Understanding Adverse Drug Reactions (ADRs)

Looking through some animal rights websites and forums I see the same misconceptions come up again and again on the subject of animal research. The first questions can be paraphrased thus:

“If animal research advances medical science, how come when the animal experiments end and the products go to market, the humans experiments begin?”

There are several reasons why we require both animal and human clinical trials. Animal research plays three roles in research – understanding, development and safety testing – you need to understand how a biological system or a disease works, then you need to model pathologies in order to develop a treatment, and finally you need to ensure that this new treatment is safe.

1. Understanding – we use a variety of techniques to understand the body and its pathologies – we might use cell cultures to understand individual reactions, population studies to find environmental causes, or fMRI to understand effects in the brain. However, it is likely that some animal studies will be needed, or relied upon, at this stage. For instance, if you want to study how the heart works you need a fully functioning one to use – cadavers are no good. Few humans would allow a researcher to open them up and run tests to see how a healthy heart works – so for this we need animals. If you want to understand how a disease works you need to see from the start what happens when a healthy body is attacked by it. It would be unethical to start infecting humans with a disease you couldn’t yet cure – so we use animal models to try and learn how a disease works – how it spreads through the body, what secondary and tertiary effects it has etc.

2. Development – now that we have some pathology in the body we understand we now need to try and treat it. Using all we know about the body, learned from both animal and non-animal methods, scientists can hypothesize as to approach needed in treating – will surgery solve the problem, do we need to give some kind of antibiotic, or is something different required? In this development stage we need a model that can be used to treat. The problem with using humans is that some of the approaches to treatment may be quite novel and we do not want to harm a human. Scientists do not have a 100% clear understanding of how a human body works (not even close) and so it can be difficult to know what the effects, or side effects may be to a treatment. To solve this, we use animals to model the disease. In some cases the treatment may come directly from the animal – for instance Herceptin, a drug for breast cancer, is a (artificially) humanized version of a mouse antibody. Insulin, a lifesaving treatment for Diabetics, was originally made from dogs.

3. Safety Testing – when a research institution comes up with a new treatment it must undergo stringent tests to ensure its safety. Before it is let anywhere near humans it must first pass animal tests to check that it’s not going to cause harm to humans in early stage clinical trials. Animal tests are not there to decide whether a drug is completely safe for market, it is there to check that the drug is safe enough for small, controlled clinical trials. Many, many drugs do not pass these animal tests – they are deemed to dangerous or ineffective to be moved on to clinical trials. To see the clear success of animal safety tests we should consider how rare it is that something goes wrong in a Phase I clinical trial (the first time it is tested in humans) – the only recent disaster Phase I was the 2006 Northwick Park  (in the UK)  disaster of TGN1412. Contrary to activists later claims that profits outweigh law suits, TeGenero, the company responsible for TGN1412, went bankrupt following the disaster. Some scientists have argued that TGN1412 was passed too quickly from animal tests to clinical trials – neither the in vitro nor the animal preclinical studies underaken by TeGenero predicted the adverse response in human volunteers. An official report published by an expert scientific group brought together by the Department of Health mad a series of recommendations to improve the effectiveness on both in vitro and animal tests used to evaluate the safety of new medicines, particularly biological molecules such as TGN1412 which have novel mechanisms of action.  The reports authors acknowledged the importance of animal research to the development of new medicines, writing that:

Animal studies taking due regard of the three ‘Rs’, (refinement, reduction and replacement of animals in testing) remain necessary for many aspects of pre-clinical development of novel agents including testing of ‘off-target’ and ‘on-target’ toxicity and understanding the fundamental biology relevant to a new medicine and its target molecules in the human. Most, if not all, new medicines arise from biological insights gained from well-designed animal studies. The key point we want to make is the importance of deciding what can be learned from animal studies in the pre-clinical development of a new medicine, and what limitations there might be when it comes to predicting the response, and dose-response relationship, in humans.

Even when the drug has passed animal tests to declare they are safe to begin human testing there are many questions – what is the correct dosage? Will the drug be effective in humans? Animal testing will suggest how a drug will react in humans – but it is not a perfect model – just as a drug will react differently in different people. What are the side effects? Some of these may have been discovered in animal tests (and been considered acceptable), but there may be some human only side effects. For this reason we need both the human and animal safety tests before we can release a drug onto the market. We should remember that no drug is released onto the market on the basis of animal tests – but rather on the results of the clinical trials (in humans) which follow.

If animal safety tests work why is it that people still die from adverse side effects?”

Many animal rights activists have fallen into the common mistake of believing that Adverse Drug Reactions (ADRs – essentially “negative side effects”) can be blamed on animal research. The first clear point is that EVERY drug has ADRs. Look in the leaflet that comes with any medicine and you will see things like “may cause drowsiness” – this is an ADR. This does not mean you WILL get this side effect, but because everybody has slightly different DNA, they can produce slightly different effects from a drug. Now lets revisit an earlier point – I’ll put it in bold – no drug is released onto the market on the basis of animal tests – but rather on the results of the clinical trials (in humans) which follow. The implication of this is that even human research cannot ensure every drug is 100% safe. Clinical trials might include several thousand people and show no statistically dangerous effects, but if 80 million prescriptions are given (as was the case for Vioxx) and a fatal side effect affects 1 in 400 (Vioxx again), then this may still cause a tragedy.

Furthermore, many ADRs are known and accepted, even before a drug finishes – or even starts – clinical trials.  Chemotherapy can carry a risk of potentially serious side effects, up to and including death – yet many more cancer-sufferers are likely to die without it – so the risk is worth it. So can we measure the potential harm that drugs are causing? Well between 1997-2000 around 150 novel drugs were approved by the FDA (and many hundreds of non-novel ones). Over the same period only 10 were withdrawn due to potentially dangerous side effects (under 7%).

Side effects of inhaler use can include sore throats and oral thrush

A further point must be made on the scale of prescriptions. The more people that take a drug, the more likely that ADRs will occur, even when it only affects a tiny proportion of the population. Let us consider the following list of medications made possible by animal research. Every year in the US there are:

  • 1,500,000 prescriptions for Erythropoietin, used to treat anaemia
  • 34,000,000 anticoagulants dispensed, this can treat blood clots which are associated with many causes of death e.g. Pulmonary Embolism
  • 95,000,000 prescriptions for asthma inhalers
  • 150,000,000 prescriptions for antibiotics, used to treat infection – the most common of which is Penicillin

Now, sadly, some people have had fatal allergic reactions to asthma medication – but we shouldn’t be throwing the baby out with the bathwater – this medication helps (and often saves) the lives of 15 million asthma sufferers in the US (which disproportionately affects children). However, if there is an ADR associated with asthma medication which affects, say, 1 in 1 million people, then 15 of those asthma suffers may end up negatively affected by the medication.

Overall, the huge majority of us who take medical treatments have no side effects at all. For more serious diseases such as cancer, we go through the treatment aware that the side effects are better than consequences of neglecting treatment. ADRs are not something which are going away any time soon, but to blame animal research for their existence shows a fundamental misunderstanding of what they are.

Tom Holder

One response to “Understanding Adverse Drug Reactions (ADRs)

  1. Vioxx is an interesting case, at the time that the larger clinical trials of Vioxx (e.g. Vigor) were being undertaken the evidence that COX-2 inhibitors might cause thrombosis by suppressing the vasodilator prostacyclin and shifting the prostacyclin/thromboxane balance towards the vasoconstrictor thromboxane was quite limited, though though it got a lot stronger in the 5 years before Vioxx was finally withdrawn.

    Unsurprisingly much of this evidence comes from animal studies, including studies in mice, rats, rabbits and dogs, so there is no basis for a claim that there is any discrepancy between the pro-thrombotic effects of COX-2 inhibitors in humans and their effects in other animals.

    Examples:
    Hennan J.K. Et al. “Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries.”Circulation. 2001 Aug 14;104(7):820-5. PMID: 11502709

    “In celecoxib-treated animals, vasodilation in response to arachidonic acid was reduced significantly compared with controls. CONCLUSIONS: The results indicate important physiological roles for COX-2-derived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased in individuals with underlying inflammatory disorders, including coronary artery disease.”

    The above study was one the first to indicate that COX 2 Inhibitors could lead to an increase in heart attacks. This study was provoked in part by the earlier observation made by scientists using a transgenic mouse model which lacked prostacyclin, that the lack of prostacyclin lead to increased susceptibility to thrombosis.

    Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, Ueno A, Oh-ishi S, Narumiya S.
    Nature. 1997, 388(6643):678-82, PubMed: 9262402

    Prostanoids are a group of bioactive lipids working as local mediators and include D, E, F and I types of prostaglandins (PGs) and thromboxanes. Prostacyclin (PGI2) acts on platelets and blood vessels to inhibit platelet aggregation and to cause vasodilatation, and is thought to be important for vascular homeostasis. Aspirin-like drugs, including indomethacin, which inhibit prostanoid biosynthesis, suppress fever, inflammatory swelling and pain, and interfere with female reproduction, suggesting that prostanoids are involved in these processes, although it is not clear which prostanoid is the endogenous mediator of a particular process. Prostanoids act on seven-transmembrane-domain receptors which are selective for each type. Here we disrupt the gene for the prostacyclin receptor in mice by using homologous recombination. The receptor-deficient mice are viable, reproductive and normotensive. However, their susceptibility to thrombosis is increased, and their inflammatory and pain responses are reduced to the levels observed in indomethacin-treated wild-type mice. Our results establish that prostacyclin is an antithrombotic agent in vivo and provide evidence for its role as a mediator of inflammation and pain.

    A 2003 review cites several other animal studies that demonstrate that COX-2 inhibition may increase thrombosis as a consequence of decreases prostacyclin levels.

    Fitzgerald GA. “COX-2 and beyond: approaches to prostaglandin inhibition in human disease.” Nat Rev Drug Discov 2003; 2: 879-890. PMID: 14668809

    “Systemic hypertensive adverse events have been reported on all COX-2 inhibitors. It is presently unclear whether their incidence differs from what is observed on traditional NSAIDs. Studies in mice indicate that the likelihood that such events might relate to the degree of COX-2 inhibition and the selectivity with which it is attained. The role of COX-2 inhibitors in atherogenesis is complex, reflecting the diverse biology of its products, which differ in predominance amongst the distinct cell types implicated in this condition.”

    Indeed in 2001 Steve Nissen, the cardiologist who was one of those most responsible for identifying the cardiac risk posed by Vioxx and other Cox-2 inhibitors noted in a letter to the Cleveland clinic Journal of Medicine that animal studies indicated that these drugs could increase the risk of heart attack http://www.ccjm.org/content/68/11/963.long

    Ultimately though the effect of Cox-2 inhibitors was subtle (since many people taking it are already in a high risk group for heart attack), and only clearly identified in studies involving large numbers of subjects, or when animal models of heart disease were studied. The cardiotoxic effects of Vioxx were just not detectible in small clinical trials or in standard preclinical animal tests using healthy animals.

    With hindsight it is easy to say that pharmaceutical companies ought to hhave paid more attention to the potential cardiac risks associated with Cox-2 inhibitors, but those risks were only starting to be identified in animal studies when these drugs were already well advanced into human trials. Of course that does not absolve them of all blame, not by a long road, as they certainly should have done more to evaluate the cardiac risks in the post-FDA approval clinical trials that were launched, as by the time these were being completes the evidence from animal studies indicated that there was a risk (though they could not quantify it the was a clinical trial can).

    There are many lessons to be learned from the Vioxx disaster, but one is certainly that in order to identify risks as early as possible there needs to be good communication between laboratory (including animal) and clinical researchers. Had this communication happened in the case of Vioxx it is probable that the drug would have been withdrawn earlier (or its use restricted more fully) and that tens of thousands of lives would have been saved.