1. Who, in the Czech Republic, authorises the testing of medicines in people?
The assessment of studies to be conducted in the Czech Republic are performed by the State Institute for Drug Control and at least one ethics committee independently of each other. The assessment of the investigational medicinal product and study design is performed by SÚKL experts in cooperation with specialists from the concerned clinical area, for which the medicinal product is intended. The object of assessment is primarily the risk for patients, objectivity, validity, and accuracy of obtained data as well as the quality of used medicines. Ethics committees focus in particular upon the assessment of ethic aspects of the study, qualification of doctors, and facilities of the site. To be able to commence a study in the Czech Republic, it is necessary to obtain both SÚKL authorisation and approval of the ethics committee.
2. How many studies per year does SÚKL authorise for testing?
The State Institute for Drug Control (SÚKL) reviews approx. 300 proposals for clinical studies per year. Due to the fact that a large proportion of the studies are long-term studies, the number of currently active studies is slightly higher.
The exact numbers of sites where studies are conducted or numbers of patients included in these studies are monitored only generally, as they alter quickly and are not relevant for the purposes of our assessments. Approximately, however, 20 – 30 thousand patients participate in clinical studies in the Czech Republic every year. With respect to the number of studies it may be estimated that clinical studies in the Czech Republic are conducted in most hospitals, particularly large ones (teaching and regional hospitals), and in hundreds of outpatient facilities, private as well as state-owned.
3. What are the conditions governing the testing of medicines in people?
Clinical trials conducted in people are governed by very tight rules. Before a medicine is given to people, it has to go through a standard preclinical testing, i.e. though certain types of tests in animals (acute and chronic toxicity tests, reproductive toxicity tests, cancerogenity tests, mutagenicity and genotoxicity tests). Afterwards, the company must obtain an authorisation/approval from SÚKL, from an ethics committee and last but not least also a consent from the patient in whom the medicine is to be tested. As part of study assessment, all data from preclinical and, where applicable, current clinical testing, which are provided in the documentation submitted by the study sponsor, are examined. The quality of the medicine as well as the conditions of its manufacture are also carefully reviewed.
Any site where a clinical study is conducted must proceed in compliance with the standards of good clinical practice. In some cases studies are conducted at sites providing advanced treatment and procedures associated therewith. This, however, depends on the nature of the study, as not every study needs to be conducted at a highly qualified, specialised workplace.
4. Are medicines in the Czech Republic tested also in healthy volunteers?
The number of studies in which people are administered a completely new substance is very low in the Czech Republic, less than 10 per year. This type of studies usually involves a very low number of participants, approx. 24 in each study, and the participants are usually paid for their participation. The amount of remuneration, however, is not assessed by SÚKL, and these data are not available to the Institute. This type of studies is usually conducted at specialised workplaces and the volunteers who have been given the medicine are constantly monitored so that adequate emergency medical care could be provided to them, if necessary.
The nature and focus of the conducted studies has not been changing significantly in the recent years – international multicentric phase III clinical trials (studies), focused primarily upon oncological and cardiovascular application, prevail.
5. What are the incentives for the volunteers, patients, doctors, and healthcare facilities to participate in a clinical study?
The motivation to participate in a clinical study may vary. In the case of testing in healthy volunteers it is possible to compensate the participation in the study by financial remuneration, which may be an incentive for some people. In the later phases of clinical studies where a tested medicinal product is administered to patients, the incentive may be the possibility of more effective or convenient treatment. For hospitals and doctors it may be the possibility to obtain a new medicine free of charge (medicines for the study are provided by the sponsor), or the possibility to learn about new methods of treatment for the concerned condition. Doctors conducting clinical studies may obtain financial support from the sponsor, which may be yet another, not insignificant, incentive.
6. Should volunteers and patients who apply for participation in clinical studies be now afraid?
In the Czech Republic, there are very few studies in which a brand new substance is administered to people (healthy volunteers) for the first time, less than 10 per year. This type of studies is usually conducted at specialised workplaces and the volunteers who have been given the medicine are constantly monitored so that adequate emergency medical care could be provided to them, if necessary.
Most of the clinical trials (studies) conducted in the Czech Republic, are, however, phase III studies. In clinical trials the participants must be always informed about expected risks in advance, but in no clinical study, like in a routine use of medicines, an absolute safety may be guaranteed.
7. How often is it necessary to stop a clinical study at a certain stage?
The necessity to stop a clinical study for an excessive risk for patients is seen very rarely. If potential risks are identified in the course of the study, it is possible to avoid them by adjusting the conditions of the conduct of the study, e.g. by an increased patient monitoring or by adding other tests, change to the selection of included patients or a reduction of the dose of the medicine. Measures like this are implemented in the course of clinical trials quite often.
8. What risks are generally associated with the testing of a new medicine?
In clinical studies, when the administration of a medicine still has not been sufficiently verified in large sets of patients, a certain risk does exist. This risk is implied particularly by the nature of the medicine and the type of the study. The most frequent risk for patients is that the medicine might cause unexpected adverse reactions which may be very severe (e.g. an escalated form of an allergic reaction), or that the medicine is not well tolerated by the patient. The most frequent risk for the sponsor is that the medicine might not be effective or that for inadequately high risks its further development and use will have to be stopped.
In clinical trials on pharmaceuticals it is impossible to rule out certain risks in advance. The tested medicine is usually not investigated to such a degree which would provide sufficient information about all of its properties when used in man. It is possible to identify many a risk on the basis of the results from testing of medicines in animals, yet for some groups of medicines it is difficult to transpose data obtained in animals to people. Such group of medicines is, in particular, the group of medicines influencing immunological mechanisms, with effects on specifically “human” enzyme systems or on diseases which cannot be modelled in experimental animals. For instance the substance TGN1412 was, before administration to people, tested on many animal models, including monkeys. The substance was administered to monkeys in doses 500 times higher than those administered to people, and yet no adverse reactions were experienced.
As has been mentioned above, absolute safety cannot be guaranteed in any clinical study, nor afterwards, in the regular use of a medicine. In clinical trials participants must be always informed on the expected risks in advance.
9. How can these risks be minimised?
Complex measures are adopted to minimise these risks. Each clinical trial must be authorised or approved by SÚKL and by an ethics committee in advance. Any risks that may be derived from preclinical testing (in animals) and from current clinical testing are carefully considered. In the course of any study, the safety of medicines is constantly monitored, and should new, serious risks be identified, the study may be even stopped for this reason. Patients must be always informed about potential risks, their participation is completely voluntary, and they may withdraw from the study at any time. Where certain risks are expected in advance, the conduct of the clinical study is conditioned by the availability of facilities of a highly qualified workplace.
10. How many studies or how many volunteers or patients are needed for the authorisation of a new medicine?
This question cannot be generally answered by giving a number of studies or a specific number of patients. It depends on the nature of the medicine (the active substance contained in the product) and the disease for which it is indented. Where a completely new medicine (a new active substance) is concerned, it is usually necessary to carry out tens of studies in hundreds of patients. In the event of a disease which occurs only rarely it is not possible to always satisfy this rule, i.e. the product may be authorised also on the basis of data from lower number of patients. For so called generic products, where the manufacturer of a new medicine uses previously known and well established active substance, it is possible to approve the use of the medicine in routine clinical practice without the need to conduct extensive clinical studies.
11. How often does it happen for a medicine which has been successfully tested in a clinical study to show such adverse reactions in practice afterwards, that it has to be recalled from the market?
It does not happen very frequently for adverse reactions to a medicine and implied risks to result in a recall of the medicine. Much more commonly, the conditions governing the use of the product are adjusted and reflected in the information accompanying the medicine (package leaflet and summary of product characteristics). SÚKL publicly informs about such situations and specific cases may be found at www.sukl.cz – Important alerts.
Although cases of product recalls are not very frequent, they are inevitable, because clinical trials on medicines are conducted under very tight conditions and usually do not fully reflect the routine use of the medicine in practice. In the course of a study, e.g. the selection of patients, correct use of the medicine, concomitant treatment with other medicines are closely monitored, no dietary supplement may be taken, no alcohol may be used, etc., which would be very difficult to take care of in the routine practice. Moreover, clinical studies are limited in time, and a number of adverse reactions are evidenced only after a long-term use of the medicine. Some of the adverse reactions may be identified as early as during a clinical study, particularly those which are implied by the nature of the active substance contained in the medicine, yet others only come up in the routine practice.
12. Who covers the costs of the study?
The costs of the study are usually covered by foreign (multinational) pharmaceutical companies, who intend to place the tested product on the market in future. This corresponds to the nature of most studies, as international studies conducted at several sites (so called multicentric studies) prevail in the Czech Republic. A smaller proportion of studies is represented by so called academic studies whose sponsors are doctors or professional associations and which are financed e.g. from grants.
13. Is Central Europe considered by pharmaceutical companies from the whole world a favourite location for the conduct of clinical studies?
The number of applications submitted in the Czech Republic suggests it is. The Czech Republic boasts a number of highly qualified workplaces which can guarantee for the sponsor a quality conduct of the study in compliance with good clinical practice and which ensure validity and accuracy of the obtained data. Other factors include, furthermore, the willingness of patients to participate in the studies and the higher numbers of patients with certain types of conditions for which the new medicines are tested.