Pharma’s Cutting Edge

Avastin Distribution Change - Open Letter

I read today’s WSJ Health Blog on Avastin thinking that Genentech had appeased eye specialists by maintaining distribution of Avastin to compounding pharmacies, but after reading the above open letter, I’m confused about Genentech’s actions in the recent past and about what it’s planning to do in the near future.  Take a look and let me know if you share in my confusion.

The decision we communicated [to cease Avastin distribution to compounding pharmacies] was not made lightly. In fact, it was guided by our company’s strong commitment to take actions that are scientifically and clinically sound and in the best long-term interest of patients, while at the same time adhering to government regulations and remaining mindful of the retinal community’s views.

The above open-letter snippet suggests that Genentech was motivated by their concerns around the safety of Avastin formulated for intravenous delivery being delivered ocularly.  They make this explicit later:

Genentech’s decision was not motivated by a desire for increased profits. We did not and do not expect that this change in policy toward compounding pharmacies will lead to any increase in LUCENTIS® (ranibizumab injection) sales. Further, we expect Avastin to be available and that physicians will continue to prescribe it for ocular indications.

So far, so good.  Genentech is making a logical argument.  Essentially it’s saying that, like Hippocrates himself, Genentech aims to first do no harm.  Fair enough, although I think it’s disingenuous of a for-profit company to imply that an important decision can be divorced from a business case, but I’ll leave that for a future discussion.

Then we get the news that FDA had inspected Genentech’s manufacturing facilities (just when, relative to the company’s compounding-pharmacy decision, we’re not told), and Genentech reacted:

…[W]e destroyed four batches of Avastin deemed unsuitable for use in the eye due to a higher visual inspection standard. (These lots would have been entirely suitable for its approved use as an intravenous cancer medication.) The action resulted in the loss of more than 350,000 vials of Avastin with a market value of more than $200 million.

Now I’m lost.  Why would Genentech have to destroy $200 million of Avastin stock intended for use as a cancer therapy (albeit used off-label for other uses, included ocular uses) to appease FDA inspectors?  Is Genentech saying that FDA mandated that Genentech produce a product capable of withstanding the same visual-inspection standards required of ocular drugs and that Genentech relented to this mandate without fighting it?  Is that what Genentech is saying?  Okay, let’s say that’s it for arguments sake.  What happens next?

The letter implies that sometime after this self-imposed drug destruction, Genentech made its compounding pharmacy decision and soon after that met with key opinion leaders to revisit the decision (N.B. no mention was made of FDA’s involvement at this KOL meeting).  Genentech communicates publicly after this KOL meeting that it will continue to supply Avastin to compounders until at least January 2008 and maybe longer if FDA approves. 

In contrast to what was earlier implied by the juxtaposition of the FDA manufacturing/packaging audit and destruction of drug, this latter sequence of events suggests that Genentech’s Avastin destruction was voluntary, not FDA imposed.  Why else would Genentech be able to decide unilaterally to continue supplying Avastin to compounding pharmacies–without FDA approval to do so–beyond November, the original date of its distribution cessation?  If FDA had ordered destruction of Avastin they would have also, it would seem, had to approve continuation of its supply to compounding pharmacies.  Yet, no mention is made of such approval.  Indeed, Genentech states that it will continue shipment of drug to compounding pharmacies after January only with FDA approval, again suggesting that FDA is having some say in how Avastin is distributed (or packaged for distribution to compounding pharmacies).

So, I’m left with a bunch of questions that leave me wondering what really happened here and what is going to happen come February 2008:

What did FDA actually find during its audit and what specifically prompted the destruction of a large amount of Avastin intended for use in oncology?  Was the destruction voluntary or FDA-mandated? What alternatives to destroying the drug were considered?

What changes to manufacturing/packaging were made following destruction of the drug, and how will such changes affect distribution to compounding pharmacies? 

Is an FDA ruling on manufacturing/packaging changes both necessary (as implied in the open letter) and sufficient for Genentech to extend distribution of Avastin to compounding pharmacies beyond January 2008?

Is Genentech planning to change the cost of Avastin for compounding pharmacies?  Will there be distinct ocular-specific and oncology-specific formulation/packaging?

When we get some answers to these questions, I’ll post an update.

Disclosure:  I have no equity or other financial stake in Genentech or its direct competitors.

Study Protocols Will be Amended in Two Small Early-Phase Prasugrel Studies

These amendments are strictly protocol-related and do not provide a basis for inferring overall outcomes of other prasugrel trials.–J Anthony Ware

Usually, a company studying an important new drug in a competitive market tries to keep progress of the program sort of, well, secret.  Certainly, Lilly and Daiichi/Sankyo are doing what they can to keep the top-line efficacy and safety results from the Phase 3 prasugel study of nearly 14,000 patients a well-kept secret until unveiled at the AHA meeting in a couple of weeks.  So, why this press release.–for two, small Phase 2 studies that Lilly says shouldn’t be interpreted as inferring anything about the “overall outcomes” of the prasugrel program? 

This disclosure has but a single interpretation; Lilly and Daiichi/Sankyo are essentially saying that this dosage adjustment news is material to investors.  There is no other reason for it that would make any sense.  In  order for the news to be material to investors it must mean that there are implications for the larger program; suspension of two Phase 2 studies for a dosage adjustment amendment, considered in isolation, would never rise to the level of being material news that must be released to investors, especially not right before Phase 3 results are expected.  Granted, these implications apparentlly do not reflect the ”overall outcomes” of the program, but that doesn’t mean they aren’t very important to the program and to the eventual approval and sales of this highly anticipated drug.  By making this announcement Lilly and Daiichi/Sankyo are admitting as much. 

“In analyzing the data and looking over the numerous studies and then considering all the patient populations, we decided it would be prudent to start considering the potential dosages,'’ said Joedy Isert, a spokesman for Lilly. “You want to make sure you provide the right dose to the right patient at the right time.” [from Bloomberg]

What a mess.  I don’t know what Mr. Isert was trying to say, but what he said was not only a cliche without substance, it was also harmful to the company, making Lilly appear derelict in its dose-finding responsibilities.  Not good; get better spokespeople. 

Bottom line–If you’re a Lilly or Daiichi/Sankyo investor on the long side, you have good reason to be concerned.

Disclosure: I do not own equity in either Lilly or Daiichi/Sankyo. 

Hey…sorry for the layoff time here at Pharma’s Cutting Edge.  You can breathe a bit easier now that I’m back.  Pun intended.

I’ve covered Exubera’s peri-approval and launch highlights in these pages, so now that Pfizer has pulled its marketing plug amidst ridiculously low sales of the first inhalable insulin I figured I’d a retrospective of those posts to aid the research of lessons-gatherers near and far.

In April 2007, I waxed philosophic as Exubera was hanging on by a thread:

Recognize in yourself your reluctance to change your opinion as evidence mounts to the contrary; the strength of your unwillingness to change your mind is proportional to the strength of your held opinion.  This is hardly a novel insight, as published evidence supporting it dates to at least the 1950’s.  In behavioral circles, it’s known as attitude strength, or as I like to call it, stubborness.  You might not be able to overcome your stubborness, but you might be more willing to hedge your bets if you can admit to it.

Following the launch of Exubera in July 2006, I set the stage for one of the moore interesting drug launches of the last few years:

This will certainly be one of the more interesting product launches in diabetes care ever. I’m intrigued by competing factors clinicians, patients, and third-party payers will weigh when deciding to use/reimburse for the drug: convenience (multiple injections vs. multiple inhalations; syringes and needles vs. an inhalation device), dose tailoring (extreme flexibility vs. limited flexibility), cost (3x to 5x higher for Exubera), toxicity (an increased risk of lung toxicity and lung function testing before use for Exubera), and Pfizer’s powerful position in the industry.

In May  2006 I extensively reviewed the drubbing Pfizer took from the UK’s nice.  As it turned out, apparently, NICE’s views of the relative quality-of-life benefits of Exubera were shared by doctors and their patients in the U.S:

It’s always a tall order to demonstrate ICE [incremental cost-effectiveness] for a new therapy with similar average efficacy as older therapies. Toss in the fact that the new therapy must cost two to three times as much as older therapies in order to meet profit margin requirements, and economists are faced with a nearly untenable situation. It’s rarely in the company’s best interests today to take extraordinary risks to demonstrate ICE convincingly prior to first launch if the risks aren’t necessary to gain marketing approval and at least Tier 3 coverage in the U.S., understanding that reimbursement in countries like UK is unlikely.

Following approval of Exubera in the U.S., I reviewed the contents of its prescribing information for physicians (i.e. its label):

Patients with Underlying Lung Diseases: Unlike the smoking contraindication, lung diseases present a risk to the patient that has not been quantified. Unstable lung disease is a contraindication due to altered absorption of insulin. The average clinician will be confused between a stable and an unstable lung disease, as am I. The risk management program will need to address this source of confusion. Look for this imprecise labeling as a potential area for product liability issues to arise.

Prior to the review by FDA’s EMDAC in September 2005, I discussed some of the briefing information regarding pulmonary safety:

One has to wonder how Pfizer plans to manage the liability risk of Exubera. They’ve appropriately proposed a raft of post-marketing studies designed to better quantify the clinical risks of the drug in a variety of patients, but at the same time they have suggested that Exubera is safe to use in patients with mild to moderate asthma or COPD, in contrast to the internal FDA pulmonary consultant’s review, which indicated that current data were insufficient to draw such a conclusion. This leads me to believe that Pfizer is planning to fight to avoid a contraindication to use in such patients, clearly an anti-conservative position.

Hey…sorry for the layoff time here at Pharma’s Cutting Edge.  You can breathe a bit easier now that I’m back.  Pun intended.

I’ve covered Exubera’s peri-approval and launch highlights in these pages, so now that Pfizer has pulled its marketing plug amidst ridiculously low sales of the first inhalable insulin I figured I’d a retrospective of those posts to aid the research of lessons-gatherers near and far.

In April 2007, I waxed philosophic as Exubera was hanging on by a thread:

Recognize in yourself your reluctance to change your opinion as evidence mounts to the contrary; the strength of your unwillingness to change your mind is proportional to the strength of your held opinion.  This is hardly a novel insight, as published evidence supporting it dates to at least the 1950’s.  In behavioral circles, it’s known as attitude strength, or as I like to call it, stubborness.  You might not be able to overcome your stubborness, but you might be more willing to hedge your bets if you can admit to it.

Following the launch of Exubera in July 2006, I set the stage for one of the moore interesting drug launches of the last few years:

This will certainly be one of the more interesting product launches in diabetes care ever. I’m intrigued by competing factors clinicians, patients, and third-party payers will weigh when deciding to use/reimburse for the drug: convenience (multiple injections vs. multiple inhalations; syringes and needles vs. an inhalation device), dose tailoring (extreme flexibility vs. limited flexibility), cost (3x to 5x higher for Exubera), toxicity (an increased risk of lung toxicity and lung function testing before use for Exubera), and Pfizer’s powerful position in the industry.

In May  2006 I extensively reviewed the drubbing Pfizer took from the UK’s nice.  As it turned out, apparently, NICE’s views of the relative quality-of-life benefits of Exubera were shared by doctors and their patients in the U.S:

It’s always a tall order to demonstrate ICE [incremental cost-effectiveness] for a new therapy with similar average efficacy as older therapies. Toss in the fact that the new therapy must cost two to three times as much as older therapies in order to meet profit margin requirements, and economists are faced with a nearly untenable situation. It’s rarely in the company’s best interests today to take extraordinary risks to demonstrate ICE convincingly prior to first launch if the risks aren’t necessary to gain marketing approval and at least Tier 3 coverage in the U.S., understanding that reimbursement in countries like UK is unlikely.

Following approval of Exubera in the U.S., I reviewed the contents of its prescribing information for physicians (i.e. its label):

Patients with Underlying Lung Diseases: Unlike the smoking contraindication, lung diseases present a risk to the patient that has not been quantified. Unstable lung disease is a contraindication due to altered absorption of insulin. The average clinician will be confused between a stable and an unstable lung disease, as am I. The risk management program will need to address this source of confusion. Look for this imprecise labeling as a potential area for product liability issues to arise.

Prior to the review by FDA’s EMDAC in September 2005, I discussed some of the briefing information regarding pulmonary safety:

One has to wonder how Pfizer plans to manage the liability risk of Exubera. They’ve appropriately proposed a raft of post-marketing studies designed to better quantify the clinical risks of the drug in a variety of patients, but at the same time they have suggested that Exubera is safe to use in patients with mild to moderate asthma or COPD, in contrast to the internal FDA pulmonary consultant’s review, which indicated that current data were insufficient to draw such a conclusion. This leads me to believe that Pfizer is planning to fight to avoid a contraindication to use in such patients, clearly an anti-conservative position.