In More Misrepresentations, Fallacies, and Other Lies. Part I, I addressed propaganda employed by both animal and vivisection activists. I addressed the Intact Systems Argument (ISA) in part II, and now want to address some specific points in Holder’s essay Understanding Adverse Drug Reactions (ADRs). Holder:
Before it [a new drug] 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. (Emphasis added.)
There are several points to be made here. First, some in the vivisection activist community deny that animal models are in fact used to predict human response to drugs and disease. The deniers claim that animal models are used only to generate hypotheses and hence the use of animal models should not be judged based on positive predictive value (PPV) and negative predictive value (NPV). In the above, Holder is clearly saying animal testing prevents unsafe drugs from going to clinical trials and hence animal models are predictive for humans. He is not alone in this. I have addressed such admissions many times, most recently here. This is why I insist that any debate first address the prediction issue. Unless that question is resolved, the vivisection activist will use a version of bait and switch, claiming first that animal models are predictive in general in an attempt to sway the audience into thinking how great animal models must be. But when discussing basic science research, the vivisection activist will reverse his position without acknowledging that he was wrong in previously stating that animal models are predictive modalities. Depending on the audience, the vivisection activist can continue to go back and forth with the mutually incompatible claims.
Second, animal models are not predictive for safety or efficacy. The drug industry has acknowledged this and about the only people who disagree with them are vivisection activists. I have also addressed this many times, for example here.*
Third, the sentence, “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,” implies a distinction without a difference and is reflective of the problem with animal testing in general. A drug can sail though animal tests and still harm or even kill volunteers or patients in clinical trials. The results from the animal tests are simply not predictive for humans regarding the safety of the medication. There is no difference between how safe the drug is for a small group or the entire USA in terms of what the animal tests reveal. However, Holder’s assertion is correct in the sense that because only a small group of people is tested in clinical trials, not every side effect will manifest. Because different genotypes will react differently and more genotypes will be exposed to the drug after its release to the entire population, more side effects will then be seen. But this has nothing to do with animal tests; it is simply representative of the reality that complex systems react differently to perturbations such as drugs. I have addressed the inability of animal models to predict safety/toxicity many times as well.*
Fourth, another problem with the safety/toxicity issue lies in the fact that vivisection activists will at times claim that animal tests protect all patients after a drug is released so they can credit animal models for safe and effective drugs. However, at other times the vivisection activist will make the more modest, and correct, claim that animal tests are really supposed to protect just the volunteers and patients taking the drug during clinical trials. This is done in order to avoid taking responsibility for bad outcomes from drugs. In reality, animal tests protect neither humans in clinical trials nor patients in general. But the lack of consistency on the part of the vivisection activist community allows them to go back and forth as needed for the challenge they are addressing. This is the same thinking that allows some vivisection activists to claim that “no scientist uses animal models as predictive modalities,” while others clearly acknowledge that scientists do in fact so use some animal models. I am happy to address the false and mutually exclusive claims made by vivisection activists but quoting a response of mine to the “they are never used as predictive modalities” argument as a response to the “they predict safety for humans in clinical trials,” is disingenuous.
Holder continues: “Many, many drugs do not pass these animal tests – they are deemed to dangerous or ineffective to be moved on to clinical trials.” Holder is correct. And that's the problem! Because the animal models are not predictive, unsafe drugs go to clinical trials and good drugs never make it to clinical trials. This is the reason the National Cancer Institute has stated that patients have lost cures for cancer because of animal testing. (Gura 1997) Early human testing, as acknowledged by industry, would allow scientists to match genes to effects and side effects thus going a long way toward making personalized medicine a reality, in addition to bringing down the cost of drugs.
Holder: “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) . . .” To begin with, society does not have access to a vast majority of that data. It is proprietary and the drug companies simply do not release it. So any statement such as Holder’s is unfounded. But we do have some data. Horstmann et al. (2005) reviewed 460 Phase I National Cancer Institute trials, of which approximately 25% of the trials were First-In-Man (FIM) trials, involving 11,935 adults that occurred between 1991 and 2002. Horstmann et al found that serious nonfatal effects occurred in 15% of the patients undergoing single chemotherapy, with 58 deaths that were probably treatment-related. (Horstmann et al. 2005; Chapman 2011) Society also has statements from scientists who have worked in the industry and say things like: “If you were to look in [a big company’s] files for testing small-molecule drugs you’d find hundreds of deaths.” (Marshall 2000) Chapman reinforced this stating: “. . . but other incidents of harm [besides TGN1412], even death, to participants in Phase I trials, some then known and others unpublicized, had taken place.” (Chapman 2011) This problem could be solved by starting all dosing trials at 1ng and using microdosing protocols for evaluating the drug, as I explain in a chapter in the book New Insights into Toxicity and Drug Testing, which is due to be released in 2013.
I will continue this discussion in More Misrepresentations, Fallacies, and Other Lies. Part IV.
*For more on these topics, including the prediction issue, see:
Chapman, Audrey R. 2011. "Addressing the Ethical Challenges of First-in-Human Trials." J Clinic Res Bioeth no. 2 (4):113. doi: 10.4172/2155-9627.1000113.
Gura, T. 1997. "Cancer Models: Systems for identifying new drugs are often faulty." Science no. 278 (5340):1041-2.
Horstmann, E., M. S. McCabe, L. Grochow, S. Yamamoto, L. Rubinstein, T. Budd, D. Shoemaker, E. J. Emanuel, and C. Grady. 2005. "Risks and benefits of phase 1 oncology trials, 1991 through 2002." The New England journal of medicine no. 352 (9):895-904. doi: 10.1056/NEJMsa042220.
Marshall, E. 2000. "Gene therapy on trial." Science no. 288 (5468):951-7.