As per ICH S9 (Current Step 4 version dated 29 October 2009 page 5) Nonclinical Evaluation For Anticancer Pharmaceuticals: Genotoxicity studies are not considered essential to support clinical trials for therapeutics intended to treat patients with advanced cancer (terminally ill patient). But for those patient who are on very early stage of malignancy, whether the same drug can be used for therapeutic purpose.....without much knowledge about the genotoxicity...as the issue is not addressed by ICH guidelines.

As per my understanding if the drug need to survive in the market----genotoxicity must be carried out to decipher the % of damage to normal cell ....if the % of damage to normal cells are higher it may bring about havoc human suffering by disturbing normal cells physiology .....The fundamental question Benefit---Risk Ratio???????????

Again the result of genotoxicity may decode the secret behind genotocxicity...the chemical structure...Open a new area of research for more target specific product in the future for greater therapeutic benefit.

The reason why conducting genotoxicity studies in drug research area is to understand if the drug caused secondary cancers in patients. so, most cancer patients are in terminal stage and genotoxicity studies seem not meaningfull. But if we could survive the patient for 5-10 years, what will we do if secondary cancers occur due to chemotherapy during these years??

In the US, genotox studies are not required for oncology compounds. The potential benefit of short term survival out-weighs gentox considerations. Many cancer patients relapse w/in ten years regardless of the treatment, so genotox will probably remain a secondary consideration until relapse rates decline significantly.

Cancer normally has a multifactorial origin.

But if it is about a drug, you can look the mechanism of action of it and observe the adverse effects. Normally it is detailed. But the problem with cancer is that the secondary cancer can have another origin.

Dear Colleagues,

For all kind of treatment, when adressing serious or mortal diseases or not , we have always to put in balance benefit/risks for our patients.

In France in example, the process to authorised a drug to be commercialized, very severe, includes evidently in genotoxicity studies (in vitro, animals...).

In the case of oncology, most of drugs (chemotherapy) are very toxic (look at current adverse effects) and acting on cell in division, sometimes on their DNA (ie 5FU), They kill cancer cells but can create also new mutations (involved in carcinogenesis), and eventualy secondary cancers in that way.

Always, it's not an obligation' but a potentail risk increased compared to risk of treatments in other pathologies.

So, always benefit/risks: we can cure ie a breat cancer with anthracycline (and others combined drugs) , but with an increased the risk in the 5 to 20 years of myelodysplatic syndrom, and secondary leukemia,; as the frequency of MDS in a group a treated women is superior to that found in a control group of non treated patients.But without these treatments, mortality of untretaed women is evident and inferior to 5 years.

Even with no chemiotherapic treatments, like anti-hormone (tamoxifen), there is an increasing risk of secondary cancers ie uterus (necessary follow-up of these patients for a long time).

Finally, we know the genetoxicity of a lot of anti-cancer drugs, and it's a particular case considering their agreement process compared to others treatments, for other diseases.

Regards

Didier J

To complete, and more directly respond to the question:

- for others diseases than cancer: we doesn't accept a genetoxic risk (zero risk) in drug approval

- for drugs having obligatory a genetoxic risk and the cancer treatment, we accept a risk (which purcentage ? according to each drug), in balance with the mortal risk of untreated cancer.

And the drug approval also depends on the country, as underlined by Terence.

Regards

Didier

its depend your drug you just think about drug initial compound structure and also you when are you going to use may be some changes its compound structure you just think and you compare with some or genetoxic risk causing agent like functional group or pH if you see any thing is happening than you must need the than you must do the genetoxic risk experiment .i think most of reason is functional group

I think we definitely need to check he genotoxic effect of drug, otherwise it will have a higher probability to create secondary mutation leading to secondary cancer.!!! Then what is the use of the drug if it causes cancer, it may increase the survival time of the patient but not cure. If increasing the survival period of the patient is the main of the drug then we can overlook these parameters, else. its of utmost importance to check the genotoxic effect. !!!!

Without any genotoxicity data (e.g. not even an Ames test) no clinical trials will get approval by ethics committees or regulatory bodies in most (all?) countries. I strongly advise to get in vitro genotoxicity - not expensive, does not need much substance. Giving a new substance to patients (or volunteers) without genotox may be considered as violation of ethical principles. If the substance is successful in the end, that is if it becomes a useful pharmaceutical product, the missing genotox prior to first in man stuidies may come back to haunt you many years later - during marketing authorization procedures or in public media (patients rights).

bottom line: there are clear legal regulations on clinical trials - make sure 1. you comply to the local/natioal requirements 2. the trials would not create problems if the substance/product would ever go for marketing authorization in Europe or the US.

Harald,

You need genetox data if phase I trials are done in healthy volunteers. If you do your phase 1 trials directly in cancer patients then you don't need the genetox data, especially if you want a fast track approval for an unmet medical need where there is no approved drug available yet. I don't think well informed ethics committees insist on genetox data if they understand the unmet medical need for the patients. When in doubt, you can also request a pre-IND meeting with FDA so that you can be sure of what FDA wants which can be used to justify ethics committees.

It is unusual that a developmemt program is ready to go into humans and there is not in vitro genotox whatsoever. Assuming of course, we talk about small molecules - the story is different for e.g. monoclonal antibodies and other protein-based products. There certainly is a rationale that dependeing on the patients genotoxicity or no will not make any difference. Still, a small molecule used in humans without any genotox is very unusual - in parallel to the preclinical development program this data are usually routinely created. Anyway, I would advise to make sure with FDA.

Harald, few more points. You may know that some anti-cancer drugs may act via disrupting spindle formation during cell division. Such drugs will be genotoxic, resulting in chromosomal aberrations (aneuploidy) and chromosome breaks. Any chemical targeted with this mechanism of anticancer activity will have genotoxic activity.

I don't know if you are aware, recently celgene bought a company named avila. Celgene, we all know is specialized in cancer chemotherapy. Avila's platform is reactive chemical molecules that covalently attach to proteins and presumably to DNA. I bet most of these compounds are genotoxic too. It depends on the scientist who can explain to the ethical committee about the "unmet medical need to the cancer patient" and a ""remarkable difference it will make in patient's life" is very criticall.

You perhaps are aware that radiation therapy is still common in cancer therapy which are unmanagea ble with chemotherapy and surgical therapy. Radiation is a well known genotoxin and FDA approved.

The bottomlin - one has to evaluate "unmet medical need", "the benefit versus safety" "target under evaluation" all are important to consider and if needed prioritize the studies as required. There is no point in conducting genetox studies when we know the mechanism of action will no doubt result in genotixicity (eg., spindle poisons). We tend to avoid such targets for ethical reasons, but at the end we are not considering the unmet medical need for the patient, which is I think is the most ethical component, not the genetox issue.

So, Jasminka,

You do concur that genotoxic effects could be used for specific therapeutic intervention of cancers. Of course, excessive genomic instability has to be minimized. Nevertheless secondary cancers after 5 to 10 years of therapy that should be of concern but in the light of a terminally ill patients who perhaps doesn't have more than six months to live, if he lives for at least 5 years - that would be great. Unfortunately, there is no magic bullet that can be universally acceptable therapeutic drug......

As per ICH S9 (Current Step 4 version dated 29 October 2009 page 5) Nonclinical Evaluation For Anticancer Pharmaceuticals: Genotoxicity studies are not considered essential to support clinical trials for therapeutics intended to treat patients with advanced cancer (terminally ill patient). But for those patient who are on very early stage of malignancy, whether the same drug can be used for therapeutic purpose.....without much knowledge about the genotoxicity...as the issue is not addressed by ICH guidelines.

As per my understanding if the drug need to survive in the market----genotoxicity must be carried out to decipher the % of damage to normal cell ....if the % of damage to normal cells are higher it may bring about havoc human suffering by disturbing normal cells physiology .....The fundamental question Benefit---Risk Ratio???????????

Again the result of genotoxicity may decode the secret behind genotocxicity...the chemical structure...Open a new area of research for more target specific product in the future for greater therapeutic benefit.

It is better to test genotoxicity of a drug before it is tried in humans. Since secondary cancers are very common, the possibility of induction of cancers by the drugs used in cancer therapy needs studies.

In cancer you need kill the young cell because those are more active in cell division (like the cancer cell). All medicines and radiation aim is to reduce DNA activity of replication, and for this the cell division. Cancer medicine decreases DNA activity, and cancer make the contrary. But in the intent of compensating the less DNA activity it's possible to cause an unwonted side effect. But all this effect are studied. Oncologists must know all this and act as the case.

Jasminka,

Thanks. The issue is the regulatory agencies normally require three different genetox studies - these are very specified. (1) A test for gene mutation in bacteria

(2) An in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay.

(3) An in vivo test for chromosomal damage using rodent hematopoietic cells.

for ICH guidelines on conducting these studies, please check http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/securit/s2b-eng.php

The kind of studies you are proposing are not required by regulatory agencies although they would be interesting research results as an add on supportive studies.

Yes we do need genotoxicity studies for drugs that are designed for cancer in the future. You are right that the regulatory groups do not impose genotoxicity for cancer drugs but they do impose on testing for impurities in the drugs that may be toxic. However, I think that as more and more nanomaterials enabled drugs for cancer are developed, cancer drug genotoxicity may become a routine requirement in the future for non-agressive cancers such as thyroid, prostate, testis cancer, and the like but not for agressive ones such as cancers of the liver, bile duct, and pancreas.

All drugs in the USA require this to be FDA approved.

Edward,

Not really, Go check out the ICH guidelines

I think, for developers, it's a matter of resource and risk. How much resource is needed to conduct genotoxicity study? And how much it can reduce the risk for further development. In my experience, among all studies in pre- or non- clinical studies, genotoxicity studies is relatively cheap, and as for Ames test, 70% accuracy. So why not?

This depends of the patient. Correction of doses are fundamental. The lost of weight, for example implies less doses.

Dear Subrahmanyam Vangala

The main objective of conducting genotoxicity studies is to evaluate their effect on dividing stem cells present in your bodies (like Pluripotent stem cells - Bone marrow cells, dermal stem cells even your Germline cells). The genotoxic effect of drug can transform your normal pluripotent cells to oncogenic cells at person level and induce ploidy in germline cells hence hereditary level / or can act as teratogenic agent.

Evaluating of our drug with battery of in-vitro genotoxic test system in various cell line models like AMES (OECD 471); chromosomal aberration (OECD 473); Micronucleus test (OECD 487) - Gene level targets; Tyrosine kinase assay - Cell signaling level; DNA polymerase activity; Topoisomerase activity - DNA synthesis level; Teratogenic assay - Embryonic level etc, can give broad idea about choosing safe effective concentrations, mode of action and also give you broad idea about target site specific to enable the drug full potential. In-vitro hepatic model clearly examines how effective the drug is metabolized, their membrane damaging activity and cytotoxic dose to liver etc. Unscheduled DNA synthesis (UDS) test with mammalian liver cells in vivo is to identify substances that induce DNA repair after excision and removal of a stretch of DNA containing a region of damage induced by chemical substances (solid or liquid) or physical agents in the liver

Even to cancer patients apart from the cancerous cell division there are other kind of cell division too occurs inside their body and also you have to know that how far your drug is going to damage their liver and to know your drug's half life. Hence, regulatory agencies like ICH, OECD, FDA are strongly recommend’s these in-vitro genotoxic test models has very essential for developing a drug even for cancer patients.

All the best

II. THE STANDARD TEST BATTERY FOR GENOTOXICITY (2)

A. Rationale (2.1)

Registration of pharmaceuticals requires a comprehensive assessment of their genotoxic potential. FDA S2(R1)

Edward,

There are exceptions. According to ICH S9 (Current Step 4 version dated 29 October 2009 page 5) Nonclinical Evaluation For Anticancer Pharmaceuticals: Genotoxicity studies are not considered essential to support clinical trials for therapeutics intended to treat patients with advanced cancer (terminally ill patient). Somnath also mentioned this earlier

Chiu Li Wang, It is not the question of cheap or fast. It is the question of what do you with the data and ethical considerations??? Many anticancer drugs kill cancer cells through genotoxic mechanisms. Then, if you say a genotoxic compound cannot be used in a cancer patient, then it will be very hard to discover new anti-cancer drugs.

A dying patient need medicine immediately. If people stop using the available drugs thinking that this drug may secondary cancers (after 5 to 10 years) because it is genotoxic, then this patient will die in the next couple of months.

Dear Sundarajan,

We are talking about regulatory issues here. Genotoxins have no threshold. Even one hit can lead to cancer. So, you cannot use the data to calculate safe concentrations. Only positive or negative. A weakly positive compound or a compound positive in one test and negative in another test doesn't mean anything. Even one test resulting in positive geneotoxicity, will create several regulatory hurdles.

"Genotoxicity" and "Clinical use" are not exclusive. You can still use compounds with genotox properties, but with limited patient population and more regulation to fallow. One good example is the notorious Thalidomide. It still in use today, but in very limited patient population, and with lots of documentation and monitoring work to keep it safer when using it.

The other thing is that the mainstream of new cancer drug development now is targeted therapy, most of them working on kinase inhibition, which means it does not directly work on DNA. You can find lots of new targeted cancer drug, ex. Iressa, Tarceva, Sutent, ...etc, most of them does not directly work on DNA. From clinical opinion, genotoxicity studies just give you an clue of when and to whom you should use that drugs, and to what extent. Its not exclusive. Its a risk-and-benefit judgement. To a greater scope, generally speaking, cancer drugs, because it is used to treat lethal disease, it can bare a little bit wider toxicity properties than other drugs, especially chronic diseases like hypertension, diabetes, hypercholesterolemia, which normally require much better / narrower toxicity properties.

To circumvent the toxicity of conventional drugs, targeted 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. Targeted delivery coupled with nanomaterials 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. In a few years, more will be known about the efficacy of targeted nanomaterials-mediated delivery of drugs. Of course, toxicity of the nanomaterials will also need evaluation. If successful, no matter what the conventional drug is for-DNA or kinase inhibition, targeted nanomaterials-based drug delivery is anticipated to minimize or eradicate toxicity of the conventional drugs.

I agree with Zoraida: targeted treatments are the future : drugs coupled with antibodies,in vitro "education"of immune cells to specifically recognize cancer cells, nanomaterials. But I think for these last ones, we have to follow-up ona long period patients, because we don't know very well at the moment the long term effects of introducing in body this sort of materials . Because they are not eliminated and persist in the body (and also in nature) indefinitively , with some "toxic" effects not well defined.

Regards

Didier

My last comment was referring to drugs approved for human use.

I am not concerned about drugs approved for human use. I am only concerned to discover new drugs for cancer therapy where there is no medicine already available (unmet medical need).

Drugs approved for human use, the major interest is to characterize the genotoxic impurities and eliminate them from new batches of drug. That is a toltal different issue.

Sorry, I only work with drugs for human use. There may be removable or nonremovable genotoxic impurities in any drug, but the drug itself may be genotoxic to lab animal species, and in-vitro as well.

Dr. Russak and Dr. Didier, thank you for the healthy exchange of information for Dr. Vangala's Q. A lot more studies on nanomaterials toxicity and mechanism of clearance need to be performed now and in the future so that they can be used for human use without much fear. There are a few studies that have been conducted on nanomaterials showing assimilation into the human metabolic pathways but this is only for a few. Furthermore, long term studies need to be performed to evaluate all the possible routes of assimilation or maybe deposition in various organs, we still don't know. Some nanomaterials that have shown toxicity in vitro and in small animal studies will definitely not be sued for such purposes but there are a number of biocompatible ones that are good candidates for targeted timed release drug delivery.

Although one may not care about the genotoxicity of a drug used for treating terminally ill cancer patients it is prudent to conduct studies on genotoxicity of anti-cancer drugs as it will encourage physicians to avoid their use in cancer patients (childhood) with long term survival prospect, encourage the drug companies to discover non-genotoxic analogues and also the patients to be monitored for the side effects following the use of genotoxic drugs, particularly cardiotoxicity ( genotoxic agents potential atherogens).

Definitely, we need. For example, Imatinib was designed to target BCR-ABL fusion tyrosine kinase in patients with chronic myeloid leukemia (CML). A “magic bullet” effect of imatinib due to its high rate of CML cure in an early phase of disease was ascribed to specific inhibition of oncogenic BCR-ABL tumor “driver”, and this afforded strong grounds for introducing the “oncogene addiction concept”, according to which tumor cells are dependent on a single activated oncogenic protein or pathway to maintain their malignant properties (Santos et al., 2011; Sawyers, 2009). However, it is well evidenced that imatinib also targets the receptor tyrosine kinases (c-KIT, PDGFR, CSF1R, and DDR) and non-receptor tyrosine kinases (BLK, ARG, LCK, and LYN) as well as RAF kinase family members (BRAF and CRAF) and the oxidoreductase NQO2 at the therapeutic concentrations (Anastassiadis et al., 2011; Breitkopf et al., 2010; Davis et al., 2011; Hantschel et al., 2008; Kitagawa et al., 2013; Packer et al., 2011; Steegmann et al., 2012). Imatinib (as well as nilotinib and dasatinib) was documented to induce spindle defects, numerical and structural centrosome and chromosome alterations in human and mammalian cells in vitro in a dose-dependent manner. Also, these inhibitors affected centrosomes and spindles and induced de novo chromosomal aberrations in CML cells as well as in BCR-ABL-negative hematopoietic progenitor cells in vivo (Cohen et al., 2002; Fabarius et al., 2005, 2007, 2008; Bacher et al., 2005 Giehl et al., 2010; Haaß et al., 2012). Furthermore, the most widely used plant-based bioassays for the detection of genotoxins demonstrated that imatinib at low concentrations caused induction of micronucleuses, which are formed as a consequence of numerical and structural chromosomal damage (Pichler et al., 2014). Importantly, Imatinib therapy-related secondary malignancies were observed (e.g., Verma et al., 2011; Helbig et al., 2015) (from the submitted manuscript in revision: Stepanenko and Dmitrenko, Pitfalls of the MTT assay: direct and off-target effects of inhibitors may result in over/underestimation of cell viability/growth inhibition. Gene. 2015)

Any chemical targeted with this mechanism of anticancer activity will have genotoxic affect

We do. Even though these drugs are used for anti cancer activity genotoxicity may enhance genetic instability of tumour cells leading to new mutations affecting therapeutic outcom.