FDA Approval Process Disregards Safety: Vioxx For Juveniles; Pargluva / Symlin f

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Sun, 30 Oct 2005 15:17:06 -0500

[sSRI-Research] FDA Approval Process Disregards Safety: Vioxx

For Juveniles; Pargluva / Symlin for Diabetes

 

 

 

 

FDA Approval Process Disregards Safety: Vioxx For Juveniles; Pargluva

/ Symlin for Diabetes

 

 

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

FYI

FDA Advisory hearings aside, nothing better encapsulates the agency's

disregard for drug safety issues as does FDA's approval of Vioxx for

children just weeks prior to Merck withdrawing the drug from the

market because of its lethal effect.

Although Dr. David Graham, FDA's medical officer who had analyzed

Vioxx post-marketing data, warned about the drug's lethal effect

(August 25, 2004), FDA administrators ignored his pleas and permitted

the company to misinform the public with its advertisements that

assured doctors and consumers that Vioxx was safe and effective.

 

FDA's decision to approve Vioxx for children (Sept 8, 2004) was

reached at the same time that Merck decided to withdraw the drug

because it caused cardiac arrest and killed people.

 

FDA's continued disregard for safety in its haste to approve new

drugs, is demonstrated by a data analysis published in JAMA (On

October 21, 2005) revealing that a diabetes drug, muraglitazar

(Pargluva), that the FDA had deemed " approvable, " in fact poses

serious risks of death:

 

" Muraglitazar appears to increase the risk for morbidity and mortality

in diabetic patients during relatively short-term treatment. The

estimated magnitude of this risk is substantial with [relative risks]

RRs indicating a doubling for irrevocable, major end points and

composite outcomes. The consistency of these RRs suggests that this

result is not due to chance. Accordingly, muraglitazar should not be

used or approved to treat patients with diabetes until an appropriate

dedicated trial to assess cardiovascular outcomes is performed..This

agent should not be approved to treat diabetes based on laboratory end

points until safety is documented in a dedicated cardiovascular events

trial. "

 

See: http://jama.ama-assn.org/cgi/content/full/294.20.joc50147v1

October 26, 2005, The Wall Street Journal published a profile of Dr.

Robert Misbin, one of the few FDA medical officers willing to

criticize the agency about drug safety issues. Dr. Misbin, an expert

on diabetes drugs who fought for the removal of Rezulin, a diabetes

drug that caused liver damage.

 

Dr. Misbin worked together with another FDA officer, Dr. Dragos Roman,

and discovered that Symlin caused patients to black out and crash

their cars. The drug appears to cause hypoglycemia, or low blood

sugar, a condition that can lead to disorientation and blackouts. A

review of the data revealed that in Type I ( " juvenile diabetes " )

patients, " the rate of car accidents involving hypoglycemia was much

higher for those on insulin plus Symlin (15 of 1,179 patients) than

for those on insulin plus a placebo (two of 538). "

 

In written remarks presented to a July 2001 meeting of an FDA advisory

committee, Dr. Misbin called the safety findings " alarming " and the

drug's long-term benefits " trivial. " He noted that " Diabetics would do

just as well sticking to insulin alone. " The drug was not approved at

that time, but on March 16, 2005 it was approved without a warning

about car crashes which Dr. Misbin had been urging FDA administrators

to require.

 

A poignant element to the story is Dr. Misbin's efforts to reach out

on a human level to Dr. Orville Kolterman, Amlyn's expert who had

worked on the development of Symlin for decades. Through the years,

the two had socialized with mutual friends. In his personal

communication, Dr. Misbin acknowledged his regret but stressed his

recommendations were prompted by safety concerns: " I ask that you

recognize that as a medical officer at FDA, I get to count the bodies

when things go wrong. "

 

The company promptly used his personal communication to get Dr. Misbin

ousted from the review team. Demonstrating that in the dog eat dog

business culture, there is no room for human exchanges.

 

Back stabbing comes with the territory of being a whistleblower.

Whistleblowers cannot expect earthly rewards except their clear

conscience and the knowledge that they are doing the right thing. The

Journal reports:

 

" His overriding concern was that patients wouldn't see or would ignore

the warning to avoid driving after using Symlin, the way that warnings

about liver testing for Rezulin were disregarded. He felt the drug's

benefits, particularly for Type 1 diabetes, didn't outweigh that risk.

" I don't see how there won't be innocent victims. "

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

~~~~~~

FDA reviewer battles the drug his boss approved

Wednesday, October 26, 2005, p. 1

By Anna Wilde Mathews, The Wall Street Journal

One night four years ago, Food and Drug Administration drug reviewer

Robert Misbin lay awake worrying about a diabetes treatment called

Symlin, which he feared could cause patients to black out and crash

their cars. Prodded by Dr. Misbin and others, the FDA was about to

block Symlin from going on the market.

 

Dr. Misbin felt bad for an old acquaintance, Orville Kolterman, who

had spent nearly a decade working on the drug at Amylin

Pharmaceuticals Inc. At 3 a.m. he decided to explain his stance in a

letter to Dr. Kolterman.

 

" I ask that you recognize that as a medical officer at FDA, I get to

count the bodies when things go wrong, " Dr. Misbin wrote. " I cannot

forget the experience that I had in the not too distant past of

receiving a letter (one of several letters) that said, 'My uncle was a

wonderful man. Why did you approve a drug that killed him?' " Dr.

Misbin signed the letter " Bob, " and used his home address.

 

Amylin wrote back to Dr. Misbin's boss, saying it was " extremely

uncomfortable " about working with Dr. Misbin. Soon afterward, Dr.

Misbin was removed from the FDA Symlin review. The drug took another 3

1/2 years before it was finally approved in March of this year. The

company agreed to a strong warning label and marketing restrictions.

 

The battle over Symlin provides an inside look at the FDA drug-review

process and how the agency balances the benefits and risks of new

products. It also shows some of the conflicts in a hierarchical

bureaucracy where the officials nominally on the bottom rung are also

doctor-scientists with years or decades of experience in their fields.

 

Dr. Misbin is one of a few FDA officials who have criticized the

agency's decisions when they believed life-or-death health issues were

at stake. These employees generally keep their jobs, since the FDA is

wary of conducting what might look like a crackdown on

whistle-blowers. David Graham, a safety official, has spoken out since

last year accusing the FDA of failing to pay enough attention to

drugs' side effects. Dr. Graham continues to hold his FDA post.

 

Aside from his early-morning epistle, Dr. Misbin has twice given

information to Congress about problems he perceived in FDA-approved

drugs. Without telling his boss, he recently contacted Mothers Against

Drunk Driving in an attempt to get publicity for Symlin's risks. The

former University of Florida professor, who makes about $150,000 a

year at the FDA, continues to review major drugs for diabetes and have

a role in decisions with multibillion-dollar implications for

pharmaceutical companies.

 

Dr. Misbin, who holds a medical degree and has specialized in

diabetes, joined the FDA in 1995 and soon focused on the diabetes drug

Rezulin. After the drug's approval in 1997, some patients suffered

liver failure and died. Dr. Misbin, who had taken over responsibility

for Rezulin from another reviewer, initially defended the drug and

recommended broadening its use.

 

But in early 2000, after the FDA approved two other treatments that

appeared less risky, he began campaigning against it. Haunted by

reports of fatal liver failures and letters from grieving relatives,

he prodded the FDA to ban Rezulin. When the agency didn't move quickly

enough to suit him, he sent Congress internal FDA emails and other

documents that later surfaced in the media. In March 2000, Rezulin was

withdrawn from the U.S. market.

 

Dr. Misbin received nationwide publicity for his leaks and the FDA

investigated whether he had broken any rules. The investigation was

closed without any disciplinary action, according to Dr. Misbin. An

FDA spokeswoman declined to comment.

 

Nine months after Rezulin's withdrawal, the agency received the Symlin

application. If approved, it would be the first new treatment for Type

1, or " juvenile " diabetes, since insulin. It would also treat the

more-common Type 2, or adult-onset, diabetes. The drug, injected

before meals and used with insulin, is a synthetic version of a

hormone named amylin that diabetics either lack or don't have enough

of. The San Diego biotech company Amylin, named after the hormone,

says its drug can give diabetics better control over their blood

sugar, which can reduce the risk of complications such as blindness or

kidney failure.

 

Dr. Misbin, who had been assigned to follow Symlin years earlier as it

worked its way through clinical trials, tackled the application,

focusing on how well the drug worked. A new FDA reviewer, Dragos

Roman, focused on safety.

 

Early on, the potential for hypoglycemia, or low blood sugar,

concerned both men. The condition can lead to disorientation and

blackouts. Insulin alone can cause hypoglycemia, but Dr. Misbin

noticed that when Symlin was added to insulin in clinical trials the

condition occurred at a higher rate.

 

Dr. Roman pointed out something else: Among Type 1 patients, the rate

of car accidents involving hypoglycemia was much higher for those on

insulin plus Symlin (15 of 1,179 patients) than for those on insulin

plus a placebo (two of 538). A 34-year-old driver went the wrong way

on a highway and ended up in the emergency room. Dr. Roman concluded

that two deaths involving Symlin patients might be linked to

hypoglycemia: a 48-year-old man who died of a seizure as his wife

scrambled to get orange juice to boost his blood sugar and a

35-year-old involved in a car crash after taking the drug just one day.

 

To Dr. Misbin, the car accidents were " a big red light. " He had

learned a painful lesson from Rezulin, where rare signs of potential

liver damage, but no deaths, surfaced in preapproval trials. While

regulators hear plenty about a drug's benefits from its maker, " the

people you don't hear from are the ones who will be hurt, " he says.

" When tens of thousands of people take it, anything can happen. "

 

In written remarks presented to a July 2001 meeting of an FDA advisory

committee, Dr. Misbin called the safety findings " alarming " and the

drug's long-term benefits " trivial. " Diabetics would do just as well

sticking to insulin alone, he wrote.

 

The company's presentation was led by Dr. Kolterman, a diabetes

specialist who had met Dr. Misbin socially several times over the

years in the company of a mutual friend. While Dr. Kolterman

acknowledged a hypoglycemia risk, he said it was mainly in the first

month or so after patients started the drug. He denied that the car

crash victim's death was caused by the drug.

 

The advisory committee, consisting of outside experts, found Symlin

effective, contradicting Dr. Misbin's argument on that point, but

rejected the drug on safety grounds including the hypoglycemia risk.

The FDA agreed and later told the company it needed to find a better

way of dealing with the hypoglycemia risk.

 

As Dr. Misbin lay in bed a few weeks after the committee meeting, one

thought stuck in his mind. He believed that Dr. Kolterman had refused

to look at him while he made his presentation. The next day he mailed

his letter. " What I wanted to say to him was, 'Don't hate me, because

I'm doing my job. You may disagree with me, but don't hate me,' "

recalls Dr. Misbin.

 

He addressed the letter " Dear Orville " and acknowledged " the anger

that you must feel toward me. " He added, " I believe that some people

at FDA previously have been too eager to ingratiate themselves to

Industry (sic) and that patients have died as a result. The strong

language of my review was an attempt to try to prevent history from

repeating itself. " It was a reference to Rezulin.

 

Eight days later, Dr. Kolterman wrote back that he " strongly disagreed

with the conclusions put forth in your letter. " Dr. Kolterman says in

an interview that he remembers watching Dr. Misbin closely during his

presentation. He calls the reviewer's letter " unorthodox " and " puzzling. "

 

Amylin then sent a letter to David Orloff, Dr. Misbin's boss at the

FDA, raising concerns about " the unbalanced content and tone of his

medical review on Symlin. " Amylin said it was " extremely uncomfortable

about trying to work with Dr. Misbin given all of his actions and

comments. " The letter didn't specifically ask for Dr. Misbin to be

removed from the Symlin review but did ask that he not review another

Amylin diabetes drug at an earlier stage called Byetta.

 

Dr. Orloff, who is head of the Division of Metabolic and Endocrine

Drug Products, removed Dr. Misbin from the Symlin review and assigned

Byetta to another reviewer. In comments relayed through an FDA

spokeswoman via email, Dr. Orloff says Amylin was " justifiably

concerned " by Dr. Misbin's private letter and had reason to believe

that the reviewer had adopted a " fixed opinion " on Symlin no matter

what future studies might show. Also, Dr. Orloff says he prefers

having one reviewer on a drug and Dr. Roman was the logical choice

because he had focused on the drug's safety. Asked why he didn't

punish Dr. Misbin for speaking out of turn, the boss says the reviewer

" was free to have his own feelings. "

 

Dr. Kolterman says Amylin would have been " perfectly happy to work

with " Dr. Misbin if it was a " collegial, productive working

relationship. " He notes that at one point Amylin actually asked for

Dr. Misbin's presence at a meeting to ensure the company answered his

questions.

 

Dr. Misbin says he believes his boss's decision was " defensible, "

given the tension with the company. In a diary entry for Aug. 29,

2001, Dr. Misbin wrote that he might actually be in " a stronger

position making my case behind the scenes " about Symlin.

 

In fact, Dr. Misbin mostly stayed out of deliberations over the next 3

1/2 years. In December 2003 the FDA once again turned away Amylin's

application after Dr. Roman concluded that severe hypoglycemia was

about twice as frequent among patients taking Symlin in a new study of

Type 1 diabetics.

 

Amylin eventually persuaded the FDA to accept the results of studies

in which diabetes patients knew they were taking Symlin and could

adjust doses of the drug and insulin to avoid hypoglycemia, which was

caused by the two drugs taken together. Normally, to prevent bias, the

FDA prefers studies in which a drug is compared to a placebo and

patients don't know what they're taking. Agency officials accepted

Amylin's argument that the additional studies, which showed a lower

risk of hypoglycemia, reflected the real-life conditions under which

diabetes patients treat themselves.

 

In a review completed Feb. 18 of this year, Dr. Roman said the risks

had been " identified and addressed " through the new research. If

patients didn't drive cars for two to three hours after taking Symlin,

the risk of hypoglycemia-induced accidents " will be practically

eliminated, " he wrote. He found Symlin generally effective (though

only modestly so for Type 1 diabetes) and said it could lead to weight

loss for Type 2 diabetics. He recommended approving the drug for those

who can't control their blood sugar with insulin alone. Dr. Orloff

concurred.

 

On March 16 of this year, the FDA approved Symlin. The company agreed

to a ban on consumer ads and promised to conduct a further safety study.

 

The approval surprised Dr. Misbin, who says he assumed that Symlin's

risk couldn't be eliminated. He was further upset when he saw the

drug's FDA-approved label. While the label carried a black box -- the

sternest warning -- saying that Symlin was associated with higher risk

of severe hypoglycemia, it didn't specifically mention the car crashes

observed in some studies. The label did caution patients not to drive

or operate heavy machinery in the first three hours after a Symlin

injection.

 

In his diary entry for March 18, Dr. Misbin referred to the lack of a

mention of motor-vehicle accidents. " 5 AM Can't sleep, " he wrote.

" Symlin approved without MVA in label or enough about hypo. Disappointed. "

 

His overriding concern was that patients wouldn't see or would ignore

the warning to avoid driving after using Symlin, the way that warnings

about liver testing for Rezulin were disregarded. He felt the drug's

benefits, particularly for Type 1 diabetes, didn't outweigh that risk.

" I don't see how there won't be innocent victims, " he says. " How many

people have to lose how many pounds to justify the death of one kid on

a bicycle? "

 

Amylin hasn't received any reports of accidents associated with the

drug and believes it is safe, Dr. Kolterman says. The FDA's Dr. Orloff

says the label is " more than adequate " in describing safety issues and

the drug's " risk versus benefit is favorable. "

 

In the past few months, Dr. Misbin has swung into action. He regularly

does Google searches for " Symlin " and " accident, " and has made his

concerns known to staff members for Sen. Charles Grassley, who held

hearings last year about the now-withdrawn painkiller Vioxx. The

senator hasn't taken any action on Symlin.

 

In August, Dr. Misbin sent a letter to Mothers Against Drunk Driving,

urging the group to post the Symlin warning label on its Web site. In

the letter Dr. Misbin said the FDA removed him from the Symlin review

" after I expressed concern that this drug might increase the risk of

motor vehicle accidents. " He didn't mention the dispute with Amylin

over his private message to Dr. Kolterman. Dr. Misbin was careful to

tell MADD that his letter was " personal and should not be taken as an

official communication from FDA. "

 

The FDA declined to comment about Dr. Misbin's recent activities.

Amylin says it isn't aware of them. MADD hasn't posted a warning on

its site. A spokeswoman for MADD says via email that the organization

focuses on drunk driving and can't address all the substances that

might impair someone behind the wheel.

 

 

 

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