Download VIRAL HEPATITIS

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.
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