38 replies to this topic

[Tedsey]

I cannot add anything here but support and a cynical comment.  The wording "enjoy a chronic phase" struck me as extremely odd.  I cannot imagine that anyone with CML is enjoying their chronic phase.  I sure am not.  But it beats the alternatives.  I wish you the best of luck.  In a perfect world, no one would be left out because their condition is rare, esp. within another rare condition.

[Trey]

Now I finally see.  Dr Apperley is saying the 49% are "unmet needs" from the "Unmet Needs in CML study".  So these are something called "unmet needs", not Gleevec resistance.  I must admit this "unmet needs" thing is beyond my understanding.  Anyone who increased Gleevec dosage is counted in this 49%.  Anyone who decreased Gleevec dosage is counted in this 49%.  Anyone who took a Gleevec break to get their blood counts up are counted in this 49%.  The conclusion must be that Gleevec is an abominable drug not worthy of existing.  Dr Druker must be an evil man for burdening the world with such a worthless drug.  We are indeed doomed, but grateful to Dr Apperley to finally know that a BMT is our only answer.

Quoting from your reference where Dr Apperley told the FDA committee considering appoval of Omacetaxine:

"44.6% were IM resistant and/or intolerant (as reported in the medical  chart if resistance/toxicity led to a change in or discontinuation of IM  use) at some time since IM initiation. 20% stopped and did not restart  IM during the study period. 23% stopped IM temporarily due to toxicity (median duration 22 days), of  whom ~30% had >1 such interruption. The most common increase was 400 to 600 mg (33%); most common decrease was 400 to 300 mg (39%)."

So if the stats are counted as normal people would count them, then we are back to the 18% from the IRIS study (Dr Apperley says 20% -- close enough) that discontinued using Gleevec for various reasons.  So now I understand.  I have tried to sort his out because I do not want CML patients to be needlessly alarmed by poor statisical methodology.  Thanks.

[cherylannes]

Hi Trey,

Actually, no, I don't think you see, because we both do not have the slide that she used at the FDA ODAC meeting.  I merely pointed you to the UNIC study because I am aware of it, but it is not the information she used.  The UNIC study is data from quite a few countries, not just Northwest England that Dr. Apperley was pointing out to the FDA ODAC Committee.

Let's be clear, if a patient has to have their doses of the drug increased, then this is an indication that the drug may not be the best choice for this patient.  However, you cannot say that entirely, unless of course even at the higher dose, patients are not seeing their level of disease going down, or stabilizing for that matter.

I am not sure how you feel qualified to try to speculate about how people may think of Dr. Druker.  Clearly, you are arriving at the wrong conclusion.  I was fortunate to attend the European School of Hematology (ESH) meeting in Bordeaux, France last September.  The International CML Foundation headed by Dr. John Goldman and Dr. Tim Hughes and comprised of all CML experts from around the world, honored Dr. Druker with the Janet Rowley award.  Everyone in the room gave Dr. Druker a standing ovation - including Dr. Jane Apperley.  Dr. Druker's acceptance speech thanked all his colleagues around the world for picking up the ball and rallying behind him when he approached everyone to say that he felt they were working on a drug with extremely good potential.  Everyone believes that indeed Gleevec is a top notch drug.  This discussion here on this thread should not be misconstrued to lead people to think otherwise.  I would further add that I have enjoyed a fantastic private lunch with Dr. Druker, Suzan McNamara and Richard R. at ASH in 2005, and have had the opportunity to chat with him on several occasions.

The discussion we are having here is simply to point out that the disease isn't finished with us yet, it has more tricks up it sleeve for us and there are many patients (the minority, but fellow human beings none the less) who have needs that are not currently met.

As for your comment on the BMT issue, you do not seem to be aware that there is currently a very critical issue in the UK.  The government through their National Institute for Health and Clinical Excellence (NICE) have decided that the second generation TKI's such as Dasatinib and Nilotinib do not confer any additional benefits than currently met with Gleevec, therefore CML patients cannot access these drugs at the moment.  This is why you will hear Dr. Apperley talk about BMT.  Unfortunately in the UK, their government is saying patients who fail first line Gleevec, can access a BMT if they are eligible, but not second line TKI's - there is a massive petition going on right now for that.  Needless to say I have already signed that one as well ( http://www.cmlsupport.org.uk/).

You say you are worried about alarming patients with the statistical analysis.  Should patients be alarmed by any of this discussion? No, but hopefully they will feel more adequately informed and realize that although we have made great strides in this disease and the majority of CML patients are well served, there are very clear unmet needs for the minority of patients.  It is for those patients that we must all come together.  I am fortunate for the responses I have had in my near ten year battle with this disease.  I have utilized many options - Interferon to Gleevec, back to Interferon, then to Sprycel, now on a combination of Interferon and Sprycel.  I am appreciative for all these options and happily note that a few of the options would not even be available to me if it were not for the tenacity, commitment, and dedication of wonderful Dr. Druker.

" 1 in 5 patients does not achieve a CCR, 1 in 14 patients will advance to AP/BC, 1 in 33 patients who achieve a CCR will relapse" Ref. - O'Brien SG, Guilhout F, Goldman, JM et al, International Randomized Study of Interferon versus STI571 (IRIS) - 7 year follow up; sustained survival, low rate of transformation and increased rate of major molecular (MMRI) in Pts with newly diagnosed Chronic Myelogenous Leukemia in Chronic Phase (CP) treated with Imatinib (IM); Blood, 2008; 112 (11) Abstract 186.

I just merely want to point out that it is that 1 in 5, that 1 in the 14 and that 1 in the 33 that is the face of humanity - these are the people who have unmet needs. We should all be thankful that our doctors are celebrating the success of Gleevec, yet continue to understand that there are those among us who need additional options and these are who it is all about.  Go back to the first post on this thread and consider that.  The good news is that since then we now have about 539 signatures!

http://www.petitiononline.com/mod_perl/signed.cgi?FDAOMACE

Cheers all - have a lovely rest of the long holiday weekend.

Cheryl-Anne

[jm2002au]

Hello Cheryl-Anne,

Thanks for putting the petition together. Just wondering what and when the next move will be regarding the petition?

Will the FDA be sent this petition soon in the future? Are they aware of it at this moment?

Regards,

Nathan

[cherylannes]

Hi Nathan,

We are not aware if the FDA know about the existence of the petition.  We will be formally presenting the position to the FDA.  That is why it is essential to accrue so many signatures.

Please help us by making sure you have as many of your friends and family sign the petition.  We all need clarification on this matter, it is very urgent.

Thank you for your support.

May we all be well and healthy.

Cheryl-Anne

[Trey]

While people are waiting for the results of this petition effort, just FYI here is some information that provides a little background into the FDA actions.

The FDA has made a conscious decision to take a firmer stand on the issue of non-standardized diagnostic testing used to support all drug approvals, not just in this case:

http://myraqa.com/blog/new_tougher_fda

"FDA is aware of the issues of traceability and standardization, and  though they acknowledge that they don't have any specific regulatory  authority to force manufacturers to tie their results to some gold standard, they can  (and will) hold them more accountable for the analytical performance and  clinical utility of their tests."

There is an opposing citizens petition that urges the FDA  to stop approving drugs where the diagnostics testing is not considered  adequately standardized to prove drug performance:

http://www.medicalnewstoday.com/articles/152084.php

Here is the short form of the meeting minutes from the FDA meeting on Omacetaxine and why they voted 7 to 1 against approval until they receive answers to their questions:

(Start at page 7)

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM207638.pdf

Quoting from the FDA meeting minutes:

"Major issues with this application are listed below:
1.
A single, small and incomplete efficacy study (CML-202) is submitted to support this application
Study CML-202 planned to enroll 100 patients; however, the NDA submission only included the efficacy and safety data from 66 patients. The Applicant continued to enroll 31 additional patients after the data cut-off for these 66 patients with a current enrollment of 97 patients. Thus, data from approximately one-third of the patients enrolled on this efficacy trial are missing from the current submission. FDA believes that any efficacy claims for the accelerated and blast phase cohorts are insufficiently demonstrated due to small sample sizes.
2.
One-third of CML-202 patients submitted to the FDA are ineligible per protocol-defined criteria
Thirty-five percent of CML-202 patients did not have a confirmation of their Bcr-Abl T315I mutation status by the central laboratories at the time of enrollment, a required study entry criterion. The regulations governing the contents of an NDA submission, 21 CFR314.126, state that for a trial to be considered adequate and well controlled, "The method of selection of subjects provides adequate assurance that they have the disease or condition being studied." The applicant did not meet this criterion.
3.
Assays with different performance characteristics were used at the two central laboratories to detect the T315I mutation
The Applicant used two different assays at the two central laboratories for the confirmation of T315I mutation status prior to patient enrollment. There were no bridging studies performed to support assumptions about the similarity of the enrolled patient population tested at each site.

Performance characteristics of an assay should be known prior to widespread use of the assay and drug use based on this assay. These characteristics include sensitivity, specificity, limit of detection and reproducibility of the test and its ability to identify eligible patients. Information for the assays to detect the T315I mutation has not been submitted to FDA's Center for Devices and Radiological Health (CDRH).
The lack of having a uniform in vitro diagnostic test creates uncertainty about patient selection both in this trial and, more importantly, in a post-approval setting. If a patient does not harbor the T315I mutation but is falsely identified as having such a mutation by these un-reviewed assay methods, the patient may not receive more effective, less toxic therapy, such as dasatinib or nilotinib. Conversely, patients with a false negative test result would receive an ineffective therapy.
4.
Low response rates observed in the efficacy study
Due to the single-arm trial design and lack of historical control to compare the efficacy results, the clinical meaningfulness of the observed low response rates is unclear.
5.
Safety concerns regarding the overfilled vial size
The Applicant has presented an overfilled vial size that contains more than twice the average dose of omacetaxine used in the efficacy and safety studies (CML-202 and CML-203). FDA has concerns about the potential for overdose as well as the environmental impact of drug disposal."

[cherylannes]

Hi Trey,

Let me respond to your post in bullet form to correspond with your points.  This way it will be easier for the over 2,000 people who have read this thread to follow what the issues are.

Your first paragraph, which we will call point one: Correct, the FDA do want to take a firmer stand.  That is what this petition is all about.  We are not in disagreement with this.

Paragraph two - This is a bit of a different situation than the one we are facing as there are labs in every university along with specialty labs that currently do Karyotyping, FISH and PCR for CML patients.  Standardizing this broad network so that patients can go to their local Hem/Onc and access these diagnostic tests is the critical issue here.  It is not as easy as creating a standardized essay.  I implore you to go and watch a PCR test be done for example, you will understand precisely why it isn't standardized as of yet.
 
As for your points listed under "Major issues with this application are listed below: (I am not sure where this quote ends as there is no ending quote on the sentence)

Point 1 - It is well known that the incidence of the T315I mutation is rather small - hence the need for the petition.  This patient group will go for transplants if there are available matches, and some patients have opted to go back to Hydroxyurea, this may have to do more with age than for the younger patients.  Several factors are at play in order to accrue patients for this trial.  However, that does not mean that the very specific needs of this patient population should not be met.  Again, it is about choice.

Point 2 - Precisely why we have this petition.  All of the patients in the trial had their T315I mutation confirmed at their local lab and this was corroborated by the rising PCR number (not standardized either), increase in FISH (not standardized either) and Karyotyping in some cases (not standardized either).

This is how the patients were accrued to the trial:  First they had to show through PCR (non standardized) and FISH (non standardized) that there was loss of response of the current treatment.  Then mutation testing (non standardized) was done to detect the presence of the T315I.

Point 3 - Exactly - assay's were different at two labs - they are not standardized.  Assay's are different in many labs for PCR's and FISH - they are not standardized!!!  But the concern that patients may not receive the other drugs is mute.  Even the FDA's own experts made the case very clear when they said the patients who have to show clear relapse via FISH and PCR which indicates that none of these other TKI's would no longer benefit the patient.  In fact it was pointed out that with the early Phase II trials of Dasatinib, when patients who had the T315I shoed much higher rapid selection for the mutation and needed to be quickly removed form the TKI.  The same thing happens with Nilotinib or any TKI.  It is unethical to keep patients with a T315I mutation on any of the TKI's alone as there is no clinical benefit to the patient.  If you read Patient Susanne Carrow's story on our website you will find that she was left on Nilotinib and IFN while she waited for this trial to start.  However, that combination would not have brought her back to CCR.  Omactexaine as a single therapy for Susanne did bring her back to CCR!!! That was three years ago, you might notice she posted here on this thread.  She has bought a precious three additional years with OMACETAXINE - tell her that she isn't worth it?  I certainly would not - I signed the petition.

Point 4 - low response rates in this patient population is an unfortunate situation. Bio medical ethics is my passion and I can say that for ethical reason's the trial can not be designed differently. There is nothing to currently treat T315I, this isn't like when Gleevec was being held to the IFN standard, there is nothing to treat T315I.

Point 5 - Regarding the overfilled vials.  My disclosure - before becoming a CML patient I was the product specialist & International and global Marketing Director for a very large injectable drug company - specifically contrast media for radiology, cardiology and nuclear medicine procedures.  We overfilled any liquid vials used to reconstitute lyophilized product to make up for the fact that it is often very hard to get the liquid amount out of the vial that was necessary to reconstitute.  My guess is that Omacetaxine is being provided in a lyophilized form precisely because there is such a small market for it and lyophilized forms have longer stability ranges.  Every single one of the patients that I met with have had no problem with reconstitution of the drug and self injecting. While we are on the subject of self injecting, Trey, have you specifically ever injected Pegylated IFN in the non reconstituted version?  I have.  I have reconstituted it myself as my dose was not in the range of the handy prefilled syringes.  Not surprisingly, the vial was overfilled.  This is usually done at the manufacturing level for a variety of reasons. To my knowledge no patient over dosed themselves, the range of the overfill is safe.  And one more point that all the patients I spoke to said, "Hey, when you are on your last option, you can do things you never thought you could do, reconstituting this drug is a non issue - it does what it is supposed to do".

 
What I find puzzling is why would one patient such as yourself, seemingly enjoying a good response to the therapy, would not just sign your name to a petition? The aim of which is asking for clarification and assurances that ALL FURTHER DRUGS TO TREAT CML are not unduly held back from the market and that patients can access them and smaller companies can still bring their innovations to the market.  The CML market is not owned by anyone other than we the patients.  And WE THE PATIENTS are SAYING that ANYONE who has ANYTHING to offer this patient group is welcomed to this market.

1002 signatures and counting - folks we need more!

Show your solidarity - if you haven't signed yet, please do so now!  We need as many drugs as possible to fight this insidious disease!
http://www.petitiono...E/petition.html

[Tedsey]

This is a very late response, but sometimes, I re-read and try to catch up, remember who is who, etc.

Thank you Phil for setting this straight.  What you say is true.  One of the best professors I ever had was from the U of Chicago, (not a slouch), and taught statistics.  He made me learn to love numbers, (but I only have a rudimentary knowledge of them).  However, he always gave us the caveat that the numbers are only as good as the study.  Through school, I had to analyze many a research study.  It is very important to look at every part to see how it was put together.  However, who has the time unless you are a publisher or grad student?  So, I rely on abstracts and outcomes (too much).  But publishers or study review boards don't always know.  Things slip by that look useful, but are not.  We just have to trust that researchers are ethical, and good at testing out hypothesis in careful and accurate ways, then apply the right numbers.  Research is good obviously.  And as fast as science goes today, what is supported over and over is the best bet, and that still takes time (obviously).  Anyway, it is hard when you feel you have to beat the clock.  But sometimes people accidentally come across what works or what cures.  Miracles happen (not talking about divine intervention, but would take it).  Ah-ha and eureka moments exist.  And I shall end with, because of research, TKIs are buying a lot of us a lot of time (even those of us who have to go to  SCT/chemo--the shot gun approach, using Trey's analogy, has kept many alive or cured).  Gotta take it for what it is worth.  Some research not so good.  Some well done.

[Trey]

Sorry if I did not make it clear that 100% of the paragraphs 1 - 5 were copied and pasted exactly from the FDA meeting minutes.  None of the paragraphs are my comments, opinions or additions.  It is simply provided as info for those interested in this issue.

[cherylannes]

The final and only quesiton the FDA asked for and voted on was the need for a standard test for detecting the T315I mutation.

I really hope that if anyone has had there interest piqued they go to the link below, and download the entire transcript.

Trey, you might want to know that we have consulted with the doctors at MD Anderson who are behind this drug.  We have been supported to do this petition which was our own idea, from every major CML expert in this country and indeed from many other countries as well.

You need to ask yourself why these top notch doctors believe in the urgency of this petition. 

Heres the link to the transcript, I hope more people read it: http://www.fda.gov/A...e/ucm195226.htm

Thanks to everyone who have signed it already - if you haven't signed it yet, please read it and sign it if you are inclined!

Cheers!

Here's the link to the petition:  http://www.petitiono...E/petition.html

[cherylannes]

Two very interesting videos from some top notch doctors regarding their thoughts on strategy for treating CML.

These are short video clips and very informative.

http://www.youtube.c...feature=related
http://www.youtube.c...feature=related

Enjoy!

Cheryl-Anne

[cherylannes]

Please read the "Live from ASCO" update in the new thread I started

Cheers!

Cheryl-Anne

[cherylannes]

We will be preparing the petition for presentation to the FDA ODAC committee next week.

Thanks to everyone who have signed it already - if you haven't signed it yet, please read it and sign it!

Join us in solidarity!  72 hours before the hearing took place is not the time to question testing techniques especially when none of the tests used to diagnose or monitor this disease are standardized.

Here's the link to the petition:  http://www.petitiono...E/petition.html

[jm2002au]

Cheryl, was the petition presented to the FDA successfully? Any feeling on the future of this drug?

Best wishes

Nathan

[cherylannes]

Hi Nathan,

So Sorry for taking so long to reply, we've been quite busy!

The petition was formally sent to the head of the FDA Oncology Drug Advisory Committee, Dr. R. Pazdur.  It was sent jointly by the CML Society of Canada and the National CML Society US.  We sent a covering letter outlining why we had started the petition and what we hoped to achieve.  The entire petition with all the names of the signatories was sent along.

At this point we are just waiting to hear back from them.  We sent it off last week.

We will keep everyone informed of the response and thank everyone who kindly signed the petition and helped with it.

Together we are one - ONE MASSIVE VOICE OF PATIENTS!

Cheers,

Cheryl-Anne

[cherylannes]

Update :

There is a press release out in the public domain dated July 14th, regarding the meeting that ChemGenex had with the FDA.

From the press release: "The recent Type A Meeting, which included discussion of a regulatory path forward,
addressed outstanding issues regarding the previously received Complete Response letter
dated 8 April 2010.

Based on the discussion with the FDA, ChemGenex intends to combine data from its two
pivotal studies, Study 202 and Study 203, and submit a New Drug Application (NDA) for
OMAPRO for those patients with CML who have failed prior treatment with two or more
currently approved tyrosine kinase inhibitors (TKIs). The proposed indication of this new NDA
will be for the treatment of CML patients who have failed two or more TKIs, regardless of
their mutation status.

"The FDA's agreement that a combined data set could serve as the basis of an NDA in a
third-line setting provides us with a pathway to an expanded indication for OMAPRO to treat
CML patients who are resistant to at least two TKIs," said Adam Craig, MD, Chief Medical
Officer of ChemGenex."

So this is obviously exciting news, but represents a delay none-the-less.

Greg and I feel that the petition was positive as it raised the issue of the lack of standardized testing and paved the way for a mutual agreement.

The good news is that this means now of course that all patients will have another option for treatment should they fail two or more TKI's.

Cheers,
Cheryl-Anne & Greg Stephens

[CallMeLucky]

Great work Cheryl-Anne!  If it helps one person, it's worth the effort.

[Trey]

Does that mean the FDA will not reply to the petition?

[cherylannes]

Hi Trey,

Actually I think that it means that the FDA got our message loud and clear!!!

This drug very likely will be cleared for any patient who has experienced 1 or 2  failures of other TKI's - a potentially much better situation than we could have hoped for.

Thanks to all that helped us!

Cheers!

Cheryl-Anne