Tag Archives: FDA

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

A new era for embryonic stem cells

As the new president takes office and the scientific community eagerly awaits the announcement of the reversal of the ban on federal funding of most research involving human embryonic stem cells (hESC’s), there’s news that the FDA has approved the first ever trial of a treatment based on hESC’s for severe spinal cord injury.

This is a very welcome development; for a decade now hopes have been raised about the potential for hESC’s to treat a range of serious illnesses, particularly brain and spinal injuries,  but despite excellent work by organizations such as the Christopher and Dana Reeve Foundation no treatments have yet reached clinical trials in patients.  This is not a criticism of hESC’s, underneath the hype is the reality that hESC research is a very new science. After all the first hESC’s were produced by Professor James Thomson and colleagues at the University of Wisconsin-Madison a mere ten years ago, and a lot of work has been necessary to ensure that hESC therapies are safe and effective enough to justify human trials.

The treatment developed by Geron uses a type of cell known as an oligodendrocyte progenitor cell (OPC) that was derived by growing  hESC’s  under carefully controlled conditions. OPC’s  in their turn develop into oligodendrocytes, cells that forms a sheath around the nerve cells and are vital to the proper function of the nervous system.  In rat studies the scientists at Geron showed that OPC treatment could restore the ability to move after severe spinal injury.  Subsequent safety studies in rodents indicated that the injected cells remained within the nervous system and did not produce teratomas, a type of tumour produced by stem cells that have not been adequately processed to ensure they have differentiated into a more mature cell type suitable for transplantation. An important observation made during Geron’s animal studies of OPC therapy was that the therapy worked when the cells were injected 7 days after injury but not when treatment was delayed until 10 months after injury (1) indication that early treatment was vital, and leading to the decision to treat patients 7-14 days after injury in this phase I clinical trial.

If you take a look through the Geron and Christopher and Dana Reeve Foundation websites you will see that there are many other hESC based treatments under development, and appreciate the undeniable importance of animal research to this work. With a new president who appreciates the importance of hESC research we will no doubt see more announcements of this sort, but it’s also worth remembering that animal research is crucial to other types of stem cell research, including the iPS approach we’ve discussed here and other methods we discussed earlier this week on our sister blog in the UK.

Could this be the dawn of a new era in medicine?

Update 21 February 2011: After being put on hold for over a year due to potential problems with cyst formation identified in an animal study, additional animal studies have proved reassuring and the FDA gave its approval for the trial to go ahead. Geron recently announced the enrollment of  the first patient into their phase I study of hESC based therapy for spinal injury.

Regards

Paul Browne

1) Keirstead H.S. et al. “Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury” J Neurosci., Volume 25(19), Pages 4694-4705 (2005) doi:10.1523/JNEUROSCI.0311-05.

2005

92% of statistics are taken out of context…

A better response to the “92%…” argument has been written by Robin Lovell-Badge and can be found on our website here.

I thought I’d dedicate an entire post to a certain statistic which has been repeatedly misused and misunderstood by animal rights groups.

92% of drugs that test successfully in animals fail during human trials

You will find animal rights organizations, such as PETA and PCRM, all using this statistic. Often claiming that this shows that “animal research doesn’t work”.

The statistic is from the FDA (Food and Drug Administration), used to illustrate inefficiencies in drug development. However the actual statistic is much broader, it should be:

92% of drugs fail during human trials

The original quote was:

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

Now it is true that they have passed animal testing to get to human (clinical) trials, but it also means that they have passed non-animal pre-clinical tests, such as in vitro. Consider:

92% of drugs that have successfully passed in vitro tests, fail during human trials

Misleading? Yes. So the next obvious question:

Why do drugs fail at the clinical stage?

Drugs fail clinical trials for two reasons – they don’t work well (lacking efficacy) or they are potentially dangerous. Drugs may fail at different stages of clinical trials – so sometimes a relatively rare, but potentially dangerous side effect turns up late into human trials when many thousands of humans are being used (late in clinical stages many more humans than other animals may have tested the drug – as more people/animals are tested, more side effects are discovered); equally some drugs may simply be ineffective in humans, or ineffective in enough humans (no one wants to release a drug that only works in, say, 30% of people – unless that 30% is a particular and selectable demographic e.g. children), this is bound to be the case since animals are not perfect models for humans, just as humans are not perfect models for other humans (thus why some people get adverse drug reactions and not others).

According to the FDA report, which suggests various improvements to the drug development process, the top area where improvements could be made is to improve the animal models (not remove, but use and improve – they also accept the good track record of animals for finding dangerous chemicals in toxicology tests), with the increase in genetically modified animals allowing us to create better animal models, hopefully we will see that 92% statistic drop.

It is worth highlighting that the FDA says many drugs are failing clinical trials at late stages, meaning that problems with drugs are not becoming clear until they are tested in many people – so it is a mystery as to why the animal rights groups try and put the blame solely on the shoulders of animal research.

What about the benefits of animal safety tests?

Well why DO we use animal safety tests? The 92% statistic ignores all the benefits of safety tests, so:
You have 1000 drugs entering animal safety tests
900 of them fail, of which, say, 20 might actually be safe in humans (false positive).
Of the remaining 100, 92 fail human tests

[The above stats are made up for illustration purposes. Approx 90% of drugs fail at the animal testing stage, and false positives aren't (cannot legally or safely be) measured]

Therefore:

90.5% of dangerous drugs have been kept out of clinical trials thanks to animal safety tests**

(However 92%of drugs have still failed clinical trials)

**[[Dangerous Drugs removed by animal safety tests]] / [[Total number of dangerous drugs]] = [[880/972]]

We can see that the lower statistic makes no mention of the benefits of animal safety tests made clear by the top statistic.

It is worth noting that around 90% of drugs are removed at every stage of safety tests, i.e. 90% are removed at non-animal pre-clinical safety tests, 90% at animal stages, and 90% during human clinical trials.

Check back on the website for more AR debunking!

Cheers

Tom