There may be very good reasons for exclusion of patients depending on previous therapy:

Safety ressons: if the patients received the same (or a similar) active substance (conventianl) before, it may not be possible to use the same active substance again. One example are anthracyclines and cardiotoxicity. If the patient have received the maximal possible dose, no further anthracycline can be given – no matter if this is a conventional product or a liposomal (nano) preparation.

Thank you for your responses. Does this mean that when the maximum allowable dose of a possible cardiotoxic conventional drug had already been administered to a cancer patient, the same drug even when encapsulated or carried by a nanoparticle can no longer be prescribed to the patient? What if the new formulation had not been tried before and it is just undergoing clinical trials, can they not try it on patients in stage IV or so?

Dear Zoraida, Once you have reached the limit of the allowable dose - I would be very reluctant to give the same active sunstance again - no matter what the formulation is - and thus exceed the acceptable max dose. This will mean a high risk for the patients - and possibly a reduced chance of efficacy as the conventional formulation did not work or was no longer effective. Better a patients with advanced cancer who did receive other previous therapy.

If there is overwhelming experimental evidence, that a therpeutic effects is to be expected even when the conventioanl product does not work, I think the argument could be made. But still, the more rationale choice would be patients who did not receive the max dose before.

With respect to anthracyclines, their use above MTD, has been shown when encapsulating in liposomes and other nanomedicines. The drug may show high systemic levels, but drug is not "bioavaiable". The guidelines still state drugs should not be used above a set MTD, however the goal of many nanomedicines is to atler drug disposition. Therefore, the free fraction, release rates of drug from these formulations is key to designing appropriate studies.

Dr Arnold, thank you for the clarification. The goal of nano-enabled drugs is to minimize damage to healthy cells by making the drugs undergo slow or timed release to have levels below the MTD. Hence, reaching the MTD with nano-enabled drugs is expected o be theoretically slim at any point in time. Theoretically, the nano-enabled drug is supposed to be safer than the conventionally delivered drugs.

To circumvent the toxicity of conventional drugs, targeted delivery with nanomaterial based drug delivery is used as an alternative so that majority of the drug would be delivered to the diseased cells/tissues and not on healthy cells/tissues. Through this process, the toxicity of a drug can be minimized in two ways: 1) By slow and continued release of the drugs from the nanomaterials so that the MTD is never a problem at any point in time and 2) by attaching a targeting molecule that recognizes the diseased cells/tissues so that the drug is delivered specifically to these sites and not on healthy cells or tissues. This is why targeted nanomaterial-based drug delivery is the ideal solution to minimize the toxicity of conventional drugs for various diseases but it is too early to make a generalization at this point. Thus, I was thinking that patients at the advance stages of any disease should be allowed to take targeted nano-enabled drugs even though they had taken the conventional drugs because at the present level of medicine, there is no known cure for the advance stages of some diseases such as cancer.

dear colleagues,

if nanomaterial based drug delivery succeeds, that is delivers more /free) active substance in the (tumor) target and less in the other tissues this is clearly advantageous - and may justify that more of the nano-product is given than of the conventional product. Unfortunately until now only few well designed trials are available to show that it makes a clinically relevant difference.

I think this could best be shown in a trial with two parallel arms, one with the conventional product used according to state of the art, one with the nano-product - showing better efficacy or less adverse effects, at the same dose or at a higher dose than the conventional product.

Exposing patients that exhausted their "allowance" for a specific active substance (no matter which one) to an additional treatment with the some active substance(even as a nano) will need some detailed justification - explaining why the (chance of) bebefit outweighs the (risk of) adverse effects - when the risk is considered increased due to the previous treatment with the same active substance.

Dear Harald, my concern was that for a patient who had exhausted all conventional drugs and had not been free of the disease because the drugs cure the cancer, for example, in the colon but the cancer appears in the pancreas. The part of the pancreas that shows the cancer is cut-off and that stops the spread in the pancreas but the cancer appears somewhere else...that gets cured but reappears in the liver...the form in the liver spreads so fast that now more than 80% of the liver is occupied by the cancer cells and surgery is no longer an option. What other medical solution is left for the patient at this point? Theoretically I think, I am not a surgeon or an oncologist though, the only remedy that is left is targeted drug delivery to the liver so that the rest of the healthy liver does not get affected by the drugs to prolong the availability of the remaining healthy section of the liver. If the patient is given conventional drugs, the rest of the liver may suffer and then what? Will that be the end of the fight against the disease?

Dear Zorida,

I think there are two different points of view: 1. what is the best way to DEVELOP a new nano- medicine. Here I stick to my point: including patients that were previously treated with the same active substance (though not nano) will complicate the interpretation of the studies and possibly decrease the chance to demonstrate sufficient efficacy, or a positive benefit risk ratio. These patients are expected to have less chances of efficacy (at least some will have developed resistance against the active substance) and higher risks of serious adverse effects (as the previous treatment with the same active substance already did the damage) than patients that where treated with (several) antineoplastic drugs before, but NOT with the active substance no in the nanoparticles.

This is different from 2: what can we offer for an INDIVIDUAL patient in a desperate situation. This depends much on the - I think rather personal - choices both of the patient and the physician. In a desperate situation many will try everything – beyond evidence-based clinical practice and treatment guidelines – including complementary and alternative approaches. Trying to the very last, or, as someone once said, “go down fighting” – rather than admitting that in oncology there are situations where no further treatment options are available. Situations with no treatment left that will have a chance to cure the tumor or a chance to slow down progression and therefore the only thing left is to focus on palliative measures, pain control etc. Admitting there is a end of treatment options is incredibly hard for the patient – and even for the physician it is frequently easier to suggest just another treatment (whatever slim chances this may have, and how serious the adverse effect) than openly tell the patient that there is no pharmaceutical left to fight the cancer… But this is patient care and clinical practice and not research and development.

Dear Harald, I agree with you completely. Yes, there is the research ethics that everyone must adhere to and that is for the pharmaceuticals, the CROs, and the regulatory boards. This is not the matter of life and death needs that I have referred to. The physician may not have any choice on the matter because it is usually controlled by the CRO and the sponsor doing the clinical research. And, for fear of jeopardizing the research outcome and violating the strict regulations, they will all follow the written requirements and disregard the needs of individual patients who are at the critical crossroads of needing the drugs; a matter of life and death situation. How many cases of this sort are there? Should there be exceptions to the R&D requirements in such cases?

Dear Zoraida,

Whether a physician is willing to prescribe/use an unlicensed product, that is a chemical, in the treatment of an idividual patients is a decision of patient, physician and may depend on national legal situations (including on responsibility issues, malpractice issues etc.). Sometimes even bizarre (in my personal opinion sometimes clearly unacceptable and unethical) treatment attempts are made - with impunity. This is for the INDIVIDUAL patient.

This should NOT be done within a clinical trial - deliberately including a patient that does not meet the inclusion criteria is a violation of GCP and may have serious consequences.

Bottom line: unusual individual treatment attempts should be possible (and are done) - but not in a clinical trial. "Exceptions" within the trials would jeopardize the value of the trial. In parallel with the trial, or after the patient left the trial - he or she may choose to do so any time - it is an individual decision.

Dear colleagues,

I would like mention a few points that might be of interest to you.

1. In certain tumors, a team approach involving an interventional radiologist has been tried to deliver drugs intraarterially using a catheter - especially for liver metastases (example: http://www.ncbi.nlm.nih.gov/pubmed/21944243; http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=58&abstractID=40288). Indeed this has been shown to be a preferred treatment for certain cancer types (http://www.ncbi.nlm.nih.gov/pubmed/21681380)

2. Likewise, cryoablation therapy has been used for metastatic disease in liver and radiofrequency therapy for bone metastases

3. If a patient is heavily pretreated with multiple chemotherapeutic agents and has wide-spread disease, especially one that has spread to the liver, the benefit of chemotherapy of any kind will be scientifically and ethically questionable at best. If you have a young patient with a very aggressive tumor that failed a short intense period of multiple chemotherapy regimens, may be still salvagable by a personalized approach.

4. The potential of nanotechnology-enabled delivery of drugs has to be validated in specific disease settings and each nanomedicine candidate will need to be developed individually as a unique pharmaceutical composition.

5. The off-label use of drugs has been around for a long time and indeed most of the standard treatments for childhood cancer are nased on the off-label use of chemotherapy drugs originally developed for totally different cancers in adults. BUT, what is important is that you use any of these "poisons" using stringent criteria of evidence-based medicine. There should be published evidence that a human patient has been treated safely with evidence of objective response at the level of tumor, tumor mets, or progression free survival or reduced tumor symptoms/pain for the type of cancer you are trying to treat.

Hi Fatih,

Thank you very much for your participation in this discussion. I appreciate it.

As I mentioned in my book, there are nanomaterial enabled anti-cancer drugs that are already available in the market which means that these had been tested to be effective. One of them is doxil.

So, my original concern is whether stage IV patients should be denied or given nanoenabled drugs after their cancer moves to other organs. I believe, for humanitarian reasons, that all possibilities should be exhausted to try to prolong a high quality life even when the person has cancer by giving them chance to avail of drugs in clinical trial. I had seen people with AIDS take different pills under clinical trial. Why not do the same for cancer. But, as mentioned by our colleagues, there are regulatory and ethical issues to be observed when enrolling patients in any clinical trials involving new drugs and everyone must adhere to them for health reasons and in order not to skew the results of the trials.

Dear All,

Going back to the starting point of the debate the answer to the question is clear.

Nano-enabled drugs usually are not providing more efficacy than their not nano-enabled counterparts. So treatment a specific drug resistant patient with the nano-anabled form of the same drug for which he/she is resistant would not mean any changes in efficacy or drug resistance.

If the nano-enabled drug is better than its non-nano counterpart, it is obvious that a clinical trial can be organised to test the efficacy of a nano-retreatment of a drug resistance.

On the other hand, if the purpose of the clinical trial is other, you should eliminate every source of bias which can influence your result, so the wise decision is not to treat patients who had received the same drug previously.

And, it is also possible, that the protocol will describe the investigational population, because the sponsor has its inherent right to specify its requirements regarding the study population.

And never let you allow to get out of your mind, that you can treat patients within a clinical trial, but the main purpose of the trial is something else: to test a new drug for future, meaning that you cannot blame a trial if it is not suitable specifically for one of your patient.

Hi Laszcio.

Have you worked on clinical trial before? Just wondering where you got your knowledge about the reasons for the clinical trials. If you did work on clinical trials, please enlighten us about the goals for Phase I, Phase II, and Phase III. It will be very helpful in understanding your explanations above.

My next question is, have you worked on nano-enabled drugs or nano-sized drugs for any disease therapy? If you did, please teach us how to go about it. Maybe the followers can learn from you.

Dear Zoraida, even teaching is my task in the medical university where I'm working, I'm not willing to teach basic pharmacology and clinical pharmacology for a anybody who is considered to be a professional.

I hope You'll understand it.

On the other hand, for the sake of politeness, I'm answering You.

YES, I have worked on clinical trials before, and I'm also actively participating in lots of them. Moreover I have authored some successful phase III trial, too.

Regarding Your second question, let me call back, just to make defintions clear: what do You mean under the term "nano-enabled", because probably I missed the point, knowing that couple of drug delivery system called nano-enabled.