Nine out of ten Statistics are taken out of Context

This guest post is by Professor Robin Lovell-Badge, who is head of the division of Stem Cell Biology and Developmental Genetics at the Medical Research Council National Institute for Medical Research in London. This is a very clear and thorough debunking of a common animal rights myth where they suggest that because nine out of ten drugs that pass animal tests still fail to be approved, that animal tests must not work – In this post Prof Lovell-Badge explains the true meaning of these misused and misunderstood statistics. This post is also appearing on other websites including www.understandinganimalresearch.org.uk.

Facts without context

Those opposed to animal research often point out that most drugs that pass the legally required toxicology tests in animals go on to fail in human clinical trials. They then go on to suggest that this shows that animal research does not work, or that it is proof that animals are not accurate models for humans.

However, this is misleading without an understanding of the relevant context and the reasons for the animal safety tests. Ironically, the figures cited by many animal rights activists are actually drawn from industry and are intended to explain the expense of developing safe and useful medicines.

The most frequently used statistics are

  • 90% drugs tested on animals fail” – British Union for the Abolition of Vivisection
  • 92% of drugs fail in clinical trials, having successfully passed through animal studies” – Safer Medicines Trust
  • “In fact according to the FDA’s research, nine out of ten drugs deemed successful in animal tests fail in human clinical trials” – Humane Society International

The main sources of this information come from the US Food and Drug Administration (FDA). In 2006, Mike Leavitt said:

“Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies,” said Health and Human Services Secretary Mike Leavitt.

The 92% statistic comes from an earlier report which showed only 8% of those drugs passing animal testing stages would go on successfully to be FDA approved.

“For example, a new medicinal compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market.” – Challenges and Opportunities Report, FDA, 2004

Are the figures right?

To help break down these statistics, it is useful to look at the success rates at each stage (source). In the diagram below the red percentages show the proportion of drugs that move from one stage to another – so 64% of New Molecular Entities (NMEs – essentially new drugs) will pass the animal tests (preclinical studies) and be moved into Phase 1 clinical trials in humans. Looked another way, animal experiments remove 36% of the potential drugs from moving onto the next stage. This is almost certainly a good thing as it avoids humans being given drugs which are likely to be toxic to them. The percentages at the bottom look at the percentage chance that a drug that has made it to that stage will make it all the way – so of all the drugs that make it to Phase 2 clinical trials, 12% will be approved by the FDA (and 88% will fail).

NME = New Molecular Entity. This means a possible drug that is going through trials.

NME = New Molecular Entity. This means a possible drug that is going through trials.

The first thing to note is of those drugs which pass animal tests, 94% will fail during human clinical trials stages (Phases 1 – 3)*.

* number of drugs which have passed Phase 3 clinical trials ÷ number of drugs which have passed just animal tests = 1.2 ÷ 19.4 = 6.2% of drugs which reach Phase 1 trials are eliminated by Phase 1-3 clinical trials. 100 – 6.2 = 93.8% fail.

So the failure rate is actually higher than even the animal rights organisations suggest (since they are using data from before 2006). Is this damning for animal research?

Consider that of all the drugs which pass Phase 1 clinical trials in humans, 86% will fail in later stage human trials**. Yet, we do not hear activists suggesting that humans are an entirely inappropriate model for drug development (though we should note that one human is not a perfect model for another).

** number of drugs which have passed Phase 3 clinical trials ÷ number of drugs which have passed Phase 1 trials = 1.2 ÷ / 8.6 = 14% of drugs which pass Phase 1 trials are eliminated by Phase 2-3 clinical trials. 100 – 14 = 86% fail.

Facts with context

Here is where it is important to understand a little about the drug development process.

Before the preclinical animal tests there are a large number of pre-preclinical non-animal tests done on all manner of research tools including computer models, automatic screening, cell cultures, microbial studies and more. These methods are used to (relatively) cheaply remove many potentially toxic, or obviously non-starting drugs from reaching the more expensive animal testing stage – greatly reducing the amount of animal research required for a drug to reach market.

So contrary to animal rights claims of alternative methods being better, the truth is that 94% of drugs that pass animal AND non-animal preclinical tests will fail in human tests.

So rather than damn just the animal tests, have animal rights activists managed to damn all of preclinical research? In short, no.

The role of preclinical animal tests is to check if the drug offers any potential therapeutic value and, importantly, if it is safe enough to move to Phase 1 trials in humans. This does not even mean free of all side effects, but to learn whether a drug can safely be given to humans and at what approximate dosage.

If you want to know how truly successful animal tests are, consider that in over 30 years there has not been a single death in a Phase 1 clinical trial in the UK. The last major incident was in 2006 in the Northwick Park trials where 6 people suffered extreme side effects in a Phase 1 clinical trial – though it should be noted that TGN1412 was a very novel type of molecule which was poorly understood. Considering that there are normally over 200 Phase I clinical trials each year in the UK (each involving multiple people), animal testing has been exceptionally effective at keeping dangerous drugs away from people.

Even Phase 1 clinical trials in humans are not intended to check for efficacy, but rather to assess whether a drug is safe enough to be tried in a larger number of patients (who are suffering from an illness the drug is intended to treat).

Furthermore, when a drug is licensed for use, it is on the basis of the clinical trials in humans, not the preclinical animal tests which exist to ensure that a drug is safe enough to move into Phase 1 trials. So when animal rights activists claim that adverse drug reactions can be blamed on animal tests approving the drug, remember that it is the clinical trials in thousands of people which provide the evidence of its safety.

Professor Robin Lovell-Badge

Head of the Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London

10 responses to “Nine out of ten Statistics are taken out of Context

  1. Kevin Elliott

    Good article. If I’ve got my logic sorted out properly, would it be valid to say that “94% of drugs that pass non-animal preclinical tests will fail in human tests”? I’m not opposed to non-animal tests, but they have limits.

  2. Alistair Thompson

    Excellent article. I think that the most important take home message is that animal and non-animal preclinical testing has made clinical trials much safer by eliminating unsafe and toxic candidate compounds. I do not think that many people would be willing to take part in clinical trials if a compound had not been extensively tested on animals first. I certainly wouldn’t.

  3. Good informative article, which clearly conveys the facts about requirements of animal research to animal activist, who are opposing it. As on date there are no complete alternatives available to replace overall animal experiments in new drug development process.

  4. It seems a bit out of sorts to avoid acknowledging that animal rights groups frequently cite this figure as a reason for exploring additional methodologies of drug development beyond the approach that has yielded the not-exciting 94% failure rate. It’s not so much that an alternative is better because of this scary number, it’s that there’s generally not an alternative for the whole of preclinical testing so we’re left with this scary number. And that is a real issue: how do we develop a system that doesn’t result in such a high failure rate when the cost of putting a candidate drug through the system is so incredibly expensive. Once to market, too, authorised drugs continue to cause adverse effects in the humans who consume them, the tracking of which are still as imperfect as the drug development process. In that regard, it is disingenuous to say that animal testing has saved consumers from grievous harm because so few people have died during the clinical trials themselves. And this I add as an epidemiologist on the adverse event tracking side of the equation.

    • animal tests remove dangerous drugs from reaching stages at which their adverse or toxciological effects would result in much human suffering. It doesn’t save all consumers – but that’s not it’s job.

      • It’s hard to say definitively what it’s job is, since the regulations on the matter simply say that tests systems need to reliably define a compound’s purity, potency, safety and efficacy. It gets more complicated when the entity in question is a biological or biosimilar. Nevertheless, the actual aims to a preclinical study aren’t set in stone and are typically determined (in the U.S.) in consultation between the FDA and the company hoping to begin a clinical trial. For instance, “sponsors may request to meet with FDA-reviewing officials early in the drug development process to review and reach agreement on the design of necessary preclinical and clinical studies… The primary purpose of this meeting is to review and reach agreement on the design of animal studies needed to initiate human testing,” as outlined in 21 CFR 312.82. Animal tests are one component of a suite of preclinical tests that are applied for this purpose. A more proper wording of the idea you reference is that animal tests and many other tests remove dangerous drugs from causing human suffering in clinical trials.

        And yet, nevertheless, the whole shebang isn’t very good at identifying the good drugs in the mix, which is most certainly a goal of preclinical testing. I hope we can at least agree that the ideal is to move toward systems that are better than the status quo.

  5. “Yet, we do not hear activists suggesting that humans are an entirely inappropriate model for drug development (though we should note that one human is not a perfect model for another).” As an aside, I think this is part of the larger point: humans voluntarily participate in clinical trials. Let’s please avoid demonising the other side for having a position, and let’s also avoid our own games of toying with context and characterization.

  6. I’ll say, lastly, that the potency of this 94% figure is that, no matter how many drugs then go on to fail in the human stages of testing, the central point is that any candidate drug must in every instance demonstrate some adequate measure of safety in animal models before advancing to human systems. The process itself is arranged in a way that requires compatibility with a non-human system, which is something that the field (especially via epidemiology and toxicology) has long recognized as a poor approach to identifying novel medicines. It also begs the question of what candidates have been failed out of development because of animal model data that could have beneficial effects in humans? I look forward to regulatory options in the future for industry to be able to retest promising candidates in this group in an approach that is fundamentally more human-like, as I expect there are sound therapies that emerge.

    Apologies for the sequential comments!

  7. The funniest thing is the failure to realize that a negative correlation is *just as useful* as a positive correlation. If we, counterfactually, take their claims as intended*; then we ought to still test on animals and throw away those compounds that pass, instead of those that fail.

    * That animal testing has a 90% success rate.

    • Just to add, the true success rate is “0.1(P +Animal) + P(- Human|- Animal)”. Where P(+ Animal) is the probability that a drug passes animal trials and P(- Human|- Animal) is the probability that a drug fails human trails given that it failed animal trials.