Pharma’s Cutting Edge

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.

In my last post, I  discussed what I believed would be the basis for debate and concern among the panelists at Wednesday’s FDA DMEDP Advisory Committee–the benefit to risk balance of the drug in light of modest efficacy and risk of suicidality.  This was indeed the topic of much of the committee’s deliberations.  As you now know, the committee voted unanimously (14-0) against approval of rimonabant due to a perceived unfavorable benefit to risk balance.  They also voted unanimously that Sanofi-Aventis hadn’t sufficiently characterized the safety profile of the drug.

What does this mean?  It means that this FDA division and its outside advisers, and probably much of CDER along with them, is taking the position that they want real, sustained evidence of benefits when risks during chronic use of a drug are small in number but potentially fatal.  Stated differently, risk tolerance is low among this regulatory body, and it wants to see relatively more evidence of benefit to counterweigh a risk of a serious adverse event than in the past (I’m thinking 2 to 3 years ago).  With rimonabant, they looked at a drug intended for chronic use that was associated with modest, reversible benefits on weight and markers of cardiovascular disease; no long-term cardiovascular outcome evidence; tolerance issues that promoted drug discontinuation, and an uncommon but potentially fatal adverse effect.  In the current regulatory climate, rimonabant never stood a chance.

Perhaps DMEDP and its advisers would have thought differently had rimonabant been a drug developed to treat a disease without the social baggage of obesity.  In this country, many people, including many health professionals, still consider obesity a condition caused solely by sloth and overindulgence that should be treated by willpower alone.  But I don’t think so.  Rather, I believe that this division and its advisory committee members are simply willing to be more paternalistic than in recent history, in light of missteps made by prescribers, pharmacists, sponsors and others that have led to a series of recent, high-profile drug recalls and new prescribing warnings for marketed drugs.  In essence they’re saying:  “The American public is either unable or unwilling to responsibly manage its use of new drugs.  Until that situation changes, we must intervene by taking away the tough decisions…by limiting the choices that are available to it.”

I haven’t seen FDA place a lot of the blame on itself for the inability or unwillingness of prescribers and users of new drugs to manage their use responsibly, but most senior folks at FDA must know that through their inability to demand creation and dissemination of effective prescribing information, and through their inability to demand creation of and to enforce effective new-drug risk management plans, and through their unwillingness to require the types of large trials needed to define risk before marketing that they shoulder part, perhaps most, of the blame.  None of this has to do with the needed resources for postmarketing surveillance being requested in the new PDUFA negotiations; I’m only speaking of what needs to happen before a drug reaches the market.  For that, FDA has said it has the resources it needs to do the job well.  So, why hasn’t it?

Sponsors, for their part, also shoulder significant blame for the rise of paternalism at FDA.  Perhaps they just missed seeing the writing that has been on FDA’s wall for the past few years, but I think they saw it quite clearly and chose in some cases to ignore it, hoping it would go away, and in others to address it weakly, with a wink to their investors.  Now they must overcome this guilty-until-proven-innocent mentality to market new drugs for chronic disease states, not to mention the formulary and insurance coverage hurdles awaiting new drugs once approved for marketing.  The regulatory landscape won’t change for quite a while.  If anything, we haven’t seen the top of this wave.

Sponsors, if you hadn’t heeded prior warnings, you’ve now been clearly warned:  It’s up to you and you alone to demonstrate that your new chronic-use drugs work as intended, using highly relevant and generally accepted measures of effectiveness; that they can be used safely, where safely means that the risk of use is very clearly outweighed by the benefit, even if that means you must find ways to limit risk by restricting the user base and creating redundant methods of safeguarding their proper use.  New chronic-use drugs must also be priced so as to be fiscally viable to large purchasers, and their value must not be a matter of faith but rather of overwhelming evidence.  Which other companies are in late stages of development with CB1 antagonists?  That would be Pfizer, Merck, and Solvay/BMS.  We’ll see soon if they have been paying attention.

Sanofi-Aventis made many of the right moves with rimonabant.  They misstepped by not gathering safety information in a way that could be used to create a sound risk-management strategy. There is time for them to make amends, in part, by gathering more evidence of both efficacy and safety.  Should S-A be able to generate evidence from the CRESCENDO outcomes study already in progress that very obese users (i.e. BMI >40) experience a meaningful reduction in their risk of cardiovascular events while using rimonabant, they will go a long way towards tipping the scales in favor of benefits.  In the meantime, S-A must collect more evidence from Europe that shows the drug can be used safely in the “real world”.  This, combined with some way of predicting suicidality through the use of simple baseline measures, other than or in addition to weight and history of depression, should suffice to create a viable risk management strategy.  Whether S-A would want to launch in the U.S. with a restrictive prescribing strategy and its attendant black-box warnings is another question. 

Today, the UK’s Office of Fair Trading (OFT) issued its commissioned report of the UK’s pharmaceutical pricing scheme.  Before you say, “so what?” consider that UK drug prices are directly referenced by countries representing 25% of the world’s pharmaceutical sales.  Still uninterested?  Thought not.

You will not be shocked to learn that the OFT believes UK’s current pricing scheme results in government money wasted on drugs.  Can you imagine them concluding that the UK is getting exceptional value for the money it’s spending on drugs?  I’ve never seen a report from any government’s office concluding that its government was getting a bargain.  The UK’s damage according to OFT?  About 500 million pounds in 2005, or about 4.5% of what the UK spent on drugs that year.

If you don’t have to read the entire report, consider yourself lucky and just read the Executive Summary, which certainly provides the salient points.  For now, though, take look at this snippet from the Executive Summary, which provides the government’s “compelling argument” for price controls on pharmaceuticals:

A major reason for the existence of a UK-wide drug pricing scheme is the difficulty the NHS [UK’s National Health Service] has in ensuring drugs are prescribed in a way that delivers value for money.  Informational and incentive problems result in a situation in which prescribers are often not sensitive to or even aware of the prices of the drugs they prescribe. This is particularly the case in primary care, which accounts for some 75 per cent of pharmaceutical expenditure in the NHS. Evidence we have collected from a survey of 1000 GPs suggests they have weak knowledge of the prices of some of the most widely-prescribed drugs in the UK.

Moreover, under current arrangements, there are high levels of prescribing for some products that cost much more than available substitutes but deliver very similar benefits to patients. This raises a major question as to whether value for money is being secured. Neither are patients price sensitive: they contribute through prescription charges to less than five per cent of expenditure on prescription pharmaceuticals – a lower rate than in almost all other countries in the world.

These demand side problems provide a compelling argument for some form of pricing scheme.

Let’s review this rationale, in case it wasn’t entirely clear:  Doctors don’t know what drugs cost and they are not incentivized to consider costs when prescribing.  Patients also don’t know what drugs cost since they pay only about 5% of their actual cost out of pocket.  This information asymmetry (an economist’s catchphrase that means exactly what you might think) leads to demand-side imbalances that maintain artifically high drug prices.  And the solution to this demand-side imbalance??  Well, it’s price controls, of course.  If you’re scratching your head, do not be concerned, it means only that you are a creature of logic.  Sadly, it would seem you have few kin among those recommending health policy in this UK office.

Just a quick update on NICE’s technology appraisal of Exubera, Pfizer’s inhaled insulin.  In May, I reported on the draft NICE tech appraisal in an in-depth review.  NICE issued their Final Appraisal Determination on October 12th, and the period for appeal ends tomorrow.  If Pfizer does not appeal the FAD, it will be used as the basis for a NICE guideline.

This appraisal provides good insight into stringent requirements for cost-effectiveness demonstrations, particularly regarding evidence standards.  Whatever you might think of it, this is where evidence-based medicine lives today.  If you’re not already familiar with it and you work in the industry, this appraisal is a good opportunity to gain familiarity.