Pharma’s Cutting Edge

Consumers Union Petition

Petition for Better Reporting of Drug Side Effects
I support requiring all drug ads to include a 1-800 number and website so citizens can report drug side effects (petition docket 2008P-0012/CP1).

All too often, drug advertisements fail to present the benefits and risks of using prescription drugs in an accurate and balanced way. It is often the newest drugs that are the most heavily advertised, and it is these drugs whose side effects we know the least about.

The current system for collecting information about side effects catches only a fraction of actual cases. The recent law passed to require print drug ads to provide a 1-800 number and website (FDAAA — P.L. 110-85) is a step in the right direction, but should be extended to include TV ads which are viewed far more frequently and with a greater command of the viewing audience.

Increased reporting of adverse events will help in the earlier detection and better analysis of problems. All television ads should contain information on how patients can report side effects to the FDA.

As you can read above, Consumers Union is trying to improve surveillance of drug safety by promoting patient reporting of “side effects” in drug ads.  A representative of the organization had asked me to blog about the petition, so I am. 

I oppose their effort. Here’s why.

Probably around 1% of adverse reactions to drugs are reported via FDA’s Medwatch system.  Most reports come from healthcare professionals, based on my experience reviewing such reports in the 90’s.  That’s the way it should be, and we need to encourage more of it. 

On the other hand, encouraging more reporting af “side effects” by consumers might actually have its intended effect, which could completely break an already shaky surveillance system. 

Pasive surveillance of reported events can be an effective way of uncovering signals that a drug is associated with rare but potentially serious adverse effects (like hepatic toxicity) or with adverse effects that occur on a background of a common disease (like heart disease) at moderate relative risk (like the risk of heart attack with Vioxx, for instance). 

There are real challenges when interpreting data from such types of surveillance programs.  The most obvious challenge is that there is no concurrent control group for comparison to the drug-treated group (when there is a concurrent control group, we’re speaking of a form of surveillance that is different from the type I’m describing).  A less obvious challenge is separating signal from noise in the data.  Signals are so-called true-positive adverse event reports.  Noise comes from false-positive reports.  Safety surveillance systems strive to maximize signal and minimize noise in order to provide the best possible opportunity for making correct inferences from the data. 

When there is a low percentage of adverse events being reported overall, as in the current environment, the signal is low, and so the detrimental effects of any noise are amplified.  The situation will be improved by encouraging more adverse reports with a high chance of being true-positives and by discouraging reports with a high chance of being false-positives.  How do we do this?

We don’t do it by encouraging patients to fill out Medwatch forms or by calling 800 numbers.  We do it by making it much easier for doctors to capture and transmit adverse events that are possibly or probably related to drugs and by making it much easier for FDA to capture and analyze such reports.  The technology for facilitating such data capture and interchange already exists.  The technology on the doctor end is the electronic medical (health) record (EHR).  Interchange allowing upload of data to FDA can be facilitated using the HL7 data standard known as ICSR.  And on the back end, FDA already uses analytical tools that can make sense of the incoming data.  It is simply a matter of mandating use and providing funds for its implementation. 

Doctors can’t afford EHR for the most part, which is the main reason why its adoption has been so painfully slow.  In an EHR environment, a passive surveillance system can flourish by giving doctors easy, pain-free ways to report anonymized AE reports directly to FDA or other surveillance agencies (like CDC).  It can be as easy as adding a couple of tick boxes and a “send” button to a standard electronic patient encounter form (okay there’s more to it than that, but no so far as end-users can tell).

The US government has not done enough to encourage adoption of this technology, which would really improve drug safety surveillance.  The government should be buying EHR systems and associated training and support for every physician office until the technology achieves saturation.  By becoming the buyer, HHS can mandate that systems be sematically interoperable (be able to talk to each other and to FDA unambiguously).

The cost wouldn’t be as high as you might think.  According to the 2007 US economic census (2002 data), there are roughly 205,000 physician offices in the US.  Some of these offices (let’s say for argument-sake it’s 10%) already have EHR systems, but let’s figure that the government provides support for every office.  Because of discounts from competitive bids, the average cost per office will be much lower than it is today.  Let’s say it’s $50,000 per office on average.  That’s roughly 10.25 billion dollars to outfit, train, and support every physician office in the US with an EHR system and to guarantee that the systems will be interoperable with each other and with FDA.  That’s about what the US is spending each month in Iraq.

That’s what Consumers Union should be pushing for.  Adding to the noise of passive surveillance data will only make a bad situation worse.

S. Sen. Grassley: Secures independent review of FDA approvals based on narrow health benefits - FierceBiotech

In his letter to the GAO, Sen. Grassley asks for an investigation into FDA’s use of surrogates for product approval and whether FDA has appropriately followed up drugs approved initially based on surrogate markers.  He cites recent examples of Avandia and Vytorin as cases where the system hasn’t worked as intended.

Is he right?

Avandia was aproved on the basis of a surrogate marker, HbA1c, but the marker is a surrogate for the effects of chronic hyperglycemia on the body.  It is not a proven surrogate for the outcome of heart disease, as Sen. Grassley implies. 

The effects of chronic hyperglycemia in patients with Type 2 diabetes that are well established include heightened risks of diabetic microvascular disease, which is associated with diabetic nephropathy, retinopathy, and neuropathy and their sequelae.  There is decent evidence that reduction in chronic hyperglycemia reduces the risk of these serious health outcomes.

There is also reasonable evidence for associations of chronic hyperglycemia with other diabetes sequelae that relate to microangiopathies.  The evidence for an independent effect of chronic hyperglycemia in Type 2 diabetes on macrovascular diseases, which include heart disease, is much weaker.  Therefore, to say that FDA failed in its duties by approving a drug based on its effects on hyperglycemia alone is disingenuous. 

On the other hand, I’ve long supported large premarketing simple safety studies for drugs to be used chronically in large populations (see here, for example), so if Sen. Grassley’s intention is to try to make such studies a requirement, I support him.  I just don’t support his implication that FDA shouldn’t have relied on reduction in HbA1c as a demonstration of efficacy.  It was then and is now an adequate surrogate endpoint for many of the detrimental effects of chronic hyperglycemia due to Type 2 diabetes.

The other chosen example, Vytorin, is another poor one to use against the choice of a surrogate to claim eficacy.  As I’ve explained in an earlier post, the ENHANCE study did not establish the lack of efficacy of Vytorin or Zetia, as Sen. Grassley implies.  It merely demonstrated that in a highly selected population of patients with atypical hypercholesterolemia, the use of Zetia with statin failed to reduce progression of carotid intimal thickness, itself an unproven surrogate measure for the outcome of cardiovascular death or disability.  Genuine cardiovascular outcomes studies with this class of drug are underway.

Was Sen. Grassley wrong to imply that makers of drugs used to lower LDL-C or raise HDL-C should be required to do hard outcomes studies prior to approval?  Yes and no.  For the statin class, there’s little doubt that using LDL-C as a surrogate is justified, given the benefits on heart disease risk reduction shown with several class members, at least in patients with established heart disease at baseline.

For other classes of drugs, including the class containing Zetia/Vytorin, I think he’s mostly right, with one exception.  There are some diseases independently associated with high cholesterol in the blood that are amenable to treatment with drugs that lower blood cholesterol.  However, these conditions are rare and typically affect only those patients with very high lipid levels.  So, generaly speaking, I agree with the implication and with the sentiment.  Drugs used to lower LDL-C that will be used primarily by people like me who hope to reduce their risk of heart disease should be studied rigorously in the premarket setting, and such study should include evaluation of their effects on disease outcomes, rather than unproven surrogates (both LDL-C and CIMT, in the case of Zetia/Vytorin).

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.

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.