old, 7-12 years-old and 13-18 years-old. In teenagers between the

ages of 16-18, it is suitable to use the same documents intended for adults. Nevertheless, IC in

the youngest age group remains questionable.

Prior to signing, the trial subject must be provided with all the complete information at

least to the extent stipulated by legal regulations. Information should include research

objectives, CT objectives, a description of planned therapeutic methods, the rights and

responsibilities of the trial subject during the clinical trial, the benefits of the clinical trial for

the trial subject and also any foreseeable risks or possible difficulties, and, if there are any,

a description of other possible therapies. Another section should address the conditions of the

therapy and compensation in the case that the trial subject’s health would be affected in

connection with their participation in a CT. It is also important to notify the TS that there is no

monetary compensation connected with their participation in the CT. However, in most cases,

the trial subject can have their travel costs or other expenses covered. Information must

always include personal data confidentiality clause, an agreement to make the data accessible

to specified persons, and the conditions for publishing the obtained results. The patient should

also be informed of the CT’s duration and the total scheduled number of subjects participating

in the clinical trial. In connection with the trial subject’s rights, the sponsor is obliged to

divulge any new facts which may have an immediate impact on the trial subject, and should

include the trial subject’s right to withdraw from the CT at any time, and even to withdraw

their IC. However, the TS should also be duly informed of the consequences of such

a withdrawal in regards to the overall evaluation of results. The investigator-doctor should

also inform the trial subject about any circumstances that may result in the premature

termination of the trial subject’s participation in the CT, especially with respect to any change

in their health condition.

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42

Obtaining informed consent constitutes a prerequisite of the trial subject’s acceptance

into the clinical trial. However, there are situations when IC cannot be obtained because the

patients are unable to provide informed consent. In compliance with GCP, when a subject is

unable to provide their IC because they are incapable of entering into legal transactions

(usually minors), IC can be obtained from their authorized legal representative.

Adults that are unable to provide their IC due to their health condition and who have

a legal guardian (authorized legal representative), IC may be provided by this legal guardian.

For subjects that do not have a legal representative, e.g. in the case of acute deterioration of

their health (trauma), it is possible to enter these circumstances into the protocol and ask the

ethics committee to express their opinion. The ethics committee is entitled to participate in the

decision-making process regarding inclusion of each such patient in the CT. Should the health

condition of the trial subject improve and the trial subject is able to comprehend and provide

their IC, the investigator is obliged to obtain their IC without any delay.

4.1.5. INVESTIGATIONAL PRODUCT AND PHARMACEUTICAL DATA ON INVESTIGATIONAL PRODUCTS

An investigational medicinal product (IMP) is a pharmaceutical form of an active

ingredient or placebo being tested or used as a reference.

In cases where the medicinal product is used in compliance with the registration process,

including indications, dosage, dosage form and no additional tests are planned, i.e. no

intervention into the registered standard use of the medicinal product is in question, the CT is

called the non-interventional clinical trial, and does not require the approval process described

below and GCP rules.

The pharmaceutical data on investigational drugs is stipulated by law and constitutes

one of the fundamental parts of CT documentation on investigational products. This data is

submitted together with a Request for Opinion of a Clinical Trial on a Medicinal Product to

the regulatory body authorized to issue such an opinion (SÚKL).

The applicant must describe the investigational product from the perspective of its

category group and drug form in which it will be administered. The applicant must also

describe the applied manufacturing processes, which must comply with GMP, including

antiviral measures, if required. Competent authorities may also require further documents on

the quality of the investigational product or may contact a qualified person at the

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manufacturer’s site. Applicable legislation specifies requirements on the holder of marketing

registration that concerns production and quality assurance.

Here are the maximum requirements for any new, unregistered medicinal products:

a) The name of the investigational product, dosage form(s), strength(s);

b) A list of all medicinal and non-medicinal ingredients;

c) Names and addresses of all manufacturers participating in the production of the

investigational product including their function in the production chain; there must

also be a list of organizations that carry out the blinding of samples;

d) Good Manufacturing Practice Certificate – proof that GMP is adhered to during the

entire manufacturing or preparation process e.g. Good Manufacturing Practice

Certificate issued by SÚKL or certificates of state inspections or statement of a person

responsible for the quality assurance during the entire CT;

e) Data for active substance(s) – their chemical name and formula, manufacturer’s

name and address and quality criteria. In the case of new substances, i.e. a substance

that is not already contained in a registered product in the world, there must be

a required confirmation of identity and structure, control analytical methods, data on

the stability and characteristics of batches used in preclinical studies and planned to

be used in the CT;

f) Quality criteria;

g) A brief description of the manufacturing process (general description of the individual

steps with an emphasis on removal or the inactivation of viruses in cases where products

contain substances of biological origin, and information on the possible blinding);

h) Control analytical methods;

i) Stability data, or the proposed shell life and storage conditions.

Inspection authorities focus on specific factors; the scope of the presented information

depends on the medicinal product’s stage of development. At the beginning of the process,

emphasis is placed on its identification and control of the active substance; final specifications

and complete data on the substance and on the medicinal product is obviously submitted at the

end of the whole development process. Also considered, is whether or not a newly developed

substance or a new preparation contains a known substance, along with the subjects’ exposure

to it with respect to the scope, objectives and expected duration of CT.

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4.2. REQUEST FOR AUTHORIZATION OF A CLINICAL TRIAL

As already mentioned, the CT sponsor is obliged to ask for and obtain approval from

an ethics committee and of the State Institute for Drug Control prior to the onset of the CT.

This process can also be viewed from the perspective of the content and the formal

requirements.

Any decision of the EC also depends on whether or not it is a multicentre CT or a one-

site CT. Based on this fact, the application is sent to the appropriate EC for multicentre CTs

and local ECs, where individual investigations belong. The list of documents that must be

submitted to these two types of ECs, is different, as was specified earlier.

Since the Czech Republic entered the European Union, the application form for SÚKL

has been uniform for all European member countries. Every CT application must be presented

on a uniform European form and registered in a European database (EUDRA) under a unique

EUDRA CT number that contains the date of issue, serial number and control number. The

requirements on the application form, its content and formal arrangement are defined in the

SÚKL materials. A decision must be issued within a time stipulated by EU regulations: within

60 days by SÚKL and 45 days by EC, and it is paid for both the EC and SÚKL.

4.3. SUPERVISION OVER CLINICAL TRIAL

Supervision over the CT can be divided according to the subjects that are authorized

and obliged to carry out supervision, i.e., sponsor supervision, SÚKL supervision and EC

supervision. The aim of supervision is always to ensure compliance with scheduled methods

that were proposed by the sponsor and approved by the regulatory body and ethics committee.

It is given by Law that the sponsor must ensure supervision over the CT by

monitoring. Sponsors often hire specialized monitors from the field of contract clinical

research. In lengthier studies, the sponsor also implements audits that can be either internal,

(i.e. supervision is secured by a sponsor’s employee) and/or external, in which the audit is

carried out by independent GCP auditors.

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45

Besides the sponsor, SÚKL and the EC also carry out CT supervision. SÚKL applies

mechanisms described as direct, i.e. inspections that are carried out directly on site by SÚKL

inspectors, or indirect, i.e. through sponsor’s reports. ECs use similar supervision methods,

except that they do not have their own inspectors; their members do have the authority to

implement monitoring visits at the CT site. Ethics committees in the Czech Republic work on

a voluntary basis whereas employees of regulatory authorities implement their tasks within

the scope of their employment.

4.4. INTERIM REPORTS AND REPORT ON CLINICAL TRIAL TERMINATION

Every CT evaluation is documented in various reports. The most common are the

monitoring reports. Monitors should prepare these reports and send them to the sponsor after

every monitoring visit to the investigator’s site. The sponsor should act on these repots and,

based on the information from the monitor or auditor, should take whatever necessary

measures are needed, and then prepare a report for SÚKL and the EC.

Monitoring reports differ according to SOP (Standard Operating Procedure), which the

monitor must adhere to. However, the basic information obligatory in all of the reports is the

same. General information include specifically: the date and CT site and the names of the

present investigators, co-investigators and the monitor’s name. Then the monitoring visit’s

purpose must be described, i.e. what was controlled and discussed along with the monitor’s

comments emphasizing the CT specifics, deviations and insufficiencies and any proposed

remedies and tasks. Most SOPs include a list of control tasks that constitutes a part of the

commented report. There is a different list and report content for the site selection, for the first

visits, interim monitoring visits and for the final visit when the site terminates the CT.

The sponsor is, in compliance with the applicable legislation, obliged to send interim

reports to SÚKL and the EC once a year (in the case of minor TSs, once every 6 months) which

summarizes information about the CT, including the number of TSs, the occurrence of ADRs,

audit results (if there were any), and new events which occurred in connection with the CT.

Furthermore, the sponsor must, on a yearly basis, send pharmacovigilance reports on ADRs,

and, after the CT, submit a report on the termination. The report on the CT termination is not

the same as the final report, which summarizes the CT and evaluates the results using statistical

analysis. The content of the CT termination report as well as the content of CT final report must

comply with ICH GCP and is detailed in Decree on GCP.

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4.5. CLINICAL TRIAL FINAL REPORT

The CT final report represents a summarizing document that provides an evaluation of

results obtained during the particular CT. The final report is a document necessary for the

registration proceedings. The results provided therein also constitute a certain amount of basic

information regarding the investigational product that will subsequently be presented to

specialists as well as to the general public.

Data that must be provided in the final report and their arrangement is stipulated by

Decree in GCP.

In the introductory section, it must describe all of the subjects participating in the

clinical trial, important time intervals and a summary of the objective and results.

The second section of the final report contains data on the plan and conditions under

which the CT should have been conducted, including information on terminology, ethical

aspects, trial subjects, investigators and cooperating specialists, e.g. biostatisticians and

clinical consultants.

Another section constitutes an introduction to the CT with an emphasis on the

categorization of the CT within the overall process of the drug’s development, justification of

the monitored parameters and planned objectives of the clinical trial. This section also

includes a detailed plan of the CT, including the results evaluation schedule.

The following chapters describe the actual CT, trial subject´s that were actually

included in the CT and an evaluation of results on the investigational medicinal product,

especially from the perspective of its efficacy and safety.

There then follows a discussion, summary and conclusion. The final part of the report

provides the tables and graphs that were not included in the body of the report, along with the

references. Amendments constitute a substantial part of the report. They contain all of the

documents that were used, from the protocol to the lists of trial subjects.

As is clear from the above description, the final report is often a document of several

hundred pages.

The final report is kept in the possession of the sponsor and it is usually archived

during the entire existence of the medicinal product.

SUBJECTS ACTIVELY PARTICIPATING CT

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5. SUBJECTS ACTIVELY PARTICIPATING IN THE CLINICAL TRIAL, AND THEIR SCOPE OF RESPONSIBILITY

In the CT, as well as in other areas of human activities, a mutual understanding is

crucial for effective cooperation, and this requires a common understanding of the used

terminology. Except for the basic terminology, the CT may use some specific terms that are

summarized in the Glossary.

The scope of responsibilities is defined according to GCP and SOP and shared by the

sponsor, monitor and investigator. GCP obliges all participants to behave and act in a way

that ensures that the data obtained is reliable, internationally acceptable, credible and useable

for publication, while respecting the trial subjects’ rights.

No activities carried out during clinical trials should be mistaken for standard clinical

routine work; the rules of a consistent and methodical research should always be adhered to.

5.1. SPONSOR

The sponsor has, according to the applicable legislation, the most responsibilities. The

sponsor shall safeguard the implementation and maintenance of quality assurance,

management systems and the application of SOP during the CT, including the contractual

outsourcing of certain responsibilities to CRO.

Generally, the sponsor is responsible for the specialist consultancy for the CT, the

study schedule, study management, and data processing and storage for an adequate period (at

least 15 years, according to GCP).

The sponsor also nominates investigators based on their expertise and experience and

enters into contracts with them, which oblige them to:

- Implement the clinical trial in compliance with GCP;

- Precise recording of data;

- Agree with monitoring, audit and/or inspection;

- Store all documents stipulated in the protocol and by GCP.

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GCP does not rule out the situation where the sponsor and investigator may be the

same individual.

Remuneration of investigators must also be contractually fixed but contracts with

trial subjects who participate in the CT without a direct therapeutic effect and with healthy

volunteers are not required.

Prior to the onset of the clinical trial, the sponsor must obtain and check approvals

from administrative authorities and the ethics committee.

The sponsor must put a great emphasis on the investigational product quality, its

manufacturing, packaging, transport and labeling.

The sponsor is also obliged to ensure trial subjects’ rights and integrity protection.

The sponsor is co-responsible for the close monitoring of the occurrence of adverse effects

and for informing the authorities along with all investigators.

According to Czech legislation, the sponsor must be a natural person or legal entity

responsible for the initiation, management, organization, control and/or funding of the CT.

The sponsor is specifically obliged to:

• Appoint investigators;

• Submit the application and inform SÚKL about the CT commencement and

termination, the occurrence of adverse effects, about changes and alterations, and send

reports in given intervals;

• If the sponsor is a pharmaceutical company, they must provide the investigational

medicinal product to the investigators; however, if the sponsor is the investigator, an

academic institution, a healthcare facility or a state, providing the investigational

medicinal product is not obligatory;

• Ensure the contractual insurance of the sponsor, the investigator and indirectly, of the

trial subject;

• Proceed in compliance with GCP.

Requirements regarding CT insurance are not identical in all EU countries. In the

Czech Republic, it is given by law that the CT can be implemented “only if the liability

insurance for the investigator as well as for the sponsor was concluded prior to the

commencement of the clinical trial; furthermore, the sponsor must provide insurance for the

trial subject in case of injury to their health due to their participation in the clinical trial”.

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Monitoring is, from the perspective of the clinical trial, a specific activity that starts

prior to the commencement of the clinical trial and continues throughout the entire clinical

trial and then ends with the control of archived documents after the CT termination. The aim

of monitoring is to control:

- Protection of rights and quality of life of trial subjects;

- Accuracy and credibility of the obtained data;

- Compliance between the study management and the latest protocol version, GCP and

valid legislation.

GCP devotes an entire chapter to the compliance and noncompliance with the study

conditions. Noncompliance with documents can be discovered by any CT participant; most

often it occurs in patients due to the nonobservance of therapeutic regimen and in doctors due

to the nonobservance of the protocol.

The sponsor can also carry out an audit, as one of the CT quality control methods.

An audit is an independent control with an aim to assess adherence to the regulations and the

protocol, SOP, CGP and administrative demands, or it may only focus on a specific CT area.

Except for the sponsor, a CT audit or inspection can be required by the administrative

authorities, e.g. SÚKL, or the Ministry of Healthcare.

5.2. MONITOR

The monitor in the CT is a person that ensures the implementation of several activities

given by law. The monitor may be appointed by the sponsor and becomes one of the

sponsor’s employees or the sponsor may take advantage of monitors contractually provided

by the CRO, which has now become a common practice. The list of the monitor’s activities is

very long. Whereas a new monitor mediates only the basic contact between the sponsor and

investigator and provides for compliance control, a more experienced monitor usually ensures

that various related activities are initiated. Such monitors are in most companies called CRA,

i.e. clinical research associates. However, the main task of the monitor is to mediate contact

between the sponsor and the investigator and inform each other. The monitor is appointed by

the sponsor and he acts on their behalf in compliance with SOP, visits investigators and

controls the implementation of the clinical trial.

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Monitor’s responsibilities specifically include:

- Mediate communication between the sponsor and the investigator;

- Control compliance with requirements by the investigators and by the healthcare

facility;

- Control compliance with the requirements on the investigational medicinal product;

- Control compliance with the protocol;

- Control the informed consent and whether it has been properly signed by the trial

subject;

- Control source documents;

- Control filling of the records;

- Inform the sponsor of the numbers of trial subjects accepted into the study;

- Inform the sponsor of mistakes and changes by the investigator or at the CT site;

- Inform the sponsor about adverse effects;

- Inform investigators about new facts.

The monitor should proceed according to a SOP approved by the sponsor. The

monitor must also record and present all information in a written report.

Monitoring report should contain a summary on the purpose of the monitoring visit,

and standpoint on important findings, measures or recommendations with an aim to ensure

compliance.

The sponsor must characterize the report and document how the report was addressed.

5.3. INVESTIGATOR

The investigator is the doctor who is responsible for the implementation of the clinical

trial on site. If there is more than one investigator on one site, one of them is appointed as the

principal investigator. If the CT is implemented in several healthcare facilities, more often in

additional countries (i.e. multicentre CT), a coordinating investigator is also appointed.

The principal investigator is responsible for the implementation team on site. The team

usually consists of the principal investigator, sub-investigators and other personnel, usually

nurses, administrators, data managers, etc.

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The basic responsibilities of the investigator, i.e. of the person responsible for the CT

implementation on site, are given by GCP and by law. GCP pays a great attention to the

investigator because they play a substantial role in obtaining quality and scientifically valid

results, as well as ensuring adherence to ethics standards during the clinical trial.

GCP stipulates the requirements for the medical qualifications of the investigator, their

active preparation for the given clinical trial and their responsibility for other persons who

will participate in the CT.

Furthermore, the investigator must remember that their foremost duty is to provide

medical care to the trial subject. The investigator should be a partner of a local ethics

committee, he obtains informed consent, adheres to the protocol, and properly handles the

investigational product. The Investigators should work with precision, interpret the results

with minimum bias, cooperate on interim reports and the final report and report adverse or

unexpected events without any delay.

The investigator is obliged to:

• Familiarize themselves with the clinical trial

This means that the investigator should understand the clinical purpose and

characteristics of the investigational medicinal product that can be obtained from the

summary of results available in the Investigator’s Brochure (IB). In registered drugs, the IB

can be replaced by the Summary of Product Characteristics (SPC) or other updated

publications. This also means that the investigator must study in detail the appropriate

approved documents such as the protocol, case report forms and other documents that serve

for direct entry of the TS’s information, e.g. Patient’s logbook. Furthermore, the investigator

must study documents approved by the ethics committee for obtaining of the informed

consent, i.e. the Information for the Trial subject and the Informed Consent Form. These

documents are prepared by the sponsor, who also chooses the investigators for the particular

clinical trial. The investigator approves the protocol by adding their signature.

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• Facilitate necessary organizational steps on the CT site

The investigator must prove their expertise to implement the clinical trial by

submitting their curriculum vitae (CV). They should also prove that they have enough time

and sufficient means to prepare for the CT and to conduct it. The investigator must also

estimate the number of trial subjects suitable for the given CT.

The investigator is also responsible for the team of co-investigators, who are

authorized and registered to participate in the clinical trial. The investigator must provide

them with sufficient information on the clinical trial in question, and, if the CT is carried out

in a healthcare facility where the investigator is employed, they are obliged to inform their

employer about the CT.

The investigator is obliged to provide correct and timely data that is required by the

protocol and recorded on the trial subject into the CRF. This data must correspond with the

source data in the medical records. In case the healthcare facility carries out laboratory or

other specialized tests, the investigator must also participate in obtaining certificates for each

laboratory.

Only people authorized by the investigator can enter records into the CRF and they

must observe the rules for the recording, alterations and corrections according to GCP. In case

of corrections, a date of correction and signature must also be added.

The investigator signs the protocol, CRF and evaluation site reports to express

agreement with the documents required by the protocol and SOP.

• Obtain informed consent of the trial subject prior to their acceptance into the trial

It is the exclusive responsibility of the investigator or co-investigator to inform the

trial subject about the CT and then obtain the subject’s IC confirmed by their signature. With

minors, information must be presented in a form corresponding to the age of the trial subject

by an experienced pediatrician, and it is also recommended to obtain not only the IC of the

parents (or adoptive parents, foster parents) but also the IC from the child that corresponds to

the child’s understanding of it.

In cases where the trial subject is unable to provide their IC, it should be stated in the

protocol how the IC will be obtained from their legal representative (for minor) and/or in

cases when the prospective subject does not have a legal representative, who and how the

third-party IC will be obtained and how the IC of the trial subject will be obtained as soon as

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the subject is capable of providing it. This procedure must be described in the protocol, and

approved by the EC which supervises its observance.

According to the GCP, the investigator may not inform the trial subject’s general

practitioner on the subject’s participation in the CT without the subject’s explicit consent.

Should the trial subject prematurely terminate their participation in the CT, which they are

entitled to do by law, the investigator should make an adequate effort to find reasons for the

IC revoking without infringing upon the trial subject’s rights.

The investigator should also inform the TS about any concurrent diseases

accidentally discovered during the clinical trial, which would not have been addressed in the

IC.

• Ensure safe handling of the investigational product, its proper storage and return

The investigator shall accept responsibility for the evaluation of the investigational

product that he obtains from the sponsor through a pharmacy. The investigator is provided

with the investigational products for free when the sponsor is also their manufacturer.

However, they do not have to be provided for free if the sponsor is a research institution or

a state facility. The investigator must provide for and check the correct usage of the

investigational medicinal product used by the trial subject, its correct storage and proper

handling with the product. The investigator can charge their cooperatives, a nurse, or parents

for an outpatient’s clinical trials concerning minors or the trial subject themselves with these

activities. However, there should be a written record of such authorization, otherwise the

investigator is obliged to keep records of the given and returned investigational products –

with an aim of keeping track of the product’s consumption. This document should contain at

the very least the date, amount, batch number or code in blinded studies, expiration data

and/or trial subject identification code.

• Report without any delay any serious adverse event (SAE) to the sponsor

The investigator must assess adverse events and the related factors. Whereas during

a standard medical practice the doctor must report any ADRs directly to SÚKL, in the case of

clinical trials, the investigator must report ADRs observed in trial subjects participating in the

clinical trial to the sponsor, who is responsible for all the reporting. The sponsor is usually

informed through the monitor.

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54

Clinical trials also pay close attention to adverse events (AE), which are any

unfavorable health reactions occurring in the TS during their participation in the clinical trial

when they are exposed to the therapy described in the protocol. Some adverse events may

occur due to the administration of the investigational product and these are called adverse

drug reactions. Other forms are serious and non-serious reactions. Any suspicion of ADR

must be reported and the reporting procedure differs from the reporting of an adverse event

unrelated to the evaluated medicinal product. Nevertheless, the investigator must notify the

monitor (sponsor) of any such event including their opinion as to the cause and connection

with the evaluated product.

• Ensure protection of health and life of the trial subject

In compliance with the law, the investigator must be educated in medicine, i.e. the

investigator must be a doctor and able to implement special activities in connection with the

CT. However, the investigator must always act as a doctor foremost and they are therefore

obliged to provide adequate care to the trial subject in whom an adverse effect might occur,

even in cases when such an AE does not have clinical manifestations and is only traceable

through deviations in the laboratory tests.

• Report any serious event to the sponsor

The investigator must inform the sponsor, usually through the monitor, of any new

facts that occur in connection with the clinical trial. These facts may concern the trial

subject’s health condition or the revocation of the IC, personnel changes in the investigator’s

team, or technical or administration changes in the healthcare facility, etc. Some information

must be provided immediately, e.g. information of serious adverse events. Any other issue

can wait until the standard scheduled monitoring visit.

• Ensure confidentiality of all information

The investigator must keep confidential all information regarding the clinical trial

and all related information, not only about the protocol and the trial subject, but also about the

sponsor and CRO. All information entrusted to the investigator is deemed confidential until

the authorized party allows for their publishing. The code of the trial subject can only be

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55

declassified in randomized controlled trials in compliance with the procedure stipulated in the

protocol. The investigator is obliged to store documents that identify the trial subject for

a period of 15 years, unless stipulated otherwise.

Keeping the confidentiality of the obtained information does not infringe upon the

investigator’s obligation to allow the sponsor, monitor and/or competent authorities and the

ethics committee to control, audit or conduct an inspection of the records.

5.4. TRIAL SUBJECT, SUBJECT, HEALTHY VOLUNTEER, PATIENT

The trial subject is a person that participates in the clinical trial, either as a recipient of

the investigational medicinal product, or as a member of the control group. The trial subject

can be a patient who participates in the clinical trial or healthy volunteer in the instance of the

first administration to the human subject, when the therapeutic goal is not the main objective

yet. However, the so-named vulnerable subjects should not be accepted into the CT without

a therapeutic objective.

“No one shall be subjected to torture or to cruel, inhuman or degrading treatment or

punishment. No one shall be subject without his free consent to medical or scientific

experimentation.” (UN, General Assembly, 1966)

Vulnerable subjects are subjects, whose free will to participate in the clinical trial can

be unfavorably influenced by the expectations of benefits (no matter whether justified or not)

connected with their participation in the study and/or worries of repression by their seniors

within some hierarchical structure in the case that their refusal to participate (e.g. students of

medicine, pharmacy, stomatology, students of healthcare colleges, subordinate hospital and

laboratory staff, employees in the pharmaceutical industry, members of military forces and

people in penal facilities.) Other groups of vulnerable subjects includes patients with

incurable diseases and people who are treated without their consent, pregnant and nursing

women, people in nursing homes, unemployed, beggars, patients in critical emergency

situations, members of ethnic minorities, the homeless, refugees, people deprived of legal

capacity and people unable to provide their consent for the participation in the clinical trial.

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5.5. CLINICAL / CONTRACT RESEARCH ORGANISATION – CRO

The CRO is usually a company employing specialists in CTs, their preparation,

implementation, checking and supervision, final evaluation and the closing of CT sites. The

CRO may be a natural person or legal entity that is usually in a contractual relationship with

the sponsor, for whom they provide for one or more activities connected with the CT

stipulated by the law. However, when the sponsor delegates some of their duties and

responsibilities to the CRO, they are not released from their legal responsibility. The CRO

usually works for more than one sponsor and similar to the investigators, they unlike the

manufacturers of medicinal products are not interested in the business activities of

pharmaceutical companies and therefore are not susceptible to bias. Their activities ensure

maximum transparency, credibility and verification of the results. At the same time, they

ensure the adherence to the rules and obligations stipulated ICH GCP.

The CRO can have various numbers of specialists, from several hundreds in large

international CROs to small groups or even individuals who only focus on CT monitoring.

Individuals that are hired for CT monitoring and that work independently are called freelance

monitors. Teams that work in CROs can differ in size and in the professional experience they

offer. Except for monitors, these teams have project managers, specialized doctors, pharmacists

and bio-statisticians, quality control specialists, and personnel that create the documentation.

5.6. LEGAL REQUIREMENTS PRIOR TO THE CT COMMENCEMENT

1. The sponsor/CRO must obtain a statement from SÚKL and the ethics committee;

2. The sponsor /CRO must enter into the following agreements:

- insurance of the investigator and of the sponsor

- agreement with the investigator/healthcare facility defining the scope of

responsibilities

3. The investigator must obtain the informed consent of the trial subject/their legal

representative.

When all mentioned conditions are fulfilled, the clinical trial is open for recruitment of trial

subject.

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57

6. GLOSSARY

The use of a clearly-defined terminology is undoubtedly an important first step.

The following glossary offers an explanation of the basic terms and vocabulary used in the

area of clinical trials that may have different meanings in other fields of discipline, e.g. audit,

protocol, sponsor, source documentation, standard operating procedures, etc.

Word-for-word translations from English and back into English can sometimes bring

conflicting information into a study. Many specialists therefore use both terms, i.e., in English

and in their own language. Furthermore, supervisory bodies in most countries usually accept

English documentation accompanying clinical trials. The only exception is materials for trial

subjects, which must be in their native language or in a language that can be perfectly

understandable to the subject.

Adverse Drug Reaction / ADR

- is an adverse and unexpected reaction to the administration of an investigational drug. It can

have a form of adverse effect, which was already observed and described in the

investigational drug, or an unexpected adverse effect, which has not been described in the

given investigational preparation to date.

Adverse Event / AE

- is any unfavorable change in a trial subject’s condition (clinical symptoms or laboratory

findings) after the subject has been administered the investigational preparation, even though

it is not known whether or not the preparation caused the adverse event.

Amendment (to the protocol)

- is a written description of changes in the protocol or formal clarification of inaccuracies in

the protocol, or it is written after the creation of the protocol and constitutes its inherent part.

Audit

- is the systematic and independent supervision over the activities and documentation

connected with a clinical trial, in order to check that all necessary activities connected with

the clinical trial are being implemented, and that all the instructions are being recorded,

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58

analyzed and observed in compliance with the protocol, along with the sponsor’s standard

operating procedures, good clinical practice and legal regulations.

Bioequivalence

- is proof that the pharmacokinetic parameters for the compared drugs, particularly regarding

the available amount and release speed of the active substance defined, are not significantly

different.

Blinding / Masking

- is a procedure during which one or more participants of the clinical trial is not informed of

their allocation in the therapeutic group. This simple blinding is usually applied on trial

subjects, while a double blinding is usually applied on the trial subjects, their investigators,

the monitor and the data analyst (biostatistics).

Case Report Form / CRF

- is a printed or electronic document designed for the recording of all data on the trial subject

required by the protocol; a completed CRF is a property of the sponsor.

Clinical Evaluation of Drugs / CED / Clinical Trial / Clinical study

– is any systematic testing implemented on human subjects to discover or verify clinical,

pharmacological or other effects, and/or to determine adverse effects and/or to study the

pharmacokinetic characteristics of a drug, or to compare the characteristics of several drugs in

order to verify their safety or effect. The terms clinical evaluation, clinical trial and clinical

study are synonymous.

Clinical Trial Study Report / Final Report

- is a written description of the clinical evaluation of any therapeutic, prophylactic or

diagnostic administration of a drug for human subjects. The description contains clinical and

statistical data, results and analyses summarized into one report (see ICH Guidelines for

Structure and Content of Clinical Study Reports)

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59

Comparator (Product)

- is an evaluated drug that is being compared to the drug tested during a particular clinical

trial. It can be a registered or unregistered efficient drug or an inefficient placebo that does not

contain the effective substance.

Compliance

- is the relationship between the implementation of a clinical trial and the accepted required

conditions: an adherence to all requirements for the given clinical trial stipulated in the

protocol, any additional documentation, the requirements of regulatory bodies and ethics

committees, good clinical practice and legal regulations.

Contract Research Organization /CRO

- is any person or organization (trade, academic or other) under contract to the sponsor that

provides for one or more of the sponsor’s responsibilities related to the clinical trial.

Documentation

- includes all records (including written, electronic, magnetic and optical records, electronic

records of examinations, x-ray images and electrocardiograms, etc.) describing or recording

examination methods, results and the results of trials, as well as records of the factors and

circumstances having an impact on the clinical trial, along with a record of the adopted

measures.

Double Blinding

See Blinding

Essential Documents

- are documents that, individually or as a set, allow for the evaluation of the performance of

the clinical trial and to evaluate the quality of the obtained data, especially the protocol, IB,

CRF and information for the trial subject.

Ethics Committee / EC / Independent Ethics Committee / IEC/ Research EC / REC

- is an independent body, which acts as an independent advisory committee and, according to

its scope of competency, can have the form of constitutional, national or international

committee. An ethics committee consists of both healthcare and scientific professionals and

non-medical members – laics. Its responsibility is to protect and guarantee the rights, safety

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60

and well-being of human subjects involved in a clinical trial. The committee reviews and

judges the clinical trial protocol, the suitability of the investigators and facilities, the methods

and documentation prepared in order to obtain and record the informed consents of the trial

subjects. An ethics committee should be independent in its decision-making process regarding

both the sponsor and the investigator. The legal status of independent ethics committees, their

working methods and legislation may differ from state to state. However, ECs should always

act in compliance with good clinical practice. The network of ECs in the Czech Republic is

divided according to their competency into either multicentre or local ethics committees. Ethics committee for multicentre clinical trials / MEC / multicentre research ethics

committee / MREC

– is an ethics committee that reviews all related documents and conditions of a multicentre

clinical trial. In the Czech Republic, it can also fulfill the role of a local EC, even for an

investigator from a different healthcare facility, in case such a facility does not have its own

EC. The decision of a MEC is valid and final for the entire Czech Republic, and there is no

opportunity for an appeal.

Generic Drugs/Generics

- are medicinal products that contain the same active substance as medicinal products. Generics have the same drug form and indication as original preparations, and can only be manufactured after the expiration of the patent protection of the original medicinal product.

Good Clinical Practice / GCP

- is a standardized and internationally-acknowledged requirement for the planning,

implementing, controlling, monitoring, auditing and analyzing of clinical trials. GCP includes

the requirements on clinical trial reports, ensuring that all data and results are credible and

exact, that all of the rights and integrity of trial subjects are protected, and that all data

concerning these trial subjects is kept confidential.

Hospital/Institution

- is any public or private facility that provides healthcare services and implements clinical

trials.

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61

Informed Consent / IC

For a trial subject to participate in a clinical trial, it must be by written consent. This consent

must contain their personal signature along with the date signed. It must be provided

voluntary, appropriately documented and provided by a person eligible to give such consent.

Its text must be written in a language that is understandable to the subject. It is obtained by

a process by which the subject voluntarily confirms their willingness to participate in

a particular clinical trial after they have been duly informed of all aspects and factors of this

clinical trial that are important for their decision-making process. In the case of persons who

are incapable of giving their informed consent (vulnerable subjects), informed consent may be

provided by their legal representative or, in specific cases, it can be obtained after the trial

subject becomes capable of providing it, upon approval by the EC.

Inspection

- is an activity conducted by supervisory authorities consisting of official reviews of

documents, records and other sources, that the authority considers relevant to the clinical trial.

This activity can also be focused on individual tasks and steps of clinical trials, and can be

implemented at the site of a clinical trial, in a sponsor’s facilities or in any other facilities

subjected to such an inspection.

Institutional Review Board / IRB

- is a committee that consists of doctors, scientists and non-medical members; it has been

established for a particular institution and assesses professional, ethical and legal aspects of

a given clinical trial. In some countries, such boards can substitute for ethics committees.

Interim Clinical Trial / Study Report

- is a report on the current clinical trial, which is compiled on a yearly basis for SÚKL and

EC, and in the case of minors, once every six months. It contains overall data on the numbers

of trial subjects, reports any occurrence of adverse events and on other relevant, significant

events. In studies with a scheduled interim analysis it also contains the results of these

analyses.

GLOSSARY

62

Investigator

- is the doctor responsible for the clinical trial at the site of its implementation. If the trial is

conducted by a team at the trial site, the responsible investigator is called Principal

Investigator / PI

Investigator’s Brochure / IB

- is a systematic summary of all data, both clinical and non-clinical, regarding the evaluated

preparation that is relevant to the given clinical trial. This summary should be updated at least

once a year.

Investigational Product / IP/ Investigational Medicinal Product / IPM

- is a medicinal preparation containing an effective substance or preparation containing only

excipients, a so-called placebo or a comparator. It can be either an unregistered or registered

preparation that is used in a clinical trial differently than in the registered way, including

indication, potency or a drug form, to obtain further information on an already registered

preparation.

Legally Acceptable Representative

- is a person or legal entity authorized (in compliance with the applicable legislation) to give

their consent on behalf of a subject or patient who is unable to provide such consent, in order

that they may participate in a clinical trial. E.g. parents in the case of minors, adoptive parents

or foster parents and legal guardians.

Local Ethics Committee / LEC / Local Research Ethics Committee / LREC

- is an ethics committee that expresses its opinion about the investigator and the capacity of

the related healthcare facility to meet the conditions required for a particular clinical trial. The

decision of LEC is valid and final for the respective evaluation site.

Monitoring

- is a supervisory role over the clinical trial in order to check its compliance with the protocol,

SOP, good clinical practice and legal regulations, and to provide a contact between the

sponsor and the investigator.

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63

Monitoring Report

- is a written report from the monitor that is sent to the sponsor. It describes the state of the

clinical trial at a particular site, reports on the cooperation with the investigator, trial subjects

and the occurrence of unexpected events, etc.

Multicentre Clinical Trial

- is a clinical evaluation implemented in compliance with one protocol on one or more sites in

either the Czech Republic or abroad.

Non-interventional Trial

- is a medicinal preparation used in compliance with its registration, including indication,

dosage and drug forms; no further examination is planned, i.e. no intervention in the standard

registered usage of the given drug. It is not subjected to approval.

Protocol

-is a written document on the schedule of the clinical trial that describes the goal,

arrangement, methods, statistical data and organization of a clinical trial, including its

alterations and amendments.

Quality Assurance / QA

- includes all scheduled and systematic methods used to ensure that the clinical evaluation is

carried out and that all of the data obtained is recorded and evaluated in compliance with GCP

and valid legislation.

Quality Control / QC

- includes working methods and activities focused on quality control assurance, verifying

whether all of the requirements regarding the quality of all activities connected with the

clinical trial are being met.

Randomization

- is the process of allocating trial subjects into designed groups, for example, therapeutic,

comparative, control and bias-prevention groups, using the method of random sampling.

Regulatory Authorities / Competent Authorities

GLOSSARY

64

- are authorities that are authorized to implement regulatory precautions. During the clinical

evaluation of drugs, they review presented clinical trials, their schedules and outcomes, and

are authorized to carry out inspections. In the Czech Republic, this authority is the State

Institute for Drug Control – SÚKL.

Serious Adverse Drug Reaction / SADR/ Serious Adverse Reaction / SAR

- is an adverse effect (see SAE) that is life-threatening, or resulting in death, hospitalization or

its prolongation, or resulting in permanent or serious damage to health, leads to invalidity, or

congenital defect in future descendants.

Serious Adverse Event / SAE

- is an adverse event (see SADR) that is life-threatening, or resulting in death,, hospitalization

or its prolongation, or resulting in permanent or serious damage to health, leads to invalidity

or a congenial defect in future descendants.

Source Data

- are the original records and data recorded in the medical records.

Source Documents / Original Medical Record

- are the original documents containing data and records (e.g. from hospital, body temperature

records, daily medical records, medical history, results of examinations, trial subjects diaries,

questionnaires, records on administered drugs, records obtained from automated medical

examination systems, microfiches, images, photographs, microfilms, magnetic media, X-ray

images, records kept in pharmacies and laboratories, participants in the clinical trial, etc.).

Sponsor

- is a person, company, institution or organization that bears the responsibility for the

preparation, implementation, completion and occasional financing of a clinical trial.

Standard Operating Procedure / SOP

- is a detailed description of the methods adopted for individual activities. Its aim is to ensure

comparable quality, to facilitate control and to ensure the reproducibility of individual tasks.

Subinvestigator / Co-investigator

GLOSSARY

65

- is every member of the clinical trial team who has been designated by the investigator to

carry out various activities connected with the clinical trial, and who is also subordinate to the

investigator.

Summary of Product Characteristic / SPC

- is a summary of all substantial data that is significant for the use of the medicinal

preparation. The SPC content is stipulated in a regulation.

Therapeutic/ Clinical equivalence

- is proof of the identical therapeutic effect of the effective substance in various preparations,

usually implemented during the process of introducing generics.

Trial Subject / Subject / TS

- is a person participating in a clinical trial either as the recipient of the evaluated drug or a

member of a control or comparative group. This includes healthy volunteers and patients.

Unexpected AR

- is an adverse effect whose symptoms are in contrast with up-to-date information on the

preparation (SPC, IB).

Vulnerable Subjects

- are persons who may have provided their consent under pressure from their superiors, or

may fear the consequences of their refusal to participate in a clinical evaluation of a drug.

They may be influenced by their subordinate position towards the investigator, e.g. medical

students, nurses and laboratory employees, etc. Others in this group include the incurably ill,

people in nursing homes and the unemployed and homeless. Also are included people with

limited or deprived legal capacity who are unable to provide their informed consent. Others in

this group would also include people who are not citizens of the Czech Republic, persons

under 18 years of age, pregnant and nursing women, persons under custody or arrest or

imprisoned, soldiers, or people who have been provided medical care without their consent.

Well-being (of the trial subject)

- is the favorable physical condition and countenance of the trial subjects.

GLOSSARY

66

World Medical Association Declaration of Helsinki

- are ethical principles for medicinal research with human subjects. They were adopted in

1964 and have been gradually updated during assemblies of the World Medical Association

(WMA). Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and

amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975, 35th WMA

General Assembly, Venice, Italy, October 1983, 41st WMA General Assembly, Hong Kong,

September 1989, 48th WMA General Assembly, Somerset West, Republic of South Africa,

October 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000,

a Note of Clarification on Paragraph 29 was added by the WMA GA, Washington 2002, and

a Note of Clarification on Paragraph 30 was added by the WMA GA, Tokyo 2004, 59th

General Assembly, Seoul, South Korea, Oct. 2008, 64th General Assembly, Fortaleza, Brazil,

Oct. 2013 in which not only formal changes were made.

ABBREVIATIONS

67

7. USED ABBREVIATIONS

ADR / AR – Adverse effect /Adverse Drug reaction

AE – Adverse event

CE – Clinical evaluation (of medicinal products)

CIOMS – The Council for International Organizations of Medical Sciences

Cmax – maximal concentration

CRA – Clinical research associate / Monitor

CRF – Case report form

EC – Ethics committee

EMA – European Medicines Agency

GHS – Globally harmonized system

GMP – Good Manufacturing Practice

GLP – Good Laboratory Practice

IB – Investigator’s brochure

IC – Informed consent

LD50 – Median lethal dose

LEC – Local ethics committee

MEC – Ethics committee for multicentre clinical trials

MP – Medicinal product

QA – Quality assurance

QC – Quality control

SAE – Serious adverse event

SAR / SADR – Serious adverse (drug) reaction

SPC – Summary of product characteristics

SUSAR – Suspected Unexpected Serious Adverse Reactions

SÚKL – State Institute for Drug Control

Tmax- time to reach Cmax

T 0.5 /T 1/2 – elimination halftime

TS – Trial subject

LITERATURE

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8. LITERATURE

1. Applied Clinical Trials, Vol.8, No 12, Dec.1999

2. Brown L.: A practical Guide to the EU Clinical Trials Directive, Brookwood Booklets, pp 1-47, 2005

3. Clinical Pharmacology – The European Challenge, WHO Regional Publications,

European Series, No39, 1991

4. Controlled Clinical Trials, design, methods and analysis, Elsevier,1998

5. Directive 2001/20/EC

6. Haškovcová H.: Lékařská etika, Galén 2002

7. Pokyny SÚKL (KLH, UST, PhV)

8. International Ethical Guidelines for Biomedical Research Involving Human Subjects, CIOMS and WHO, Geneva, 2002

9. ICH GCP, Směrnice E6: Good Clinical Practice, Int. Conference on Harmonization of

Technical Requirements for Registration of Pharmaceutical Products for Human Use, 1996

10. Niederland T.R., Dzúrik R. a kol.: Klinické skúšania nových liečiv, Osveta 1993

11. Munzarová M: Lékařský výzkum a etika, Grada, 2005

12. Munzarová M.: Vybrané kapitoly z lékařské etiky IV – K etické problematice

výzkumu za účasti lidských subjektů, LF MU v Brně, 2000

13. Operational Guidelines for Ethics Commitees that Review Biomedical Research, WHO, 2000

14. Du Souich P., Erill S., Orme M.: The IUPHAR Compendium of Basic Principles for

Pharmacological Research in Humans, IUPHAR University of California, 2004

15. Spilker B.: Guide to Clinical Trials. Lippincott – Raven Publishers. New York, 1996

16. Strnadová V., Munzarová M.: Úloha etické komise při posuzování grantů na klinické hodnocení, Prakt. Lék., 83, 2003, No.1, p.42-44

LITERATURE

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17. Strnadová V.: Klinické hodnocení na prahu 21. století, Farmakoterapie č. 2, 2005, s. 186-191

18. Convention for the protection of Human Rights and Dignity of the Human Being with

regard to the Application of Biology and Medicine (Oviedo, 1997), Sb. mezinárodních smluv č. 96/2001

19. Decree No. 226/2008 Coll. on good clinical practice and detailed conditions of clinical

trials on medicinal products, as amended

20. Vlček J., Ropek J, Král K: Farmaceutická kontrola, str. 141 – 174 v Vybraná farmaceutická odvětví, edd. Vlček J, Dalecká R: Professional Publishing 2004, (ISBN: 80-86419-69-X).

21. Vlček J., Dalecká R., a kol.: Základy farmakoepidemiologie, farmakoekonomiky a

farmakoinformatiky (2nd ed.), REMEDIA, 2005, ISBN 80-903555-0-1

22. Act No. 378/2007 Coll. on pharmaceuticals, as amended

ISBN 978-80-7305-738-1

Autoři: Strnadová Věra MD, PhD

Název: Preclinical and Clinical Drug Research and Development

Ústav: Ústav humánní farmakologie a toxikologie

Počet stran: 70

Vydání: 1. vydání

Vydavatel: Veterinární a farmaceutická univerzita Brno