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Monthly Archives: July 2011
In the early stages of development a new drug must be tested in a series of human clinical trials. The earliest phases of trials aim to assess the safety and tolerance of a drug in human volunteers. In planning such trials you face an obvious question: what initial dosage to use? Of course, you want to do your best to avoid giving human volunteers drugs at dosages that may be harmful to them. So you ask yourself — Is there any way to get some information about safety limits before proceeding with exploratory human studies? Specifically, could data in pre-clinical studies where we expose cell cultures or animals to the drug be used to predict the maximum human tolerance dosage for the drug?
In one classic study, Freireich et al (1966) performed a quantitative comparison between the toxicity of anti-cancer agents in mouse (and other species such as rats, dogs, and monkey) and the human maximum tolerated dose. All species provided good predictability of human response, but let us look in detail as some data from the mouse.
These investigators measured the dosage (in milligrams per surface area) at which 10% of the mouse population died (so-called lethal-dose 10%, or LD10) and compared that to the maximum tolerance showed by human volunteers. The comparison was done across 18 different anti-cancer drugs. The data are re-plotted below with the x-axis representing the LD10 value in mice and the y-axis the maximum tolerated dosage in humans. The actual data points are the open blue circles and the red line represents the best linear fit.
The correlation coefficient — a measure of association between the mouse and human data — is 0.95. A perfect agreement between mouse and human response would have resulted in value of 1.0. If there was no relationship whatsoever between the two datasets, as claimed by some opponents of animal research, the correlation coefficient would have been near zero. As it turns out, 90% of the variability in the human data is accounted for the mouse data. The likelihood of such figure resulting by chance is less than 1 in a billion. In other words, the association between the mouse and human data is highly significant.
To illustrate the meaning of these numbers consider the following scenario. Assume you are in the possession of this graph and you are asked to volunteer to participate in a clinical trial for a new potential anti-cancer drug which has an LD10 value in mice of 10 mg/m2. Would you be willing accept an initial drug dose of 100 mg/m2? What if the LD10 value of the proposed drug was instead 10000 mg/mm? Would you now be more or less willing to accept participation in a trial with initial drug dose of 100 mg/mm2?
Was the graph useful to you in making a decision about your participation on this clinical trial? Would you rather make your decision based on such data or by flipping a coin? Do you honestly believe the two methods equivalent? Don’t you think it would be important for scientists to obtain such information before proceeding to inject arbitrary doses of a drug in human volunteers?
True, toxicology assessments are not perfect and they can be improved. In fact the methods for the evaluation of novel cancer therapeutics have indeed been improved over the past decades. There is also no doubt that, in this process, we are morally obliged to seek alternatives to the use of animals in drug screening and testing, and work in this area is actively pursued. If such methods can be developed and validated they should be adopted. It should be noted, however, the use of animals in toxicology is arguably one of the least common uses of animals in science. Attempts to equate toxicology testing to the whole enterprise of animal research make no sense at all.
Anyone confronted with the above evidence that continues to argue that in going into a clinical trial “you might as well flip a coin” is simply not credible: pre-clinical trials in cell cultures and animals have predictive power.
Anyone claiming to be in a possession of a theory that proves animals cannot be predictive of human response is wrong — as this position is refuted by the data.
Anyone denying the uncountable contributions of animal research to human health is intellectually dishonest or ignorant of medical history.
One of the goals of Speaking of Research and Pro-Test for Science is to communicate facts and information about the responsible use of animals in biomedical research. A second, equally important goal, is to try to understand the impediments to dialogue and establish a two-way conversation with animal activists and members of the public that are truly interested in an honest and open discussion.
What have we done in this regard?
In 2010 Drs. David Jentsch and Dario Ringach, along the student group Bruins for Animals, organized a discussion panel at UCLA that was considered a good first step at establishing some sort of meaningful dialogue with opponents of animal research. The event was marred by multiple attempts from animal extremists to derail these first efforts to open a conversation. They were unsuccessful.
It is clear that despite much calls for open debate on the use of animals in scientific experimentation some animal extremists do not want such conversation to takes place. As an example, after the panel discussion a local group of animal activists led by Pamelyn Ferdin (wife of Jerry Vlasak, press officer for the Animal Liberation Front) continued their outrageous home demonstrations targeting the very same UCLA faculty that organized the event. This outrageous behavior resulted in a decreased willingness from many among the UCLA community to continue planning additional meetings.
Despite such state of affairs, in Feb 2011 Dr. Ringach and Robert C. Jones (an animal rights philosopher from California State University at Chico and a participant in the our 2010 discussion panel), organized a one-day symposium on the similarities and dissimilarities of human and non-human primate cognition. This was done with the agreement that any ethical debate on animal experimentation must start with clear scientific understanding of what is known about animal minds. The symposium featured a very interesting set of presentations and discussions. Video of this event is available online.
In the last two years Dr. Ringach participated in two debates on the use of animals in research. The first one at the Institute for Human Values in Health Care at the Medical University of South Carolina, where he debated animal rights philosopher Dr. Nathan Nobis. Manuscripts resulting from this symposium will be published by the American Journal of the Medical Sciences shortly. A second debate took place at Rutgers Law School, where he debated animal rights scholar Prof. Gary Francione. A video of this event will also be made available online by Rutgers University in the near future.
We are often asked by colleagues and institutional officials if these efforts have been worthwhile. The results have been mixed. One one hand, despite all the associated problems, these activities have served to establish personal lines of communications with animal activists that are truly willing to listen to the other side, and the public get the message that all those involved in the responsible use of animal research are ready explain their side of the story. On the other hand, these activities have certainly drawn increased threats and violence from animal rights activists that disapprove of civilized engagement. True, such behavior from a minority of animal rights extremists was anticipated. What was not anticipated was the nearly absolute silence from the rest of the animal rights community on this issue.
As the scientific community reflects as a whole on the value of holding such events we cannot help but wonder — where are the animal rights activists and organizations that deplore violence and are interested in an honest and open dialogue? Please step forward and tell us — what have you done to foster dialogue?
Speaking of Research
A once-a-day pill is effective in preventing HIV infection, according to two big new human studies released last week. This could add a preventive pill to the toolkit of HIV prevention, alongside condom use, abstinence, and vaginal microbicides.
Of course, these human trials would not have been possible had the drugs not been first shown to work in animal studies. Both trials were conducted in Africa. In one, conducted in Kenya and Uganda, 4,758 couples where one partner was infected with HIV and the other uninfected took a daily pill containing a mix of tenofovir and emtricitabine, called Truvada, or a placebo. The Truvada pill reduced the infection rate by 73 percent.
In a second study, 1,200 sexually active young adults in Botswana took daily Truvada and their infection rate was 63 percent lower than placebo.
All participants in both studies also received condoms and counseling on HIV prevention. The successful trials follow two other studies. Truvada showed a success rate as high as 90 percent in a trial involving gay men in six countries released last year. But another trial in African women was stopped early because it did not appear to be working – possibly because the participants were not taking their medicine or giving it to others.
Tenofovir, one of the key drugs in the Truvada pill, was also the key ingredient in a microbicidal gel shown to prevent HIV infection in a major trial last year.
So what’s the connection to animal research? These are all large trials conducted in human beings – the gold standard for figuring out if a treatment is going to work or not. But you can’t start handing out pills and intervening in the lives of thousands of people unless you have a pretty good idea that it’s going to work. In the case of tenofovir and other anti-HIV drugs, part of the route from lab bench to clinical trial was through testing in monkeys infected with simian immunodeficiency virus (SIV), the closest known relative to HIV. Success in those monkey experiments meant that tenofovir could go forward – and help save lives around the world.
The British broadsheet newspaper, The Guardian, has a poll on its website about views on animal testing – please go and show your approval for this important tool in the development of modern medicine:
No need to sign up to vote, however you will need to if you intend to leave a comment as well (the more pro-voices heard, the better).
This poll comes on the back of a report which says animal testing in the UK rose by 1% in 2010 – reflecting an increase in previous funding in medical development (in many areas, some of which has been used for research on animals). There were some interesting comments left as well:
yes….and I say this as a vegan
I was completely opposed to animal testing until I visited one of thee facilities and actually dabbled in it myself. The benefits to mankind are massive and without it many drugs and treatments could never have been developed – if we want to advance medical science it is, for now, a necessary evil.
Animal testing is absolutely crucial for drug discovery – every drug on the market today has been tested on animals – it’s both crucial and a legal requirement. Animal testing saves human lives.
All potential new drugs are thoroughly tested on enzymes and cells before they go into an animal, so only compounds which seriously look like they could become a drug go into an animal. Unfortunately, even with all of our present-day knowledge, in vitro testing, and computer simulation, there is still no way of knowing how a drug will behave in a human, so animal models are the best we have, by a long way.
Animal testing in the UK is highly regulated and has some of the highest standards in the World. A home office licence is required for all proceedures.
People who say no to animal testing know nothing about the drug discovery process. Millions of humans lives have been saved as a direct result of animal testing. Anyone who has ever benefited from taking a drug or pharmaceutical product in this country has benefited from animal testing, so is a hypocrite if they object to animal testing.
So show your support, and include your vote.
Research!America, a not-for-profit public education and advocacy alliance, has been polling the public on their views on animal research for the last decade. In 2011, when asking whether people “believe the use of animals in medical research is necessary for progress in human health”, found:
At first, these results may seem positive – twice as many people believe that animal research is necessary as do not. It should be noted that the question asks for a belief about the efficacy of animal research rather than a moral position on it, but it is likely that the results would be close either way. Nonetheless, these seemingly positive results hide a downward trend over the past decade.
The first point of interest is that in 2008, when Research!America stopped providing a “don’t know” option, those who would otherwise claim ignorance have sided against animal research. However, even with the “don’t knows” added to the “no” vote, there has still been a definite rise in those who do not believe that animals are necessary to medical research. With support now dipping below 70% it would seem that it is now more important than ever to ensure that the public is aware about the links between animal research and the medical benefits that they help to develop It is up to scientists, universities and other research institutions to ensure that the media is provided with the information to allow them to include animal research in their stories.
It’s been a little while since I’ve had much free time to devote to blog writing, and I’m only too aware of all the exciting examples of how animal research is advancing medicine. These have ranged from successful development of bronchial thermoplasty for treating severe asthma thanks to studies in dogs, to the launch of clinical trials of embryonic stem cells in the eye disease dry AMD and Stargardt’s macular dystrophy following promising results in mice and rats, to the development in mice of artificial intestines for transplants, among many others.
This morning my attention was caught by an exciting report on the BBC this morning about the first successful transplant of a synthetic windpipe, developed by seeding a scaffold made from a novel nanocomposit polymer with stem cells taken from the patient himself.
This operation was performed by Professor Paolo Macchiarini, who has already performed several successful trachea transplants using a scaffold manufactured from decellularised donor tracheas, a technique that was developed through careful research on animals, as Bianca Summons discussed on this blog back in 2008.
The latest transplant is a further development of that technique, but uses a scaffold constructed from the novel nanocomposit polymer polyhedral oligomeric silsesquioxane-poly(carbonate-urea)urethane (POSS-PCU), developed by a team at University College London led by Professor Alex Seifalian, in place of the decellularised donor trachea. This novel polymer was thoroughly evaluated in sheep over a three year period, where it was found to be biocompatible and non-toxic, showing no evidence of degradation or inflammation, and superior to other polymers used for tissue engineering purposes. This has led to the novel polymer’s evaluation in a range of applications, including heart valves, blood vessels and the artificial trachea reported this morning.
Avoiding a reliance on the availability of a suitible donor trachea gives this new technique a significant advantage over the decellularised trachea approach, and is another great example of how fast the field of tissue engineering is moving.
I do have one complaint, it would have been better if the BBC report and UCL Press release had acknowledged the role of animal research in making this advance possible. Clearly even in the UK there is still some work to be done on that front!