New Orleans – it is rare to see a doctor publicly hang another out to dry, let alone an investigator in a clinical trial, but that’s what appeared to happen earlier today in the CLL press briefing at the 2013 Annual Meeting of the American Society of Hematology.

ASH 2013 CLL Media Briefing ASH 2013 ABT 199 CLL TLS Death blamed on Failure to Follow ProtocolReaders of this blog will recall that the phase 1 first-in-man CLL trial for ABT-199/GDC-0199 (AbbVie/Genentech), a selective bcl-2 inhibitor was suspended earlier this year after 2 patient deaths due to Tumor Lysis Syndrome.  It was shocking to many to hear that a 56 year old man on the trial dropped dead in his bathroom having been dose escalated straight from 150mg to 1200 mg of this highly potent drug.

In response to my question today at the ASH media briefing about the protocol that allowed such an aggressive dose escalation, Professor John F. Seymour, Chair of the Department of Hematology at the Peter MacCullum Cancer Center in Melbourne, Australia told the assembled media:

“There was certainly protocol specified monitoring requirements at 8, 12 and 24 hours after each dose escalation. The circumstances where the death occurred there was not vigilance around the monitoring of those results, nor action around some of those changes. So I think it was a combination of circumstances of previously unrecognized risk at a dose escalation step and inattention to some of the protocol required monitoring criteria.”

I was surprised by the above response, given that my question must have been anticipated by AbbVie, and presumably Prof Seymour was media briefed beforehand given the AbbVie “media minder” was in the press room.

The answer also raises the question of whether the trial was adequately monitored by AbbVie. All clinical trials conducted under an IND have to be monitored by clinical research associates (CRAs) employed by the trials sponsor or a Contract Research Organization (CRO) acting on their behalf.  Their job it is to ensure a site follows the protocol and that everything is conducted according to good clinical practice (GCP) standards.  Did AbbVie trial monitors review the monitoring requirements with the site, and follow-up to ensure these were complied with?

In addition to the ABT-199 single agent first in man CLL dose escalation death, Professor Seymour told the media about another ABT-199 death:

“There is another currently accruing study of combination of ABT-199 + Rituxmab and there was one death on that trial also.”

This has not previously been reported.

You can listen to Professor Seymour’s complete answer to my question in this SoundCloud:

After the press briefing, the AbbVie Program Director for ABT-199 sought to justify the dose escalation clinical trial strategy arguing that although they had seen tumor lysis syndrome in initial doses, they were not aware it could be a problem on subsequent doses, and that having dose escalated from 150mg to 800mg without problem, this justified a dose escalation from 150mg to 1200mg.  I leave it to readers with more experience in hematology to judge the merits of this approach.

As Professor Seymour noted, all the IRB and ethics committees in the trial did approve the study protocol, which raises questions about how effective these are at judging the merits and risks of first-in-man trials with novel agents or whether they are just a rubber stamp.

ABT-199 is an exciting drug with a lot of promise, but the AbbVie handling of the tumor lysis syndrome deaths remains a PR failure in my book.

Not only that, but what I think was an overly aggressive clinical trial strategy, irrespective of who designed it and signed off on it, cost the company several months of time in a highly competitive market when they had to suspend recruitment.

I have no idea whether AbbVie have sought FDA Breakthrough Therapy designation, but it’s hard to believe the FDA would consider granting it to ABT-199 in CLL while there are patient deaths and concerns remain about tumor lysis syndrome.

Professor Seymour will be presenting updated results for ABT-199 in CLL on Tuesday at ASH (Abstract 872).

Update December 14, 2013

ASH 2013 ABT 199 CLL Presentation 300x225 ASH 2013 ABT 199 CLL TLS Death blamed on Failure to Follow ProtocolPremium Content Subscribers can read about::

1) the ABT-199 phase 1 CLL results presented at ASH 2013 by Professor Seymour and the modified clinical trial design put in place when the trial resumed in June 2013: ASH 2013 Novel Treatments for CLL.

2) a new target for ABT-199 for which there is a strong preclinical rational: ASH 2013 BH3 profiling identifies new targets for Bcl-2 inhibitors.

3) the future potential of ABT-199 in combination with obinutuzumab (Gazyva) that was discussed in an interview with Deepak Sampath from Genentech that took place at the AACR-NCI-EORTC Molecular Targets meeting in Boston: Gazyva and ABT-199 in CLL and NHL, an interview with Genentech’s Deepak Sampath.

Update Jan 3rd, 2014: Study CRA says protocol violations and non-compliance were known and ignored by CRO & AbbVie

I was shocked to receive today a comment that you can read below by the former Clinical Research Associate (CRA) for the ABT-199 CLL first-in-man study who says the sponsor (AbbVie) and Clinical Research Organization responsible for study management both ignored protocol violations at the site where a patient subsequently died due to tumor lysis syndrome.

If protocol non-compliance was known to the CRO & Sponsor it’s hard to understand why those concerns were not acted upon and whether the patient death that occurred might have been avoided if they had been addressed or the site discontinued.

Given the public interest in ensuring that anyone participating in a clinical trial can be assured the protocol will be followed, and that trials will be run in accordance with good clinical practice (GCP) & Federal Regulations, I contacted AbbVie and Genentech (who are co-developing ABT-199/GDC-0199) for a response to the allegations made, which if true are quite shocking.

Greg Miley, AbbVie Vice President of Commercial & Health Communications did not respond to a voicemail left. Genentech Product Public Relations responded to an email sent to a company spokesperson by saying they would look into this. I will update the post when a corporate response is received.

Update Jan 6th, 2014: Genentech & AbbVie Response

This evening I received an email from David Freundel, Director of Public Relations for AbbVie, who offered the following reply on behalf of Genentech and AbbVie:

“Patient safety is a priority for both companies, and we take the conduct and management of clinical trials extremely seriously. We are reviewing the details raised in the recent post.”

 ASH 2013 ABT 199 CLL TLS Death blamed on Failure to Follow Protocol

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