Volume 1, Number 6: December 1998
A Clinical Trial Comparing Three
Antithrombotic-Drug Regimens after Coronary-Artery StentingThe hidden epidemic of
cardiovascular disease
Recombinant human nerve growth factor in
the treatment of diabetic polyneuropathy. NGF Study Group.Clinical trials in developing countries:
scientific and ethical issues A Clinical Trial Comparing Three
Antithrombotic-Drug Regimens after Coronary-Artery Stenting
Source: NEJM 1998; 339:1665-71
Background: Antithrombotic drugs are used after coronary-artery
stenting to prevent stent thrombosis. We compared the efficacy
and safety of three antithrombotic-drug regimens -- aspirin
alone, aspirin and warfarin, and aspirin and ticlopidine -- after
coronary stenting.
Methods: Of 1965 patients who underwent coronary stenting at 50
centers, 1653 (84.1 percent) met angiographic criteria for
successful placement of the stent and were randomly assigned to
one of three regimens: aspirin alone (557 patients), aspirin and
warfarin (550 patients), or aspirin and ticlopidine (546
patients). All clinical events reflecting stent thrombosis were
included in the prespecified primary end point: death,
revascularization of the target lesion, angiographically evident
thrombosis, or myocardial infarction within 30 days.
Results: The primary end point was observed in 38 patients: 20
(3.6 percent) assigned to receive aspirin alone, 15 (2.7 percent)
assigned to receive aspirin and warfarin, and 3 (0.5 percent)
assigned to receive aspirin and ticlopidine (P=0.001 for the
comparison of all three groups). Hemorrhagic complications
occurred in 10 patients (1.8 percent) who received aspirin alone,
34 (6.2 percent) who received aspirin and warfarin, and 30 (5.5
percent) who received aspirin and ticlopidine (P<0.001 for the
comparison of all three groups); the incidence of vascular
surgical complications was 0.4 percent (2 patients), 2.0 percent
(11 patients), and 2.0 percent (11 patients), respectively
(P=0.02). There were no significant differences in the incidence
of neutropenia or thrombocytopenia (overall incidence, 0.3
percent) among the three treatment groups.
Conclusions: As compared with aspirin alone and a combination of
aspirin and warfarin, treatment with aspirin and ticlopidine
resulted in a lower rate of stent thrombosis, although there were
more hemorrhagic complications than with aspirin alone. After
coronary stenting, aspirin and ticlopidine should be considered
for the prevention of the serious complication of stent
thrombosis.
The hidden epidemic of cardiovascular disease
Source: Lancet 1998;352(9143):1795.
Ask any doctor what the leading cause of death is in developing
countries and the answer will be predictable and
correct--infection, specifically of the lower respiratory tract.
The surprise comes when you report the second commonest cause of
death: ischaemic heart disease. Of the 50 million people who died
in 1990, 6?3 million succumbed to coronary disease, 57% of whom
lived in developing nations.
Why? The reason is the health transition that is sweeping the
developing world. Demographic changes are driving up numbers of
older people in the population. According to the latest UN
figures, the number of older people (aged 60 years or more) in
less developed countries will increase from 171 million in 1998
to 1594 million by 2050. There are also changes in underlying
health determinants--eg, increases in smoking, cholesterol, and
blood pressure. And improvements in medical care have tended to
focus on treatment rather than prevention, thereby failing to
tackle the epidemic of heart disease at its root cause.
Can anything be done to make a difference? Inevitably, leadership
from WHO is crucial to any global effort. Gro Harlem Brundtland,
WHO's new Director-General, has already made a striking early
impact in Geneva. Her two high-profile cabinet projects are the
Roll-Back Malaria campaign and the Tobacco Free Initiative (TFI).
TFI is a key component of any strategy to tackle heart disease.
But by itself, TFI is not enough.
The cardiovascular diseases programme at WHO began in 1959, but
it was only in 1973 that a fully integrated community-based plan
was introduced to include the developing world. The need for
reliable epidemiological data was the priority but research and
training in cardiovascular disease prevention were additional
goals. Despite these early efforts, which have continued at a low
level for more than 20 years, the widely accepted view is that
they have not been sufficient.
With WHO only at the margins of this debate, the US Institute of
Medicine's initiative on "Control of Cardiovascular Diseases
in Developing Countries", published earlier this year, was
especially welcome. The report concluded that cardiovascular risk
factor prevention and low-cost management were feasible. But
calculation of the precise magnitude of the cardiovascular
epidemic remains an essential prerequisite before population-wide
strategies for prevention can be considered.
A limitation to the bold programme set out by the Institute of
Medicine is the lack of national capacities for research and
development. WHO, together with non-governmental organisations,
must help to develop local research cultures. One organisation is
singled out for special praise by the Institute of Medicine.
"The International Clinical Epidemiology Network (INCLEN)
has a training program for clinical researchers, social
scientists, statisticians, and health economists from selected
academic institutions in developing countries. Although it is not
specifically directed to [cardiovascular]-related research, this
program has augmented the capacity for health research in
developing countries through multidisciplinary and international
collaboration." For instance, more than 450 INCLEN-trained
fellows have conducted research in 24 developing countries,
including multicountry investigations of heart disease.
INCLEN was founded in 1980 and has depended on the commitment of
the Rockefeller Foundation for much of its funding ever since. In
recent years, INCLEN has raised US$10 million from other sources
for research and training. However, INCLEN's future is now
threatened as Rockefeller rethinks its spending strategy under
new leadership. No organisation should expect continued support
without proving its value. But INCLEN has repeatedly shown that
its concerns with individual and population perspectives,
cost-effectiveness, and the social determinants of health and
disease make it an important part of the Institute of Medicine's
vision. We hope that the Rockefeller Foundation will soon
reaffirm its financial
support for INCLEN at a vital moment in the history of health
care in the developing world.
Finally, WHO must reclaim the lead by making cardiovascular
disease its third cabinet-level project. By doing so, Brundtland
would signal a shift in her long-term agenda to meet the needs of
developing countries, not only now but also well into the next
century.
Recombinant human nerve growth factor in the
treatment of diabetic polyneuropathy. NGF Study Group.
Source: Neurology 1998 Sep;51(3):695-702
BACKGROUND: Preclinical studies have demonstrated that nerve
growth factor may prevent or reverse peripheral neuropathy. We
have therefore tested the effects of recombinant human nerve
growth factor in patients with diabetic polyneuropathy.
METHODS: A total of 250 patients with symptomatic diabetic polyneuropathy randomly received either placebo or one of two doses of recombinant human nerve growth factor for 6 months. Patients were assessed for symptoms and signs of polyneuropathy before and after treatment. RESULTS: Compared with placebo, recombinant human nerve growth factor led to significant improvement after 6 months of treatment, as measured by the sensory component of the neurologic examination, two quantitative sensory tests, and the impression of most subjects that their neuropathy had improved. Three prospectively identified multiple endpoint analyses indicated improvements in the nerve growth factor treatment groups over the placebo group in all three analyses (p = 0.032; p = 0.008; p = 0.005). Recombinant human nerve growth factor was well tolerated, with injection site discomfort reported as the most frequent adverse event.
CONCLUSIONS: Recombinant human nerve growth factor appears to be safe and shows preliminary evidence of efficacy in patients with symptomatic diabetic polyneuropathy.
Nerve Growth Factor promising in diabetic neuropathy (Lancet 1998;352(9133):1039.)
Results from the first randomised trial
of recombinant human nerve growth factor (rhNGF) in diabetic
neuropathy suggest that the therapy is safe and may prevent onset
and progression of neuropathy, says lead author Stuart Apfel
(Albert Einstein College of Medicine, New York, NY, USA).
"Our results are very exciting because right now we only
have palliative treatment--nothing to help the nerves become more
resistant to injury and function better". But, warns Apfel,
everything will depend on the results of European and US phase
III trials now underway.
In the US phase II study, 250 patients with symptomatic diabetic
neuropathy received either placebo or rhNGF 0?1 ?g/kg or 0?3
?g/kg three times a week for 6 months via self-administered
subcutaneous injection. Improved response to heat and cold, and
trends toward improvement in other sensations, were seen in
treated patients. 75% of patients given rhNGF but only 49%
patients given placebo reported symptom improvement, suggesting
"a beneficial effect of rhNGF overall". The authors
acknowledge, however, a major drawback in their study, namely,
that it became unblinded because of injection site reactions.
This led most
patients--and the investigators examining them--to correctly
guess who was receiving rhNGF.
Clinical trials in developing countries:
scientific and ethical issues
Source: Medical Journal of Australia 1998; 169:545-548.
Introduction:
Controversy over AIDS clinical trials in developing countries has galvanised public attention and divided the medical research community.The trials in question, in sub-Saharan Africa and Thailand, use randomised, placebo-controlled methods to test the effectiveness of interventions in preventing perinatal transmission of human immunodeficiency virus (HIV).At least nine of these trials have received US government funding through the Centers for Disease Control (CDC) or National Institutes of Health (NIH), while five are funded by other foreign governments, and one by the United Nations Program on AIDS (UNAIDS).
Debate was sparked in September 1997 by an article and an editorial in the New England Journal of Medicine. The editorial likened the trials to the notorious Tuskegee study of untreated syphilis (1938-1972), a US government study that continued to follow the natural progression of syphilis in a cohort of poor African American males long after penicillin became widely available. This comparison prompted two prominent members of the journal's editorial board to resign, and drew a rebuttal from the CDC and NIH.
In October 1997, investigators discontinued use of placebos in an NIH-funded study of two short-course zidovudine regimens in Ethiopia.Then, in February 1998, the CDC and the Thai government announced that their placebo-controlled study of a short-course zidovudine regimen in Thailand had shown a 51% reduction in perinatal HIV transmission rates.At the same time, they announced that further use of placebos would cease in both this study and another in Cote d'Ivoire.The CDC, NIH, UNAIDS, and France's National Agency for AIDS Research (ANRS) have called for international dialogue on the "far-reaching scientific and policy implications of these findings".
Nonetheless, a range of other foreign-sponsored clinical trials continue in developing countries, as does the debate about their ethics. To date, this debate appears to have generated more heat than light: the lines of arguments are often unclear, and it is difficult to isolate the central points of disagreement. For example, both critics and defenders of the trials claimed that the Thai findings vindicated their respective positions.In this article, we outline the main arguments and propose a framework for analysing some of the scientific and ethical issues.
The arguments:
The critics' main objection to the trials is that investigators withhold an effective therapy from women and children who are randomised into control arms. Deprivation of a therapy known to be effective, albeit in an intensive and expensive form, has been construed as "ethical relativism". It is argued that this violates the principle that protections given to human subjects abroad should be "no less exacting" than those given in sponsoring countries. Two similar studies under way in the US gave all participants access to zidovudine and other antiretroviral drugs.
Arguments from defenders of the trials are interrelated, but may be divided roughly into three categories:
More ardent defenders combine strands of difference and process arguments and caution against an "imperialism" that would second-guess the willing participation of individuals in the developing world.
Ethical Principles in international human research
A decade ago, Marcia Angell (now Executive Editor of the New England Journal of Medicine) asked whether ethical standards should be "substantially the same everywhere, or is it inevitable that they differ from region to region, reflecting local beliefs and custom?" Today it is widely accepted that all research subjects are entitled to minimum guarantees that are transnational and non-negotiable. Realisation of these entitlements is, of course, a separate matter. However, institutional mechanisms for promulgating and applying human subject protections have advanced considerably, hurried on by several scandals and major public inquiries. Many countries, including Australia, New Zealand, and the United States, use formal ethics review committees and similar criteria to evaluate any government-funded study involving human subjects, wherever and however it is conducted.
Among the minimum guarantees, formalised in the World Health Organization's Declaration of Helsinki and reiterated in guidelines promulgated by governments and institutions, are:
When investigators from one country conduct research in another country, it is appropriate to add to this list of minimum guarantees the requirement that:
However, determining whether such benefits are likely to accrue can be problematic, because researchers and government officials in the host country will often have a vested interest in ensuring that the research proceeds.
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