Tuberculosis (TB) is an infectious disease usually caused by the bacterium Mycobacterium tuberculosis. Tuberculosis generally affects the lungs, but can also affect other parts of the body. According to Mayo Clinic, the bacteria that cause tuberculosis are spread from one person to another through tiny droplets released into the air via coughs and sneezes.
“Once rare in developed countries, tuberculosis infections began increasing in 1985, partly because of the emergence of HIV, the virus that causes AIDS. HIV weakens a person’s immune system so it can’t fight the TB germs. In the United States, because of stronger control programs, tuberculosis began to decrease again in 1993, but remains a concern.”
Dr Deborah Cohen, the BMJ’s Associate Editor led the investigation, which revealed the “pick and mix” approach to animal research, raising wider questions about unaccountable regulatory decision making, a lack of oversight and transparence, and lack of clarity about what data are required when one moves from preclinical animal studies to clinical human trials.
In clinical medicine, clinical trial registries help prevent selective presentation of evidence. However there is no comparable mechanism for preclinical evidence.
Experts thus warn that this investigation comprises just one example of “a systematic failure” afflicting preclinical research and call for urgent action
“to make animal research more fit for purpose as a valuable and reliable forerunner to clinical research in humans.”
The BMJ investigation is centred on MVA85A, a vaccine developed by researchers at Oxford University to boost the effectiveness of the BCG vaccine and provide extra protection against tuberculosis. The vaccine was reported to have been shown to be effective in animal studies. However, it did not prove beneficial when tested in a large clinical trial in South African infants in 2009.
This apparent disparity between the animal and human results has prompted major funders of TB research to rethink their funding priorities. Allegations have been made insisting that this debacle has slowed progress in the entire field. However, an independent systematic review in 2015 concluded that the results of the animal studies had been overstated.
Moreover, it appears that while the clinical trial was in the late stages of preparation, a study in monkeys ought to have raised doubts about the effectiveness of MVA85A. Despite the monkey study being too small to draw firm conclusions, the results sparked concerns in academic circles.
However several months after the monkey study had ended, these results were not included in information submitted to regulators for approval and funding of human trials of MVA85A. Oxford researchers publicly relied on claims that the vaccine had been shown to be safe and effective in animal studies, yet played down their significance when speaking privately.
The BMJ investigation also shows the difficulties in obtaining basic information, such as the study protocol and the application for ethical approval to conduct the study, leaving questions about the exact purpose of the monkey study unanswered.
According to Jonathan Kimmelman, Associate Professor in the Biomedical Ethics Unit at McGill University in Canada, this is not an isolated case.
“It’s widely recognised that animal studies intended to support drug development are often riddled with flaws in design and reporting. But it sometimes feels as if regulators and ethics committees missed the memo. Unfortunately, there are other cases where new treatments were put into human testing on animal evidence that was foreseeably flawed, incomplete, or even negative, he says.”
In an associated editorial, Malcolm Macleod, Professor of Neurology and Translational Neuroscience at the University of Edinburgh said:
“We need to develop better and more systematic ways to establish when a drug is ready for clinical trials in humans – and importantly, when it is not.”
The story of MVA85A also raises questions about how researchers and institutions respond to criticism, he adds.
“Until our institutions recognise that their core purpose is to produce research of value to society they risk a slow decline in their reputation, and possibly a faster and more serious erosion of public trust in science. In these troubled times that public trust is more important than ever.”
Merel Ritskes-Hoitinga and Kim Wever at the Department for Health Evidence in The Netherlands say
“improvements in the design, registration, reporting, appraisal and transparency of animal studies are urgently needed.”
They call on funders, journals, regulators, academia and ethics committees to lead “a culture change” to realise the potential of animal studies to transform human health.