Questions regarding the FDA 'reviewers"...

[savzak]

These are questions I’ve had since I read the briefing documents and the same questions re-occurred as I watched the blogging on the 1st during the ADCOM.
 
First, if there had been no ADCOM, would these same reviewers still have reviewed the application and commented on it for purposes of approval consideration? I assume so. The FDA obviously has to have the application reviewed and evaluated and there is no reason to think one group does it for an ADCOM and another group does it for approval purposes.

Second, what is the scope of the reviewers job duties in the context of an ADCOM? My guess: The FDA scheduled the ADCOM for a reason. Either they wanted responses from the committee on genuine concerns or they wanted cover before approving Afrezza. Either way, the reviewers job is to play the role as an advocate on the negative side, knowing full well that the company will advocate the other way. The point is to make the committee see the good and bad of each issue before they make their recommendation. It would do the FDA little good to have an ADCOM if the FDA representatives are just going to come in and agree with the sponsor that the drug is wonderful and safe. To get a meaningful decision (and one that gives the FDA the cover they are likely looking for) they need to take the negative side of the issue in the documents and in the presentation.
 
Finally, assuming the reviewers comments were genuine and they really are skeptical of efficacy and all that, what is their roll in the actual approval decision? Is there job limited to reviewing the application and producing the brief for the ADCOM? Or do they sit on the committee that actually makes the decision on approval?

If anyone has any knowledge on these inner workings at the FDA, I would appreciate your thoughts.

Thanks.

[esstan2001]

savak,

you've made a very reasoned assessment and I can not add other than to speculate that the reviewers will take their (adjusted for the Adcom) recommendation to the supervisors, which make the decision.

The only comment I can add, from watching 4 AdComs and a reading a lot of review and commentary is that:
there has been a lot of staff turnover at the FDA.
The experienced old salts are mostly gone.
In their place, mostly green kids.
A lack of continuity of knowledge about drug history in reviews due to the dearth of experienced staff.
A mandate to protect the public from risk of ... [fill in the blank]

The evolved purpose of the AdCom has become (IMO) to provide a blanket of cover for the FDA.
Having said all this, I still do believe we do get the nod (even after Al gave Margaret Hamburg a hard time a few years ago on how FDA aversion to risk has entirely been blown out pf proportion). 

[babaoriley]

The hearing was distasteful to me as being too adversarial. Nothing wrong with pointing out issues, stating facts, but to look really hurt and upset when their side "lost" - that just doesn't sit well with me. The FDA is supposed to help in the process of bringing drugs and devices to market that can help people in need. These "green" kids as esstan properly characterized them, were about winning; maybe it's just human nature and simply can't be helped, but, again, it just didn't play well with me. Those FDA "kids" all looked as if they were participants in the Hunger Games, for goodness sakes!

[harshal1981]

Reviewers' job is to rip apart companie's claim. They are employed to have "guilty unless proven otherwise" attitude. They do not make decisions. They prepare a review report for decision makers. There are minimum 8 decision makers on any drug. It looks very similar to AdCom panel (Endo / Onco/ Pulmo etc., Device, Toxicologist). The decision makers are seniors in general. Their job is to take objective view at the sponsor's application just like AdCom panel.

Now howmuch politics palys role in decision review at FDA, god only knows. Time and again, reviewers blow the whistle when controversies are created due to negative side effects of drugs that are approved by FDA (Vioxx / Ketak). Which is bound to happen when reviewers had pointed out sever side effects but some how politics may have played its role and decision makers approved it. (or it may be the case that decision makers really gave the drug benefit of doubt and approved it, but then drug killed several dozens of people before FDA could pull it back and hence it is kind of "after the fact" scenario when junior reviewers try to "blow whistle" and claim that we all said no and they still approved it).

In our case, Cancer risk is there but it is well within FDA's risk appetite. Look at any GLP-1 diabetes drugs including Victoza. Victoza infact showed cancer signs in mice and rat models as well as during the trial and it still was approved. In Afrezza's case, two non-smoker cases were age of 70 when lung cancer risk is very high. Those who argue that from probability view point, there has to be 2 such cases on placebo arm as well... but then they forget the theory of probability - chance of 50:50 is true when you have infinite events. Meaning, if toss a coin 4 times, it may not show 2 head and 2 tails. In fact there may very well be a case when it may show all 4 head or 4 tails. But eventually they will balance to 50:50 when you have 1000 or 10,000 tosses (infinite events for practical reason).

Any way. I think approval is kind of inevitable now but couple of more cases of lung cancer reported in non-smokers and the drug revenue can potentially come to virtual zero in few weeks. That risk and uncertainty will show some weakness for sure in SP until at least a year.

[babaoriley]

Fine, harshal, but I don't have to like it!!! LOL!

"Any way. I think approval is kind of inevitable now but couple of more cases of lung cancer reported in non-smokers and the drug revenue can potentially come to virtual zero in few weeks. That risk and uncertainty will show some weakness for sure in SP until at least a year."

Yes, indeed, harshal, ELAN comes to mind as a drug that had set sail and ran aground abruptly, can't remember exactly what bad thing they found, but stock absolutely cratered. Take profits along the way.

[harshal1981]

did you see the slide that FDA presented about Exubera's priscription vs. month chart? It showed steep decline after they announced 4 cancer cases. and of course, dropped further when they announced they are discontinuing product.

[jpg]

Hi Harshal,

I was around and actively following this as a physician when Pfizer pulled the plug. I would say it was the other way around and that Pfizer seemed to have done this lung cancer thing on purpose. I remember having been very surprised by the speed at which they moved on this and with the very weak information they had. I think they wanted to stop selling the drug and that the easiest way to do this was by 'taking the high road' and basically follow a scotrch earth policy to the whole inhaled insulin field. Pfizer at it's corporate best basically. Contrast that to the very big fight they put up when Lipitor came up as being associated with cancer. Who here even remembers that statins and Lipitor might be associated with cancer?

Basically they agressively publicized and blew up their own product. I am certain they would have been a bit more 'introspective' had the sales been 10 times what they were. i think this will be one of the 2 new shorts battleground.

JPG

[harshal1981]

JPG. I do see your point here. I think they must have realized that this Jumbo inhaler is not going to pickup sales no matter what so they took the excuse of cancer cases (all in smokers) and made and exit. Publicizing cancer risk also likely played a role in Lilly's and Novo's decision to kill their inhaled insulin programs as well. May be also the fact that once they knew Pfizer is no longer going to eat their share, they had no motivation to continue investing in inhaled insulin program when cancer risk perception is so high. May be they couldn't justify to board/share holders after negative publicity from exubera. I remember readinga a very good article about devices that Lilly and Novo were working on and they very pretty bad in terms of user interface too. So it see your point that exubera exit may have been very well executed strategy on Pfizer's part.

Well, in any case, I just hope that we never see any non-smoker cancer case in below 70 age patient and we should be all good. SEER data clearly shows lung cancer risk is exponentially high in higher age group of 65-80. So FDA will panic less if they see more non-smoker lung cancer cases in that age group.