It seems to me that "die" means "end".

Your responses rephrase my question? But without providing the articles I request.

Best

Robert

Dear Robert

I don't think many will report any 'death' or failures of Trials as such. They will be reported using some other phrases to cover up, like 'It was a success because it gave an opportunity to prepare alternative drugs' (like the examiner who told the student after theory, practical and viva that he has been given an opportunity to improve himself' or like the Govt telling the research Labs (when the cut the Funds) that they have been given the opportunity to get external funds).

Whaat you may have to do is search with Phase II as a key word,, read the abstract and decide whether it was failure or success and then search for Phase III for each drug that had completed Phase II.

It will be a herculean task, but will be a good study, possibly not undertaken before.

Good Luck and Best wishes

Narayanan

Thank you very much Narayanan for your response.

I share your nice response on the "diplomatic" way, but you forgot to mention one category of humans also dealing with the development of anticancer drugs, e.g. the financials who support the enormous costs linked to late stage clinical development.

These people claim that the "big problem" today in oncologfy development is the huge failures of positive Phase II clinical trials in Phase III ones.

I tried your approach but I got no convincing data. I indeed collected an enormous list of Phase II clinical failures, but I did not find "top articles" on this subject ...

Best regards

Robert 

Dear Ross.

It possibly is because no one has thought of analysing the reasons for failure. I think this is an important area. You should actually consider this as a Golden opportunity and go ahead, especially since you seem to have a lot of data. Collect for successful trials too, and do a comparative analysis, with help of a good Biostatistician. There are good ones in RG too.

Get ahead Sir

Narayanan

Dear Narayanan,

I really like the "Dear Ross" which is a nice "summary" of my first and last name, i.e. RObert kiSS ... Usually, people who know me call / name me "Bobby" ...

Whatever it can be, I am too old to engage myself alone in this task that you previously labeled as "herculean" ... even if I weight > 100 kg!

If you are ready to take the challenge, why not writing together a review on this subject, and inviting those RG community members who would actually contribute to this project?

You are perfectly right in indicating that there are very good biostatisticians in the RG community and that it is mandatory to have a biostatistician on board.

I think about Jochen Wilhelm (RG score = 235!!!!) ...

Best regards

Robert

Dear Bobby

Sorry for the mis-spelling. I think my mind intended Boss, which we use instead of Sir and gives a sort of elevated but closer relation ship!

I have left Medical field, except for discussions in RG, and does not feel upto the task.. I am now fully engaged in Linguistics (!), of all things.

I will try to find out the names of Biostatisticians whom I follow in RG and give them to you. You can discuss with them regarding the variables/parameters to be selected. Most tedious work will be data collection. Which I hope you may be able to enstrust to your Juniors or ex-Students.

Any way you can start writing the Introduction, lacunae in the problem etc.

Narayanan

Thank you very much Narayanan!

Have a lovely day!

Robert

Thank you

Narayanan

I have seen nothing special during the last 5 years and heard nothing new from big Pharma.

Thank you Michel.

It seems that we have not the same "sources" ...

Kind regards and hopefully meeting you soon.

Robert

There are many answers for this question but I will focus on only one: Phase II studies evaluate the single agent activity of a new agent or modality against a a specific subtype of cancer. And the activity is measured by accepted objective response criteria such as tumor reduction by a certain amount (in solid tumors) or remission (for hematologic malignancies). In Phase III trials (except for non-inferiority trials), one needs to show that the addition of this new agent does improve the efficacy of the (or one of the) standard regimen(s) available for that cancer. An agent found active in a Phase II trial may not kill those cancer cells that are capable of resisting the standard treatment regimen and hence not add to the benefits of the standard regimen. Furthermore, Phase III trials (typically) use more stringent outcome measures such as survival or progression-free survival (solid tumors)/disease-free survival (hematologic malignancies). The fact that an agent is active in Phase II studies does not mean it will improve the survival outcome when added to a standard regimen. The exception would be if you did not have any standard therapy for a particular form of cancer; then the single agent Phase II data (especially if they are impressive) would likely be indicative of a single agent Phase III (vs Placebo) trial. Such a trial design would be unethical in most instances as patients in the control arm should be entitled at least to the available most effective standard regimen. I hope this very limited scope answer will provide some of the insights you were seeking. Best.

Thank you very much Fatih.

You bring actuall rational ellements in your response.

Best regards

Robert

Dear Robert,

Our group recently looked into this for our "Repurposing Drugs in Oncology" ReDO project (http://www.redo-project.org/publications/). I think the best and most reliable estimate comes from Hay's article in Nature Biotechnology (http://www.ncbi.nlm.nih.gov/pubmed/24406927). The phase III to application rate is probably the answer to your question. With a 45% figure for all oncology indications, it means 55% of all oncology drugs deemed sufficiently successful in phase II to be moved to phase III actually failed during phase III.

I hope this helps.

Best wishes.

Gauthier

http://www.redo-project.org/publications/

http://www.ncbi.nlm.nih.gov/pubmed/24406927

Dear Gauthier,

Thank you for your response and the attached documents, all of them being actually gorgious!

It was my sincere hopes to have access to these kind of documents!

Do you know that we are located at about 25 km from each other ...? I am ready to share with you a drink (or several!) at my full invitation!

Best regards

Robert

Ryder and Weiner report on the 2012 Edition of the Principle of Clinical Pharmacology by Atkinson AJ et al. that the survival rate of drug candidates would be 25-40% and 50-66% in Phase II and phase III trials respectively, with higher percentages for biologics agents and lower for the small molecules. The data refer to all pharmacological areas and not to oncology in particular. Primary reasons for higher failure rates were reported to be the inability to demonstrate clinical benefit and the massive proliferation of previously unexplored targets that will not be confirmed to have an impact on a more clinical ground. I think that these considerations would be particularly true as  the oncology trials are concerned. The reference reported was DiMasi JA et al. Clin Pharmacol Ther 2010; 87:272-277. You can also read other papers of the same author that address more specifically the field of cancer drug development. Best regards

Thank you so much Maria for these great infos!

Kind regards

Robert

You may find a connection to your question in this JNCI article,

    PMID 21131576 Ocana A, Tannock IF, 2011

        http://jnci.oxfordjournals.org/content/103/1/16.long# 

       http://jco.ascopubs.org/content/30/6/661.long 

          http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241518/

            http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1837599/

               http://www.nejm.org/doi/full/10.1056/NEJMsa1008268

      http://pharmaresearchdevelopment.blogspot.com.es/2010/12/clinical-trial-in-nut-shell.html

           http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504361/

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634626/ 

  NCCN had in 2014 an activity entitled: 'Understanding Clinical Trials and the use of Drug Compendia to Identify Appropriate Care'

   Also-> Nature Reviews Drug Discovery, 13; 179-196, 2014

1. Contemp Clin Trials. 2011 May;32(3):446-52. doi: 10.1016/j.cct.2011.01.010. Epub

2011 Jan 23.

Analysis of tumor burden versus progression-free survival for Phase II decision

making.

Fridlyand J, Kaiser LD, Fyfe G.

Genentech, South San Francisco, CA, USA. [email protected]

PURPOSE: There have been recent recommendations to use percentage change in tumor

burden (dTB) as a primary endpoint in randomized Phase II trials. We assessed

whether dTB is better for the decision to start a Phase III trial than is

progression-free survival (PFS).

METHODS: We repeatedly sampled patients from six large randomized trials to

obtain simulated Phase II trials. We derived PFS and dTB endpoints on the trial

patients and determined the fraction of simulated trials with positive results

for each endpoint. We supplemented these analyses with regression analyses to

assess the ability of PFS and dTB to predict overall survival (OS).

RESULTS: The best PFS endpoint included tumor assessments through 6 months after

the last patient enrolled. With 70 patients in each simulated Phase II trial, the

estimated rate of a correct 'Phase III go' decision ranged from 0.74 to 0.91

across the six parent studies. The best dTB endpoint was the last dTB through 6

months after the last patient enrolled, with corresponding rates of 0.54 to 0.81.

The PFS rate was better than the dTB rate in five studies. PFS and dTB are

individually statistically significant predictors of OS (p < 0.05). In all six

studies PFS added significantly to the regression models with dTB included, while

in only two studies did dTB add significantly to the regression model with PFS

included.

CONCLUSION: Analysis of PFS in randomized Phase II trials generally leads to

better 'Phase III go' decisions than does analysis of dTB. Tumor burden analyses

should be used in supportive analyses to a primary PFS analysis.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21266203 [PubMed - indexed for MEDLINE]

LINKS   USA GCP course crotraining.co.uk  AstraNova

European Medicines Agency

emea.europa.eu     

EudraCT Public website

https://eudract.ema.europa.eu/  

EudraLex - Volume 10 Clinical trials guidelines

http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm  

Welcome to the ICH official website 

http://www.ich.org/  

U S Food and Drug Administration 

http://www.fda.gov/  

WHO | World Health Organizaton

http://www.who.int

Thank you so much Joe!

Take care.

Robert

Thank you so much Alvaro for your interest in this subject I raised ... but ... unfortunately ... I do not understand Spanish ....

Do you have its translation in English?

All the best

Robert

Thank you so much Alvaro!

Take care

Robert