Day 2 of the FDA Avandia Panel- Live Blogging the Morning


11:59: Marciniak claims RECORD suffers from “differential informative censoring”– a great way to influence mortality statistics!

11:57: Marciniak says the problem in reporting events was NOT at the sites, it was from the middlemen. Says GSK tried to influence adjudication.

11:50: GSK clarifying concerns about RECORD.  Nearly all diabetes trials are open label. GSK says apparent imbalance in adjudications is due to endpoint forms vs SAE forms. Also silent MIs were never an endpoint. Also GSK made every attempt to get vital status of patients.

11:42: Moss asks Homes about 2 GSK representatives on steering committee. Moss says on his trials we never let industry reps on steering committee. Homes notes that the steering committee was firewalled from the data. And also concedes that the data was transferred from Quintiles to GSK.

11:33: Furberg to Homes: unacceptable high number of patients in RECORD with missing vital status. “almost unethical.” Homes disagrees, says the number of missing vital status is similar to other trials. We’ve no reason to believe those lost to followup are any different from the rest of the population.

11:28: Gerstein won’t say how TIDE will deal with slower than projected enrollment. The Fleming-Gerstein exchange may be VERY important this afternoon. If the committee agrees with Fleming’s skepticism then it may be all over for Avandia.

11:27: Gerstein: more than a 1/3 of TIDE sites waiting for panel decision before enrolling patients. We think we can recruit the 15,000 remaining patients in 18 months.

11:25: Fleming to Gerstein: admires passion for RCTs but wonders about performance standards. TIDE enrollment goal is incredibly daunting. What is the acceptable time limit of the trial?

11:15: Kaul to Graham: not persuaded that the equipoise for TIDE has been broken. Aren’t the estimated risks within the bounds of ascertainment error? Graham: we’re going to have to agree to disagree.

11:13: Nissen to patient representative: important not to confuse tolerability with efficacy

11:05: Chair halting semantic discussion so committee can move on to panel questions to presenters. Let the questioning begin!

11:00: Here’s the wording of Question 2, which they don’t seem to like:

Considering the available data, do you find that rosiglitazone (choose 1):

are sufficient to raise significant safety concern

A. Increases the risk of ischemic CV events in patients with Type 2 diabetes relative to non-TZD anti-diabetic agents.

B. Does not increase the risk of ischemic CV events in patients with Type 2 diabetes relative to non- TZD anti-diabetic agents.

C. I am not able to make a finding AorB.

10:55: Konstam doesn’t like the wording of the questions, esp question 2. What level of certainty is required? Del Pan says committee members will set their own bar to answer these questions and they’re interested in the reasons for the members’ decisions.

10:51: Del Pan discussing the questions committee will be asked to vote upon. Here is a link to the questions.

10:49: Del Pan: Lots of different data streams to synthesize… We’re going to ask you to discuss the strengths and weaknesses of each. Separately address ischemic risk and mortality.

10:40: The real fun is about to begin. Gerald Dal Pan, Director of OSE, CDER, FDA will deliver the charge to the committee.

10:22: Sidney Wolfe talking. No surprise he doesn’t like rosi.

10:18: Yusuf asks why no meta-analysis of all TZDs? would avoid selection bias of doing analysis of just 1 agent. Any conclusion of short-term studies could be misleading. Yusuf says a large part of scientific community shares his views.

10:17: Letter from Salim Yusuf being read at committee. He’s co-PI of TIDE. Slamming Nissen meta-analysis.

10:10: Endocrine Society punts. Wants to retain choices for physicians but says FDA needs to evaluate the evidence. Click here for Endrocrine Society Statement.

9:43: Now the open public hearing. This might be amusing. 8 speakers scheduled. Chairman invites audience to take a break now.

9:28: Goodman/IOM report: torturous logic of noninferiority trials excludes people who understand the clinical issues

9:13: IOM report now being presented. Not specifically about Avandia. Coffee time.

9:11: Follman: GSK meta-analysis “unreliable and we should ignore it”

9:01: Follman raises 3 questions (from his slides):

  • Is the body of evidence sufficiently different from 2007 to change that decision?
  • Public Health. Should we think of the overall consequences of a market w/ versus w/o rosiglitazone?
  • Drug Umpire. For rosiglizazone is the evidence clear‐cut to approve or disapprove?

8:31: Dean Follman from NIAID now up. Slides. Speaking on strengths & weaknesses of different studies and designs.

8:28: Gerstein said 1,120 patients enrolled so far. Would be much higher without the controversy.

8:24: Gerstein conclusion: this discussion has implications well beyond one drug. They will effect how novel therapies are assessed. We can choose the easy way and make decisions based on epidemiology and small short trials. Or we can insist on high quality evidence from independent long term randomized trials that can provide unbiased evidence. Will we accept second best when we can do the best?

8:20: Matt Herper: “I am very sympathetic to Gerstein. I’m willing to grant equipoise to crazier ideas. But why wasn’t this done before?”

8:19: Marc Pfeffer is chair of the TIDE DSMB

8:17: Contrary to what was said yesterday: 70% of TIDE patients will come from developed world.

8:15: TIDE will have 84% power to detect a 17% TZD reduction in events. 80% power to detect 20% difference between the drugs. 100% power to detect 33% difference.

8:12: Gerstein: 2 primary outcomes of TIDE: a) Does adding a TZD (either rosi or pio) for up to 5.5 years reduce MACE vs. placebo? b) Is rosiglitazone non-inferior to placebo with respect to this primary composite outcome after 4.5 years?

8:06: Gerstein cites ACC/AHA statement that no association between rosi and heart disease. “You can’t rely on epidemiology studies. Epidemiological data such as we heard yesterday is fraught with biases.”

8:02: Gerstein: the uncertainty of yesterday demonstrates equipoise, and therefore the validity of TIDE.

8:00 AM: First up is Hertzel Gerstein on TIDE. Here are his slides.

7:49 AM: Day 2 is about to get underway any second. You might find it easier to follow this on twitter. Preliminary activities now underway. The real fun begins at 8 AM with the TIDE discussion. Click here for the FDA briefing materials.


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