I know that you will all be surprised to hear that I have not had a response from Kathleen Sibelius, nor from the FDA for that matter. I did hear from the FNIH group however. They were upset that I seemed to dismiss their effort before the results were out in the form of docket submissions. Although I remain skeptical, I await further developments and I am truly not dismissive of their efforts – just skeptical and more than a little frustrated. I also recently received a copy of the IDSA submission to the FDA docket on the Draft Guidance on HABP-VABP kindly provided by the IDSA. (The submission does not yet appear on the regulations.gov website so I cannot yet provide a link for you). I am afraid that I once again lashed out in frustration for which I must apologize to IDSA. That said, I am disappointed in their watered-down response to the FDA on the proposed endpoint of 28 day all cause mortality. Here’s what the IDSA says.
IDSA concurs (see our position paper) that, based on currently available data, all-cause mortality is the most appropriate endpoint for a NI HABP/VABP trial. This position is based on the well established effect size of active antibacterial therapy vs. inactive (i.e., “discordant”) therapy for HABP/VABP using a mortality endpoint. Unfortunately, despite active investigation of available datasets and literature, there are very few data currently in the public domain which establish an antibacterial effect size for any non-mortality, clinical endpoint. However, mortality is an insensitive endpoint (i.e., less likely to detect true differences in antibacterial efficacy than clinical endpoints), and clinical response is the preferred endpoint clinically. Therefore, IDSA urges industry and academe to conduct new studies, and reevaluate existing datasets, to establish antibacterial effect size for clinically meaningful endpoints. Upon completion of such analyses in the future, IDSA urges FDA to move rapidly to enable NI studies of HABP/VABP to use clinical primary endpoints.
In my view, the last thing we need is to await more studies before we rescind the use of the mortality endpoint. As noted in a previous blog, the current construction of the trials and called for in the FDA guidance is completely infeasible and should be immediately changed to the more feasible clinical endpoint until such time as some other endpoint is shown to allow for feasible trials. In the meantime, one of our most critical needs for new antibiotics, nosocomial pneumonia, will go without any new development for the foreseeable future at least in the US. Is this what the IDSA wants? Is this what any of us, including the FDA wants?
Why is it so hard to construct trial designs that can be done on planet earth? Why do we feel the need to change an approach that has served us well for the last 20 years? Have we approved ineffective antibiotics?
Europe recently completed its Scientific Advisory Group meeting on antibiotic development. If they go the way of the FDA, we are truly lost. But here I remain optimistic. As long as the US market share for antibiotics continues its inexorable decline and other markets continue to emerge, and as long as there is a way forward to register new antibiotics in these markets via Europe or other regulatory agencies, there is hope – just not for Americans.
Comment from Brad Spellberg, IDSA Antimicrobial Availability Task Force:
ReplyDeleteFirst, I can’t of course speak for anyone else, but to me, there is absolutely no need for you to apologize! You are passionate about this topic for very understandable reasons. I can assure you that I was not offended at all by your e-mail or any of your blogs.
Second, re: HAP/VAP, I do not agree that mortality, by itself, is infeasible. In some ways, I think mortality is easier to show non-inferiority than clinical. Think about it this way. The chief argument that many make against mortality is that it is affected by many factors (i.e., underlying disease) other than the HAP/VAP, and that therefore many non-antibiotic factors affect mortality, which makes it hard to discern an affect of antibiotics for mortality. In a superiority trial, that indeed would make it hard to show that antibiotics had an effect. In a non-inferiority study, the exact opposite is true. Remember Bob Temple’s famous saying, “The easiest way for a sponsor to show that its new drug is non-inferior to a standard comparator is to enroll patients into the study who don’t have the disease being studied. That way neither drug will work and the new drug will be non-inferior to the old drug.” So, if many factors mask the effect of antibiotics in both arms, it will be EASIER to show non-inferiority.
We of course do agree that mortality is INSENSITIVE for distinguishing less effective from more effective drugs, and that clinical response is more clinically relevant and desirable. But, frankly, it is absolutely impossible, on any scientific basis, to argue that one should do non-inferiority study for clinical endpoints when there are no HESDE for clinical endpoints for HABP/VABP. If we push the argument for clinical endpoints absent HESDE, we lose all credibility. It is on sponsors and academia to create HESDE for clinical endpoints to enable such endpoints in a HABP/VABP study.
Finally, you should know that there has been some serious soul searching by yours truly, as I think you know, on this whole FDA issue. What I found when I corresponded with other members of our task force, is that similar feelings of frustration were present. I think our general feeling is that FDA is not movable on any of these issues, and that it may well come down to the need to hurry them to finalize their guidances so that the clock begins ticking on sponsors submitting protocols. When FDA sees that no protocols are being submitted, they will have no choice but to modify things. Short of this, none of us have been able to figure out to make them “grow a backbone” and stand up to do what’s right.
As for me, I am 100% supportive of every statement you’ve in your blog.
This comment has been removed by the author.
ReplyDeleteBrad's reply -
ReplyDeleteMy response is that I am not comforted either. I agree with you 100% that allowing things to grind to a halt by releasing infeasible and irrelevant guidance documents will kill American citizens, period. It is bad for our patients. That is IDSA/AATF’s primary concern. The question is not, are we comforted? It’s what to do? We have tried every conceivable mode of communication we can with FDA at all levels. We have spoken to Congress directly on this issue. We have written scientific articles on this topic. We have presented at FDA AIDACs, at numerous public workshops, etc. You and I both wrote books on this topic. I’ve been on Katie Couric, Dr. Oz, and The Doctors on syndicated television talking about this stuff. Nothing has worked. I wish we knew how to make a movie, a la Al Gore, but alas that is a skill set that is beyond me, personally.
I am at a total loss as to how to get this message across. And my conclusion is, quite simply, that the primary concern (whether consciously recognized or not) at the agency level is to not be called up before Congress to get blasted about Ketek part 2, and not to be written up in the NY Times for Ketek part 2. If you consider things from that perspective, every decision made and guidance released makes perfectly logical sense. The FDA has fallen under the Jedi-mind-trick-like powers of radical skeptics, and those inside FDA who recognize that this is illogical, unreasonable, and crazy are just not in a position to make a difference. So, for now, we appear to be stuck.
However, it is reasonable to think that as resistant organisms kill more Americans every year, and fewer and fewer new drugs make it to approval, and protocols are not presented to FDA, that FDA will indeed be forced to rethink their position on these issues. That may be where things go. Not because we want them to, but because we’ve tried everything we can to change things and we have not been able to find a way that works.
Mortality is not infeasible in and of itself – I agree. But it is infeasible at a 10% NI margin or an OR margin of 1.67. If they increase the margin to 15-20% - OK. And such a margin is, in my view, quite justifiable. But I agree that mortality is still insensitive.
ReplyDeleteSo why put an infeasible design out there? Why not keep the old design while awaiting the studies you suggest rather than putting an impossible design into a guidance document? Sorry – I do not understand their reasoning – especially in the current environment where companies are merging and/or shutting down antibiotics research at an accelerating pace.
I would have preferred that the IDSA pressed FDA for a feasible design altogether or to simply rescind the new guidance. I was and am still disappointed.
By the way – no phase III protocols being submitted is not good for anyone – not the FDA, not IDSA, not American citizens, not the world . . . And what makes you think that they will modify their stance even then? And if they do – won’t it be too late? The clock is ticking on the entire antibiotics R&D enterprise and I’m afraid that there is no superhero to save the day.