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).

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.

PDUFA H.R. 3580 (2007)

In a 405-7 vote, the U.S. House passed legislation reauthorizing PDUFA.  The full-text link to the approved legislation is above.  Here are some highlights of the bill focused on amendments to laws affecting regulation of drugs (devices are also covered under the bill), which must now be passed by the Senate without further amendment (as early as this afternoon) and signed by the President before becoming law.

1. Fees: Total revenues from fees comparable to prior fees are set at $392.8M during FY 2008-2012, a 51% increase over FY 2007 expected revenues. In addition, fees are set aside specifically for drug safety, beginning at $25M for FY 2008, and progressively increasing to $65M by FY 2012.  Congress eliminated the orphan-drug exception to fee collection from companies with more than $50M in gross worldwide revenues for the preceding 12 months prior to the exemption request. Congress authorized collection of an advisory review fee for DTC ads submitted for advisory purposes to FDA prior to their public dissemination. The fee may not exceed $83,000 per advisory review and may not increaase more than 50% year over year. Total revenues from such fees are set at $6.25 M for FY 2008-2012.2. Drug Safety Surveillance: The expected scope and performance of drug safety surveillance supported by FDA is increased, with Congress explicitly authorizing use of “improved adverse-event data-collection systems…and improved analytical tools.”

3. Pediatric Research:  The Pediatric Research Equity Act and The Best Pharmaceuticals for Children Act are reauthorized with minor modifications.

4. FDA Modernization: The Reagan-Udall Foundation is authorized.  This non-profit foundation’s purpose is to advance FDA’s mission to modernize development of medicines, foods, and cosmetics, accelerate innovation, and enhance product safety.  The Office of The Chief Scientist is created to “oversee, coordinate, and ensure quality and regulatory focus of the intramural research programs…” of FDA.  Public-private partnerships between FDA and non-profit institutions to advance FDA’s Critical Path Intiative is established.

5. Conflicts of Interest: Waivers allowing financially conflicted experts to participate in advisory committee meetings are expected to to drop by 5% per year from the base year waiver percentage of 2007 (set as 100%) from 2008 through 2012, such that the percentage of meeting exceptions granted in 2012 will be 75% of that in 2007.

6. Clinical Trial Databases: The amount of information captured for the U.S. trial registry is significantly expanded to include more data pre-trial and links to results from trials, including results that are written in language comprehensible by lay audiences.  Result updates are to be made annually. HHS has three years after passage of PDUFA 2007 to implement this expansion fully.

7. Postmarket studies and surveillance:  Entire sections are added regarding postamarket studies and risk evaluation and mitigation strategies.  Probably the most important new addition is the requirement that sponsors respond to FDA notice of a postmarket safety issue with a supplemental label change.  FDA decides unilaterally when to make such notifications.  The sponsor’s proposed label change change is subject to review and discussions.  However, such discussions may last only 30 days following FDA notification, and within 15 days after conclusion of discussions, FDA may issue an order directing the labeling change. Within 5 days of this order, an appeal may be made using normal dispute resolution procedures.  Similar rules regulate notifications of a need for risk mitigation strategies.  Should sponsors fail to respond appropriately to FDA postmarket safety or risk mitigation notifications, drug products would no longer be qualified for sale in the U.S.

Congress has also authorized development of postmarket risk identification and analysis methods that includes linkages among multiple sources of data, with goals of at least 100,000,000 patients [under analysis] by 2012. FDA is authorized to seek public-private collaborations to improve its postmarket risk identification and analysis methods.

8.  Television and other DTC ads: FDA is given authority to require submissions of TV ads no later than 45 days before they are aired. FDA will establish standards in the next 30 months that will be used to determine whether a major statement relating to side effects or contraindications is presented appropriately. First-offense fines for false or misleading DTC ads are $250,000, with $500,000 per each subsequent violation.  A report on DTC ads and their benefits to subsets of the general population will be filed within 24 months of PDUFA 2007 passage.  A schedule for payments of fines, including fines for recurring violations, has been added to the enforcement rules.

9.  Citizens Petitions:  FDA may now deny a Citizen Petition whose primary purpose is to delay approval of an application and if it does not raise valid scientific or regulatory issues.  The 30-month exclusivity period for generics is extended if a Citizen Petition was filed against its approval and is denied.  The length of extension equals the time period between filing of the Petition and the Agency action on the Petition.  An annual report to Congress describing Petitions that resulted in delayed approvals of generics will be submitted.

10.  Postmarket drug safety information for patients and providers:  FDA must improve its procedures for internet-based dissemination of drug information to include a central clearinghouse of safety data and label information and enabling “patients, providers and drug sponsors to submit adverse event reports thrugh the Web site.” FDA will also establish an advisory committe on risk communication.

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There’s lots of well-intentioned stuff here, although one has to wonder how well some of the “wish list” items for FDA future operational improvements can be encouraged into action by legislation.  It seems to me as if  Congress is trying to substitute itself for effective FDA and HHS leadership, and that will never work.  Indeed, the best potential FDA leaders will be discouraged from taking the job if Congress is viewed as their micromanager.  That said, at least this Congress has made it known explicitly what it overwhelmingly believes are the top priorities for this Agency, and its hard to argue against their priorities.