22 replies to this topic

[Nath]

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I guess the FDA really does have something against this class of drugs.

When their to treat IBS that is, nevermind this class of drug has been used for years. It looks like we are still paying the price for the incompetent prescibing of Lotronex which is now 6-7 years ago.

[Kathleen M.]

"Endpoints" would have to do with what results you are looking at.So for something like diabetes or high blood pressure that is fairly straightforward. Significant change in blood sugar or pressure.What do you measure for IBS? I'm not sure there is an "industry standard" or even "doctor agreed upon" measurements for IBS-relief.Given that often the who the doctor thinks is better and who the patient thinks is better data do not always line up, it isn't that clear what you should measure all the time.I don't know that this is asking them to prove the disease exists, but to do something before moving on to decide what the appropriate measurements are. It also doesn't mean to me that "IBS is no big deal". Just it isn't the easiest thing to measure the improvement of, and maybe it is time to have someone systematically decide what measurements really are the ones to make. The FDA having been burned before may not be willing to just go with whatever someone did before is AOK this time and we aren't going to even bother to worry our heads about how you figure out if someone is better or by what amount.Like I said with IBS it isn't that straight forward. Do you look at quality of life endpoints, or do you just look at # of stools per day, subjective measurements of pain, or something more objective. Part of this is the whole problem of you can't really just take a quick blood test and tell if someone has IBS or not.I know in the past there have been a few papers that came out before a study that seem to be about proving the measurement device will measure something useful before spending the big bucks on the big trial.I don't know what endpoints they used for phase II, but if you pick the right ones sometimes you can alter whether something looks effective or not. Not knowing what the Phase II endpoints were (or what other companies really used before off the top of my head) I could see where one might want a review before doing the final huge study. After all if you pick the wrong endpoints it is really expensive to redo a few thousand patients. Even worse letting something be approved that doesn't help and ends up killing a bunch of people.I do not know if what they are measuring is somehow different than what went before, but one of the complaints about previous IBS drugs is that even though they are better than placebo, they don't seem to help that many more people. If you find the right endpoints you may be better able to demonstrate it works and lower the very high # of placebo response. Making it so you really know the benefits.The FDA is kinda between a rock and a hard place on the IBS drug issue, and I can understand why they may err on the side of over-cautious. Especially since they are accused all the time of being lapdogs of industry and approving whatever industry wants all the time.It's sad that politics plays so much of a role sometimes.K.

[jjohnson]

Nath,Good find, thanks. Where did you get this article? I checked both Google and Yahoo News this morning and did not come across this article. Any chance you could post a link?I think this is really unfair to Astellas and IBS patients. Just as a company can not alter the endpoints once they have been agreed to (such as by changing the definition of "satisfactory relief" midway through a study to distort the results) the FDA shouldn't be allowed to change the rules after the fact either. Astellas gave them what they no doubt asked for when the phase II protocol was agreed to. But I suppose the FDA can do whatever the hell it wants.As for validating the "disease itself," I'm sure Drs. Gershon, Drossman, Chang, Camilleri, Talley and hundreds of other extremely qualified experts could testify to the fact that it does really exist.

[Kathleen M.]

OK, I wasn't sure how it was defined. I trust you without the references IBS drugs are always going to be a problem after the Lotronex debacle.I'm not sure if "sexy" is what gets things taken seriously. After all asthma a few decades back was not taken seriously even though it kills people, it just had that "it's only a stress thing" attached to it as well.I do agree there is an uphill battle for any IBS treatment (and a few other diseases).I that this has happened for other drugs that there have been debates about endpoints. Especially for things that treat chronic illnesses that eventually kill you. No one can do the 15 year study to see if the death rates are different (and sometimes that gets done later, and sometimes it doesn't work out the way you expect like for HRT and heart attacks in woman). So you end up having to choose some other endpoint and sometimes there is debate about which one.Endpoints are not just an IBS problem, IMO, it even happens for "sexy" diseases as well. K.

[Nath]

JJ, I get the daily newsletter from thepinksheetdaily.com and grab their free 30 day trial when info on any IBS drug comes up, which is rare. Thats the whole article minus the info on other drugs they are developing and the usual general company info they add to the articles. I didn’t want to rip 100% of the article from a subscription site.Im in total agreement with JJ, their are plenty of other illness which have to rely on subjective means of evaluation, mental illnesses and chronic pain come to mind. I think we still suffer the stigma attached with IBS even after all the good work done to bring Lotronex back. If this was a "sexy" disease then it would be taken more seriously. Take the turn around the perception of anorexia in the past 10 years as an example.We generally suffer in silence, so there is no real pressure for the FDA to risk a Vioxx especially with Lotronex on their minds everytime a drug of this class comes up for review.

[jjohnson]

This report from Decision Resources lists Astellas' ramosetron and Alizyme's renzapride (a drug in phase III for IBS-C) as potentially the biggest grow drivers for the IBS market in coming years alongside Zelnorm. It doesn't mention anything about the recent snafu or any possible release date, but just thought the people reading this thread might find it of interest.http://www.medadnews.com/News/Index.cfm?articleid=412050

[jjohnson]

Kathleen,I think you raise a lot of valid points but all the same it seems hard to escape the conclusion that Astellas Pharma and IBS-D patients have gotten the short end of the stick here.GSK, Novartis, Solvay, and Alizyme were never asked to do these kinds of studies before their drugs were cleared for phase III. In this case, Astellas Pharma used the Rome II criteria and the "satisfactory relief" standard used for studies of previous drugs was also adopted for ramosetron.Based on what we know, I still can not think of any reasonable explanation for why these special endpoints, whatever they might be, could not be addressed as a part of the phase III program rather than an ex-post facto prerequisite to said program.I know that the FDA is still frequently considered a lapdog of the drug industry despite every objective piece of evidence to the contrary (e.g. the unending litany of "approvable" letters that bankrupt one small company after another.) This is a frequent accusation by the plaintiffs' bar and their "objective" mouthpieces like Public Citizen. But you'll have to forgive me if my empathy for the FDA is in short supply these days.

[Nath]

Astellas To Explore IBS Endpoints Before Advancing Ramosetron Into Phase IIIFebruary 01, 2007 Astellas Pharmaceuticals could enter U.S. Phase III studies with its diarrhea-predominant irritable bowel syndrome agent YM060 (ramosetron) as soon as the first half of 2008, Executive VP Toshinari Tamura told analysts during a third quarter earnings call Feb. 1.However, before the trial can gain approval, FDA has asked the Tokyo-based company to conduct an exploratory study to identify "special" endpoints for IBS, Tamura said. "They are asking us to review the disease itself and consider what would be the most appropriate endpoints and to validate those endpoints."In completed Phase II studies in Europe, YM060, a 5-HT3 receptor antagonist, showed "good efficacy using the endpoints we set," he said. Tamara said FDA has no problems with safety or with the data obtained with the European study endpoints. "They are satisfied with that - they are asking for additional endpoints."Novartis' Zelnorm (tegaserod), a 5-HT4-receptor inhibitor is approved for treatment of IBS with constipation. During a recent earnings call, Novartis Pharmaceuticals CEO Thomas Ebeling touted the blockbuster potential of the IBS therapy, which had sales of $561 million in 2006

[jjohnson]

Nath & Grant,I agree this is disheartening. Just what the hell does "explore and validate the primary endpoint" mean, I wonder? It almost sounds like the FDA wants them to do phase II all over again.I suppose we'll have to start looking at ramosetron as just one of several drugs that may make it to market somewhere in the neighborhood of 2010, with the exception that it already has some strong data supporting it and may be available in exactly one country (Japan) before that time. I just hope we're not all still here in 2010 with all the same dashed hopes wondering about the drugs that might be out in 2015.Anyway, Astellas still hasn't posted that webcast. If it is up tomorrow I should have time to give it a listen and will let you guys know if there is any information.

[jjohnson]

I'm very sad to report to you guys that it looks like the FDA has ordered Astellas Pharma to complete some sort of "exploratory study" before it can proceed with phase III in the US.This could delay the start of phase III by as much as a year or more. I will try to listen to the accompanying webcast tonight (hasn't been posted yet) and will let you guys know if there is any additional info.I guess the FDA really does have something against this class of drugs.http://www.astellas.com/global/ir/index.html(Click on Presentation Material for 2/1/07)

[jjohnson]

Kathleen,Actually,"satisfactory relief" is a defined term and is not as vague as you would think. I think it is something like more than 50% improvement in symptoms on more then 50% of the days studied. (I'll have to double check this.)There was some debate on this in the peer reviewed literature a few months ago, with some scientists attacking the standard and others defending it. I'll try to dig up some links tomorrow but I'm a bit tired right now.I think with some disorders there is by necessity some degree of subjectivity in determining the efficacy of drugs. For example, with PPIs they could measure healing in the esophagus but certain criteria are still pretty subjective, and at the same time, no one at the FDA suggested that, say, Nexium had to be evaluated by a different set of criteria than Prilosec had been some years earlier. And when it comes to drugs like antidepressants, we are entering a realm of almost pure subjectivity.I think you're right to point out that we shouldn't jump to conclusions based on what is written in short press release. I guess we should really wait and see but sometimes it's hard not to see IBS as being subject to a different standard than other illnesses.

[André]

Sad about reading this! Hope we have good notices about Ramosetron as soon as possible.I´ll try ondansetron. It´s the olny way that i can try here in Brazil.:/Best wishes for all,André

[jjohnson]

Kathleen,Thanks for taking my word for it without references. But if anyone is curious, here is an article by Whitehead and colleagues taking issue with the "satisfactory relief" standard:http://www.ncbi.nlm.nih.gov/entrez/query.f...l=pubmed_docsumAnd here is an editorial by from the same issue of Am. J. Gastro. on the subject by Schoenfeld and Talley. I seem to recall when I read this on the journal's website that they at least to some extent defended the standard, using the examples of alosetron and tegaserod. Not sure it really comes across in the abstract, though.http://www.ncbi.nlm.nih.gov/entrez/query.f...t_uids=16696786Nath,Many thanks again for retrieving that article. If it wasn't for you, we would still be totally in the dark about this.

[Kathleen M.]

It is hard to know what the logic is behind this particular ruling is based on a short press release kind of thing.However I think the pressures being put on them may be behind the we need to change the standard of what "relief" is for IBS.I'd rather see them put the roadblock up now to say we need to set the standard than have them do the tests and then be told that isn't the right endpoint.They might not be able to afford to redo all the tests."Satisfactory relief" is pretty vague, I would personally prefer something a little more objective, and I think there are some measurement protocols they could use from other research studies without having to spend years reinventing the wheel.I know it's frustrating when this nonsense goes on.K.

[pooman]

No doubt if it produced a 4-hour hard-on and caused hart attacks and strokes the FDA would have no problems with it. It all comes down to money and demand. Maybe we should all send a pile of poop to the FDA in protest.

[hanna]

Are we ever going to find 'satisfactory releif for ibs in our future?' with the way ibs is viewed by fda? Maybe or maybe not the next generation will have the smart drugs to treat ibs. What endpoints were/are used for ssri drugs to treat mental illness or depression? Ibs is said to affect about 25% of the population. Doesn't anyone who works in the fda have ibs, doesn't anyone???? If some top dog gets ibs then endpoints would change very quickly. Just venting.

[jjohnson]

"No major changes" in the development status of ramosetron according to the Q&A in the webcast that accompanies Astellas' annual results. The design of the additional trial required by the FDA for phase III clearance is in its "final stages," though the trial itself hasn't started yet.http://www.astellas....l/ir/index.html

[NHow]

Astellas got approval to prescribe Remosetron in Japan in Oct, 2008. Their website said it is for males...no mention of females. Does anyone know if/when it may be approved in the EU/UK or USA? And how about female sufferers of diarrhea predominant IBS? I thought women had it more frequently than men.

[jjohnson]

NHow -I've still been checking up on this drug from time to time and haven't really heard much. At some point they did mention that that additional study was almost done, which may have been like 6-8 months ago though I can't really recall (we had a newer thread on this drug that got lost when the board server crashed in November). Since then, nothing. The Japanese approval was good news but would be nice if they could get this drug to phase III already. Anyone remember when we once thought this might be out in 2008?

[John W]

Does anyone know of an online japanese pharmacy we can order Ramosetron from?