Belarus

I.Kh. Marakhovski, MD,PhD

Director of the Republican Specialisation Center of Gastroenterology.

Current Position: Director of the Republican Specialisation Centre of Gastroenterology of the Ministry of Public Health of the Republic of Belarus, Professor of Medicine of the Medical Electronic Department of  Radioelectronically University.

Clinical activities: Membership of the Medical Council of  Supreme Certification Committee of  State Ministers Council of  Belarus, Senior Consultant of the Medical Centre of the Academy of  Sciences of  Belarus and Ministry of Public Health. The Local principal responsibility for the Gastroenterological field in the Republican project «Health Promotion Care in Belarus", Principal Investigator in 3 multinational and multicentre clinical trials(1995-1998)

Memberships: President of the Byelorussian Gastroenterology Association, Chairmen of the International Department of the Physicians Association of the Republic of Belarus, member of the European  Association for Gastroenterology and Endocopy,  member of the Research Committee (1994-1998) and member of the Nominate Committee of the General Council (1998-2000) of the World Organisation of Gastroenterology(OMGE). Member of the Editorial Broads of several journals: Medinica, Problems of Gastroenterology, Russian Journal of Gastroenterology, Hepatology and Coloproctology.

Publications: 40 articles, 46 abstracts, 4 books, 8 innovations

Awards: Individual scientific awards from the International Sores's Foundation in 1993

Introduction.

The an ancient Romans mistrusted  medicaments. Even the Elder  Pliny ( Gaius Plinius Secundus)  believed that all drugs were very harmful for the stomach. In his famous book «Natural history» is a famous and the typical  tombstone inscription « He was slain by a physician’s mob». As time passed, doctors of the royal house became known as «staff poisoners». 

At the present time approximately in 1 out of every 5 case of the drug medications produces an adverse as a result of incorrect labelling of the drug active admixtures, not accounting for the local environmental  conditions  and other causes. In  1986 the Minister of Public Health of the USSR stated that  about 20 percent of the hospital beds  in  the country were occupied by  patients with complication related to  medicaments and  in Europian countries about 7-10 percent(1) 

Today, it is obvious that drugs are an important aspect of health care. However, we cannot ignore the potential dangers associated with the use of various drugs. Estimates of drug efficacy, safety and effectiveness must be made based on regulations of national and international regulatory authorities if the drugs are to be of any real good.

Warranties of correct and optimal pharmacotherapy (medication) and patient protection from the potential adverse reactions of  drugs is based on  the system of drug registration and clinical trials. Drugs registration and clinical trial systems exist throughout the world, including Belarus. 

The Republic of  Belarus has a  typical  European continental  climate and  occupies an area of  207 600 square kilometres with seven large administrative territorial areas - oblasti.

As of 1997, the average annual number of the population was 10 298 200 with a population density of 49.7 per square kilometre.

The urban population (68.2 percent in 1993 and 69.3in 1996) is similar  to that of Norway(70 percent in 1993) and  other European countries. Minsk  the capital of Belarus has the population of 1 800 000. Belarus, like other countries in central and eastern Europe, is undergoing a period of political, economic and social transition. This transition principally involves two important changes: the democratisation of the political system and the introduction of a market economy. Change, however, has not been confined only to these two areas, it has affected all sectors and has had a gradual impact on the overall economic and social development of the people of Belarus.

One of the areas where the effects of change are given evident  is in the health sector. Health policy, the structure and organisation of health services and, most importantly, health status, have all been affected by the transition that started in 1990. To assess the changes and their effects objectively, three  important considerations should be noted:

1.In spite of high hopes among the health and medical professions, and among the wider public for rapid and effective reform of health services, change has been slower in the health sector than in other economic and social sectors

2. The immediate effects of transition on health services and health status have tended initially to be negative rather than positive.

3. As in other sectors, the healthcare system  is predominantly a state centralised system of the planning and the control.

By 1997, there has been some transitional changes in health services. The responsibility for running state hospitals, polyclinics and associated dispensaries was handed over to  municipalities, who were then allocated money from the national budget to finance their range of services. The municipalities can decide how their budget is to be allocated ( i.e. for health services or any of the other services for which they have responsibility). Physicians were given the right to have private practices, resulting in the emergence of  a small private sector. Professional associations developed and began to play a role  as advocates of higher salaries for health professionals and as new partners in the health policy decision-making process and ethical principles.

The importation, production and distribution of drugs and pharmaceutical products is no longer a state monopoly.  Conseguetly many new importers entered the market, private pharmacies opened and within a very short period of time the number of pharmacies doubled. The mechanism for fixing the price of drugs was also abolished.

Despite the positive aspects of these changes, there were   negative experiences: the increase in importation and distribution of pharmaceuticals, the appearance of private pharmacies and abolition of a fixed price system for pharmaceuticals, meant that  the same product was often sold at different prices by different pharmacies. As competition increased, the cost of drugs increased.

Spokespersons, known as «detail men»(2,3) from numerous  appeared companies and often practiced drugs advancement by means of personal contacts with the physicians. They attempted to influence physicians to use the products of their respective companies, even if clinical and scientific side effects of the products could cause potential hazards for patients.

Drug registration

Clinical trials are closely connected with the state national centralised pharmaceutical registration system. Today  the industrial production of a medical drug can occur in the Republic of Belarus only if it is officially registered in the Ministry of Public Health of the Republic of Belarus.

In brief the drug registration procedure consist of  several stages. A more detailed presentation follows this brief summary.

1.   Official presentation of documentation about the drug to the addressed to Ministry of Public Health

2.   Preliminary evaluation of the documentation for completeness.

3.   Expert review to determine the expediency (suitability) of the proposed drug.

4.   Expert review of the pharmacological  properties of the drug.

5.   Inventory of available clinical trials for the proposed drug.

Pharmacology and Pharmacological Committee meets to review the results of the above stages. A decision is then made to either register the drug or to approve a clinical trial for a drug. 

These procedures are regulated  by the  Ministry of Public Health (See Appendix A).

The pharmaceutical company or drug manufacturing entity arranges for the delivery of all documentation to the Pharmacology and Pharmaceutical Committee of the Ministry of Public Health. 

 After primary checking for completeness three experts: a pharmacist, a phrmacologist and an internal medicine or clinical specialist (or clinical subspecialist), review the documentation. 

They consider the clinical and  pharmacological features of the drug features and its active and inactive  substances and comparing with this features existing analogues.

The expert conclusions are  discussed by an  Administrative Committee of the  Pharmacology and Pharmaceutical Committee which than decides whether the drug should be registered (or reregistered) without the need for additional clinical trial study. If it is determined that additional clinical study is necessary, trials will be initiated to provide additional chemical, preclinical, and bioequivalence (the absorption rate of different formulations of the same drug or chemical) data. These data (and results) are than submitted to the Pharmacology and Pharmaceutical Committee for a final decision.

A drug becomes registered with the release of an insurance certificates. As of 1997, the fee to register a drug is US$ 1.000; the reregistration fee is US$500.

The validity of a drug registration is 5 years. At the end of 5 years, any data acquired from postmarketing clinical trials must be evaluated. Then a decision about prolonging the registration or cancelling the certificate is made on the basis of this new data.

In Republic of Belarus as of 01 January 1997, there are 3 360 drug registrations in effect, of these, 115 drugs were produced in Belarus, 2 835 were produced by foreign companies and 410 were produced by New Independent States including of the Baltic region.

Eleven drugs  that were submitted for registration were disallowed due to discrepancies in the documentation. From 1992 to 1997, 37 drugs, including 12 drugs produced in Belarus, were subjected to clinical trials.

Resources for clinical trials

There is appreciable medical  and scientific potential for  clinical trials in Belarus official data  as to the number of physicians, pharmacists, hospitals and hospital beds as compared with the  other European countries are presented in the  Appendix B.

It is also important to note that Belarus has a 5 Medical Institutes(Universities) and 1 Institute for Medical Postgraduate Education.  Into healthcare  system are included  900 hospitals(1247 hospital beds per 100 000 ) with an average length of stay of 15,4 to 15,8 days, and more than 80 specialised Diagnostic and Consulting Centres for different medical subspecialties.

The Prime Medical  Management Department  of the Ministry of Public Health has more  than 70 Head specialists of different medical specialities,  who organise and assess  drugs  clinical trials. The list of Centres  and Head Specialists is reviewed once every 2-3 years, with changes made as necessary. The current list (as of 1997) is given in Appendix C

National Medical  Centres render highly specialised medical care, diagnostic, consultation and treatment to the population and in Centres provide a medical postgraduate education. One of the main fundamental purposes of the Centres  is an appraise  and recommend for application on the territories of Belarus, drugs, medical equipment and reagents, and  new methods of diagnostics,  treatment and disease prevention.   The Chief of the Centre  is the Head Specialist of the Ministry of Public Health in the medicinal speciality of the  Centre.     All Centres are located in large hospitals equipped modern diagnostic and  laboratory technology.

For example: the Republican Specialised  Centre of Gastroenterology has an out-patient department that annually consults and  examines about 6000 patients and in-patient department  with 80 hospital beds that annually treats 1500-1800 patients. The Centre appraises and introduces 1-2 new methods of diagnostics  and 1-2 clinical trials each year. Centre has clinical, scientifically and pharmaceutical departments.

Each Centre reports its recommendations to the Ministry of Public Health. Each Centres can choose the drugs that will be studied in a clinical trial according to special provisions  stated by  the Ministry of Public Health.

Medical background for clinical trials.

One of the purposes of clinical trials  is to improve the practice of medical care and good clinical trials arise from clinical requirement. A motivation for choosing a particular drug for a clinical trial is its potential therapeutic benefit in treating a specific disease or ailment

In Appendix D is primary data regarding various disease in Belarus and other countries. According to data from 1996, the following diseases and ailments were registered in Belarus(prevalence per 100.000 population):

digestive system ailments  - 91344,

respiratory system ailments -  36651,4,

cardiovascular disease -  11 941,6,

nervous system ailments -  11403,5,

bone and reumatological diseases - 7 024,9,

infection and parasitic diseases - 5 754,6,

pancreractic diseases - 140,6

peptic ulcer for children - 475,9,

peptic ulcer for adults -  1970,1,

Cancer incidence were 293,0(1996 data) and  by 35% is primary localised in digestive system(4).

The Gastroenterology Centre annually  consults and treats more than  1500 cases of peptic ulcer, 400-500 chronic liver diseases, and 100-150 inflammatory bowel diseases. The city of Minsk has registered annually newly-diagnosed(incidence)  more than 2 000 patients with peptic ulcer and the same number of patients with gallstones, plus 7000 patients with Helicobacter Pylori associated chronic gastritis(10).

The local legal bases for clinical trials.

The foundations for  clinical trials are base on the following regulations and judicial documents

·     The Constitution and Healthcare Law (Statute)  of the Republic of  Belarus - « O zdravookhranenii».

·     The Authorisation Order to Medical Application and Industrial Production of a New Drug (effected 04 October 1993).

·     The Provision  Order for the Registration of Foreign Drugs (effected 20 September 1993).

·     Demands for Preclinical Studies of  New Pharmacologic Substances of the Pharmacological Board of the USSR Ministry of Health (effected 25 April 1984).

·     The Law Standards of the Republic of Belarus:

« The National Certificate System: Drugs Certificate» -  based on statement in Cabinet.

« The Order of the Development,  Matching and  Statement of  Pharmacopoeial Articles»  - based 

on statement in Cabinet.

·     Statute about Drugs - still under consideration

·     The Consensus of NIS Countries about  Collaboration in the Field of Standardisation, Registrations and the Monitoring(control) of  Drugs Quality  and Medical Technique (effective in 1993 with addendum from 18 December 1996)

·     The Physician Ethical  Codex (effective and accepted in 1998 by the 1^st Byelorussian Forum of Physicians

·     Patients Rights Statute - still under consideration.

·     Decree « Republican Scientifically-Practical Centres»

·     Some of the positions in these documents have  particular significance to clinical trials. Article No 23 (Carrying out the clinical and medico--biological researches in the medicine) from The Healthcare Law (Statute)  of the Republic of  Belarus - « O zdravookhranenii».

«With medicinal or scientific claims in medical establishments by high skilled(qualified) specialists and physicians clinical and medico-biological research may be conducted and any medical intervention on human(man) can be done only with written informed consent of the adult’s person undergoing research, and acquainted with aims of the studies, the expected results and  potential consequences on its health. Clinical and medico-biological research and studies may be conducted on humans after they have been scientifically confirmed.

Clinical and medico-biological researches and studies must be stopped on request as well as in cases of adverse health or life events of  the persons undergoing research.

A study may be sanctioned by the agency commission of the health care facility.

The responsibility for all studies belongs to the experimenter(researchist/investigator) as well as the commissions who authorised the study.

Clinical and medico-biological research and studies is prohibited on underage(minor) persons and on citizens suffering mental(psychic) impairments or mental diseases».

The principal  provisions of this Article must be applied to all clinical investigations that may have an impact on the health, life, safety and well-being of citizens of the Republic of Belarus. 

Next important documents for the clinical trials realisation are «Demands to Preclinical Studies of the New Pharmacologic substances of The Pharmacologic Board USSR Ministry of Health» and « The Order of the Development,  Matching and  Statement of  Pharmacopoeial Articles». These documents contain necessary provisions for execution of the pharmacopoeial article as the principal document for a new drug. 

On the basis of the pharmacopoeial article new agents are registered in the Republic of Belarus. The following information must be included in all submitted documentation:

·     -physico-chemical description of the active and inactive substances

·     -control test for active substance

·     -instruction for use

·     -description of the method for receiving active substances

·     -control test for active substances during storage (minimum 1 year)

·     -preclinical data: acute and chronic toxicity,  teratogenicity, mutagenicity and embriotoxicity,

·     -efficacy  in experimental animals and animals receiving overdoses

·     -active substance  pharmacokinetics in animals

·     -project of clinical trials

·     -results of phase 1 clinical trial

·     -results of phase 2 clinical trials

·     -results of phase 3 clinical trials

In 1997 drug  manufacturers in  Belarus validated 50 new pharmacopoeial articles and 80 changes to workable pharmacopoeial articles. About 200 drafts of the pharmacopoeial articles reside in the  Ministry of Public Health  as the result of changes of  archaic normative documentation provided by the former USSR Ministry of Health. Temporary pharmacopoeial articles on new drugs are appraised on their documentation and samples provided from the first  5  batches of the drug produced.

Belarus also  participates  on an international level consensus  papers that contribute to standardisation and the common demands of clinical trials. « The Consensus of NIS Countries about Collaboration in the Field of Standardisation, Registrations and the Monitoring(control) of Drugs Quality and Medical Technique» is consensus between NIS countries to accept and  follow to the Good Manufacturing Practices(GMP) and the World Health Organisation Good Clinical Practices(WHO GCP) for  every countries that signs this document.

Moreover, in the past 3 years, agreements have been signed with other countries relating to control and standardisation of  drug applications:

·     Agreement with the Agence du Medicament(France) collaboration of drug standardisation, registration and  monitoring (effected 8 March 1995)

·     - Memorandum of  understanding with the U.S. Food and Drug Administration(FDA)    to cooperate and exchange information for the purposes  of   introducing pharmaceuticals and biological substances  in Belarus (effected 25 March 1996)

·     -Agreement  with the Ukraine Ministry of Health for  standardisation and the drug quality monitoring(effected 21 April 1995)

·     -Agreement with the Latvia Ministry of the Public Health for collaboration in the fields of  drug registration and  monitoring of  drug quality(effected 19 September 1996)

Terminology

In any specific branch of medicine there must be a distinct understanding of the essential significance of fundamental terminology(conceptions). Effective communication requires agreement on  basic terminology. Terminology refers to proper terms, but semantics teaches the meaning of the terms. Both semantics terminology and semantics are dynamic and changing as the subspecial ties of medicine evolve on the local, national and international level.

The documents discussed  above  summarise and allude to the principal concepts involved in clinical trials.

The following sections give definitions of concepts associated with clinical trials and adequate to its understanding in Russian terms. 

Clinical Trials(general definition)

A clinical trial is  pre-planned studies of the safety, efficacy or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favourable and unfavourable effects.

Clinical Trials, Phase I

 A phase I clinical trial is a studies  performed to evaluate the safety of diagnostic, therapeutic or prophylactic drugs, devices or techniques in healthy subjects and to determine the safe dosage range (if appropriate). These tests also are used to determine pharmacologic and pharmacokinetic properties (toxicity, metabolism, absorption, elimination, and preferred route of administration). They involve a small number of persons and usually last about one year.

Clinical Trials, Phase II

A phase II clinical trial  are usually controlled to assess the effectiveness and dosage (if appropriate) of diagnostic, therapeutic or prophylactic drugs, devices or techniques. These studies are performed on several hundred volunteers, including a limited number of patients with the target disease or disorder, and last about two years.

Clinical Trials, Phase III

Phase III clinical trial are comparative studies to verify the effectiveness of diagnostic, therapeutic or prophylactic drugs, devices or techniques determined in Phase II studies. During these trials, patients are monitored closely by physicians to identify any adverse reactions from long-term use. These studies are performed on groups of patients large enough to identify clinically significant responses and usually last about three years.

Clinical Trials, Phase IV

 Planned post-marketing studies of diagnostic, therapeutic or prophylactic drugs, devices or techniques that have been approved for general sale constitute Phase IV clinical trial. These studies are often conducted to obtain additional data about the safety and efficacy of a product.

Controlled Clinical Trials

A controlled clinical trials involves one or more test treatments, at least one control treatment, specified outcome measures for evaluating the studied intervention, and a bias-free method for assigning patients to the test treatment. The treatment may be drugs, devices, or procedures studied for diagnostic, therapeutic or prophylactic effectiveness. Control measures include placebos, active medicines, no-treatment, dosage forms and regimens, historical comparisons, and so on. When randomisation using mathematical techniques, such as the use of a random numbers table, is employed to assign patients to test or control treatments, the trials are characterised as randomised controlled trials . However, trials employing treatment allocation methods such as coin flips, odd-even numbers, patient social security numbers, days of the week, medical record numbers, or other such pseudo- or quasi-random processes are simply designated as controlled clinical trials.

Multicenter Studies

 A multicenter study is a controlled study that is planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations. An example is a multicenter study of congenital cirrhosis  in children.

Clinical Protocols

A clinical protocol is a precise and detailed plan for the study of a medical or biomedical problem and/or plans for a regimen of therapy.

Feasibility Studies

 Feasibility studies  determine the advantages or disadvantages, practicality or capability of accomplishing a projected plan, study or project.

Pilot Projects

A pilot study demonstrates on a small scale whether or not a specific method or procedure will work on a larger scale.

Sampling Studies

A sampling study involves a number of subjects who are selected from all subjects in a defined population. Conclusions based on sample results may be attributed only to the population sampled, not to the population as a whole.

Therapeutic Equivalency

Therapeutic equivalency is the relative equivalency in the efficacy of different modes of treatment of a disease. It is  most often used to compare the efficacy of different pharmaceuticals to treat a given disease.

Ethics Committees

Ethic Committees have a variety of purpose: direct educational programs;  provide forums for the discussion of ethical issues among hospital or medical professionals and others;  serve as an advisor and/or as a resource to health professionals involved in biomedical decision making and  review and evaluate institutional experiences related to decisions having biomedical or ethical implications(5,6).

Evaluation Studies

An evaluation study determines the effectiveness or value of processes, personnel, and equipment or the material for conducting such studies. For drugs and devices, clinical trials, drug evaluation and drug screening  are possible evaluation studies.

Investigational New Drug Application

An investigation New Drug Application is an application that must be submitted to a regulatory agency (e.g. Ministry of public Health in Belarus) before a drug can be studied in humans. This application includes the results of previous experiments; how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is presumed to work in the body; any toxic effects found in animal studies; and how the compound is manufactured(7).

Drugs, Investigational

Investigational drugs are drugs that have received special commission approval for human testing but have not yet to be approved for commercial marketing. This includes drugs used for treatment while they still are undergoing clinical trials. This also includes drugs under investigation in foreign countries.

Treatment Outcome

Treatment outcome is an assessment the results or consequences of management and procedures used in combating disease. In determines the efficacy, effectiveness, safety, practicality and so on, of these interventions.

Medical Futility

Medical futility is the absence of a useful purpose or result in a diagnostic procedure or therapeutic intervention. A treatment is futile when it does not improve the condition of a patient, maintains permanent unconsciousness or cannot end dependence on intensive medical care(8,9).

Treatment Failure

A treatment failure is unsuccessful medical treatment. By assessing  unsuccessful results or consequences of management and procedures used in combating disease, one can obtain a measure of the quality of health care.

Adverse Drug Reaction Reporting Systems

Adverse drug reaction systems are systems for collecting reports from government agencies, manufacturers, hospitals, physicians and other sources on adverse drug reactions. In Belarus all adverse drugs reaction must be documented in  patient’s medical history and reported to the hospital administration for careful consideration  on a special  standing commission the Treatment Control Commission (Lechebno Kontrolinai Komissia)

Language and Terminology

Beylorussian  laws requite that  all documents for clinical trials be in Russian. This creates terminological difficulties because Russian medical literature has a number of differences in medicinal terminology when compared to English literature, thus an understanding of the full valve of clinical trial is clouded. A concrete discussion of a clinical trial protocol will help to illuminate and correct differences in terminology.

Due to terminological difficulties in the field of the Specialisation Centre of Gastroenterology published (in Russian) several articles(8) and a book of primary gastroenterology clinical and diagnostic terms(Basic international terminology and diagnostic criteria. 1995) and  assisted in the translation into  Russian  of  «Terminology, Definitions and Diagnostic Criteria in Digestive Endoscopy. OMED Nomenclature of Digestive Endoscopy»  which  was published  in 1996 in Germany.

Because there are differences in language, a pharmaceutical company must adopt to the language and medical practices of the country in which it witches to register a drug or perform a clinical trial.

Moreover, correct clinical trials are possible at the correct terminology recognition and for this purposes is very actually to Russian version of the Guideline for Good Clinical Practice ICH(12).  

Protocol of Clinical Trial

The organisational phase of a clinical trial is just as important, as the logistics in order to produce a successful clinical trial. The participating personnel at various levels are expected to develop cases, recruit and train   patients, develop scoring patterns and coordinate tests, as well as incorporate validation studies at each step of the process. Therefore a critical aspect  of a good clinical trial is the availability of all  necessary information. The protocol involves more than just performing the trial, also involves checking the quality,  reliability and clinical interest of the planned findings. Consequently, it is recommended that a clinical trial protocol  contain the following information:

·     - A study acronym and identification of the trial

·     - The objectives of the trial, with the motivation, the hypothesis tested, the expected effect clearly stated and a description of the prior target population and the eligible population

·     - A review of pertinent background literature

·     - A rationale for the choice of treatments, in particular the control

·     - A description of treatments: dosage, formulation, administration, out-patient or in-patient,  initiation location( e.g. hospital, clinic), duration

·     - A design (open, double-blind, single-blind, crossover, parallel groups, factorial, etc.)

·     - A definition of primary and secondary outcomes with measures, validation procedure and rationale

·     - Measures of adverse events

·     - Sample size with a detailed rationale, with particular emphasis on the expected effect

·     - The method of treatment assignment; the randomisation method and the practical procedure  (central, local, boxes, envelopes, computer, etc.) should be carefully presented

·     - Methods for and level of treatment masking

·     - Follow-up methods

·     - Data collection methods (paper and mail, computer network, etc.);

·     - Methods for quality control and assurance

·     - Methods for analysis

·     - Organisational structure, especially for multicentre trials;

·     - A list of participating units and centres and their responsibilities and a list of participating personnel

·     - Efficacy and safety monitoring techniques and responsibilities with allowance for multiple statistical testing and a summary of decision rules

·     -  Application for an Ethical Committee

·     - The planned start and end dates for the trail

·     - A list of  patients enrolled and randomised

·     -Compliance measures with rules and regulations

·     - A description of the study population: demographic data, risk profile, concomitant diseases

·     - A baseline comparison of the treatment groups

·     - Censored data: indicate the number of cases (per treatment group) at each point on the time scale; give tabulated data from the actuarial analysis as an appendix or indicate from whom data may be obtained

·     - A comparison of possible outcomes by risk subgroups, sex, or any important/controversial

·     - A list of known adverse events: types, severity, indicate when an adverse event leads to withdrawal  from treatment

·     - The study sponsor(s).

Conceptual Foundation for Local Ethical Principles

In Belarus the following  international documents for the realisation local ethical principles for  medical practice in general and clinical trials in particular are part of national law:

«The Universal Declaration of Human Rights»(1948)

«The European Social Charter»(1961)

«The Declaration of Helsinki» (WHO adopted version  1964)

«The Declaration on the Promotion of Patients’ Rights in Europe» (WHO 1994)

«The Declaration on the Promotion of Patients’ Rights in Europe» also applies to health care system and is reflected  in the local official documents, as  «The Physician Ethical  Codex»  and «The Patients Rights Statute» is currently being prepared by the Ministry of Public Health and the Council of Ministry of the Republic of Belarus. 

These documents illustrate the importance of medical ethics in clinical trials.

A physician should always follow the principle « Noli nocere». A physician should always act in the best interests of his or her patient. Weakening the physical, mental or moral condition of a patient, as well as harming the patient's material condition, ether intentionally or through negligence, is impermissible. A physician should not be indifferent in cases when such harm to the patient is made by third party. A physician should always carefully assess predictable risks in comparison to potential benefits, connected with medical intervention, especially in cases when such intervention is associated with pain or other factors that may harm the patient. The cure should  not be worse than the illness.

A physician should not: use his or her knowledge and status of medical profession for nonhuman purposes or use medical intervention or abandon it without sufficient reasons or  apply any sort of pressure to the patient as a form of punishment or in the interests of the third party.

A physician should not impose on the patient his or her own philosophical, religious, and political views. The processes of diagnosis and treatment should be free from any personal prejudices and other nonprofessional considerations. A physician should  not misuse his or her professional status or the patient's mental incapability as a means of gaining profit. Intimate (sexual)  relations with a patient,  bribery or extortion must be always avoided. .

A patient's voluntary informed  consent should be regarded as the result of an effective therapeutical partnership between him or her and the physician not a spontaneous expression of the patient's will.

The development of a patient's sense of responsibility for his or her  actions should be considered as one of the main goals of the physician's behaviour while at the same time establishing a therapeutical partnership with the patient. As a rule, the intentional(withdrawal) of a patient from treatment(not caused by an adverse event) is a result of the inadequacy of such a partnership and, as such, is always a matter of physician responsibility and conscience. Any acceptance for treatment or withdrawal from treatment must be informed and voluntary.

No medical intervention can be done without the informed consent of a patient, except when: a patient is not capable of giving such consent due to his or her  physical or mental condition or when a patient is dangerous to other people. In such cases, compulsory measures taken by a physician are necessary and ethical. However, such measures should be taken only in strict accordance with the law and only for medical reasons. A physician should notify the authorities in charge when a patient is withdrawn from compulsory measures.

Any research involving patients should be conducted only when a patient's consent is obtained and the research has been  approved by the Ethical Committee. Every research project involving patients should be preceded by a careful assessment of predictable risks in comparison with potential benefits to the patients. Concern for the interests of the patient involved in research must always prevail over the interests of science and society. In any research involving patients, each potential subject of the research must be adequately informed of the aims, methods and anticipated benefits and risks of the study. The patient should also be informed that he or she is free to withdraw from participation in the research at any stage and for any reason.

A physician should guarantee the patient's rights. Only then should a voluntary informed consent be obtained. The refusal of the patient to participate in the research must never interfere with the physician-patient relationship.

The investigator is responsible for abiding with ethical norms in accordance with local regulations. Before a clinical trial is initiated, the investigator must received official permission from the local Ethical Committee. The Ethical Committee should obtain from the investigator and the sponsor the following documents in Russian: trial protocol with amendment, informed consent form, investigator qualifications and curriculum vitae and any documents for patient protection (e.g. risk insurance). The Pharmacology and Pharmaceutical  Committee must grant permission before a drug can be registered in Belarus. Several Independent  Ethics Committees are now active in medical associations including the  Byelorussian Association of Physicians and the Byelorussian Gastroenterology Association. 

From July 1998 the Ministry of Public Health together with the Byelorussian Association of Physicians official accepted special conditions for organised an Independent Ethics Committees in every medical foundation and institution and regional and Central(Republican)  Ethics Committee.

Conclusion

The Republic of Belarus has officially  accepted  the WHO GCPs for clinical practice and the GMPs for manufacturing practice. Local laws have been established to carry out these standards in existing health care system in order to achieve good clinical trial  results.

Drug clinical trials can be realised through drug registration as follows:

Company/ Contract Organisation

Pharmacology and Pharmaceutical Committee of the Ministry of Public Health

Specialisation Centre/ Institute

Company/ Contract Organisation

Clinical  Trial  Report of results to the Ministry  of  Public Health.

Alternatively, the following process may be used:

Company/ Contract Organisation

Specialisation Centre/ Institute

Clinical  Trial

Report of results to the Ministry  of  Public Health.

All trials on new drugs without data from Phase I clinical trials can be started only after  permission has been received from the Ministry of Public Health.  All documents must be presented in Russian . Qualification of the Centre/Institute is confirmed by a special  Ministry of Public Health  fiat(decree). All clinical trials are restricted to either a hospital or a Centre.

Clinical trials also require permission from the Ethical Committee before they can be initiated. Proof of qualification of the investigator is provided through special agreements approved  by the Centre director and validated with the Centre stamp. The agreement for a clinical trial is  duly signed by the  Company(Sponsor)/ Contract Research Organisation and Centre/investigator.  It indicates all responsibilities and duties, including financing and insurance. Notification in writing must be given  to the Ministry of Public Health, the director of Centre/Institute and the Head Specialist at the Ministry of Public Health. Information during the clinical trial, such as annual and final reports, are to be sent  to the Ministry of Public Health, the administration of the Centre/Institute Administration, the Ethical Committee and, in cases adverse drug reaction, to the Treatment Control Commission. Premature ending or elongation after the end date of a trial  must be indicated in  writing with  an explanation of all details related to a premature end or an elongation of the trial. This notice is to be sent to each of the entities given.

Clinical trials involving  minors or pregnant women is forbidden in Belarus. Clinical trials  with soldiers and healthy volunteers is possible provided informed consent in writing is received from the subjects. The investigator should send the official report after trial termination to the administration of the Centre/Institute with six mounts, the administration must revise(if necessary) report, approve and forward to the Ministry of Public Health and the Ethical Committee.

 Clinical practice in general and clinical trials in  particular are  periodically inspected by local health authorities and a special  commission  of 3-5 persons. These inspections occur once every two to three months. The clinical trial report along with patient medical histories and all other patient patients medical documents must be archived for 30 years, after the conclusion of a clinical trial.

References 

1.   Keees de Joncheere. Using medicament: review of practical prescription. Medicina. 1998, 2, 24-26

2.   Lexchin J., Doctors and detailers. Therapeutic education or pharmaceutical promotion? International Journal of Health Serice, 1989;19(4), 663-679.

3.   Shashindran C.H.and Sethuraman K.R., Integrated orientation programme for intems on quality care. Essential Drugs Monitor. 1995, No.5(20). p.24.

4.   Public Health in the Republic of Belarus. An official statistics collection. 1997, Minsk, Medical Statistical Department of the Ministry of Public Health of the Republic of Belarus, 3-340.

5.   Editorial. Physician Ethical Codex. Medicina, 1997, 4, 3.

6.   Instruction. Hospital Administration Terminology. 1995, Moscow, 5-15.

7.   PMA. 1994. New Medicines in Development. Series published by Pharmaceutical Manufacturers Assotiation.

8.   Scheiderman L.J., Jecker N.S., Jonsen A.P., Medical futility: its meaning and ethical implications. Ann Intern Med. 1990 Jun 15;112(12):949-954

9.   Engekhard H.T., Khushf G., Futile care for the critically ill patient(review article). Current Opinion in Critical Care. 1995, 1, 329-333

10.Marakhovski I.Kh., Standards in Gastroenterology (review). Medicinskie Novosti, 1998, Suppl 3 2-62.

11.Marakhovski I.Kh., Possibilities of improving the specialised gastroenterology assistance. Zdravookhranenie. 1998, 6, 33-36.

12. ICH. Harmonised Tripartite Guideline for Good Clinical Practice. 1996. Brookwood Medical Publications Ltd. Orchard House, Brookwood, Surrey GU24 OAT, UK.

Appendix A

Appendix B

Ëèäåð îáðàçîâàòåëüíûõ ïðîãðàìì â îáëàñòè ãàñòðîýíòåðîëîãèè è íóòðèöèîëîãèè â Ðåñïóáëèêå Áåëàðóñü

Îòïðàâèòü ñîîáùåíèå belgastr@mail.ru ñ âîïðîñàìè è çàìå÷àíèяìè îá ýòîì âåá-óçëå.
© 2002 Êàôåäðà ãàñòðîýíòåðîëîãèè è íóòðèöèîëîãèè
Äàòà èçìåíåíèя: 04.07.2004