FDA on Monday announced that it was looking to withdraw approval for the low-blood-pressure treatment midodrine hydrochloride because the companies manufacturing the drug failed to provide data from post-approval studies.

The kicker: The drug was approved 14 years ago.

FDA gave midodrine hydrochloride—branded by Shire as ProAmatine and produced by a half-dozen generics firms—the green light in 1996 as part of the fast-track approval program designed to speed to market drugs for diseases with no current treatments.

The catch is that FDA requires post-market clinical trials to ensure that the drug is meeting risk/benefit endpoints. In other words, the regulatory body wanted to make sure no hiccups occurred with the treatment when it hit the general population.

In response, Shire—who acquired the drug when it bought Roberts Pharma in 1999—chose to withdraw the drug as of September 30. The drug firm made it clear that the withdrawal had nothing to do with any safety concerns. In addition, Shire stated that it had conducted post-market trials in conjunction with Roberts, but FDA felt the results were “inconclusive.”

According to a release by FDA, none of the companies selling the drug have provided any data to prove that the treatment is beneficial. That said, some 100,000 people were treated with the midodrine hydrochloride last year alone.

“We’ve worked continuously with the drug companies to obtain additional data showing the drug’s clinical benefits to patients,” stated Norman Stockbridge, director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research. “Since the companies have not been able to provide evidence to confirm the drug’s benefit, the FDA is pursuing a withdrawal of the product.”

FDA stated that patients currently on midodrine hydrochloride should not stop taking the medication. Shire now has 15 days to respond to FDA’s inquiry and provide some data supporting the drug. Shire did not respond to calls as of Monday afternoon. In addition, it’s unclear as to why FDA waited so long to ask for more data and whether any adverse reactions have been reported pertaining to the drug.

“This repeal effort was started by legislators concerned that the law is hurting the state’s economy,” explained PhRMA’s Senior Assistant General Counsel Marjorie Powell in a prepared statement. “And it is certainly true that it adds an extra level of administrative complexity for companies in the state. Pharmaceutical marketing is already effectively regulated by such federal government agencies as the Food and Drug Administration.”

The Massachusetts ban was part of the larger Health Care Cost and Quality Act. Although the bill is best known for extending health insurance almost universally in the state, it also created a new code of conduct for sales reps and established penalties for wayward reps of up to $5,000 per violation. It also created the Massachusetts Public Health Council, which has the power to create rules further limiting marketing practices.

Last year the Council passed new rules for both pharma and medical device companies, making Massachusetts the state with the most comprehensive marketing and disclosure code. The rules specifically mandate disclosure of fees, payments and other compensation to doctors; ban promotional items such as pens and mugs; and restrict meals to those provided at training or educational events. Payments for research and clinical trials, rebates and discounts, prescription drugs provided for patient use and demonstration units for charity care are exempt. All other payments of $50 or more must be disclosed.

Currently, Vermont and Maine have bans on all food service “gifts” to physicians. Minnesota limits gifts to under $50, while California, Louisiana, Maine, Massachusetts, West Virginia and the District of Columbia all require pharmaceutical and biotech companies to report marketing spending on physicians, but do not ban food service outright.

“This is a critical milestone on the path to potential approval for short-course therapy with Cladribine tablets, moving us one step closer to meeting an unmet need as an oral, disease-modifying drug available for relapsing MS,” stated Fereydoun Firouz, president and CEO of Merck’s US affiliate, EMD Serono, in a release.

FDA originally rejected Merck’s application for any kind of approval in November 2009, prior to the release of CLARITY trial data. It’s possible that FDA reconsidered the application after reviewing the positive results from the two-year global study of 1,326 patients suffering from relapsing-remitting MS.

According to Merck KGaA, patients taking the short-course tablet treatment experienced “rapid and sustained improvements in clinical and magnetic resonance imaging outcomes, which were accompanied by rapid and sustained effects on blood-cell subtypes implicated in the pathogenesis of multiple sclerosis.”

Gavin Giovannoni, principal investigator of the study, told ThePharmaLetter, “The introduction of an oral therapy, particularly one that has no short-term side effects and is as easy to use as oral Cladribine, will have a major impact on the treatment of MS. However, the use of this drug as a first-line therapy will have to be weighed up against the potential long-term risks which have yet to be defined.”

Side effects included headaches, upper respiratory tract infections and nausea—similar to adverse reactions experienced by patients taking the placebo.

Merck is neck-and-neck with Novartis, which received priority review for its own MS tablet-based treatment, Gilenia, in February. There are currently no non-injectable MS treatments on the market, so an early approval is going to be a big win for patients and a financial windfall for whichever company is first to market.

This is a huge problem for Roche who purchased the treatment as part of its merger with Genentech. The drug firm could see sales drop by $1 billion if FDA agrees with the panel and ceases use of the drug for breast cancer. The drug earned Roche $5.7 billion in 2009.

“We are disappointed by the committee’s recommendation and believe Avastin should continue to be an option for women with this incurable disease,” stated Sandra Horning, Roche’s global head of clinical development hematology/oncology, in a release. “We will continue to discuss the data from the more than 2,400 women who participated in three Phase III studies with the FDA. This recommendation does not impact Avastin’s approved uses for other cancer types.”

Avastin (in combination with chemotherapy) was given fast-track approval in early 2008, because it treated HER2 negative breast cancer, a form of the disease with few treatment options. FDA requested that Genetech release the results of two post-market trials to determine how effective the drug is at improving patient lifespan.

According to the two trials, the treatment only slowed cancer progression by approximately a month and didn’t do anything to boost patient survival. Additionally, patients taking Avastin had more adverse reactions than patients taking chemotherapy alone.

FDA will give a final ruling on Sept. 17.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 10–6 against recommending approval for the drug, a combination of phentermine and topiramate. Phentermine is the ‘phen’ in infamous weight-loss drug Fen-phen, which was pulled form the market in the late ’90s due to its damaging effects on the heart. Likewise, topiramate was studied several years ago and was also found to be beneficial, but not without serious side effects.

The panel concluded that the drug is effective, and data shows that people can lose anywhere from 6 percent to 10 percent of body weight, if taken in conjunction with a diet and exercise regimen. However, the committee was concerned about increased risk of psychiatric and cognitive issues uncovered in Vivus’ trials, and said that there was a lack of data to rule out cardiovascular risks and the drug’s potential to cause birth defects in women who become pregnant while taking it.

There were also concerns because 18 percent of participants taking a high dose withdrew from trials after experiencing mild side effects, such as tingling of the hands and feet, headache, and constipation. About 40 percent of all participants either taking high or low doses of Qnexa did not complete the study for various reasons.

The FDA usually follows the recommendation of its advisory panel, but the split vote, and some of the comments by panelists, may leave the FDA room to approve the drug.

The majority of the panel found there was a greater risk of major adverse cardiovascular events (heart attacks, strokes, etc.) for patients taking Avandia than those taking other diabetes drugs. (It didn’t find an increase in mortality, however.)

During the meeting, GSK trotted out details from its RECORD study that supported its hypothesis that Avandia benefits Type 2 diabetes patients in the long run and does not cause an increase in risk.

The company also released a statement July 13 echoing what it had told the Senate Finance Committee and FDA months before: Avandia critics are cherry-picking documents that support their claims of increased risk of adverse cardiovascular events; furthermore, comparisons that favor Takeda’s rival diabetes drug Actos are invalid, since one of the studies did not compare the performance of the two drugs in regards to cardiovascular events.

The “trial” itself played like a game of statistics ping-pong, with different analyses and accusations of data manipulation batted around by both sides. The sheer number of trial design flaws worked in both parties’ favors, and the debate over which studies should be included in decision-influencing meta-analyses raged throughout both days.

But much of the damage to GSK’s case had already been done before the meeting: Reports of study coverups (in The New York Times, no less) and paper ghostwriting have been plaguing the company for months. And the company announced on Tuesday it would settle around 10,000 suits for a total of $460 million. The suits alleged the very problems Avandia critics have vocalized over the last several years.

One of the reviewers to recently join the critics was Thomas Marciniak, who blasted GSK’s lynchpin RECORD trial for not only being poorly designed, but also poorly executed. Marciniak found numerous instances of ignored or severely delayed reporting of cardiac events in Avandia patients. He also argued, in his slides, that he has no bias, as “neither [his] job nor (for [him]) hundreds of millions of dollars are riding on the results.” And, far from GSK’s claim that RECORD vindicates its drug, Marciniak said he found that the study does suggest Avandia increases the risk for heart attack.

FDA doesn’t have to follow the panel’s recommendation. But the agency’s ultimate decision on Avandia’s fate will be indicative of the direction commissioner Margaret Hamburg’s regime is taking: Will it lean towards getting—and keeping—as many drugs into the market as possible, or will it take the safer route of risk management?

Biotech firm InterMune took an ugly hit on Tuesday as news broke that its lung disease drug Esbriet (pirfenidone) will require additional clinical studies, and won’t be getting the seal of approval from FDA any time soon. The news caused InterMune’s stock to drop a staggering 78 percent, according to Reuters. Analysts have downgraded the stock to values as high as $60 and as low as the mid-teens.

Esbriet is being used in trials to treat patients suffering from idiopathic pulmonary fibrosis (IPF), a debilitating and deadly lung infection that causes inflammation and scarring. People suffering from the disease typically have only two to five years to live and a 20 percent survival rate.

The treatment was involved in two large-scale clinical trials, but the drug failed to meet its endpoints in one. However, the Phase III data that the company collected was expected to be enough to get the green light from FDA.

In a complete response letter to InterMune, FDA requested another clinical trial to further prove the efficacy of Esbriet, beyond the endpoint met in the previous study. There are currently no FDA-approved medications for IPF, and an FDA advisory committee recommended that the treatment be approved back in early March.

Dan Welch, chairman, CEO and president of InterMune, said that he intends to meet with FDA as soon as possible to find out why its committee rejected the drug, and understand how to expedite the approval process. The bad news is that the meeting may not occur for 60 to 90 days.

Welch would not elaborate on the kind of data FDA would like to see, or what type of trial the regulatory body is looking for, nor would he comment on previous discussions with FDA.

FDA, on Monday, announced that it was reviewing whether a certain class of prostate cancer drugs could lead to diabetes, stroke, death, or heart problems.

The drugs in question are gonadotropin-Releasing Hormone (GnRH) agonists, marketed under a number of monikers, including Vantas and Lupron. These treatments are used to slow the growth of prostate cancer by decreasing the amount of testosterone created by the body.

“While our review of these prostate cancer treatments is ongoing and there are some limitations to the data, FDA believes it is important to tell patients and health care professionals that there may be an increased risk of serious side effects,” stated Robert Justice, director of the Division of Drug Oncology Products in FDA’s Center for Drug Evaluation and Research.

Doctors are being told not to suspend treatment, but to be aware of the risks and watch patients closely for diabetes of cardiovascular disease.

We typically don’t get emails from FDA  asking for information about stolen goods with massive bold letters, but that’s what just came into our inbox. Looks like a transport truck containing a mix of GlaxoSmithKline’s pharmaceutical and over-the-counter medications was jacked in Puerto Rico on January 29, and the feds are looking to the general public for any information. It’s curious that it took more than three weeks to announce the news. No word on whether the theft was just now discovered, or if they are reaching out to us because all other leads have run dry.

Below is a list of the stolen drugs. Please contact 1-800-551-3989 if you have any information about this incident.

NDC     Description     Lot #   Quantity

(Unit of Sale)
0173-0697-00    Advair Diskus 500/50mcg 60 Dose 9ZP2144 2
0007-5500-40    Albenza 200mg 112s      9B001   4
0007-3152-13    Avandaryl 4mg/2mg 30s   9ZP2540 48
0029-3159-00    Avandia 4mg 90s 9ZP2237 48
0029-1527-22    Bactroban Cream 15gm    C433259 160
0007-4139-20    Coreg 3.125 100s        MTSR1212        4
0007-3370-13    Coreg CR 10mg 30s       9ZP4771 96
0007-3371-13    Coreg CR 20mg 30s       9ZP0413 95
0007-3372-13    Coreg CR 40mg 30s       9ZP3661 224
0007-3373-13    Coreg CR 80mg 30s       9ZP3920 16
0173-0201-55    Daraprim 25mg 100s      A44519  3
0173-0470-01    Epivir 150mg 60s        9F004   3
0173-0470-01    Epivir 150mg 60s        9K007   9
0173-0662-00    Epivir HBV 100mg 60s    9D003   1
0173-0471-00    Epivir Oral 10mg/ml 240ml       9E003   12
0173-0719-20    Flovent HFA 110mcg 120 Actuation        F0638   48
58160-825-51    Havrix 720 ELU Tip Lok 10s      AHAVB371BA      1
0173-0260-35    Lanoxin Inj 0.5mg/2ml 50s       8M920   2
0173-0713-25    Myleran 2mg 50s 809980  1
0007-4883-13    Requip XL 6mg 30s       9ZP3419 2
0173-0750-00    Treximet 85mg/500mg 9s  8ZP2362 60

Show Notes:
This week we discuss:

• Pfizer’s medical education relationship with the Canadian Medical Association
• Journalists take FDA to task for not being transparent enough
• Layoffs and job cuts at Sanofi-Aventis
• New report shows that DTC receives more funding than sales calls in certain drug categories
• CEO compensation bump in life science

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