One example of this that I have heard about has been thalidomide. Thalidomide was used to treat nausea and morning sickness in pregnant women in the 1950’s. Previous studies in mice showed that thalidomide was not a risk in mice, but it is in humans. It caused limb deformities/absence and phocomelia in the unborn babies and was withdrawn from the market in 1961. The mechanism of action was and is still not well understood. In this case, animal models were not an ideal representation of possible risks. Furthermore, thalidomide is used in healthy, non-pregnant patients to treat a variety of conditions such as erythema nodosum, leprosy, actinic prurigo, cancer, and HIV. It was unknown that it could have a negative effect on embryonic development at that time and previous data could not indicate the possible risk. Oftentimes, with these risks and outcomes, there are lawsuits that allow the patient to have some kind of compensation for their loss.

Hi All,

I found that interesting as well. I believe the partial answer to your question is that there are unexpected results sometimes, even if extensive animal trials have been done. There can be cases where we would expect certain side effect, but in reality, they are much worse than first thought.

I looked up to see if there were any recent cases of this occurring and found a case from a little over a year ago. A new painkiller was in clinical trials after undergoing pre-clinical trials on animals. It was a trial done on six patients, and all faced severe side-effects with one being brain-dead. There was a number of investigations launched into this accident, but I was unable to find the outcome. However I think it is clear from this case that when these accidents do occur, the company needs to ensure they followed all guidelines for proper clinical trials.

Source: http://www.sciencemag.org/news/2016/01/more-details-emerge-fateful-french-drug-trial

-Andrew Nashed

Both of the cases provided above are great representation of a clinical trial going wrong. Companies before reaching the clinical trial stage, they make sure the pre-clinical trials are successful and the device is effective. Also, the company makes sure to allocate enough budget just in case the unexpected results occur and is able to compensate the patients accordingly. This is not the goal of course but it is something that needs to be planned. In addition, there are instances that even during the clinical trials there are no unexpected results but once the product reaches the market, the side effects start to surface. This can be due to having a larger population than from the clinical trials and the issues have a greater chance to occur.

It's really hard to have a animal study fully represent the potential effects of a drug/medical device within a human. There are so many variables within a human that can drastically effect how the drug/medical device will respond or more importantly how those items will effect the body. In the case where unexpected results occur, there could be a chance that the clinical trial is stopped, if the results are unfavorable to the study. As luisa mentioned above, budget fluctuation can increase efforts to address unexpected results, and compensate patients that were effected. In addition, there should be a level or risk included into a budget to compensate potential negative effects that the new product could have on patients when the product is released into the market.

Hi All,

I believe that all of you have touched upon very valuable points. I would like to emphasize that pre-clinical trials (animal trials) are not a safety indicator for many devices. For example, Inhalation devices are not usually tested on animals due to the different anatomical properties between humans and animals. In the case of death being one of the potential harms of the clinical study, the manufacturer and/or study sponsor should ensure that all risk management processes have been implemented in order to reduce such risk to the lowest possible case. If that risk cannot be eliminated or reduced, the manufacturer can do a risk/benefit analysis to determine if the benefits of the product outweighs the risk of death.

I would like to answer the original question and add the points about general clinical trials without the animal studies that have not been mentioned.
"how can you possibly predict that beforehand"? we don't. There can always be an unforeseeable risk that we hope it will not be there. In all the studies that I have worked in, there was always this line in the consent form. All clinical studies I participated in weren't required to have animal study because the risk was minimal and the animal model was not appropriate/translatable. Although we always include the may-seem-rare risk that can happen (for example subject has to stand so there's a fall risk), there can always be other risk lurking around so we just have to be cautious with each step of the process.

As the previous commentator mentioned previously, it is difficult to predict adverse effects of a product using collected data from pre-clinical trials. Indeed, pre-clinical trials holds value but it can only be represented to a certain point before reaching into the "grey area" in terms of the product having human risk. Previously mentioned, companies attempt to ensure that clinical trials are conducted successfully but even so, it was seen by previous cases that human risk is still present. Companies try to forecast this potential risk when testing new products, a budget is set aside to compensate the affected patients, indeed the informed consent does cover the company legally to a certain degree. This would explain why companies always must disclose any side-affects once a drug is passed and released, because there is always a risk in any drug.

CAR-T therapy is an upcoming cellular therapy to treat cancer. It has been recently shown to be successful with ALL patients. However, this wasn't the case in July 2016 Leukemia CAR-T trials. Three adult leukemia patients died in a trial of a new cellular-level medicine, CAR-T. Patients experienced cerebral edema. The sponsoring medical professionals were from Juno. Although, they argued that cerebral edema is an expected reaction to these types of patients, but the trials were halted and in under FDA review.

Clinical trials help doctors to assess if the new medicine is more effective or safer than old medicines or treatments, and to determine the correct dosage of the medicine. Terrible things do happen as indicated by the incident in France and another recent well-publicized case of six healthy men experiencing organ failure after taking a research drug in London’s Northwick Park Hospital. Some volunteers have received confidential compensation payments. The purpose of the clinical trials is to see what unexpected side effects emerge, and how severe or common they are. So as well as experiencing the benefits of a new medicine, there may also be side effects for some people.In company sponsored clinical trials, compensation should be available for participants who suffer personal injury (including death) caused by participation in clinical trials.

If the subject were to undergo unexpected outcomes and no longer wants to take part in the trial, it is up to their discretion to continue or to end their treatment. Informed consent includes consent throughout the entirety of the trial. If at any point the consent is to be withdrawn, the company must respect that. In the event of unexpected or harmful results, the company should evaluate their process and pull back the specific drug or treatment they are testing and refine it and undergo preclinical testing again before bringing it to clinical trials. The original treatment should not be approved.