|
Ups
and downs in drug development
Drug
manufacturers must provide scientifically accurate information,
written in non-technical language, for doctors and patients, says
Dr Krishan Maggon
Among
the responses received to my earlier articles, one of the key points
made was that all ragaglitazar related events were part of a normal
drug development process. The ups and down are part of all new drug
development cycles just as in human lives. Very few drugs on the
starting blocks make it to the market. The Indian discovered drugs
must show superior safety and efficacy profile in comparison to
existing drugs as well as drugs in development. There are few if
any absolutes in terms of safety of drugs. Aspirin the best known
and most used is well tolerated by many but poses a risk to some.
Health
and regulatory authorities like the FDA/EMEA, in each instance,
weigh the potential benefits of drugs against the risks that they
carry. For that reason, the safety and effectiveness of drugs is
a relative thing and not a matter of absolute truths. Of course,
even FDA approval is no guarantee of safety and effectiveness. Eight
new drugs approved since the mid-1990s have subsequently been withdrawn
from the market for safety reasons. Seven of these deadly drugs
were covered by David Willman in LA Times articles.
Nonetheless,
the FDA’s review ensures an objective scientific evaluation
of the relative safety of proposed products and the health claims.
The FDA does not approve drugs generally; it approves them for specific
indications. This Glitazone article attempted to provide a balanced
information, written in non-technical language, for doctors and
patients.
Disseminating
critical information
Doctors
are likely to prescribe these drugs inappropriately because they
have not been provided any of this critical information. That could
seriously jeopardize patient health. The frequency of adverse drug
reaction in the FDA/EMEA approved prescribing information is based
on patients treated for 3-6 months only. The rate increases when
data is collected for patients treated with one year, with even
higher incidences expected over longer durations of use.
Physicians
are not qualified to choose drugs for their patients without the
help of experts (FDA/EMEA) in weeding out ineffective drugs and
leaving only drugs whose efficacy has been proven in the market.
The Indian pharmaceutical market or regulatory authorities have
failed to weed out worthless or dangerous drugs, misleadingly promoted
for unsubstantiated uses. Markets do fail, particularly those that
are characterized by imperfect information, such as the pharmaceutical
marketplace in India.
There
is an urgent need for drug manufacturers to provide scientifically
accurate information, written in non-technical language, for doctors
and patients with each new and refill prescription for all prescription
drugs, in the form of Medication Guides approved by the Drug Controller
of India. The standard bioassay protocols currently enlisted to
evaluate cancer-causing chemicals in animal model systems, incorporate
two basic assumptions:
-
A chemical that causes cancer in rats and mice has a high probability
of causing cancer in humans (interspecies extrapolation);
-
Chemicals that cause cancer when administered at high doses will
also cause cancer when administered at low doses (dose extrapolation).
Carcinogenic
tests
The
default assumption is that positive effects in animal cancer studies
indicate that the agent under study can have carcinogenic potential
in humans. Thus, if no adequate human data are present, positive
effects in animal cancer studies are a basis for assessing the carcinogenic
hazard to humans. This assumption is a public health conservative
policy, and it is both appropriate and necessary given that we do
not test for carcinogenicity in humans. The assumption is supported
by the fact that nearly all of the agents known to cause cancer
in humans are carcinogenic in animals in tests with adequate protocols.
Moreover,
almost one-third of human carcinogens were identified subsequent
to animal testing. Further support is provided by research on the
molecular biology of cancer processes, which has shown that the
mechanisms of control of cell growth and differentiation are remarkably
homologous among species and highly conserved in evolution. Cohen
thrust the issue of risk assessment into the limelight with a 1990
paper (S M Cohen, et al, Science, 249:1007,1990).
In
the case of saccharin, which causes bladder tumours in male rats
when administered at high doses, the tumours are linked to the presence
of a protein in urine (au-globulin) to which saccharin binds. The
tumours occur as a regenerative effect following erosion of the
superficial bladder epithelial cells. The erosion is attributed
to a precipitate in the urine generated when saccharin binds to
the protein.
However,
a2u-globulin is specific to male rats and is not present in female
rats, mice, or humans. On the basis of mechanistic considerations
alone, humans are unlikely to develop bladder cancer as a consequence
to exposure of saccharin, even if humans consumed levels as high
as those consumed by the rat (S M Cohen, et al, Chemical Research
in Toxicology, 5:742, 1992). Genotoxic agents cause cancer by interacting
with DNA and affecting the rate of genetic damage. Nongenotoxic
agents cause cell proliferation, increasing the risk of cancer because
with each cell DNA replication cycle there is a small but nonzero
risk of genetic damage (M C Poirier, Chem Res Toxicol, 5:749, 1992).
One
study looks at the levels of dG-C8-ABP, the major DNA adduct produced
by an aromatic amine found in cigarette smoke, 4-aminobiphenyl (4-ABP),
and the concomitant bladder tumour incidences in male mice, compared
with the DNA adducts measured in the bladders of human cigarette
smokers and the increased risk of bladder cancer in male cigarette
smokers. The comparison shows that a 50 per cent bladder tumour
incidence in mice is associated with levels of dG- C8-ABP that are
nearly 200 times higher than those projected
for a 50 per cent bladder tumour incidence in humans.
There
may be instances in which the use of an animal model would identify
a hazard in animals that is not truly a hazard in humans (eg, the
alpha-2u-globulin association with renal neoplasia in male rats
(US EPA, 1991b). The extent to which animal studies
may yield false positive indications for humans is a matter of scientific
debate. To demonstrate that a response in animals is not relevant
to any human situation, adequate data to assess the relevancy issue
must be available. It is recognized that animal studies (and epidemiologic
studies as well) have very low power to detect cancer effects. Detection
of a 10 per cent tumour incidence is generally the limit of power
with currently conducted animal studies.
Differences
in metabolism
There
are important differences between rat metabolism and mouse metabolsm,
so the same mechanism may not apply. In the case of melamine, the
chemical produced bladder tumour in rats linked to bladder stones.
However in mice, it caused inflammation and epithelial hyperplasia
of the urinary bladder in male mice and bladder stones but no tumours.
In female mice only stones were observed without any carcinoma.
The
default is to include benign tumours observed in animal studies
in the assessment of animal tumour incidence if they have the capacity
to progress to the malignancies with which they are associated.
This treats the benign and malignant tumours as representative of
related responses to the test agent, which is scientifically appropriate.
Benign tumours that are not observed to progress to malignancy deserve
attention because they are serious health problems even though they
are not malignant; for instance, benign tumours may be a health
risk because of their effect on the function of a target tissue
such as the brain.
The
trials with ragaglitazar were halted because the mouse tumor could
not
be ignored and the mechanism of its formation is not known. The
press
release by Novo Nordisk pointed that only one mouse developed the
bladder
tumor. But the Novo release makes no mention of dose level and was
it
female or male animal. The company has not released information
about the
incidence of benign tumor or any precancerous cell changes. The
press
release did not mention that one out of ten animalsworks out to
a 10 per
cent incidence, which is the lowest power of detection of carcinogenic
studies. The standard GLP carcinogenic study, requires 50 females
and 50
males mice or rats per group per dose level, however only 10 animals
of each
sex are sacrificed at a predetermined time point. To this the incidence
of
benign tumors if any should be added. If a smaller number of animals
(20
per dose group ie 10 males and 10 females) were used,it may work
out to a
even higher incidence.Millions of patients are expected to take
this drug
for prolonged periods therefore the carcinogenic potential remains
a risk
unless proven otherwise. An inidence of 10% will mean, 100,000 patients
with potential risk of having cancers, out of 1 millions patients
and is a very
significant number. Under the US legal system any patients on the
new drug a confirmed carcinogen in rodents, who develops cancer
is likely to sue and
win class action, product injury and liability awards which may
bankrupt
any drug company. Death, liver failure, heart attacks, cardiac failure
and
cancer are not acceptable side effects for any antidiabetic drugs.
Sara Brudnoy. Pushing For A Paradigm Shift In Cancer Risk Assessment.
The
Scientist 7[5]:14, Mar. 08, 1993
U.S. Environmental Protection Agency, Washington, DC. Proposed Guidelines
for Carcinogen Risk Assessment. EPA/600/P-92/003C. April 1996.
http://www.epa.gov/ORD/WebPubs/carcinogen/carcin.pdf.
|
