1. REVIEW Evaluation Of Clinical Trials In Management Of Viral Hepatitis In Developing Countries By Salwa El-Sayed Abdel-Haleem Tayel Lecturer of Community Medicine Faculty of Medicine Alexandria University 2002 2. LIST OF ABBREVIATIONS HAV Hepatitis A virus HBV Hepatitis B virus HBs Ag Hepatitis B surface antigen HCV Hepatitis C virus HDV Hepatitis D virus HEV Hepatitis E virus HGV Hepatitis G virus TTV Hepatitis TT virus ALT Serum Alanine Transferase IFN- α Interferon-alpha RCTS Randomized Controlled clinical Trials 3. TABLE OF CONTENTS Page Viral Hepatitis ………………………………………………………… 1 Classification ……………………………………………………… 1 Magnitude of the problem………………………………………… 2 Transmission……………………………………………………… 4 Prevention…………………………………………………………. 5 Management………………………………………………………. 7 Treatment…………………………………………………………… 7 Principles of clinical trials……………………………………………... 7 Pre-clinical trials……………………………………………………. 8 Testing new drugs in people………………………………………... 9 Methodology………………………………………………………... 9 Selection of subjects………………………………………………... 10 Sample size…………………………………………………………. 10 Evaluation of treatment outcomes………………………………….. 10 Advantages of RCTS……………………………………………….. 12 Disadvantage of RCTS……………………………………………... 12 Clinical trials for management of viral hepatitis in developing countries…………………………………………………………….. 14 Evaluation of clinical trials…………………………………………. 15 Factors behind inadequate research in developing countries………. 18 Recommendations……………………………………………………… 19 References………………………………………………………………. 21 4. Viral Hepatitis V iral Hepatitis has been recognized since a long time and it still remains as a major public health problem world-wide.(1) The term viral hepatitis is usually used to describe infections caused by agents whose primary tissue tropism is the liver.(2) The past three decades have witnessed remarkable advances in knowledge about viral hepatitis. Before the early 1970s, two forms of hepatitis viruses existed (infectious and serum; A and B), and other uncharacterized agents were classified as "non-A, non-B." However, by the mid-1990s, understanding of these viruses on the molecular level has led to the discovery of multiple antigenitically different subsets of these agents.(3) Seven hepatitis agents have been identified with the likelihood that there are still others that await full characterization.(4) Table I shows some landmarks in the history of viral hepatitis. 1966 Dane particles shown to be HBV 1973 HAV seen by electron microscopy 1980 HDV identified 1988 HCV isolated 1989 HEV isolated 1995 HGV isolated 1997 TTV identified Classification: Hepatitis viruses have been classified into enterically transmitted hepatitis; A and E and parenterally transmitted hepatitis; B, C, D, G and TTV.(2,4) 5. Enterically transmitted hepatitis viruses cause only acute self-limited infections with rare tendency for complications or chronicity.(4) For HAV and HEV, the primary source of virus is in feces and the fecal-oral route is the predominant mode of transmission. Prevention of enterically transmitted hepatitis can be easily attained by using clean water, better sanitation and hygiene education.(1,5) Furthermore, both immune globulin (IG) and hepatitis A vaccine are available for prevention of hepatitis A. Immune globulin can be used as either pre or postexposure prophylaxis and hepatitis A vaccine can be used for pre-exposure prophylaxis.(6) In addition, for hepatitis E virus infection (HEV) a vaccine has been developed. At the 10th International Symposium on Viral Hepatitis and Liver Diseases in 2000,(7) Purcell reported that successful phase I studies using a recombinant HEV vaccine in 132 volunteers has been carried out and a phase II efficacy trial is underway in Nepal involving a total of 3,000 adult volunteers. On the other hand, parenterally transmitted hepatitis viruses are of more public health concern as they have a great tendency to produce persistent infection and chronic liver disease leading to cirrhosis and hepatocellular carcinoma.(4) Because hepatitis G and TTV are no longer believed to be major agents of liver disease,(4,8) thus searching for effective management strategies for HBV, HCV, and HDV became of great concern of intervention research allover the world. The focus of this review will be on HBV, HCV, and HDV. Magnitude of the problem: Hepatitis B virus (HBV) infects 350 million people in the world and kills about one million annually.(1) The WHO estimates that 5% of the population of the world is infected with HBV, thereby making HBV infection one of the most important public health problems worldwide.(9) It is the primary cause of cirrhosis and hepatocellular carcinoma and the ninth leading cause of death worldwide.(10) 6. In developing countries, HBV infection continues to be the single most important cause of viral hepatitis and is a formidable cause of chronic liver disease and primary carcinoma of liver.(1) The prevalence of HBV is as high as 10% to 20% in China, Southeast Asia, and sub-Saharan Africa and even higher, in many developing countries compared to as low as 0.01% to 0.1% in developed countries.(11) Hepatitis C virus (HCV) infection is a growing public health problem worldwide. Up to 3% of the world's population may be infected, equating to 170 million chronic HCV carriers worldwide in what has been called "the silent epidemic."(12) Acute infection is usually clinically silent, however, a distinct and major characteristic of hepatitis C is its tendency to cause chronic liver disease. Epidemiologic studies revealed that at least 80 percent of patients with acute hepatitis C ultimately develop chronic infection. Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. Furthermore, hepatitis C has now become the most frequent reason for hepatologic consultation and the single leading indication for liver transplantation.(13) The highest prevalence rates of HCV infection in the world have been recently reported among Egyptians making HCV a major public health problem. Infection rates ten fold higher than elsewhere in the world has been reported among Egyptians.(14) Saeed et al in 1991(15) in Saudi Arabia found that 19.2% of Egyptian voluntary blood donors were anti-HCV positive compared to 1.3-2.4% among other nationalities. In Alexandria, El-Sherbini in 1994(16) reported a prevalence rate of HCV antibodies of 20.6% among blood donors. Arther in 1996(17) reported high prevalence rates of HCV in schistosomal hepatic fibrosis patients in up to 75% of cases. Hepatitis D (HDV) requires the hepatitis B virus outer coat to replicate. Therefore, infection only occurs in patients who are already infected with hepatitis B.(2,4) HDV is largely an infection of intravenous drug users and their 7. sexual partners, but can affect all risk groups for HBV infection. It is common in southern Europe and Middle East and endemic in Japan and Taiwan.(1,9) Transmission: HBV, HCV, and HDV are bloodborne viruses and are primarily transmitted by percutaneous and mucosal exposures. Percutaneous and permucosal exposure to infectious blood and body fluids is the main mode of transmission, however, transfusion-related hepatitis has virtually disappeared in countries applying routine blood screening.(18) Due to the sharp rise in intravenous drug use, currently, injection-drug use is the most common risk factor for contracting the HBV, HCV and HDV infection worldwide.(19) In developing countries, nosocomial exposure is a leading cause of infection due to lapses in recommended disinfection techniques.(20) High prevalence of anti-HCV in hemodialysis centers, ranging from 2% to 64%, was reported.(20) Studies suggest that outbreaks of HCV transmission occurs between hemodialysis patients when multiuse medication vials and improper decontamination of shared dialysis equipment were practiced. (21) Nosocomial transmission of HBV from inadequate sterilization of medical and dental instruments, and unsafe injection practices continues to be a problem and may account for a majority of infections. (22) In Egypt, Frank et al in 2000(23) studied the role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. They found a significant association between seroprevalence of antibodies to HCV and the personal history of parenteral antischistosomal therapy (Tarter Emetic) among Egyptians. However, strict supervision on sterilization of syringes and needles was sometimes not followed and needles were frequently reused. In developing countries, percutaneous exposures in other settings such as tattooing, body piercing, scarification, commercial barbering and other practices 8. done as a part of cultural and ritual practices have been reported to be responsible for HBV and HCV infection.(9) Although, perinatal (vertical) and sexual transmission of HCV is less common and even difficult to document,(24) the perinatal transmission of HBV is of significant importance especially in high prevalence areas. Beasley in 1983(25) has shown that in South-east Asia the predominant route of HBV transmission is mother to child transmission. Women with an active HBV infection (acute or chronic) can transmit infection to their newborn either in utero or after delivery from mucous membrane exposure to blood and during the early years of life. As well as, it can be transmitted horizontally during childhood through close contact.(26) Unfortunately, the rate of progression from acute to chronic HBV is more than 90% for perinatal infection, but less than 5% for adult infection. Thus more than 90% of infants born to HBeAg positive mothers will become infected.(25-27) Prevention: The primary measure for prevention of hepatitis B is immunization; hepatitis B can be prevented using either pre-exposure prophylaxis with hepatitis B vaccine or postexposure prophylaxis with hepatitis B immune globulin (HBIG) and hepatitis B vaccine.(25,28) An effective, safe, plasma-derived HBV vaccine has been available since 1981. The current recombinant vaccines are derived from recombinant DNA technology and, unlike plasma-derived vaccines, they lack any risk of transmission of infectious agents. They are very effective and produce antibody response after three intramuscular doses, usually administered at 0,1 and 6 month.(4,29) The world Health Organization has recommended universal vaccination against HBV, with a target for the year 2001 to have an 80% decrease in new cases of HBV carriage in children. Furthermore, the combination of 9. immunoglobulin (HBIg) with HBV vaccine proved to be highly effective in preventing vertical transmission in up to 90% of cases. This combination of active and passive immunization is also highly effective in post-exposure prophylaxis following percutaneous or mucosal exposure and following sexual exposure to an HBsAg positive individual.(25,28,29) Because HDV infection is dependent on HBV for replication, immunization to prevent HBV infection is also effective in preventing infection with delta virus (HDV).(4,29) Unlike for HBV and HDV, there is neither a vaccine nor an immunoglobulin preparation that confers specific immunity to HCV. (30) Despite many attempts, no preparation has been found to be effective in this regard. Although experimental vaccines are able to induce an antibody response in a chimpanzee model, this does not confer immunity. This is probably due to the low immunogenicity and high variability of the virus.(4) Thus, the primary strategies for hepatitis C prevention are blood donor screening and risk behavior modification.(30) Mandatory screening of blood donations for is needed to reduce the risk of transfusion related infection. (30) Avoiding high-risk practices such as acupuncture, tattooing and body piercing (unless performed by properly regulated practitioners with single use or individualized equipment) are also emphasized. The sharing of items such as razors and toothbrushes should also be avoided. (9,30) Injecting drug use should be discouraged. Intravenous drug users should never share their equipments, water spoons or filters and should always use a clean needle if they are to avoid infection by blood-transmitted viruses. (9) The sexual risk of transmission can be reduced by safe sexual practice such as the use of condoms and by immunization of the sexual partners of known carriers.(4) 10. Management: Elements of a comprehensive strategy to prevent and control hepatitis C virus should include: (30) Primary prevention activities to reduce the risk for contracting HCV infection whish are emphasized. Secondary prevention activities to reduce risks for chronic disease by identifying HCV-infected persons through diagnostic testing and by providing appropriate medical management and antiviral therapy. Treatment: Concerns about sequelae of long-term infection (cirrhosis and hepatocellular carcinoma) have focused the interest on possible forms of treatment before irreversible damage is established. The mainstay of treatment of HBV, HCV and HDV infections is interferon (IFN). A range of other drugs that are much more specific in action is emerging to complement and possibly to replace INF.(31) Although there have been major advances in the treatment of chronic viral hepatitis in the last decade, the drugs used remain expensive and often have toxic side-effects, with no more than 50% of patients responding to treatment. In addition, even after an apparently successful course of treatment, the risk of relapse remains. (31,32) Thus, searching for safer and more effective treatment continues to be an area of investigation. Principles of clinical trials: The recent great expansion of molecular biotechnology and the great understanding of immunity in viral infections have led to a large number of innovative approaches for new therapeutic strategies. In addition, the increasing availability of sensitive, quantitative and affordable assays will allow clinicians 11. to refine the optimal treatment regimen and to assess treatment response. However, all new medications need careful testing and must be proved effective before they can be introduced into routine clinical care.(31) Clinical trials or experimental studies are research activities that involve the administration of a therapeutic or preventive regimen to humans to evaluate its safety and efficacy.(33) Clinical trials for management of viral hepatitis involve the direct comparison of two or more treatment modalities in human groups to evaluate its safety and efficacy. The purpose of the clinical trials is to provide clinicians with information that will help them prescribe appropriate, timely treatment for their patients.(34) Pre-clinical trials: Enough knowledge about the safety and biologic activity of the treatment is essential to allow it to be administered to patients. In-vitro documentation is required before clinical trials of any medication in human subjects are undertaken. (34) Laboratory experiments have to be carried out to find out if a new medication works on human cells in test tubes. If the drug shows promise, researchers then go to the next stage; animal studies. In animal studies, the new drug is given to animals to see how it works in a living creature. Some animal studies are toxicity studies designed to find out if a drug is dangerous to the body or to some of its organs or systems. However, other drugs may cause birth defects in the next generation. (35) Animals, such as mice and rats, have short life spans and reproduce quickly. They can be used to study both these problems. Other animals, such as monkeys or chimpanzees, are used because they are more like people or can get the same diseases as people. Testing the drug on them can give scientists a better idea of how it will affect people. However, one cannot generalize from animal studies. We should not extrapolate directly from animal studies to man and drugs have to be tested in a sample of people.(35) 12. Testing new drugs in people: If after pre-clinical studies, the drug seems to be useful and safe in animals, the drug should be tested in human. Clinical trials in human follow a set of rules called a protocol.(35,36) The protocol says who can participate, how long the study is, and which tests need to be done. The doctors and nurses should explain exactly what would happen during the clinical trial. They also should inform the participant about the risks and benefits of the clinical trial. (34) A multi-disciplinary institutional review board or research ethics committee should review all clinical trials protocols. It is clearly needed to ensure that the rights of all study subjects or patients are protected, that they are properly informed and that informed consent is obtained on signed forms. (36) Once approved, a clinical trial goes through four phases: In phase I trials, researchers give the drug to a small number of people (10-25) adult volunteers to see what dose is safe in human.(35) Phase II happens when early studies show that the drug may work well. It lasts longer than Phase I trials trying to find out what kind of side effects and the optimal dose with this medicine among several hundred patients.(36) Phase III studies are large trials documenting the efficacy and safety of the drug in patients. It may last longer than Phases I and II looks for ways to reduce the side effects and improve the quality of life. It has many patients (sometimes thousands).(35) Phase IV happens when the drug is already available by prescription in the market to check other safety issues and long-term side effects of the medicine.(35,36) Methodology The randomized controlled clinical trials (RCTS) are the standard and scientifically accepted research methodology to compare the benefit of alternative treatments.(37) A randomized, controlled clinical trial is a study 13. design in which one treatment is compared directly with another treatment to determine which of the two options would be of greatest benefit.(34,37) Selection of subjects: Subjects with a similar clinical characteristic requiring intervention should be included in the study. Inclusion and exclusion of subjects should be restrictive in order to produce a very homogenous study population.(38) Subjects included in the study must be allocated preferably randomly, to each of the treatment interventions. The strength of this approach derives mainly from assigning the treatments to patients and controls randomly.(37) The term “controlled” means that patients (experimental subjects) who receive the new medication are compared against patients (control subjects) who receive either an inactive substance (placebo) or a standard treatment if one exists.(37) “Randomized” refers to a method of assignment of subjects to either the experimental or control group by chance rather than patients’ preference or physician selection. Chance tables should make randomization. This type of allocation system is desirable because it tends to result in study groups that are comparable and important to ensure that prognostic factors that may affect outcomes are equally distributed in the control and experimental groups.(37,38) Sample size: A clinical trial must have a sufficient sample size to have adequate statistical power or ability to detect reliably clinically important differences between treatment groups that are most likely to occur.(36) Evaluation of treatment outcomes: Treatment outcomes (end points) have to be decided upon at the start of the clinical trial.(34) Types of end points can be either primary or secondary. Primary end points are objective microbiologic and serological markers that reflect the causative agent and natural history of the disease. While secondary end points include symptomatic and clinical outcome (e.g. cure, improvement, 14. or no response). Other outcome results include measures of quality of life, drug side effects, cost, benefits and length of survival. More than one end point can be measured.(35) Preferably, observations of outcome should be made double blind; that is, neither the investigators nor the subjects know whether they received the experimental intervention (e.g., a new drug) or the comparison agent (e.g., a placebo, or a standard used agent) until the trial is over. Double blinding helps to ensure lack of bias in the ascertainment of the outcome because neither the subject nor the investigator can be influenced to seek or not to seek medical care or undergo diagnostic tests based on which of the interventions was received. Then rates of measured outcomes for the different treatment groups can be compared statistically.(38) Study population (Subjects meeting entry criteria) Treatment allocation (Randomization) Study group (Experimental) Control (Comparison group) First data collection (Before intervention) First data collection (Same time as in study group) Intervention/manipulation No manipulation/intervention Last data collection (After intervention) Last data collection (Same time as in study group) Compare the results ((Schematic diagram of randomized clinical trial design)) 15. Advantages of RCTS: The primary advantage of clinical trials is that if the treatments are allocated at random in a sample of sufficiently large size, they have the potential to provide a great degree of assurance about the validity of a result.(34,37) By randomly allocating subjects to receive or not receive the agent that is being tested, potential bias is minimized. If the size of the sample is adequate, the only difference between the groups is whether they received the experimental agent.(36) So, it is reasonable to conclude that statistically significant differences in outcomes between the groups were related causally to the experimental agent. For this reason, in most instances the efficacy of a new therapeutic or preventive agent must be demonstrated in clinical trials before their licensing. (35) Disadvantage of RCTS: Although clinical trials are the gold standard for investigators who wish to design a scientifically valid study, they do have a number of limitations. First; they are time consuming and expensive as large number of subjects needs to be selected, enrolled, and followed longitudinally to detect the outcomes. Second; RCTS may pose difficult ethical problems because the new (and potentially efficacious) agent is not given to the controls.(35) Consequently, some patients might suggest that it is not ethical to withhold a potentially efficacious therapeutic agent from persons at risk (e.g., it may be difficult to have persons agree to be potential controls in studies of a promising new therapy). So patients should be told that they are part of clinical experiment and should be well informed about all treatment options, risks and benefits and the nature of randomization. The patient who agrees to participate is said to have given informed consent. In addition, none of treatment options should be known to be inferior to another or to use placebo if a standard treatment regimen exists.(34-38) 16. Ethical issues concerning research on human subjects are regulated by Declaration of Helsinki.(39) It is the most widely accepted guideline on medical research involving human subjects. This set of principles forms the basis for the International Guidelines for Biomedical Research Involving Human Subjects, The Declaration sets out the obligations and responsibilities of doctors and physicians to subjects taking part in medical research. It makes clear that research is justified only if the populations to be studied stand to benefit from the intervention. Individuals enrolled in trials must be given full information about the benefits, risks of the drug before consenting. It also ensures that effectiveness of any new trial method should be tested against those of the best current treatment, whenever this exists, rather than placebo.(39) Table II: Advantages and disadvantage of RCTS Advantages Disadvantages Gold standard for scientific validity as: Requires large samples Randomization ensures unbiased allocation of the exposure (e.g., a new drug) Financial costs are typically high Blinding ensures unbiased assessment of outcomes. Ethical issues may arise: Requires long time for follow-up Subject exclusions may limit ability to generalize findings to other patients * Informed consent. * Use of placebo. 17. Clinical trials for management of viral hepatitis in developing countries: A large number of clinical trials exploring optimal doses, duration of therapy and new therapeutic alternatives were reported all over the world and still others are being conducted. However, fewer studies are reported in developing countries.(40-43) In Egypt, Taher et al in 2002(44) studied the effects of ribavirin monotherapy on 30 chronic HCV patients. Another 30 patients receiving supportive therapy were included as a control group. The study concluded that ribavirin monotherapy was more effective than non-treated group. However, statistical analysis was inappropriate and wrongly interpreted. Abdel Moety et al in 1996(45) studied the effect of combined ribavirin with isoprinosine oral therapy on 44 patients of chronic HCV. All patients received the treatment with no control group. The study reported improvement of treated patients. Abaza in 1996(46) evaluated the dose and efficacy of INF and ribavirin in management of chronic HCV. The study included 40 patients. Ten patients received high dose of INF for 6 months, 10 patients received standard dose of INF for 12 months, 10 patients received ribavirin for 6 months and 10 patients received ribavirin for 12 months. Outcome of treatment was assessed by virological and biochemical tests. He concluded a better effect of drugs given for the longer duration based on more percent reduction of liver enzymes (secondary end points) although no reduction in virological load was observed in all patients. El-Saadani et al in 1996(47) conducted a study using mixture of herbs on 68 patients of chronic active viral hepatitis C patients. Patients were not similar in background characteristics. Only ten patients were selected as control group and left without treatment. Improvement of liver enzymes was detected in treated patients. Similar, many clinical trials investigating the use of herbal therapy were reported.(48-50) 18. Evaluation of clinical trials: As reports of randomized controlled trials (RCTs) are the "gold standard" by which health care professionals and others can make decisions about treatment effectiveness it is important to consider the methodologic quality of the trials. Different methods were developed to assess quality of methodology of RCTS of these Jadad scale(51) that depends on evaluation of three items namely; Was the study described as randomised?, Was the study described as double-blind? and Was there a description of withdrawals and drop outs? However, the Jadad scale has several shortcomings as regard validity. (51) Accordingly, evaluation of the separate components of the methodology was carried out to identify specific areas of weakness. A checklist was developed to evaluate the methodological quality of some clinical trials for management of viral hepatitis in developing countries (Table III). For the sake of comparison, two controlled trials from Europe and USA evaluating treatment regimen for management of viral hepatitis were also included.(53,54) On the bases of the evaluation of the trials, some areas of weakness in the trials carried out in developing countries compared to the western trials was observed. The following points have to be clarified 1. In most studies, there was insufficient information to review the methodological component of each intervention study. 2. Some studies were without control group(45) or very few in numbers(47). Controls are very important in RCTS so, it is questionable whether a non control experiment is appropriate to measure of change over time. (55) Controlled studies are viewed as having far greater validity in medicine than uncontrolled studies.(34,55) Control group should be of similar size as the experimental groups.(55) 19. Table III: A checklist to evaluate the methodological quality of clinical trials for management of viral hepatitis. Author Year Taher 2002 1.Are the criteria for inclusion and exclusion clearly described? 2.Were the baseline demographic characteristics of the study group mentioned? 3.How many subjects were entered in the study? 4.Was a sufficient sample size used in the trial? 5.Was there a control group? 6.Were the treatment and control groups selected randomly? 7.What was the ratio of treatment: control group? 8.Was the study described as a blinded study? Abaza 1996 (44) Abdel Moety 1996 (45) ElSaadani 1996 (47) *Poynard 1998 (53 ) *Mc Hutchinson 1998(54) Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes 60 44 40 68 832 912 No No No No Yes Yes Yes Not stated 1:1 No Not applied Yes Not stated 1:1:1 Yes Not stated 7:1 Yes Yes Yes Yes 1:1:1 1:1:1:1 Not stated Yes Yes Yes Yes Not stated Yes Yes Yes Yes Yes No Yes Yes Not applied Not stated Not stated Yes Yes Yes Yes Yes Not stated Not stated Yes Not stated Not stated Yes Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes Not applied Yes Yes Yes No Yes Yes Yes Yes Not stated Yes 9.Were the treatment regimens described adequately? 10.Were important end points Yes determined? 11. Were outcomes measured in the Yes same way for all groups? 12.Was there a description of Not withdrawals and dropouts? Stated 13.Were dropouts included in the Not final results? Stated 14.Were the side effects recorded Yes and reported? 15.Were the methods of statistical Yes analysis and power described? 16.Was every patient well informed about benefits & risks? Yes 17.Was the new therapy tested No against the best current therapy? * Studies carried out in Western countries. Not applied Not applied (46) 20. 3. Almost all of the studies were not randomized. Previous studies on research methodology(56,57) indicates that trials with inadequate randomization tend to exaggerate intervention benefits compared with trials reporting adequate randomization methods. Likewise, randomized trials without double blinding tend to exaggerate intervention effects compared with double blind trials. 4. Some studies did not describe appropriately patients’ demographic criteria.(47) However, a detailed description of both inclusion and exclusion criteria as well as the patients’ demographic characteristics is required to allow replication by other clinicians and researchers. 5. Almost all of studies used small sample size. Adequate sample size is highly needed to detect significant effect of the tested therapy.(34-38) 6. Most of the studies did not report on statistical testing or statistical power, (45-47) however, they reported favourable therapeutic effects depending only on observed differences in percent but did not subject the result to tests of statistical significance. The study should include a statement describing or giving references for all statistical procedures used. 7. All of the studies did not report on patients’ compliance to the drug. Patients who were recruited to the study but were excluded in the analysis must be described. The number and reasons for withdrawal must be stated. If there are no withdrawals, it should also be stated in the article.(34) 8. Studies using herbal therapy reported beneficial effects of the drugs based on symptomatic improvement (secondary end points). To compare between different drugs we have to relay on important end points (viral reduction) not on secondary end points (symptomatic improvement or reduction of liver enzymes). No controversy between herbal and conventional therapy. There is only medicine that has been adequately tested and that has not. However, end points used to assess treatment have 21. to be objective virological and serological markers that reflect the causative agent and natural history of the disease.(35) 9. Some studies did not give the standard therapy for management of the control group.(44,47) It is not accepted ethically to leave a group of patients untreated. However, the effectiveness of any new trial drug should be tested against those of the best current treatment as emphasized by the Helsniki declaration.(39) To summarize, inadequate methodological quality in the reported clinical trials in developing countries was related to the absence of appropriate controlled randomized trials, selection of small sample size, poor statistical analysis and use of inadequately defined endpoints for measuring outcome as well as, the nonuse of the standard appropriate therapy for the controls. All these factors limit the significance of these studies. Factors behind inadequate research in developing countries: In fact, scientific and medical research faces many complex problems in developing countries. These problems derive from various causes. Selman et al in 1998(58) suggested that many developing countries have inadequate research budget and there is growing gap in the amount of scientific resources of industrialized countries versus those of the developing world. The United Nations' Education, Science, and Cultural Organization (UNESCO) recommends that countries dedicate at least 2% of their gross domestic product to research and development.(59) However, in developing countries it is significantly less. In many developing countries, however, there is a mistaken belief that research is the sole domain of industrialized nations. Greater numbers of responsible doctors who work in clinical settings believe that research is a subject isolated from reality and such work is not important.(60) 22. Another point is lack of confidence in research and the belief that every thing that comes from overseas is better than developing countries. That is why many of clinicians prefer to be consumers rather than producers of science.(61) Moreover, the search for information occupies a fundamental part in the development of science. However, access to information in developing countries is most often fruitless because the many of the journals that researchers need are outdated.(62) Recommendations: The following is recommended: 1. Before accepting conclusions about any drug we have to ask for statistically reliable evidence. No longer do we have to rely on trial and error. Treatment decision should be based on scientifically rigorous, prospective randomized controlled trials that compare the new treatment with the standard therapy. 2. As not all physicians are involved as investigators in clinical trials, training about basic knowledge of the design, execution and evaluation of clinical trials is required in order to be able to perform a critical evaluation of published studies and to take the proper therapeutic decisions. 3. Medical education is needed to provide training in methodologically sound research, scientific methods, experimental design, statistical analysis of data and all aspects of appropriate biomedical research. 4. The components of research methodology mentioned in table III have to be commented upon in the research methodology of clinical trials in any article submitted for publication. 5. Ethical issues reported in Helsinki declaration should be emphasized. 23. 6. Clinical trials for management of viral hepatitis are needed to determine the efficacy of various drug regimens in the developing countries in view of the scarcity of data on therapy of the predominant genotype and the specific characteristic of patients. 7. Development of well-designed clinical trials have to be specifically adapted to the Egyptian context in view of the differences in the prevalent agents and the possible effect of co-infection with schistosomiasis, which may have immunosuppressive effects that influence the drug effectiveness. In addition, that treatment strategy to be adopted should depend on socioeconomic reality, availability of drugs and cost. 8. A multi-center trial with all centers applying the same treatment protocol is needed. 9. It is necessary to continue the ongoing operational research efforts for management for viral hepatitis. These studies should be done in close collaboration between clinicians and public health workers. They all have to participate in teamwork to ensure that ideas and technical abilities are fully shared. 24. References: 1. Park K. Text book of preventive and social medicine. 16 th ed. India: Banarisdas Bhanot publisher, 2000. 2. Sherlock S, Doolley J. 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