In October, the FDA and manufacturers of finished generic drugs and ingredients (Active Pharmaceutical Ingredients or APIs) reached a ground breaking agreement that can (1) ensure the safety of generic drugs and APIs wherever they are produced globally and (2) ensure that new generic drugs become available to patients more quickly.

The drumbeat of manufacturing safety problems occurring in domestic and foreign plants that produce both brand name and generic pharmaceuticals continues must be addressed. In the last week, FDA has cited generic drug maker Mylan and German manufacturer Jenahexal for manufacturing problems, while Ranbaxy settled longstanding concerns in time to launch their generic version of the block-buster drug Lipitor.

Manufacturing failures can create obstacles to the ongoing availability of affordable generic drugs, or even serious risks to patient safety. Thus this new agreement (the Generic Drug User Fee Act or GDUFA) is critical. Addressing the lag in foreign inspections is especially significant, since 80 percent of active ingredients and bulk chemicals used in U.S. medicines now come from foreign countries. Currently, the FDA does not have the authority or resources to inspect all foreign suppliers of drug ingredients. Domestic plants are inspected by FDA on average every 2.7 years. The New York Times recently reported that at its current pace, the FDA would need 13 years to inspect every foreign drug plant exporting to the United States. 

The draft GDUFA agreement is a major commitment by the industry to solve this problem by “ensuring that industry participants, foreign or domestic, who participate in the U.S. generic drug system are held to consistent high quality standards and are inspected biannually, using a risk-based approach, with foreign and domestic parity.” The industry has backed up this commitment by agreeing to provide $300M annually in user fees to provide FDA with the resources to increase inspections and to speed the review of new generic drugs. The fees would supplement FDA annual funding. 
 
Guaranteeing the availability and safe manufacturing of generics is not only critical to patient safety, but also to access to care and to the financial stability of families, health plans and public programs. Today 78 percent of all prescriptions dispensed in the U.S. are generics. In 2008, the average cost of a generic drug was nearly four times less than the brand name equivalent ($35.22 vs. $137.90). Thus, while 78 percent of prescriptions are generics, the total spending on generics accounts for just 25 percent of the total U.S. drug spending, and generics drugs have saved more than $824B over the last decade.

GDUFA can play a role in solving the problem of drug shortages, as well. Shortages can be catastrophic for patient safety, and often affect generics since they account for 78 percent of prescribed drugs. Stepped up inspections at foreign plants can prevent manufacturing problems that can lead to shortages of medically necessary drugs. Health system pharmacists, who confront these problems every day, point out that “user fees can result in faster approval processes for generic drugs” while not sacrificing  patient safety concerns. 

The FDA-industry draft agreement is now being reviewed by the Office of Management and Budget. When approved, it will be sent to Congress for action, probably to be included in the renewal of the Prescription Drug User Fee Act (PDUFA), which deals with user fees for brand-name drug approvals.

- Marcia Hams, Director of Prescription Access & Quality

In less than a month, the FDA will convene a scientific panel to evaluate emerging evidence that some of the most commonly used contraceptives – Beyaz,Gianvi, Loryna, Ocella, Safyral, Syeda, Yasmin, Yaz, Zarah, — have greater risks than other similar products. Patients and their advocates are seeking court permission to have drugmaker’s internal studies released so that FDA can see the full picture.

These drugs all contain the hormone drospirenone, while other contraceptives use a different active ingredient — progestin levonorgestrel. The FDA reports that “all birth control pills pose a risk of blood clots” but a recent British Medical Journal (BMJ) study found that contraceptives containing drospirenone were “associated with a threefold higher risk of non-fatal [deep vein blood clots]” compared to women who do not use hormonal contraception, and twice the risk of competing drugs using a hormone other than drospirenone.

On December 8, an FDA panel will likely look at the body of evidence concerning this BMJ study, and other studies listed on the FDA website. This review might tip the scales enough to add warnings to the drug’s label. Yet it remains to be seen if FDA will see all the documents it should before making a decision.

About 10,000 patients who took Yaz or Yasmin are suing the drug’s manufacturer Bayer for failing to disclose an increased risk of blood clots, and their lawyers have asked the court’s permission to submit to the FDA hearing approximately 50 documents unearthed in that litigation. The lawyers describe these documents as “internal and candid memoranda of clinical trial data and adverse event data not [before] shared with the FDA [by Bayer]”, according to a brief filed in one lawsuit.

Many readers may recall that documents concerning the safety and illegal marketing of the drug Zyprexa, the widely used antipsychotic drug, were released a couple years ago, both by a doctor retained as an expert witness, and later by the Court. This information was invaluable in alerting the public to the increased risks of death when Zyprexa is used to treat vulnerable seniors suffering from dementia. Following the pattern we saw with the pain drug, Vioxx, in 2004 and the diabetes drug, Avandia, in 2010, the Zyprexa documents showed that in the interest of maintaining the sales of their block-buster drugs, drugmakers withheld critical information from the FDA and the public — causing the deaths of tens of thousands of patients, while leaving tens of millions at risk.

The hearing on December 8 is less than a month away. We hope FDA will make sure it sees any studies that Bayer’s scientists and expert consultants did concerning the risks of drospirenone before making a decision on how to best protect the public health.

And there’s a potential conflict-of-interest issue as well. Lawyers for the injured women are concerned that some of the 13 scientific experts on the FDA panel have financial relationships with Bayer. Under the FDA rules, members of scientific advisory panels must disclose their conflicts to the FDA, and must receive a waiver in order to participate. The advisory panel could recommend that the FDA add warnings to the labels, implement other safety protocols, or even to withdraw them from the market—it should be free of industry influence.

The FDA needs complete information to do a good job, and the public needs to know who ultimately participates or votes on the FDA panel to be sure we can trust their final decision. Every day women are barraged with slick TV ads for Yaz and other contraceptives. We deserve more than marketing buzz – we need an unbiased, transparent and scientific evaluation of the drugs that makes sure women are not knowingly put risk.

(Hat tip to Pharmalot)

– Wells Wilkinson, Project Director Prescription Access and Litigation &
Marcia Hams, Director, Prescription Access and Quality

An investigative outfit’s consolidation and analysis of payments that drug companies made to doctors has refocused attention on state efforts to shine light on the financial ties between doctors and drugmakers.

Currently three states—Minnesota, Massachusetts, and Vermont—require drug companies to disclose payments to prescribers and make some of that data public. While each of these states takes a different approach to collecting and making the payment data available to the public (more on that here), information from all three have been extremely valuable in demonstrating the dimensions and scope of these marketing relationships. And now a new value to the state data has emerged: demonstrating that pharma isn’t keeping very good track of who it’s been paying what.

The ProPublica report in Monday’s Minnesota Star Tribune and here online found a series of big discrepancies between what a company said it paid a doctor on its website and what it told the state of Minnesota it paid the same person. Right now, ProPublica can only crosscheck the seven companies that have posted payments on their own websites.

Big pharma has been caught off-guard again. Like the reports earlier this fall that hundreds of sanctioned doctors were still making cash on the side with speaking gigs, some companies seem not to know who they are paying what. Despite spending billions of dollars to develop and manufacture drugs, and spending other billions to market them to prescribers and armchair prescribers (i.e. consumers), the folks who brought you Lipitor, Effexor, Zyprexa and that one that will send this to your spam folder, don’t seem to know what they paid docs to give PowerPoint presentations.

The report also gave some doctors the opportunity to say strange things:

Dr. Randy Shapiro, one of the doctors whose take was under-reported to Minnesota told ProPublica that if anything, patients should want to see their physician among the speakers on these payment lists. “If their doctor is not on the list,” he said, “maybe they should look for a different doctor.”

That’s…an interesting take. We’re not aware of any links between participation on speakers bureaus and clinical excellence or bedside manner. Based on some earlier findings (we’re thinking of the Risperdal, Biederman, and all these folks) we’re not sure that would be our prescription. (In fact, based on the mounds of evidence about the influence of even small gifts, we tend to think finding a pharm-free physician or one who is engaged on clinical projects she’s happy to tell you about, and not just the PowerPoint circuit, is the way to go).

And the top-paid physician in Minnesota, Dr. Todd Hess, a pain specialist in St. Paul who made over $364,000 last year, told ProPublica that the media is unfairly lumping these educational talks with the old pharma ways.

“This is a mountain-molehill thing,” Hess told ProPublica. “I know the problems of the past. I know what pharma has done to change those. People just can’t get over the past.”

Maybe he knows something that we don’t know, but it might not be a problem of a press corps with a too-long memory. Recently, awkward chuckles went up through the pharma news sphere when word of Abbott’s celebratory pig roast for a Maryland doc who managed to implant 30 stents in one day showed up in a Senate Finance report.

That wasn’t back in the high-flying, anything-goes 90s depicted in the recent pharma-flick “Love and Other Drugs.” It was two years ago. Teachers are warned not to grade 30 papers in one day (and this blogger can vouch for that advice). We’re pretty sure, like the Senate Finance Committee, that 30 stent operations in a day is an even worse idea.

Despite what headlined docs and pharma spokespeople say, there is still a lot of money changing hands for things of questionable clinical value. The thing about the ProPublica data is: it’s current. The stories about hundreds of millions of dollars going to sanctioned docs, the Massachusetts reports that just came out–those payments are all from 2009-present. And now we see it isn’t being recorded very well. Maybe some of these companies really did believe no one would bother to look.

“If all the reports are true I’m outraged,” Maryland delegate and physician Dan Morhaim told the Baltimore Sun.

According to the Sun, “Maryland’s General Assembly has explored limiting financial relationships between doctors and drug or device makers, but no laws have come from it,” but Morhaim said ‘it’s a continuing topic of interest’ in the next legislative session.”

While there are real and beneficial relationships between academic medicine and industry, Pew Prescription Project Allan Coukell told a Memphis paper this week that “patients deserve to know if their doctors are receiving money from drug companies.”

And patients and state lawmakers are right to be concerned about what add up to significant financial exchanges between industry and doctors willing to pitch drugs to their colleagues. We wouldn’t be surprised to see more states explore ways to keep track of or limit the types of payments industry makes to doctors. Regardless, pharma should take this opportunity to get its house in order so everyone’s on the same—accurate—reporting page by the time Physician Payments Sunshine kicks in.

–Kate Petersen, PostScript blogger

In a report on recent drug recalls, one risk analyst suggests they don’t. Aggressive cost-cutting in both in manufacturing operations and in the supply chain may be contributing to the quality problems that have led to a wave of product recalls in the drug supply recently, a Reuters report suggests this week.

Seeking out the cheapest materials, both those that go in the drugs and those involved in their manufacture and transport (like the wood pallets treated with chemicals that seeped into recalled bottles of Johnson & Johnson products and Pfizer’s Lipitor), has not only made he supply chain more complex, but diluted the control—and even awareness—drug makers have over their supply chains.

We thought this insight from the article was especially illuminating:

“Things that were off the table in the past are now on the table,” said Jim Lawton, president of Dun & Bradstreet Supply Management Solutions, which tracks and monitors supply chain risks for clients.

“As a result you’ve got all these supply chains now that are fragmented across all sorts of companies and they’re all geographically dispersed,” Lawton said.

“My guess is they (J&J and Pfizer) don’t even know who the pallet manufacturer is, and yet they’re on the hook at the end of the day for whether or not consumers think they can buy Tylenol and if it’s going to be a safe product to ingest.”

The FDA’s Hamburg agreed that supply chains are getting much more complex.
“There are many, many more players involved as a drug moves through the distribution process and at every point along the way is a point where there needs to be attention or problems may occur,” she said.

And many countries don’t come close to having the same quality control standards as a drugmakers’ home turf.

“I work with a company that had outsourced something to China and the manufacturer in China had turned around and outsourced a key portion of that to sub-Saharan Africa, and yet my customer is saying, ‘I didn’t even know we had suppliers in Africa.’ And they are just exposed,” Lawton said.

Learn more about securing the drug supply chain at the Pew Prescription Project.

–Kate Petersen, PostScript blogger

Want to find out about drug recalls when they happen? It seems FDA may need to get more involved. That may be one lesson to take from last week’s announcement that in August, Pfizer recalled 191,000 bottles of Lipitor after several patients reported a musty odor. Though it’s link to the Lipitor complaints is yet unconfirmed, a Pfizer test revealed low levels of 2,4,6 tribromoanisole in one of the lots, the same chemical used to coat wood shipping pallets that was linked to the delayed recall of millions of bottles of J&J’s Tylenol last winter.

Under current rules, companies that recall medications do not have to tell the FDA about a recall at all, much less within a certain timeframe. Though companies are required to notify the agency of chemical or physical changes, deterioration or contamination, J&J’s delayed recall and FDA notification (the company started receiving consumer complaints of musty odors in early 2008) suggests that even that reporting rule may be broadly, or loosely, interpreted by companies.

Pfizer has indicated that the recalled bottles of its blockbuster cholesterol medication came from a third-party supplier, but would not name the supplier or its location. A spokesman for the company told in-pharma Technologist that it is working with the FDA to “[change] the way that the bottles are packaged at the bottle supplier, decreasing time to delivery, and relocating some bottle production to other facilities operated by the supplier.”

Without sounding like a broken record (or an iPod on repeat), the amount of irregular, voluntary, and sometimes significantly delayed public notice of drugs pulled from the market is stacking up faster than it should, at least for the comfort of those on the public side of the equation.  Drugmakers’ conflict of interest – that is, a fear of potential sales lost by telling the public the full and timely facts about why, where, and when a drug was recalled – may be just too great to overcome with cautionary tales and promises at Congressional hearings to do better.

The FDA, free of that conflict and charged first with protecting the public’s health, is a fundamentally better steward of a recall, setting requirements for timeliness and disclosure, and overseeing–not just reactively advising–a company on when and how to remove risky drugs from the shelves. Several bills before Congress would give FDA that authority, and the Lipitor recall joins the list of reasons to give them consideration.

For more, see PostScript’s drug safety archive.

Speaking of more rapid responses, consider following “SafeRxWatch,” Community Catalyst’s new Facebook page and Twitter feed on drug safety issues.

–Kate Petersen, PostScript blogger

A significant vote by the Senate Appropriations Committee last week has focused renewed attention on vital cost-saving reforms on prescription drugs that failed to make it into health reform. At issue is the drug industry practice of paying off generic competitors of expensive brand-name drugs to delay access to low-cost generics. Community Catalyst has opposed this practice through our advocacy and with consumer class action lawsuits through our Prescription Access Litigation project.

How serious are these multi-million dollar sweetheart deals that prevent consumer and health system savings? The Federal Trade Commission, the federal government’s consumer protection watchdog, reported in January that these agreements delay the entry of generic drugs into the market by an average of 17 months. Given that generic entry can reduce the price of branded drugs by up to 90 percent, the FTC estimates conservatively that the cost of these delays is at least $3.5 billion in lost savings per year.

Through these pay for delay deals, the brand-named drug manufacturer gets to continue to be the exclusive seller of the drug and the generic manufacturer makes money for not bringing a generic (non-patented) version of the drug to market. It is then left to consumers and the government to pay the price for the high drug costs that result from these agreements.

21 new pay-for-delay deals in 2010 may cost consumers and the health care system $9 billion

The FTC warned in recent Congressional testimony that pay-for-delay agreements are becoming more common and have reached the point of being “almost an epidemic” (see graph). Deals rose from only three in 2005 to 19 last year and 21 in the first nine months of 2010. This dramatic increase followed court decisions since 2005 by a few appellate courts that, according to FTC, “misapplied the antitrust law” to uphold these agreements as not anticompetitive.

The FTC’s preliminary analysis of the 21 agreements filed this fiscal year concludes that they cost $9 billion in lost savings. Past pay-for-delay agreements to date are estimated by FTC to cost all public and private purchasers at least $20 billion — an estimate that may rise given the current spike in agreements. FTC estimates that these settlements cost consumers and our health system at least $3.5 billion a year, while other experts suggest that the potential total savings could be closer to $12 billion a year if pay-for-delay settlements were ended.

The federal government — and health reform sustainability — would benefit greatly from banning these agreements. The Congressional Budget Office estimated the savings to the federal government alone of around $2.6 billion over the next ten years.

Legislative History

A bill to ban these agreements was included in the House’s health care reform proposal last fall. Unfortunately, though a similar measure was supported by the White House and considered by the Senate, the procedural and jurisdictional rules in the Senate kept the measure from being included in the national health reform bill enacted last March.

House leaders were undeterred by this set-back and added language banning these deals to an appropriations bill approved on July 1st. Unfortunately, the Senate went on to strike this provision from an appropriations bill they subsequently approved. But two weeks ago, the bill’s longtime advocate, Senator Herb Kohl (D-WI), along with Senator Richard Durbin, succeeded in including this provision as an amendment to the Senate’s Financial Services and General Government Appropriations Act.

On July 29th, an effort by pharma to strip this provision was narrowly defeated in the Senate Appropriations Committee. Senator Arlen Specter (D-PA) had introduced an amendment to strip the provision from the Committee bill, and when four other Democrats voted with Specter, the Associated Press reported that:

“Drug company lobbyists in the audience thought they had the vote won, provided they could win over every panel Republican. But Sen. Richard Shelby, R-Ala., voted against the drug companies, helping give Kohl and Durbin [the author of the Appropriations Bill] a surprise win.”

The successful Senate Committee vote signaled to FTC Chairman Leibowitz that “the tide may be turning,” and that “consumers are one step closer to saving billions on their prescription drugs.”   The bill’s Senate sponsor, Senator Kohl, pointed out why this decision can’t come soon enough:

“The cost of brand-named drugs rose nearly 10 percent last year. In contrast, the cost of generic drugs fell by nearly 10 percent. At this time of spiraling health care costs, we cannot turn a blind eye to these anticompetitive backroom deals that deny consumers access to affordable generic drugs.”

This recent vote is a crucial step. The potential savings to both consumers and the government is substantial and is particularly important in these turbulent financial times. A New York Times editorial this week emphasized that these potential savings “would reduce the federal deficit by $2.6 billion over the next decade, freeing up money for worthy programs that would otherwise be cut.”

Why should we allow these agreements to continue to the financial benefit of only a small subset of the U.S. population when the savings that would result from banning these agreements could benefit a far greater number of individuals? It is about time for the pay-for-delay settlement to meet its long-awaited demise.

The final vote in Congress on the Appropriations bill will likely come sometime after the election. It will take vigilance and aggressive action by supporters to combat PhRMA’s tactics again — just last week they released a new report disputing the FTC analysis. But in Pharmalot, an FTC representative states: “The pharmaceutical industry can fund as many studies as it wants, but it can’t change the facts — these pay-for-delay deals cost consumers $3.5 billion a year.”

– Emily Cutrell, legal intern
– Wells Wilkinson, Director of Prescription Access Litigation project

The Food and Drug Administration will soon complete the second stage of a three-phase process to increase public transparency of agency activities and decision making. Last week, the FDA’s new Transparency Task Force concluded a three-month comment period on 21 bold new proposals to expand the agency’s disclosure practices. Community Catalyst, with the support of prominent drug safety experts Drs. Joseph Ross and Aaron Kesselheim of Yale University Medical Center and Harvard Medical School, respectively, filed comments endorsing many of these proposals with respect to prescription drugs, and recommending other improvements to promote public health and empower patients and consumers.

Seeing Clearly Now – The Importance of Transparency

The FDA task forces sees increased transparency as part of new Administration’s Open Government Initiative, and as a means to build public confidence in the FDA by making the agency’s activities and decision-making more accessible and understandable to consumers, providers and other public health experts. These 21 proposals would significantly increase access to information in nearly all areas of prescription drug regulation, from developmental studies to inspections of manufacturing and import procedures to adverse reactions experienced by patients.

Many of these common sense proposals are especially timely in light of the recent revelations about drug makers withholding critical information about drug safety studies and manufacturing problems.

For instance, the FDA recently made public a report summarizing 12 manufacturing violations and other inspection findings concerning a Johnson and Johnson plant in Lancaster, Pennsylvania. This is notable as it was the third Johnson and Johnson plant to be cited for violations this year, the same year in which the company has recalled over 130 million bottles of children’s medication due to possible contamination. A congressional investigation recently found that in June 2009 the company’s McNeil division sent in contractors to surreptitiously buy up potentially contaminated Motrin, rather than issue a formal recall of the product. One new transparency reform being considered by FDA would make information on inspections and violations at manufacturing facilities open to the public. This would inform consumers about when FDA uncovers problems in the manufacturing process—or when a company has a clean record. Increased public scrutiny of problematic industry manufacturing practices will alert consumers when problems arise, and also help force manufacturers to prioritize quality improvement.

Also of great interest to the drug safety and patient community are the proposed disclosures of the status of product applications and the release of summary clinical trial data on drug safety and effectiveness. Such information would notify patients awaiting the development of new drugs on the industry’s efforts and safety concerns and help prescribers make informed decisions. Most importantly, the disclosure would also allow independent researchers to conduct their analyses in order to complement FDA and industry research.

The recent revelations that GlaxoSmithKline withheld studies documenting the cardiac risks associated with their blockbuster drug Avandia, and selectively excluded negative data from other published studies demonstrates the need for full transparency.

GSK’s actions were nearly identical to drug maker Merck’s withholding of studies documenting the cardiac risks of Vioxx, which is estimated to be responsible for tens of thousands of heart attacks. In both cases, lack of access to this data meant that it took years for the health risks of these products to come to light.

Even so, under the current scheme, FDA sits atop a mountain of clinical data submitted with marketing applications that may help identify risks sooner. Had comprehensive clinical trial data on Vioxx and Avandia been available to independent researchers earlier, health risks associated with these drugs could have been discovered and publicized much earlier. Lives could have been saved. The FDA simply does not have the resources to perform all the analyses that independent investigators can.

These safety issues, coupled with recent manufacturing problems that have undermined the integrity of our drug supply chain, demonstrate the need for expanded FDA disclosure of drug approval information and inspection results.

Will it be a Bright Sun Shiny Day?

Aside from supporting the FDA’s bold new approach to increase transparency, we also recommended that the FDA go farther in some areas. For instance, we feel that the FDA’s proposal to disclose the scope and completion of a food recall be expanded to include any recall of prescription drugs, as well.

And while the FDA has proposed future meetings to discuss the disclosure of non-summary (or individual level) data from drug trials, we argued that the need for public access to this data is beyond dispute because it allows independent researchers to more quickly complete objective drug safety analyses that reveal risks and thus sound the alarm on patient safety issues.

(Tune in tomorrow to learn what other consumer advocate, and the drug industry said about these vital transparency reforms.)

– Ian Reynolds, Policy Associate
– Joy Lee, Policy Intern

It’s been a rough couple of weeks for GlaxoSmithKline. On the eve of last week’s FDA hearings to decide whether its former best-selling diabetes drug Avandia should still be sold, the New York Times broke news of the company’s efforts to conceal internal studies showing the drug posed a much higher risk of heart attack than its main brand-name competitor, Actos. Yesterday, we learned that a member of the FDA panel received payments from GSK. And, today, the FDA put the brakes on a new trial to compare Avandia with Actos (hat tip: Pharmalot).

But buried in the onslaught of Avandia news (perhaps on purpose?) was the PR-challenged drugmaker’s announcement last Friday that “a small number” of Advair diskus inhalers, (used to treat patients with asthma and chronic obstructive pulmonary disease) stolen from a company warehouse had made their way into pharmacies. GSK’s announcement was followed by a stern FDA warning to consumers, pharmacists, and wholesalers to cease use of the stolen inhalers, which are identifiable by lot numbers.

This story is a troubling reminder that we do not have strong systems in place in this country to ensure our drugs have traveled legitimate and safe routes during distribution. As Adam Fein points out in yesterday’s Drug Channel blog, these stolen products ended up on pharmacy shelves due to negligent purchasing. Someone involved in the distribution of these inhalers purchased diverted products from a bad actor, either knowingly or by not adequately verifying product provenance.

We need strong federal regulation requiring manufacturers, wholesalers and pharmacies to track drugs during distribution and verify products’ distribution histories, also known as “drug pedigrees.” A robust federal tracking regulation with strong drug pedigree standards would help protect consumers from unsafe products. A number of state pedigree laws exist but vary in strength. Two bills have been introduced in the House that would establish federal drug tracking systems:

H.R.2726: Counterfeit Drug Enforcement Act of 2009 (Tim Fagan Law)
Sponsors: Rep. Israel, Rep. Ackerman

H.R. 5839: The Safeguarding America’s Pharmaceuticals Act of 2008 (expected to be reintroduced this session)
Sponsors: Rep. Buyer, Rep. Matheson

We hope this latest disturbing incident serves as another stark reminder of the urgent need for Congress and the FDA to take action to address the safety gaps in the drug distribution system. As for GSK and other manufacturers—they need to beef up their security, let the public and FDA know immediately when it is breached, and embrace proposed new tracking systems.

For more on drug safety and the importance of developing a prescription drug tracking system, visit the Pew Prescription Project’s Securing a Safe Drug Supply.

– Kathy Melley, Director of Communications

Last week’s article by New York Times reporter Gardiner Harris exposed Glaxo SmithKline’s (GSK) flagrant disregard for patient safety. For 11 years GSK suppressed internal studies showing that the world’s former best selling diabetes drug, Avandia, posed a much higher risk of heart attack than its main brand-name competitor, Actos.

Last Wednesday, an FDA advisory review panel concluded a two-day hearing by recommending 20 to 12 that Avandia remain on the market with label revisions and other restrictions. This deeply divided panel included 17 votes to add warnings or restrictions on the drug, and 12 votes to remove the drug from the market.

The members voting for Avandia’s removal said the drug “has no unique benefits and therefore the benefits of the drug do not outweigh the risks.” They also pointed out that Avandia’s primary competitor, Actos, is an acceptable alternative to Avandia and therefore there is no therapeutic necessity to keep Avandia on the market.

Even the use of Actos has been called into question. Harvard researchers based at the Independent Drug Information Service (www.RxFacts.org), note that “in mid-2007 the FDA added black-box warnings cautioning that both rosiglitazone (Avandia) and pioglitazone (Actos) increase the risk of congestive heart failure. These safety concerns, along with an increased risk of fracture, have greatly dampened enthusiasm for use of both of these drugs.

The ultimate fate of Avandia now rests in the hands of the FDA. If the proposed additional warnings and restrictions are implemented, scientist Steve Nissen, who published the first study documenting the cardiac risks of Avandia in 2007, estimates that 95 percent of Avandia’s use will end. “Effectively, this drug is gone.”

Interestingly, the committee also recommended by a vote of 19-11 that the trial currently underway comparing Avandia to its rival Actos be continued, though at least one member questioned the ethics of this, given the potential risks.

The Phantom 1999 Study

We now know that GSK conducted a 1999 study comparing Avandia to its main competitor, Actos, that linked Avandia to a 43 percent increased risk of heart attacks. GSK never reported these findings to the FDA. An email from Dr. Martin I. Freed, a GSK executive at that time said:

Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK.

When another GSK official asked whether this trial and another negative study should be published, Freed responded: “Not a chance. These put Avandia in quite a negative light… [W]e would hope that these do not see the light of day.”
Other company documents reveal that in the 1990s, GSK decided against doing another study to determine definitively whether Avandia caused heart attacks because it feared that the results might hurt sales.

Litigation yields access to studies, helps expose risks

GSK’s earlier suppression of studies showing risks associated with the anti-depressant drug Paxil led to litigation and settlements that required GSK to post information online about all their clinical trials. Using this and other information, researchers Nissen and Kathy Wolski of the Cleveland Clinic published in 2007 an analysis of over 40 studies showing that Avandia increased the risk of heart attack, stroke and death in comparison to rival drug Actos.

GSK responded to the Nissen study by publishing results from their own  six-year ‘RECORD’ study. At the time, GSK asserted the RECORD study proved that Avandia posed no increased risk of heart attack or death. But reviewers have found a dozen serious incidents were excluded in the total tally of adverse events from the RECORD study. According to one FDA reviewer, “deaths that occurred while taking Avandia were inexplicably dropped from the final analysis.” Now GSK’s possible role in manipulating the RECORD study to keep their drug on the market is in question.

New evidence, studies bring risks to light

Ongoing investigations by Senator Grassley and almost a dozen new studies documenting the risks of Avandia have kept the issue alive, prompting the FDA’s ongoing review, including last week’s hearing.

One comparative effectiveness study by David Graham of the FDA was published this past June. Graham worked with researchers at the Centers for Medicare and Medicaid Services to collect records from nearly a quarter million Medicare recipients.  Elderly diabetics, who used Avandia instead of its competitor Actos, had a 68 percent increase in the risk of heart attack, stroke, heart failure or death. Graham stated:

We estimate that about 48,000 excess cases of [heart attack], stroke, heart failure, or death were attributable to the use of [Avandia] rather than [Actos] from 1999-2009.

Graham additionally stated “the RECORD study would have been dismissed as ’garbage’ if it had been used to seek the drug’s original approval.”

What’s next?

Whether the FDA will allow Avandia will remain on the market is still in question.  Beyond that, what else can we do to stop such illegal and hazardous industry behavior – the same behavior that resulted in the Vioxx tragedy, which led to up to 60,000 deaths? Litigation and other sources have revealed the suppression of drug risks concerning Vioxx, Paxil, Celexa, Zyprexa, and many other drugs. The problem seems endemic.

To begin to address this problem, FDA needs the resources and authority to examine all relevant clinical studies for data-tampering. Government and private consumer lawsuits must continue, including possible criminal prosecution. Finally, we should all remember that what you read on your drug label or hear in a TV ad may not be the whole story. Skepticism is warranted and further regulation is critical to all of us – we need medical care we can trust.

– Emily Cutrell, Prescription Access Litigation

At a time when state fiscal woes are forcing cuts in Medicaid, researchers at the Division of Pharmacoepidemiology at Brigham & Women’s Hospital in Boston and Harvard Medical School have identified a policy with at least $100 million in potential savings: make generic substitution policies work more effectively.

A new study in the July issue of Health Affairs highlights savings opportunities some state Medicaid programs could take advantage of by changing their generic substitution laws.  Currently, 39 state programs require patient consent for pharmacists to substitute a prescribed brand name drug for a generic.

Given the strong influence of pharmaceutical marketing, patients often have an unwarranted negative view of generic drugs, requesting more expensive branded options when they are not necessary.  Generics are certified by the FDA to be chemically equivalent to their brand name counterparts.  The rationale for allowing pharmacists to voluntarily substitute generics is to ensure that Medicaid is not wasting money.  Saving money protects access to care in budget-stressed programs like Medicaid.   By leaving the generic substitution decision to pharmacists, states could expect to save more than $100 million on just three top-selling medications—Plavix, Lipitor and Zyprexa— that are nearing patent expiration.

The study, led by Dr. William H. Shrank, looked at the relationship between Medicaid policies on generic substitution and the use of the cholesterol drug simvastatin vs. Zocor, its branded equivalent, after Zocor’s patent expired in June 2006.  While all states have adopted generic substitution laws, the extent to which pharmacists or patients can influence the medications they choose differs from state to state.  The Harvard researchers found that states that did not require patient consent to switch prescriptions from Zocor to the clinically equivalent, less costly simvastatin saved $15.35 per prescription on these medications in the first quarter after patent expiration.  If all states had adopted such policies, Medicaid programs could have saved $19.8 million nationwide on the introduction of simvastatin.

While patients should be empowered to participate in their own health decisions, this study demonstrates that requiring patient consent for generic substitution impedes patients from initially choosing generics even when they will eventually prefer them to the brand name.  After four financial quarters, the rates of choosing generic simvastatin over Zocor begin to converge between states that require consent and states that do not.  Patients in both states will eventually choose to take advantage of the cost savings from choosing the safe, effective, and cheaper alternative.  But for patients in states that do require consent, the cost savings come at a slower pace.  And in the case of Zocor, that meant $19.8 million in foregone savings for state Medicaid programs—savings that could have been used to protect access to care.

The study comes as welcome news for patients and policy makers at a time when state Medicaid programs are facing severe budget cuts.  Generics cost, on average, 30-80 percent less than brand name competitors.

Marcia Hams, director of prescription access and quality at Community Catalyst, stressed the great importance of these findings in light of Medicaid shortfalls in a recent BNA report.  If state programs are forced to overspend on drugs, she explained, people may  start to lose their benefits or eligibility.  The use of brand name drugs instead of generics is thus “an unnecessary cost that could endanger beneficiaries in the [Medicaid] program.”

Massachusetts Medicaid, with a very high (78 percent) generic rate and no patient consent requirement, may illustrate the point, according to Hams, although other strategies were also involved. “A study we commissioned in 2009 found that MassHealth achieved significant savings to curb increasing drug costs by using coordinated policies that increased generic drug use, while putting clinical considerations first.”

Of course, neither PostScript nor the study authors are advocating the use of generic medication for every patient or for the use of generic-only formularies.  A physician should, and can, always mandate the use of a brand name drug if necessary.  (Find out more information on the safety, value, and appropriate use of generic medications at: http://www.genericsarepowerful.org/). We agree with the study authors that a modified generic substitution policy could produce cost savings without compromising quality while leaving room to invest health care dollars more effectively and preserve vital programs.

–Joy Lee, policy intern