Hi,

One of the key elements of preclinical works on new drugs is their low or no toxicity. If it is not confirmed with certainty in the preclinical part, the risk of using them in humans is enormous. As you know, the gaps in the toxicity analysis of drug candidates even led to death in first in man studies ( for example TGN1412).

Summarising, the key conclusion from preclinical studies is whether the active substance is safe for humans, and not whether its mechanism of action in humans will be confirmed similarly to findings from the preclinical phase. It's the message.

This is why we cant as you said "expecting successful data in clinical trials although of failure in preclinical studies" because most of the problems in the preclinical phase and problems with entry to the clinical phase cover safety issues, tolerance, and toxicity of the candidate.

The success of entering the clinical phase is not only related to potency in terms of pharmacotherapy and clinical effects. As we know, the adverse drug reactions panel may be completely unacceptable and it may turn out that the share of benefits in relation to the losses suffered is deeply disproportionate.

Best regards

Tomasz

Hello

It is not possible I would say. Any candidate drug or molecule has to be first tested for its toxicity and efficacy in vitro (using cell lines) and invivo (animal studies).

The data obtained from in vitro studies will provide information on the efficacy of the drug candidate to a certain extent. It is then followed by invivo studies to confirm the efficacy and determine the LD50 value. The toxicity studies in animals will provide vital information on the toxic effects of the drug, and will be a deciding point whether to go ahead with the clinical trial.

Without having any information on a new drug candidate regarding its toxicity and efficacy, it would not be right to test the drug on human beings. It is unethical.

How can one have a successful clinical trial with good data when preclinical studies are a total failure? A good preclinical data may or may not result in a successful clinical trial. Though the physiology of animals is very close to humans it is not necessary that the data obtained from animal studies would match the data obtained from clinical trial. This is the reason why clinical trials sometimes are a failure inspite of having a good preclinical data. But yet one needs to carry out preclinical studies first followed by clinical trial.

I hope this information is helpful.

Best Wishes.

Hi.

I think there is some sort of misunderstanding to my question.

I mean after you have already finished your pre clinical oncoloy studies for both safety and efficacy and it was ok for safety whil

As all researchers know >90% of effective molecules or drugs in the pre clinical stages are not effective when applied to human in clinical trials.

Why nobody of us as researchers think about a possible efficacy in human although of absence of this effecacy for certain drug or molecule in the pre clinical stage?!

How can any researcher think about a possible efficacy in humans without having any data on the toxicity and safety of the drug ? Some data should be available to test the efficacy in human beings. To procure that data studies have to be done in vitro (cell lines) and invivo (animals). As I mentioned earlier I say it again that it won't be right to test the efficacy of the drug on humans without having the toxicity data in hand. The drug has to be safe when administered to humans. No clinical trial can be initiated without having a proper and complete data on safety and toxicity of the candidate drug.

Hi,

Now your question is complete :) Currently, there are many methods to confirm with great certainty or exclude that a drug candidate will have the same mechanism of action in the models (prreclinical stage) and the same thing will be observed in the clinical phase. So, such a bug, the gap you are talking about in theory is not possible. The fact is that it is relatively "easy" to find a model on which in the preclinical phase it will be possible to track the mechanism of action of a future drug and the effect it causes. On the other hand, it is not always possible to find a model (especially animal) that will allow you to confirm or exclude the mode of action with certainty, i.e. the so-called "downstream effects".

Another difficulty is the complex nature of the disease. The more complex target disease in its etiopathogenesis in humans, the more difficult it is to verify a drug candidate in the preclinical phase. Moreover, the etiology of many diseases is not exactly known, therefore many drugs are only symptomatic drugs. The symptoms-effects observed in the models may not be properly selected in the preclinical phase and generate an error. After all, there are many examples of drugs discovered by accident or drugs which, depending on the dose level, have different mechanisms of action. All of this can lead to the situation you are writing about.

Therefore, it is possible to imagine a situation where a drug candidate did not reach the clinical phase because the mode of action was incorrectly verified in the preclinical phase. Verification of both the mechanism and the mode of action, especially in the case of drugs with complex pharmacodynamics in the preclinical phase, may involve a risk you describe.

We can only believe that these are exceptional situations.

Best regards

Tomasz

Malcolm,

Please, reread carefully my question and both comments.

Thanks.

Yes, now I understand what you actually meant Khaled M.E Elawdan . I fully agree with Tomasz Grabowski especially the paragraph below.

Another difficulty is the complex nature of the disease. The more complex target disease in its etiopathogenesis in humans, the more difficult it is to verify a drug candidate in the preclinical phase. Moreover, the etiology of many diseases is not exactly known, therefore many drugs are only symptomatic drugs. The symptoms-effects observed in the models may not be properly selected in the preclinical phase and generate an error. After all, there are many examples of drugs discovered by accident or drugs which, depending on the dose level, have different mechanisms of action. All of this can lead to the situation you are writing about.

Tomasz Grabowski as you mentioned it is going to be risky.

Thank you Khaled M.E Elawdan for a good question.

Best Wishes.

In cell culture we can control approximately all factors in normal level except factors that being under studies; but in case of vivo , several factors can't be controlled which can be act as stimulators or inhibitors for drugs of cancer