Mannkind Slammed: No Guarantees in Drug Safety

As mentioned previously, I would have to say that Mannkind (MNKD) is in big trouble. I’d never heard of the company until the Wonder Drug Factory was closing back in Connecticut, but Mannkind was moving some of their operations into the state around then and interviewed a number of my former colleagues.

The whole inhaled-insulin idea had already taken some pretty severe blows. The massive failure of Exubera was the biggest, although a creative person could always argue that a better product with a more convenient delivery system could succeed in its place. But then Novo Nordisk (NVO) and Eli Lilly (LLY) (serious diabetes players, both of them) got out of the area before they’d even launched, deciding that it was better to write off their whole investment than to try to bring it to market. That didn’t help, which is one reason that Mannkind stock was down in the single digits, despite the company's efforts.

Well, as of Wednesday it’s down in the really low single digits. And I honestly can’t see how they’re going to revive their flagship program if the Pfizer (PFE) lung cancer data are real. The FDA is going to be very, very cautious about allowing any sort of inhaled insulin trials to proceed. I’d think that you’d have to show that your product is different from Exubera in its carcinogenic risk just to get one off the ground, and frankly, I have no idea how you’d do that. Anything that could will take years to develop and validate.

This latest result also shows some of the real difficulties and risks of drug development. After all, Pfizer and Nektar spent a very long time developing Exubera. The product was delayed and delayed while more and more clinical work was done. But in a slow-starting condition like lung cancer, those years may still not be enough to quite pick things up by the time a product makes it to market. Think of what might have happened if Exubera had been a success. . .

And that brings us back to the regulatory pre-emption topic of the other day. This illustrates why either extreme of that argument is untenable. On the make-‘em-pay side, you have trial lawyers arguing that if companies just wouldn’t put defective products on the market, well, they wouldn’t have anything to worry about, would they? Test your drugs correctly and things will be fine! But Exubera’s pre-approval life was as long and detailed as could be. The testing went on and on – and after all, insulin itself has been on the market for more than half a century. What more would a company need to say something is safe?

Then there’s the other side – total pre-emption, which says that the FDA is there to regulate and sign off on safety and efficacy, and by gosh we should have them do it. Once this mighty agency gives its stamp of approval, that settles it. But again, the FDA put Exubera through all kinds of paces. If every drug took that long and cost that much to develop, we’d be in even worse shape than we are now, believe me. So what’s the agency to do?

The truth, as far as I can see, is that no one can guarantee the safety of a new drug. If you want to take that further, guaranteeing the safety of an existing drug isn’t possible, either. Every known drug is capable of causing trouble at some dose, and every known drug is capable of causing trouble at its normal dose in some people. Every new drug has the possibility of doing things no one ever anticipated, once it gets into enough patients for enough time. Every single one.

Complete safety doesn’t exist, and never has. You can have more safety, if you’re willing to take enough time and spend enough money. But you can take all the time we have on earth, and spend all the money available, and you still won’t be able to promise that nothing bad will ever happen. Pretending that either the drug companies or the regulatory agencies can make that fact go away is a position for fools and demagogues.

Comments

[North Observer:]

I really don't understand what the fuss is all about! The numbers provided by Pfizer were 6 cases of lung cancer in 4,740 subjects. This translates to approximately 0.1%. The national average of the incidence of lung/bronchus cancers falls between 0.06 and 0.08%. In African Americans, the rate is approximately 0.1%. In smokers, which I understand were amongst the 6 reported by Pfizer, the incidence of lung/bronchus cancers is 23 times (men) or 13 times (women) higher. I am not an epidemiologist or a statistician, but it's obvious that the 6 out of 4,740 is NOT as alarming as it is made to be. (numbers taken from the CDC Fact Sheet, 2006 and the 2004 Surgeon General's report).

2008 Apr 11 01:47 AM

[Reclined:]

Well said, North Observer,

our society is obsessed with risk. With the regulatory process one can be pretty sure of not missing any MAJOR risk. Of course, there might be minor ones that will be discovered later (and pharma is much better organised to discover these than, say, toy manufacturers) and then one can still pull a drug off the market or amend its label. Since the risks are minor, little harm is usually done. But don't try to explain that to a politician who faces TV pictures of sobbing victims and the resulting public outrage.

2008 Apr 11 02:29 AM

[Ward - drXeNo:]

Hello Derek,

The topic of drug safety and the function of the FDA have been two prominent topics with my friends and I over the last few months...yes, this is what we chat about on a Friday night over some glasses of wine!

We agree that while the FDA is not necessarily to be lauded for all of their past efforts, they are significantly ham stringed in their efforts to monitor drug safety for the general public.

While I don't have a full solution worked out as of yet, I can provide some critique of the current system. The single biggest issue for the FDA is that they have no incentive for approving a drug.

Now don't get me wrong, as someone who spends their day life in the biotech industry, it infuriates me when I read about how big Pharma and biotech are only out to stiff sick patients who don't know any better...I sympathize with the FDA's plight despite the perception that all drug companies resent their administration.

Obviously, the staff at the FDA want to help patients...as do we in the drug industry, in fact it's an obsessive force...that is why we are able to sometimes work for 24+ hours straight to get that piece of data that can change a patient's life months or years down the road. What I'm trying to emphasize in this era started by Vioxx, is that the FDA has no other public incentive to approve a drug that can save lives or significantly improve the quality of life for a patient.

If a drug is rejected, the drug company gets hammered and all of the press is usually focused on their stock price. If a drug is approved, the lead scientists and PI's are lauded for their acute scientific acumen and the FDA is ignored. If a drug is approved and ends up being a huge public health disaster, the drug company is hammered (the stock price is mentioned) and the FDA is crucified for ever even considering that the drug could be of any use to the public. Thus, the FDA is then pushed to either condemn a drug or be neutral and ask for more data rather than risk an approval, which as you very eloquently point out above, is never a guarantee of safety no matter how long you study the drug or examine its data.

As I mentioned before, I'm still working on a suggested solution (I resent people who complain, yet do not provide any analysis to back up their complaints or new solutions), but I did want to add to your very perceptive discussion of drug safety.

Thank you for your article!

2008 Apr 11 02:31 AM

[North Observer:]

I have a few more questions. Is the 6 out of 4,740 fraction higher the national average? To answer that question, I would like to know the answers to the following questions:
1- Do the 4,740 subjects represent a true cross section of the population?
2- Were the geographic variations taken into account in determining the significance of that fraction...we know cancer shows geographic variations. For example, other than smoking, what fraction lives in 'smoggy' urban centers?

It is true that too much of any drug can be toxic....even too much oxygen is. But in these trials, I doubt that who are running them allow the subjects to inhale toxic levels of a trusted compound like insulin. Let's take the case of penicillin. Unlike insulin, this chemical is produced by a microorganism. A significant fraction of the population is allergic to it, in some cases fatal, yet it has been in use for over 50 years.

My point is that it was careless of Pfizer to release such 'unqualified' data. At the present time, Mannkind Corp is the only remaining player in the inhaled insulin business. When the product gets the FDA approval, which I have a feeling will be in the next few months, Mannkind will have no competitors. With the negative publicity of Pfizer'a own product, they will not be able to go back into the market.

2008 Apr 11 02:35 AM

[capgain:]

North Observer's points are cogent and, unfortunately, probably prescient. Six long-term smokers developing lung cancer is statistically significant? I think we have witnessed a knee-jerk reaction by a "player" that was not really commited to a long term investment. There are now two big "what-ifs". The first is Alfred Mann's resolve to continue pouring his own treasure into this dream; the second is an even bigger hurdle.....finding a marketing partner with the vision and fortitude to prove the nay-sayers wrong.

2008 Apr 11 10:23 AM

[North Observer:]

capgain
you guess some right and you guess some wrong. I am a player but I am also commited to long term investment. I have been with MNKD for over 8 years. Regarding the 6 subjects, I don't know if they were all long term smokers....I don't believe that information was disclosed, and correct me if I'm wrong. I would share your concern if all 6 were long term smokers and all developed lung cancer following use of the product. Reason being is that the product would appear to show specific and synergistic effect to the use of cigarette smoke (Which I believe has more carcinogens than the chemical in the product - insulin)!. Even with cigarette smoking, including second hand data, all we prove is a "CASUAL" relationship. I dare any scientist in the world to show statistical significance of the cancer in those 6 subjects to the use of that product, only if there were non smokers amongst them. Again, if the incidence was observed ONLY in smokers, then I agree that a statistical significance may in fact be there.

2008 Apr 12 12:50 AM

[North Observer:]

capgain
by the way, if you're trying to work out those numbers yourself, you will need to show a 'statistically significant DIFFERENCE' between the fraction of 6/4720 and the national average of ~80/100000; taking into account demographic and geographic variations.

2008 Apr 12 01:14 AM