Transcript Animal Experimentation in Medical Sciences: Truth on Trial

The Scientific Case Against Animal
Use in Medical Research
John J. Pippin, MD, FACC
Director of Academic Affairs
Physicians Committee for
Responsible Medicine
[email protected]
Animals in Research: HIV-AIDS
 HIV-AIDS vaccine research began in 1983
 About 90 HIV-AIDS vaccines have been successful in
animal tests (mostly nonhuman primates)
 All of more than 200 human trials of these vaccines
have failed to prevent or suppress HIV infection
 NHP research for HIV-AIDS vaccines and treatments
is now widely discredited, yet it continues
Animals in Research: HIV-AIDS
Merck’s much-hyped HIV vaccine (V520)
failed spectacularly in 2007
V520 not only failed to protect, but was
associated with greater HIV risk
An urgent HIV-AIDS summit was held at
NIH in March 2008, led by Dr. Anthony
Fauci, Director of NIAID
Animals in Research: HIV-AIDS
"Despite hundreds and hundreds of millions of
dollars, the reality in 2008 is that an HIV
vaccine clearly remains beyond our grasp."
Warner C. Greene, MD, UCSF
Co-chair, HIV-AIDS Summit
March 2008, Bethesda, MD
Animals in Research: HIV-AIDS
“No ideal model exists that can imitate the natural
history and pathogenesis of HIV infection and
AIDS in the human body, as HIV virus exclusively
infects and causes disease in humans.”
“Further, there is not one documented case
of anyone being truly cured of HIV infection.”
NIAID website (http://www.niaid.nih.gov/topics/hivaids/Pages/Default.aspx)
Animals in Research: Stroke
 More than 700 successful stroke therapies have been
demonstrated in animal tests (mostly rodents)
 More than 150 of these have been tested in humans
 All stroke treatments have failed to improve survival
 After more than five decades of animal research we
still do not have treatments to improve stroke survival
Animals in Research: Stroke
“The repeated failures of laboratory-proven
stroke therapies in humans can be due only
to the inapplicability of animal models to
human cerebral vascular disease.”
Neff S. Stroke 1989;20:699-700
Animals in Research: Cancer
 Cancer research is the highest-cost and lowest-yield
category of animal experimentation for the study and
treatment of human diseases
 At least 95% of cancer drugs safe and effective in animal
tests fail in human trials, due to inefficacy or toxicity
 New approved cancer drugs have modest benefits, usually
measured in extra weeks or months of life in an average of
only 25-30% of patients; cures are virtually nonexistent
The War on Cancer
Where Are We Now?
 Since 1971, more than $100 billion in federal research funds has
been spent on cancer research (mostly on animal research)
 Since 1971, more than $100 billion from pharma, NGOs, and other
sources has been spent on cancer research
 Death rates have declined for some cancer types, due to lifestyle
changes and earlier detection, but not due to treatments
 Overall U.S. cancer death rates have not declined appreciably since
the 1970s (SEER Cancer Statistics)
 The natural history of cancer has been redefined but not
significantly improved by animal research in the last four decades
Animals in Research: Cancer
“The history of cancer research has been a
history of curing cancer in the mouse. We
have cured mice of cancer for decades, and it
simply didn’t work in humans.”
Richard Klausner, M.D., Director,
National Cancer Institute (1995-2001)
(L.A. Times, May 6, 1998)
Animals in Research: Cancer
“Unfortunately our track record shows that far
less than 1 percent of our promising approaches
actually make the grade in patients.”
Bert Vogelstein, MD, Director of the Ludwig Center for Cancer
Genetics and Therapeutics at Johns Hopkins University School
of Medicine, and Howard Hughes Medical Institute researcher
New York Times, June 29, 2009
Animals in Research: Correlations
Between Human and Rodent Cancers
 38 chemicals that cause pancreatic cancer in rodents;
39 chemicals that cause colorectal cancer in rodents
 Review of all these chemicals as human carcinogens
 Results: None of these chemicals is known to cause
pancreatic or colorectal cancers in humans.
 Conclusion: “Rodent pancreatic and colorectal tumors
are not predictive of human responses.”
Card JW, et al. Regulatory Toxicology & Pharmacology 2012;64(3):442-458.
Animals in Research: Diabetes
 At least two dozen diabetes cures have been
demonstrated in animal studies
 All have failed in human clinical trials
 The traditional mouse diabetes model has been
discredited (Cabrera 2006; Vassilopoulos 2009),
and decades of diabetes research is compromised
Animals in Research: SCI (Paralysis)
 More than 20 treatments have cured or ameliorated
acute SCI in animal studies (mostly rodents)
 Every one of 10 RPCTs and many other trials in humans
have shown no benefits for any SCI treatments
 Standard rodent models of SCI are widely discredited
 There are still no effective treatments for SCI
Animals in Research: Poor Translation
101 “highly promising” basic science research
results in six leading journals from 1979-1983
Outcomes tracked through 2002
Only 27 were approved for clinical trials
Only five resulted in approved treatments
Only one was in routine use (ACE inhibitor)
Contopoulos, et al. AJM 2003;114(6):477-84
CONCLUSION: “Even the most promising
findings of basic research take a long time
to translate into clinical experimentation,
and adoption in clinical practice is rare.”
Contopoulos, et al. AJM 2003;114(4):477-84
Summary: Animal Research Compared to
Human Results for Some Major Diseases
Research area
AR success
Human success
HIV-AIDS vaccine
90+ agents
0/200 clinical trials
Stroke treatments
700+ agents
0/150 clinical trials*
Diabetes treatments
24+ cures
No cures
SCI treatments
20+ cures
No cures
Cancer treatments
ubiquitous
Rare, especially cures
____________________________________________________
* rtPA may improve symptoms, but does not improve mortality
Animals in Research
Pharmaceutical Development
and Drug Testing
Pharmaceutical Research in Animals:
Differences in Drug Metabolism
Aspirin plasma half-life is:
 15-20 minutes for humans
 8 minutes for rats
 1 hour for horses
 8 hours for dogs
 40 hours for cats
Aspirin and Birth Defects
In animal studies, aspirin produces birth
defects in mice, rats, guinea pigs, rabbits,
cats, dogs, sheep, and monkeys
Yet aspirin is safe during all stages of
human pregnancy
Pharmaceutical Research in Animals:
Differences in Drug Metabolism
Diazepam metabolism is species-dependent
 Single low doses can cause fatal liver failure in cats
 Very high doses (2-3 mg/kg) may be required to control
seizures in dogs, due to rapid hepatic metabolism
 This dosage would be rapidly lethal if given to humans
Animals in Drug Testing: Vioxx
 8 preclinical Vioxx studies in 6 species showed no
cardiovascular toxicities; some showed benefits
 Post-marketing study in African green monkeys
showed no cardiovascular thrombogenic effects
 60,000 Americans and 140,000 worldwide died of
MI, stroke, and heart failure
 Vioxx was withdrawn by Merck in September 2004
Human and Animal Drug Availability:
The Interspecies Scattergram
Failure Rate of Animal Research
for Drug Development
 96% of drugs safe and effective in animal tests later fail
in human clinical trials (increased from 86% in 1985 and
92% in 2003)
 Of the 4% approved, half are recalled or relabeled for
lethal or severe toxicities not detected in animal tests
 Other drugs lose FDA indications when later shown to
be ineffective (e.g., Avastin, Mylotarg, Iressa, Zetia)
[Data updated 2013 based on reports of stage-specific
clinical trial failure rates: Phase I = 56%; Phase II = 82%;
Phase III = 50%. Cumulative failure rate = 96%]
Failure Rate of Animal Research
for Drug Development
 It takes at least 100 successful animal-tested drugs to
produce one unique, effective, safe drug for patients
 > 90% of FDA-approved drugs work for fewer than
half of patients; on average, only 25-30% of patients
respond favorably to cancer and neurology drugs
Failure Rate of Animal Research
for Drug Development
 Only 1 in 9 FDA-approved drugs since 1960
provides any measureable therapeutic
advantage over previously available drugs
 A new drug that passes animal safety and
efficacy testing is much more likely to harm
than to benefit patients
Light DW. The Risks of Prescription Drugs (2010)
Criticisms of Drug and Chemical
Safety Testing in the U.S.
 National Cancer Institute (1980s)
 Institute of Medicine (January 2007)
 National Research Council (July 2007)
 Science Board of the FDA (November 2007)
 Institute of Medicine (April 2008)
 NIH, EPA, FDA memorandum (2008 – Tox21)
All have adopted or recommended in vitro and
human-based drug and chemical testing methods to
replace animal research
Reliability of Mouse Research for Major
Category of Human Disease: Inflammation
 Comprehensive review for burns, trauma, and sepsis
 Mouse models long thought to be mechanistically
reliable, but clinical translation was almost nil
 Seok et al. compared 4,918 inflammation response
genes in humans and mouse models for all three
inflammatory diseases
Seok, et al. PNAS 2013; 110(9):3507-3512.
Reliability of Mouse Research for Major
Category of Human Disease: Inflammation
 Correlation of gene responses in humans and mice
was “virtually absent”
 Conclusions: (1) “Responses in mice cannot predict
human responses”; (2) “There is no reason to believe
that the correlation would be better in any other
field”; (3) “Focus on the more complex human
conditions rather than relying on mouse models.”
Seok, et al. PNAS 2013; 110(9):3507-3512.