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Interim analyses and sequential designs in phase III studies
Approaches to interim analysis of cancer randomised clinical trials with time to event endpoints: A survey from the Italian National Monitoring Centre for Clinical Trials
Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial.
Hi JL,
I did not stated that the trial can not be stopped for efficacy after a quarterly review. I said quarterly review and interim analysis are not the same. Otherwise why they predefined the interim analysis. My view that for efficacy stop the quarterly review is not enough, they have to do the analysis also (check the stopping rule).
I did not say that none of the study was stopped before predefined interim analysis. I said I and nobody else on this board could find an example. I will be so happy if anybody could find an example, but until that we have to assume that no stop before 967 events.
Maybe ultima materia is exist ...
Pele scored 4 goals. In exchange, please do me a favor and find the study stopped before predefined interim analysis.
I am lost. Too late and full with:
Grappa bepi tosolni moscato
Carpaccio di manzo con ruccola e limone
Fricelli con tartufo e pera
"Ospiti favoriti" Crema di mascarpone con pan di spagna alle mandorle e salsa di cioccolato caldo
Tola Catarratto 2012
Sir, Yes sir.
Hi Kiwi,
My "estimates" was not based on eff%. Never mind it is 22% or 40%+, no stop before interim analysis, since none of the trial was stopped before first predefined interim analysis.
I hope I am wrong, but nobody could refer to any study that was stopped before first, predefined interim.
Sorry, but what would you like to say / suggest with this?
Meanwhile we are shareholders, we are not entitled to see all details, documents.
Hi b-,
Wow, It was so complex, but I will try:
This discussion will never bring the things better, but – maybe - we will understand it.
The condition of this determination "a substantial scientific issue essential to determining the safety or efficacy of the drug has been identified after the testing has begun" are exactly what they strictly are "the condition of the determination".
But the "the condition of the determination" are surely linked with the due registration - "in writing for the administrative record" - and the also due communication to "be provided to the sponsor" as well as "an opportunity for a meeting at which the review division director will discuss the scientific issue involved".
Your question "when was the “clock” started?" has a simple answer: the clock started when the FDA became aware of them.
Once again you shape a possible past using the present one.
The answer is "yes" for all of them, however possibility / assumption is not enough, FDA requests proof. They do not have to approve any drug based on possibility (especially if it is not an accelerated approval). It was "just" their previous, earlier practice regarding lipid-altering drugs.
Does Vascepa improve CVD symptoms? - We don't know (yet).
Fair is Fair; But Science is Science
Hi BioC,
The question was:
„Taking into account the described efficacy and safety data for Vascepa, do you believe that its effects on the described lipid/lipoprotein parameters are sufficient to grant approval for co-administration with statin therapy for the treatment of patients with mixed dyslipidemia and CHD or CHD risk equivalent prior to the completion of REDUCE-IT?”
If they asked:
„Taking into account the described efficacy and safety data for Vascepa, do you believe that its effects on the described lipid/lipoprotein parameters are sufficient to grant approval for co-administration with statin therapy for the treatment of patients with mixed dyslipidemia and CHD or CHD risk equivalent?”
The result / vote is the same. Improvement in anti-inflammatory/lipid parameters is not a target for this population, it is the tool to reduce CVE risk.
The problem (question) is that FDA did not announce their new approach (assumption is not enough, proof is necessary) in 2012. If they do it, Amarin could delay the launch of Vascepa till R-IT result (I am sure they do not launch it for Marine only if know that R-IT necessary for additional approval).
Nonsense this is a large market!
Amarin could have glided on as a mildly successful business with just the Marine indication alone.
Hi Kiwi,
I hope I am wrong and the DMC will recommend to stop before interim analysis, however I have doubt, since:
- quarterly reviews are not deep as interim analysis (ie.: did not check the stopping rule)
- all early stop were after - at least - the first predefined interim analysis
(Quarterly reviews are enough to stop due to safety or futility, but not for efficacy.)
As of today:
Median follow-up: 583 ds / 19,18 ms / 1,6 ys
15% - 561 events (258 / 303) - power: less than 90%
20% - 546 ( 243 / 303) - power: less than 90%
25% - 531 (228 /303) - power: less than 90%
30% - 516 (212 / 303) - power: less than 90%
35% - 501 (197 / 303)
40% - 485 (182 / 303)
Best,
G
b-
why this need to come up again and again with this discussion
Hi JL,
The agreement says a significant issue.
they have a responsibility to inform the counterpart at the earliest possible moment.
threat of opting out of the trial would have been more credible
If the FDA did not demand a 50% enrolled R-IT study in ANCHOR SPA, we are exactly in the same situation now. (Maybe rescission came earlier as sNDA could be submitted earlier). But FDA's demand did not affect anything else, R-IT was planned from day 1.
"The FDA demanded a 50% enrolled R-IT study, not a COMPLETED one" for sNDA (ANCHOR) submission.
Such notification would have given Amarin an early opportunity to end its study before it became overly committed.
Hi JL,
To avoid any doubt we agree that the decision was wrong, we have just different view regarding legality.
AMRN’s position is not clear / strong for several reason:
According to the Guidance for Industry / Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998), “When the pathophysiology of a disease and the mechanism of action of a therapy are very well understood, it may be possible to link specific pharmacologic effects to a strong likelihood of clinical effectiveness. A pharmacologic effect that is accepted as a validated surrogate endpoint can support ordinary approval (e.g., blood pressure effects, cholesterol-lowering effects) and a pharmacologic effect that is considered reasonably likely to predict clinical benefit can support accelerated approval under the conditions described in 21 CFR 314 Subpart H and 21 CFR 601 Subpart E”
TG is not a validated surrogate endpoint and it is not an accelerated approval.
Meanwhile I agree with you that the director could not make the determination without any new info (“just for fun”), the level / type / etc. of new info was not regulated by any guidance / policy (no requirement for significant information).
can not base a rescission on a change of opinion they have had about information that was known before the trial began.
The guidance contains the start date ( after the testing has begun) only. Nothing about the end.
new "significant" issues surfaced that raised safety or efficacy concerns
A clinical protocol assessment will no longer be considered binding if the director of the review division determines that a substantial scientific issue essential to determining the safety or efficacy of the drug has been identified after the testing has begun
SPA agreement contained a clause which allowed the FDA to retract, cancel or rescind the agreement if after the trial began, new "significant" issues surfaced that raised safety or efficacy concerns
I will update my calc. after 10-Q, but I do not think that they could be CF positive in 2015, however they could reduce the burn rate below $40M.
Good / excellent. I expected it around $20M. With $23,9M Q4 they will keep the promised $80M.
They extended the expiration of 10/16/09 warrants (from 10/16/14 to 02/27/15)
AND! the Q3 cash-flow was app. -$15.1M (cash is app. $135.4M on 09/30/14)
10Q will be released on 11/10/14
Thanks JL, it was a good find.
The IDMC usually consists of international clinical research experts, together with representatives of the sponsor and a medical statistician to provide results to the IDMC based on statistical analyses of accumulated data from all sites.
In a standard trial, safety and efficacy data are collected and reviewed by a data safety and monitoring committee during scheduled interim analyses.
Establishment of a DSMC: In life-threatening disease trials it is common to have a DSMC in the first instance from an ethical point of view. Apart from ethical and safety concerns, there are other factors that bring about the establishment of a DSMC, including the need for early stopping at the pre-planned interim analyses or need for modification to the trial design based on unblinded interim data analysis for adaptive trial designs, which tend to be more complex
BB,
I never said it's relevant to V. I said not relevant. (btw: it's not relevant to L neither since L is a Mixture and not a Fixed-Combination Drug)
Meanwhile ... done See post #36510 and 36511.
The question is not the "early stop", but "early stop before interim analysis"
Still no example ...
Since the composite measure used in this trial had not been evaluated in previous trials, two interim analyses were prespecified in the protocol to permit an assessment of the adequacy of the sample size without knowledge of efficacy. The specific techniques for assessing the adequacy of the sample size were based on methods described by Cui et al.43 The data and safety monitoring board met four times during the trial and conducted the prespecified interim analyses. The initial estimate that 800 patients (400 per group) were needed for the study to have sufficient statistical power (P<0.02) was modified to 1100 patients (550 per group) in March 2003 on the basis of the prespecified interim analyses
has been stopped early for efficacy based on a planned interim analysis showing that the primary endpoint of the trial has been met. ... The decision to stop FLINT has been based on the recommendation of the Data Safety Monitoring Board (DSMB) which reviewed liver biopsy data from before and at the end of the treatment period in approximately half of the 283 randomized patients, in accordance with a planned interim efficacy analysis.
Pharmacydude & ziploc_1 & BB,
Vascepa (and not Marine or Anchor or R-IT) was entitled for NCE, it is always started by the date of the first approval (in this case July 26, 2012).
FDA refers to the new policy / interpretation of active moiety of naturally derived mixture (one-to-many instead of one-to-one). I could not find any policy or guidance which dealing with this and I think FDA has right regarding this, since EPA is definitely an active moiety in Lovaza, HOWEVER it’ not relevant for NCE determination, since moiety is “just” an interpretation of the statue by FDA. As Amarin said: “FDA has improperly substituted the words “active moiety” for the statute’s words (“active ingredient”).”
FDA was always consistent to decide NCE based on active moiety, however it was rejected by court several times as the statue (USC) is stronger, higher level than CFR.
I do not know when, but the final court ruling will grant the NCE status to Vascepa for the period 2012 – 2017 based on statue and previous decisions. (ie.: CONFUSION PERSISTS AROUND DRUG EXCLUSIVITY AND PATENT TERM EXTENSIONS FOR NEW CHEMICAL ENTITIES)
btw: I think that the new Fixed-Combination Guidance, is not relevant to Vascepa.
Hi JL,
I did not talk about safety, just about efficacy.
The quarterly review is not the same as interim analysis. DMC recommends early stop based on stopping rules and this is "linked" to interim analysis.
I did not check all trials, but could not find any that was stopped before the first interim analysis.
Do you know any?
Early stopping of randomized clinical trials for overt efficacy is problematic
The possibility is zero, before DMC recommendation - if any - based on interim analysis.
I am saying that at their quarterly review, the data monitors would never stop the study before the interim analysis, no matter how efficacious the treatment was in comparison with placebo..
even if very persuasive statistical significance was already achieved
Hi Kiwi,
I will be slow to understand: n o s t o p b e f o r e i n t e r i m a n a l y s i s . . .
I did not say anything about why R-IT will be successful. I leave the science for you and JL.
I said, as FDA is focusing on lipid disorders, w successful R-IT, TG will be accepted by FDA as validated surrogate endpoint and TG lowering drugs could refer to R-IT.
(Correct me if I am wrong but LDL-C drug does not have to run a own, outcome study for approval.)
It was " ". I just said that analysis will be done at 967 events independently from eff.%
Central European
Eff.% is not "important". Analysis will be done at 967 events.
YTD:
523 events (224/299) with 25%
541 (242/299) w 15%
follow-up: 1,55 ys / 18,6 ms / 567 ds
Maybe ... but it was the primary ep in ANCHOR. LDL-C was accepted / validated ...
And what are the lottery number?
I hope we will hear something before the CC. If it will be during the CC: worst case (finish R-IT) or no info yet.
R-IT will / could be approved if FDA will accept TG as validated endpoint. If it is accepted other drugs could refer to it ...