Is it true that 9 out of 10 therapies that work in rats aren't applicable too humans?

[Eric.S]

If this is true this is yet another rediculous standard set by researchers? I remember reading this. What a waste of time and effort. If the rat model isn't an effective model for humans, Why use it? How can such smart men and women be so inefficient?

[Wise Young]

Originally Posted by Eric.S

If this is true this is yet another rediculous standard set by researchers? I remember reading this. What a waste of time and effort. If the rat model isn't an effective model for humans, Why use it? How can such smart men and women be so inefficient?

It is not true for three reasons. You should use your common sense to challenge such stupid statements...

Very few treatments that have been shown to be effective in rats have ever gone through clinical trials. One that did go through was methylprednisolone and that was shown to be effective in humans. Incidentally, those doctors who say that it is not effective have no credible evidence that this is so. Very few other trials have been carried out to test therapies and certainly none of that have reached phase 3 (which is the clinical trial that assess a treatment for efficacy.

Let's look at *all* the other therapies that have gone through clinical trials in the past three decades.
• Activated macrophages. This was the Proneuron trial. It showed some promise in phase 1 trials. The company ran out of money and stopped the trials.
• Diacrin pig fetal cell transplants. The treatment was tried in 10 patients, not a sufficient number of show treatment effects. It was also, to my knowledge, never tested in rat spinal cord injury models (or any kind of spinal cord injury model).
• Fampridine. This treatment was very difficult to test in spinal cord injury because because only about a third of patients who had spinal cord injury have enough axons with demyelination to benefit from the therapy. Because the benefits differ depending on what unmyelinated axons the patients have, fampridine has different effects on patients. Some may have better walking, others have better sexual function, still others have better recovery of bowel or bladder function. If you chose one of the outcome measures as the primary outcome, it would show up only in a third or fewer of the patients. For that reason, Acorda Therapeutics chose spasticity as its primary outcome measure. One phase 3 trials showed nearly significant effects but a second phase 3 trial did not show significance. In both trials, baclofen was allowed and fampridine was added on top of baclofen. Note that when Fampridine was tested in patients with multiple sclerosis, the trials showed statistically very significant effects. This is because MS is a demyelinating disease and more patients with MS will respond. However, the FDA is now warming up to the idea of allowing responder analysis, i.e. a system where one can identify drug responders and then test them using a double-blind randomized protocol. I think that another cinical trial is necessary for spinal cord injury, using drug responders and then testing them with a blinded protocol.
• HP184. This is a drug from Aventis that has a similar effect as Fampridine. The results of their trial was never published. In any case, one assumes that the trial results were negative (or else they would have trumpeted it all over the news). It seems that the same thing happened to them as to Acorda. So, Aventis is now testing HP184 in multiple sclerosis.
• Alternating electrical current. This was tested done in dogs and guinea pigs, so I am not sure whether this counts. However, a phase 1 trial in humans have shown some improvement. A double-blind randomized controlled trial is needed to establish the efficacy of the treatment.
• Cethrin. This drug was tested in rats and showed promise in human phase 2 trials. Some 36% of the patients treated with Cethrin recovered more sensation and more function expected. However, this needs to be tested a double-blind randomized controlled trial.
• Noto antibody. This drug has been extensively tested in rats and phase 1/2 trials are showing promising effects. About a third to half of the patients with ASIA A are recover more than expected. As in the case of Cethrin, this treatment needs to be tested in a double-blind randomized controlled trial.

In a lot of cases, the human clinical trials are not doing the right things. For example, the OEG treatments applied by Hongyun Huang are not relevant because he did not use cyclosporin to prevent immune rejection of the cells and we know from the rat experiments that heterografts of the cells (from one individual to another) would be rejected if immunosuppression were not used.

In some cases, I question whether the rat studies were any good. For example, an early study by researchers suggested that umbilical cord blood cells may be beneficial in rat spinal cord injury. This study used intravenous and intrathecal injection of the cells without immunosuppression and claimed that it restored walking. Nobody was able to replicate the work. This was not a group with any experience doing spinal cord injury research before. In any case, there has never been a rigorous human clinical trial of umbilical cord blood cells. We will be doing the first.

In some cases, the treatments that have been tested in clinical trials were not tested in any rat spinal cord injury model. For example, neither Fampridine nor HP 184 were tested in rats with chronic spinal cord injury. Several therapies have shown positive results in animal studies have been shown to have some beneficial effects in phase 1 and 2 human trials, i.e. alternating current, cethrin, and anti-nogo antibody.

Finally, there are many different kinds of rat models and some are not very good. You should be very skeptical of any study that reports locomotor recovery in hemisected rats. Hemisection is an "incomplete" spinal cord injury. Just like in humans, all rats tend to recover walking from hemisection (unless the hemisection was so bad that it damaged both sides of the spinal cord). Sometimes, if you test the animals very early after the treatment, a significant difference between treatment and control may occur because a treatment might make a diffference is the recovery rate. However, if you wait a couple of week, all the rats walk.

Wise.

[Eric.S]

I tried to find the article that I read that stated my original comment but couldn't find it. What I did come across a lot was peta type organizations that stated 92 out of 100 animal tests that work on animals fail in humans. I could never find a link or resource for this statement but it was pretty common. Is this just false or is there some unmentioned factor thats causing the gap between there data and yours..

[Wise Young]

Originally Posted by Eric.S

I tried to find the article that I read that stated my original comment but couldn't find it. What I did come across a lot was peta type organizations that stated 92 out of 100 animal tests that work on animals fail in humans. I could never find a link or resource for this statement but it was pretty common. Is this just false or is there some unmentioned factor thats causing the gap between there data and yours..

I would like to see any "data" from PETA. Their goal is to stop all animal research, all hunting, and all animal use, including pets. They have a long history of providing misleading information to further their goals.

There are some areas of research where the animal results have not been predictive of human clinical trials. Believe me, when this happens, the scientific peer reviewers take notice. When there are bad animal models, there is little progress in human therapy.

One very good example is traumatic brain injury. Many of the pathological changes in the human brain result from the size of the brain and the difficulty of creating human-like injuries in smaller animals such as rats. Because of this, many researchers use stroke models to try to model traumatic brain injury. What works in stroke may not work in brain. The long-used model of fluid percussion model for traumatic brain injury did not yield predictive results, leading to more than a decade of failed clinical trials and that model (to my knowledge) has largely been abandoned.

It doesn't take too many examples of failed clinical trials before pharmaceutical companies and clinicians start pointing fingers at the scientists and models.

Wise.

[Eric.S]

So do you think for the most part Rats are a good model? It scares me think that even more time and money has been wasted on a bad model, especially for SCI... Could there be a better model?

[Leif]

The better ‘model’ is to study the spinal cord more. – I agree that clinical trials are important, but so fare we have had the same NOGO for years.

We need more understandings of the cord, by more labs, them to fix it.

The pathway we see now leads to more misery, and none will believe in it.

[paolocipolla]

Originally Posted by Leif

The better ‘model’ is to study the spinal cord more. – I agree that clinical trials are important, but so fare we have had the same NOGO for years.

We need more understandings of the cord, by more labs, them to fix it.

The pathway we see now leads to more misery, and none will believe in it.

Leif,

I think we all agree that we need more basic research on the spinal cord, but I see a big barrier between the labs and the clinical trial. So I think we should have a smooth flow of potential therapies from labs to patients.
Here in Italy we took more than 5 years to start a clinical trial with Epo VS Methilprednisolone and now the clinical trial is going very sloly because there are no money for it and a few spinal unit do not enroll patients just because of money!

[Keith]

My answer to PETA = PEOPLE EAT TASTY ANIMALS,
Time for a venison steak.

[Wise Young]

Originally Posted by Leif

The better ‘model’ is to study the spinal cord more. – I agree that clinical trials are important, but so fare we have had the same NOGO for years.

We need more understandings of the cord, by more labs, them to fix it.

The pathway we see now leads to more misery, and none will believe in it.

Leif,

I hope that we will have some time to spend together in Florence this coming fall. It is really critical that people do *not* go for one extreme or the other, i.e. "stop-the-animal-experiments-and-do-just-clinical trials" or "we-need-only-basic research-because-no-therapy-works".

Both animal studies (preclinical) and clinical trials are essential for progress. Histoy is replete with examples of slow progress in fields where there is no animal model and poor understanding of the disease. For example, for a long time (and even now to some extent), we don't have a good animal model of traumatic brain injury and, as a consequence, we have very few therapeutic candidates for clinical trial in head injury.

Spinal cord injury models are much better than head injury. For example, we have the best standardized and precise spinal cord injury contusion model, as well as uniform outcome measures in the field. People do not have to use the model or the outcome measures (about half don't) but they have access to the model and standardized outcome measures if they need it.

We still don't know which spinal cord injury models are most predictive because so few of the therapies have gone to trial. However, in my opinion, that model is the contusion model. While hemisection and transection models may be useful for answering specific mechanistic questions, they do not represent clinical spinal cord injury and they introduce factors that I believe are mostly irrelevant to human spinal cord injury.

People here have heard me disagree with the concept of "scar" blocking regeneration. I agree that scars may develop in spinal cords that were injured with a penetrating wound. This allows fibroblasts (scar-forming cells) to invade into the spinal cord and form a fibrous scar. However, the vast majority of spinal cords are "contused" or "compressed" and there is only glial proliferation. I object to the use of the word "scar" for glial proliferation, which is necessary for repair of the blood brain barrier.

Both preclinical (animal) and clinical studies are necessary. In general preclinical studies tend to be cheaper than clinical trials. For example, a laboratory can do a year's word of experiments with $300K Euros but this is barely enough to treat 10 patients with a drug, much less surgery and rehabilitation. We now have many therapies that have made animals walk but very few that have actually gone to clinical trial.

I know that there are many people who want to get into clinical trials. This is certainly preferable to their going overseas to clinics that are asking people to pay for experimental therapies that have not been shown to be safe or efficacious for spinal cord injury. While clinical trials have the same risk, I think that is is paramount that people do not get charged for experimental therapies and that each experimental therapy be rigorously evaluated for safety and efficacy. Receiving money for a therapy is a conflict of interest and any doctor or clinic that is dependent on that money will have a hard time being objective about the therapy.

Wise.

[Sue Pendleton]

"However, the FDA is now warming up to the idea of allowing responder analysis, i.e. a system where one can identify drug responders and then test them using a double-blind randomized protocol. I think that another cinical trial is necessary for spinal cord injury, using drug responders and then testing them with a blinded protocol."

Why bother with yet another clinical trial of what already is known to work in some incompletes? It's bad enough that when the FDA is finally handed a drug that preserves or improves function in MS it needs more time to do whatever solely because it's the first drug that doesn't just slow progression....and can be given orally (read cheaper). Is that time so the RABC drug makers can figure out how to keep their profits up and test it in conjunction with their drugs? Yup, sounds like a conspiracy theory from a normally sane individual. But isn't shortening the trial process an abnormal but legally used process when something obviously works and has few side effects?