March 04,2008

Grassley secures review of FDA approvals based on narrow health benefits

WASHINGTON — Senator Chuck Grassley has asked for an independent assessment ofhow the Food and Drug Administration follows up on the effects of medicines that it approvesbased on narrowly defined benefits.

“The way things have turned out with drugs like Vytorin and Avandia raise enoughquestions that a review is warranted,” Grassley said. “It’s not clear if the FDA’s own policiesare being enforced internally, where the agency is supposed to require companies to performfollow-up studies. These policies are designed for patient safety.”

Grassley’s questions stem from a practice of the Food and Drug Administration to usegoals called surrogate endpoints to study whether a particular drug achieves a certain benefit,such as lowering blood sugar in diabetics. Grassley said it’s critically important that the agencyadhere to its complementary policies that require drug-safety reviewers to follow up on drugsthat are approved based on surrogate endpoints.

“The public relies on the FDA to keep it safe from dangerous drugs and not just stick tonarrow judgments that may not incorporate overall health,” Grassley said. The diabetes drugAvandia was approved because it lowered blood sugar but later found to increase the risk ofheart attack, even though lower blood sugar is tied to lower heart attack risk.

The Government Accountability Office, which is the investigative arm of Congress, hasagreed to conduct the review that Grassley requested in the letter posted below.

February 28, 2008

The Honorable David M. Walker
Comptroller General
U.S. Government Accountability Office
441 G St, NW
Washington, D.C. 20548

Dear Comptroller Walker:

The Food and Drug Administration (FDA) has approved several drugs that appear tohave little to no effect in protecting lives and increasing health. For instance, FDA recentlyapproved Genentech's cancer drug, Avastin, to treat breast cancer.[1] Genentech's studiesshowed that Avastin halted tumor growth, but that breast cancer patients did not livesignificantly longer than those that did not receive the drug. Surprisingly, FDA's own advisorypanel argued against the approval over concerns that Avastin's benefits do not outweigh its toxicside effects.

Further, a study last year found that Avandia, which controls glucose levels, wasassociated with an increased risk of heart attack. And last month, Schering-Plough and Merckannounced that Vytorin, which controls cholesterol levels, provided no benefit to cardiovascularoutcomes.

In all three cases, these drugs were approved by FDA because they had an effect onsurrogate endpoints (tumor growth for Avastin; glucose levels for Avandia; and cholesterollevels for Vytorin). However, none of these drugs were studied sufficiently to see if they addedany benefit to the health and/or lifespan of the patient. Typically, such results can be foundthrough phase IV trials.

Therefore, I request that the Government Accountability Office conduct an inquiry intothe FDA's approval of drugs based on surrogate endpoints, including an examination of FDA'sprocess to ensure that drugs approved on surrogate endpoints are both safe and effective. Inparticular, GAO's inquiry should include an analysis of the following:

-- The number of drugs that were approved based on surrogate endpoints;

-- The surrogate endpoints that FDA uses to approve drugs;

-- For each of these drugs identified, the date each was approved and whether FDA requiredthe companies to complete phase IV trials;

-- For each of these phase IV trials, the date they were started and the date they werecompleted and/or are expected to be completed;

-- Describe the tools that FDA has to compel companies to complete phase IV trials;

-- Describe any actions that FDA has taken against companies for failing to complete phaseIV trials or failing to complete trials in a timely manner; and

-- Describe any additional powers that FDA may need to compel companies to completephase IV trials, in the event the tools that FDA has presently are insufficient.

Thank you for your attention to this important matter.


Charles E. Grassley
United States Senator
Ranking Member of the Committee on Finance

[1] Perrone, Matthew "Cancer Drug Ruling Will Have Wide Impact" Associated Press, February22, 2008.

Associated Press

FDA's Review Process Under Investigation

Tuesday March 4, 12:53 pm ET

By Matthew Perrone, AP Business Writer

Concerns Over Blockbuster Drugs Vytorin, Avandia Prompt Investigation of FDA Review Process

WASHINGTON (AP) -- The government's watchdog agency is investigating whether theFood and Drug Administration's drug-review process cleared two blockbuster medicationswithout sufficient proof of their safety or effectiveness.

Sen. Charles Grassley said Tuesday the Government Accountability Office has agreed tostudy a much-debated method for approving drugs used to clear GlaxoSmithKline PLC'sdiabetes pill Avandia and Merck & Co. Inc. and Schering-Plough's cholesterol drug Vytorin.

The Iowa Republican requested the investigation after recent studies suggested the drugsmay not lower the risk of heart attack and artery-clogging plaque, as assumed by millions ofpatients and doctors.

"There's enough of a pattern of problematic drugs to ask for an independent review ofhow the FDA follows up on the effects of medicines that it's approved," said Grassley, in astatement.

FDA cleared Avandia because it helped control blood sugar, which many doctors believedecreases diabetics' risk of heart attack. But the agency came under fire last year when ananalysis showed Avandia could actually increase heart attack risk.

FDA argued that it has never required diabetes drugs to show lower heart attack risk, andthat lowering blood sugar alone is an important benefit.

The agency approved Vytorin, which combines Schering-Plough's Zetia with Merck'solder cholesterol drug Zocor, based on its cholesterol-lowering capability. But a study releasedearlier this year showed Vytorin was no more effective at limiting plaque buildup in neckarteries than Zocor alone, which is now available as a low-cost generic.

At issue now is whether FDA should approve drugs based on biological measures, likecholesterol and blood sugar, without evidence they improve more meaningful measures likesurvival.

FDA's Director for Medical Policy Robert Temple said the agency has used severalalternate study goals, often called surrogate endpoints, to approve drugs for decades.

For example, HIV drugs are cleared based on their virus-lowering power, an effectivepredictor of survival.

Drug industry advocates favor shorter study goals because they involve smaller, lessexpensive and faster trials.

Longer trials, they say, may actually jeopardize patients.

"It's probably unethical to do an overall survival study where you're going to have HIVpatients taking a placebo for 10 years," said Alan Goldhammer, vice president with thePharmaceutical Research and Manufacturers of America.

But those who criticize FDA's handling of Avandia and Vytorin say surrogate endpointsaren't the problem. Rather, it's when FDA doesn't demand follow-up studies to prove drugsdelivered on the predicted benefits.

"These studies are often never done, so we're left without the knowledge we need to usethese drugs wisely," said Dr. Steve Nissen, chairman of cardiovascular medicine at the ClevelandClinic. "And obviously we've paid the price for that with the safety issues and lack of efficacyissues with Avandia and Vytorin."

Nissen wrote the analysis that showed Avandia raised the risk of heart attack. Last yearFDA said the drug's risks were still unclear and asked GlaxoSmithKline to study its effect on theheart. Results from that trial aren't expected until 2014 -- 15 years after the drug was approved.

Schering-Plough and Merck are working on a study to determine if Vytorin extendspatients' lives. Results from that study, which FDA did not request or require, are expected in2011.

When the agency does require follow-up studies of drugs, its track record is poor formaking sure companies complete them. A 2006 investigation by the Health and Human ServicesDepartment inspector general concluded FDA could not readily identify what progresscompanies made on the studies.

In its most recent report, FDA said 900 of more than 1,200 studies required of drugmakers had not even begun.

Under a law that takes affect next month FDA can fine companies up to $1 million forfailing to honor drug study commitments.

Grassley argued for higher fines, and in his request to GAO asked investigators whetherFDA needs more authority.

The agency shows no sign of scaling back its use of surrogate endpoints.

Last month FDA cleared Genentech Inc.'s drug Avastin for use in breast cancer patientswho have not taken other drugs. Agency reviewers based their decision on Avastin's ability toslow the spread of cancer. Previously FDA had approved drugs as a first-choice option forcancer patients if they extended, or improved the quality, of patients' lives.

Associated Press
February 21, 2008

Cancer Drug Ruling Will Have Wide Impact

By MATTHEW PERRONE, AP Business Writer

(AP) -- A decision expected Friday on federal approval for Genentech's Avastin cancerdrug could have ramifications for all companies developing cancer medicines.

Genentech made its case for Food and Drug Administration approval of Avastin using awidely debated measure of drug effectiveness that focuses on tumor growth, not patient survival.

Industry executives are closely watching the decision to see whether the measure willpass muster with federal regulators.

Approval is far from certain, and many experts say the agency may delay a decision untillater this year.

Avastin is already approved for advanced colon and lung cancer and was Genentech'sbest-selling drug last year, accounting for $2.3 billion in revenue. An additional use for advancedbreast cancer patients who have not had chemotherapy would drive new revenue for thecompany.

In December, a panel of outside FDA advisers voted 5 to 4 against Genentech'sapplication, arguing the drug's benefits did not outweigh dangerous and toxic side effects. FDAis not required to follow the panel's advice, although it often does.

At issue is how the agency judges the effectiveness of cancer treatments. Traditionally,FDA only approved cancer drugs that extended the lifespan of patients. However, in recent yearscompanies have studied alternate measures of a drug's effectiveness. One of the mostcontroversial measures is so-called progression-free survival, or how long the drug halts thespread of cancer.

Genentech's studies of Avastin showed that while the drug halted tumor growth for morethan 11 months, breast cancer patients didn't live significantly longer than those who didn'treceive the drug.

Genentech has argued that stopping tumor growth benefits patients physically andpsychologically, even if it doesn't increase life expectancy. But many experts are skeptical.

"Why would it improve your quality of life to know that you have no disease progression if youstill aren't going to live any longer?" asked Dr. Kay Dickersin, Director of the Center for ClinicalTrials at Johns Hopkins University.

Dickersin said that if FDA approves Avastin based only on slowing tumor growth, itcould lower the bar for future drug approvals.

American Cancer Society spokesman Dr. Otis Brawley said it's possible Avastinimproves quality of life - but the company hasn't shown that.

"Unfortunately, there was no real quality-of-life measurement in this study," saidBrawley, who previously served on FDA's panel of cancer experts. "My interpretation of FDAbylaws is that I cannot approve a drug based on disease-free survival unless I have evidence ofimproved quality of life."

Genentech's Vice President David Schenkein points out that FDA has already approvedtwo drugs for breast cancer based on slowed disease progression: GlaxoSmithKline's Tykerb andBristol-Myers Squibb's Ixempra.

But those drugs were approved for patients who had already failed to respond to othertherapies. Genentech wants Avastin approved as a first-in-line treatment for breast cancer.Schenkein argues that delayed disease progression has advantages to overall survival as astudy goal.

"A trial that has to wait to record overall patient survival will take many more years andbe much larger," said Schenkein. He added that companies may be able to bring more medicinesto market faster using goals besides survival.

Given the tough medical and ethical questions surrounding Avastin, Stanford Groupanalyst Gregory Frykman says there is a 40 percent chance FDA will delay a decision to reviewnew data expected from Genentech later this year.

Regardless of when FDA makes a final decision, he writes, "it will provide insight intothe agency's tolerance for a non-survival endpoint" for the approval of new cancer drugs.

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