The FDA issued a warning letter to medical device giant Johnson & Johnson (NYSE:JNJ) saying that the company could face penalties including fines and injunction for failing to report incidents where its OneTouch Ping and 2020 insulin pumps may have caused death or serious injury.

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In an inspection of the West Chester, Pa.-based plant, the federal watchdog agency found that J&J’s Animas Corp. never reported on 1 complaint about series patient injury and delayed reporting 2 other incidents to the FDA.

The affected patients were hospitalized with diabetic ketoacidosis – a complication caused when patients lack the insulin to break down blood sugar, high blood sugar, respiratory failure and coma, according to the letter.
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The watchdog agency ordered the J&J subsidiary to explain, by Jan. 20, why it kept selling pumps known to fail. The company is also required to submit a plan to ensure that its failure to notify the FDA of devices that may cause serious injury or death in patients doesn’t have a repeat performance.

Animas spokeswoman Caroline Pavis told the Huffington Post that the company failed to report the 3 patient incidents to FDA because they involved patients that weren’t using the pumps as directed.

In 1 case, the patient ignored an alarm signaling that a cap had come off the machine, preventing insulin from being pumped into the body, Pavis told the new site.

Animas’ insulin pump problems are just the latest in a string of bad regulatory publicity for the New Brunswick, N.J. based medical device giant.

Just last week, the FDA ordered Johnson & Johnson, along with 32 other companies, to take another look at complication rates associated with their vaginal mesh products.

The watchdog agency asked a total of 33 companies to conduct 3 years of safety and effectiveness trials under growing concerns after deaths and injuries linked to the products spiked in recent years.

Subsidiary DePuy Orthopaedics could cost the med-tech titan up to $1 billion in lawsuits concerning metal-on-metal hip implants that were found to shed minute metal particles into a patient’s bloodstream over time.

Lawsuits over the ASR implant have piled up across the country, accusing DePuy of manufacturing a defective product, failing to warn patients and doctors of problems with the implant and negligence in designing, manufacturing and selling the product.

In an emergency conference call with investors and the press Friday morning, Cardinal Health Inc.’s chairman and chief executive officer, George Barrett, rebuked the DEA’s decision to interfere with the Lakeland facility.

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Barrett said the suspension was based on allegations that some of the prescriptions filled at four pharmacies were not written for legitimate medical reasons.

“We are outraged that the DEA took this action,” Barrett said. “We will seek today a temporary restraining order with the federal district court to block what we believe is an overly aggressive and counterproductive action by the DEA.”

A DEA spokesperson declined to comment on the case.

Barrett emphasized that the four pharmacies in question held valid state board of pharmacy and DEA licenses at the time.

“We are being held accountable for parts of the supply chain that we do not control,” he said.

Cardinal Health, a multibillion-dollar health care services company based out of Dublin, Ohio, has tussled with the DEA before. In 2007, DEA agents from the Miami field office suspended some operations at the Lakeland facility, located at 2045 Interstate Drive, claiming the distribution center sold large quantities of controlled substances to rogue Internet pharmacies, according to a previous DEA release.

In 2008, Cardinal agreed to pay $34 million to settle claims that it failed to report ­suspicious sales of controlled substances.

About 200 people are employed at the Lakeland facility, a spokeswoman said.

Barrett said large volumes of drugs will often trigger an investigation by the federal agency. The CEO characterized the investigations as “exasperating.”

In order to curb any lapse in distribution, Barrett said another Cardinal facility, one in Jackson, Miss., will pick up the slack and deliver necessary medications to the company’s customers. Those customers include hospitals and large chains, he said.

Many of the Class 1 drugs distributed by Cardinal treat epilepsy, sleep disorders and severe pain, he said.

When asked about the size of the volume of medication investigated by the DEA, Barrett declined to comment.

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“This is a blow to Britain’s R&D base and Unite will be doing everything possible to minimize compulsory redundancies at Alderley Park,” one of two UK facilities that is likely to be effected, Linda McCulloch, Unite national officer, tells The Manchester Evening News. “If the company can afford a 10 per cent hike in its dividends, then it can afford to retain these roles.”

To what extent the unions can succeed is, of course, unclear. But they may be emboldened by events in Switzerland, where Novartis recently agreed to rollback some of the 1,100 layoffs planned at various facilities. After three months of sustained pressure, the drugmaker abandoned plans to close one plant and will eliminate fewer jobs than planned at another. Tax incentives played a part in the reversal (read here).

Protesting job cuts, in fact, has become a recent industry trend. Two weeks ago, Roche employees in Poland demonstrated against hiring practices (read this). And last fall, a coalition of community groups, labor unions and activists held a vigil outside a Pfizer R&D facility in Connecticut to protest decisions to close various operations after receiving government subsidies (look here).

Nonetheless, the AstraZeneca employees face an uphill battle as the drugmaker braces for patent expirations on some of its biggest-selling medicines: the Crestor cholesterol pill, the Nexium acid reflux med and the Seroquel antipsychotic. The drugmaker also warned that profits may fall up to 18 percent this year. At the same time, AstraZeneca will buyback $4.5 billion in stock to appease investors.

The latest cuts, which brings to more than 30,000 jobs spread over three restructurings announced in the last few years, are expected to save $1.6 billion annually by 2014. And while investors dumped AstraZeneca stock after the news was announced, Wall Street likes where the cash is headed. “The (AstraZeneca) board continues to support a ‘progressive’ dividend policy, and we continue to be impressed by its commitment to returning cash to shareholders,” Leerink Swann analyst Seamus Fernandez wrote in a note to investors.

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At the same time, Lilly ceo John Lechleiter requested that he not receive an increase in his $1.5 million base salary or incentives “in light of the business challenges the company faces.” This is the third year in a row he has taken this step. Nonetheless, his bonus target is 140 percent of his base salary (see page 30 of the SEC filing) and his total compensation was valued at $16.4 million .

During his tenure, the 58-year-old Lechleiter has tried to adopt a decidedly different posture from some of his peers. Besides his approach toward compensation, he emphasizes his background as a scientist and has repeatedly rejected suggestions that Lilly should solve its pipeline woes by seeking a big merger. Meanwhile, he continues to bet on risky Alzheimer’s meds under development.

Two years ago, Lilly had to halt two studies of its gamma-secretase drug, called semagacestat, after worsening dementia symptoms in late-stage clinical trials. Key study results for another med, called solanezumab, are due by mid year. “If the (Alzheimer’s) opportunity fails, we believe Lilly may be forced to reconsider its business strategies in the next year. On the flip side, a clearly positive outcome for solanezumab would significantly improve Lilly’s long-term growth outlook,” Deutsche Bank analyst Barbara Ryan wrote in an investor note last week.

The urgency behind her prediction was underscored when Lillly last week reported 2012 forecasts that missed analyst estimates and lower-than-expected revenue for its Zyprexa antipsychotic – sales fell faster than forecast due to generic competition. How much lower? Sales for the pill dropped 44 percent in the fourth-quarter to $749.6 million.

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A U.S. Food and Drug Administration (FDA) inspection had found some products manufactured by Poly Implant Prothese (PIP) were “adulterated,” the letter said. French regulators say they can’t be sure now if they even saw it on the FDA’s website.

In the following decade, substandard silicone implants made by PIP were implanted into hundreds of thousands of unwitting women around the world. The French government in December advised 30,000 women to have their implants removed, warning the devices had an unusually high rupture rate and may contain industrial-grade silicone.

The lack of transatlantic communication is just one problem highlighted by the scandal. The affair is rooted in an alleged fraud, in which PIP is suspected of duping inspectors and flouting safety rules.

But some doctors, regulators and even the medical devices industry itself say the affair also exposes Europe’s weak regulation system – one that allowed PIP to operate for longer than it could have under a more rigorous regime.

They point to an ad hoc system of product approval and a lack of vigilance once a device is on the market. And they say the process is so byzantine, no organization is truly taking responsibility for keeping the public safe.

“Unsafe at any speed – that’s one description I’d use for medical device regulation in Europe,” said Nick Freemantle of University College London, who has published studies on the way medical devices get to market.

Trish Groves, deputy editor of the British Medical Journal says there’s “definitely a risk other poor products will get through, because the system is so very weak.”

French health authorities acknowledged as much in a 175-page report on February 1. “Radical change” is needed in Europe to assure proper surveillance of medical devices, said the health department’s general director Jean-Yves Grall.

FDA ACTED SOONER

The FDA got onto PIP when the company sought approval to sell saline implants in the United States in 2000. The FDA rejected the application. Its warning letter cited PIP’s failure to investigate deflation problems with the implants, as well as a failure to report more than 120 complaints about them from customers in France and elsewhere.

“Given the serious nature of these violations … all devices manufactured by PIP … may be detained without physical examination upon entry to the United States until these violations are corrected,” said the letter, dated June 22, 2000.

The FDA believes its rigorous standards stopped U.S. patients from being exposed to the PIP implants, said William Maisel, deputy director and chief scientist for devices.

In the European Union, where more than 500,000 medical devices are sold, from dentures and wheelchairs to pacemakers and implants for breasts, buttocks and testicles, the system is both less thorough and more complex than the U.S. regime.

Medical devices are regulated under the Conformite Europeenne, or “CE mark,” system – sometimes known as the “kite mark” for its distinctive shape. The CE mark is also used for household gadgets like electric toasters or coffee machines and for children’s toys and mobile phones.

Getting a CE mark is tougher for devices like pacemakers or implants than for toys or toasters. But the badge of approval can still be gained with relatively few tests – certainly less scrutiny than the extensive clinical trials required for pharmaceuticals.

“CHALK AND CHEESE”

The EU and U.S. systems are as different as “chalk and cheese,” said Freemantle. In the United States, medical devices are tested by serious regulatory scientists at the FDA, in a process that resembles a new drug submission. Europe’s system, he said, is “more like an old-boy network.”

Because Europe has no centralized process for approving medical devices, manufacturers don’t go directly to a national or Europe-wide regulator. Instead, they seek a CE mark through any one of around 70 to 80 organizations known as Notified Bodies, which largely are private companies.

The Notified Bodies are scattered across all 27 EU member states and range from large companies to small firms with just one or two employees. All are authorized to give a stamp of approval to a new product. They are tasked with checking the product does what it’s supposed to, has been tested in a lab, or is similar to other devices on the market. And Notified Bodies can suggest to manufacturers that they contract out testing to small laboratories, who may themselves be authorized by a separate agency.

Scientists who published a review of the system in the European Heart Journal in May 2011 found that the fragmentary setup encourages manufacturers to shop around for countries or Notified Bodies most likely to offer hassle-free certification.

A 2010 survey of medical device manufacturers by researchers at Stanford University found that high-risk devices took an average of 54 months to get through the FDA to market, but just 11 months in Europe.

The medical technology industry says it recognizes Europe’s system is flawed.

John Brennan, director of regulatory and technical affairs at industry trade body Eucomed, which represents some 22,500 medical technology companies in Europe, said the system is constrained by “an excessive level of confidentiality, a lack of effective central coordination and the perceived lack of clinical data and involvement of authorities.”

The European Commission, which oversees the laws governing devices regulation, said the Notified Bodies’ quality looks uneven. It began working on new proposals to tighten the system long before the PIP scandal erupted, it said.

“The present legislation gives too great a margin of maneuver to organizations that certify medical devices,” said the Commission’s Director General for Health and Consumers, Paola Testori Coggi. The system is “imperfect” and has “a lot of space to improve.”

“SMOKESCREEN”

Once the Notified Body’s initial job is done and a product is on the market, it’s up to national regulators to keep a look out for problems and ensure the Notified Body is keeping tabs.

In the PIP case, that national regulator was the Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS), which has the power to take a medical device off the market. The Notified Body that gave PIP authorization to trade was a private German firm called TUV Rheinland.

AFSSAPS – already set for an overhaul following a scandal over diet pills which France withdrew in 2009 after they were blamed for at least 500 deaths – told Reuters that responsibility for checking medical devices like breast implants lies with the manufacturer.

It said the regulatory focus should be on TUV, whose inspectors would visit PIP’s headquarters once a year, assess standards, review paperwork and then report back to the company and German authorities in case of problems.

TUV said the implants themselves were tested by two French laboratories, which were in turn authorized by another French agency called COFRAC. Both labs confirmed they had tested PIP’s implants. One said its tests were only mechanical, such as rupture tests; the other said it had tested the implants’ contents for toxicity, but would not give details.

COFRAC, a government-funded non-profit body, said it was not responsible for the output of a lab and could not guarantee test results. COFRAC does not answer to AFSSAPS, but is audited internally and by peer review.

For its part, TUV was only responsible for auditing PIP’s manufacturing process, said spokesman Hartmut Mueller-Gerbes. TUV relied on PIP to disclose any operational alterations, such as a change in the kind of silicone it was using. If PIP said nothing, TUV would assume everything was unchanged. Audits were based on the assumption that a firm is responsible and liable, and would have too much to lose to cut corners, TUV said.

Germany’s Zentralstelle der Laender fuer Gesundheitsschutz bei Arzneimitteln und Medizinprodukten, or ZLG, monitors TUV. It said inspections are announced a few weeks in advance, as stipulated in EU rules, and a wide range of documents are checked once a year.

PIP’s founder, Jean-Claude Mas, testified to police that PIP hid a paper trail documenting large purchases of non-authorized raw materials which may have aroused TUV’s suspicions.

It all adds up to what Richard Horton, editor of The Lancet medical journal, calls a “smokescreen of device regulation which is putting patients at risk.” The whole system is “based on the idea that you wait until something goes wrong before you take any serious action.”

“STRESS TEST”

It isn’t clear how AFSSAPS missed the warning from American regulators. AFSSAPS said it can’t be sure whether someone saw the letter. It watches the FDA’s site, but not systematically.

Jean-Claude Ghislain, its director of evaluation for medical devices, said AFSSAPS had not been informed by the FDA of its concerns over PIP in a “proactive” way. “We cannot check at every moment other countries’ health-authority websites.”

The FDA suggests the French could have been more attentive. “We don’t as a routine provide publically available information to other regulators, because it’s easier and more efficient for them to use the public website,” said the FDA’s Maisel.

His boss, FDA Commissioner Margaret Hamburg, said regulators on both sides of the Atlantic should see it as an opportunity to “look at our systems and see how we can strengthen them.”

The European Commission says it wants to reinforce rules and improve cooperation. It has written to French and German authorities, spokesman Frederic Vincent said, so they can explain “who did what and when.” When it gets the answers it needs, the Commission will conduct a “stress test” on the case to see what lessons can be learned.

Until the system is improved, “we’re sitting on a time bomb which could explode at any moment,” says The Lancet’s Horton. “No government anywhere in the EU can be sure that medical devices in their country are safe and effective.”

It’s claimed that the FDA installed spyware to monitor personal email accounts

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Iowa Republican Senator Charles Grassley – a powerful member of the judiciary committee that has jurisdiction over areas like civil liberties and constitutional law – has asked FDA commissioner Margaret Hamburg to provide details about who authorised the monitoring of employees and why some of the plaintiffs are no longer employed by the agency. Hamburg has until 17 February to supply her answers.

In the lawsuit filed on 25 January, six whistleblowers claim that the FDA secretly spied on them for two years. They say that the agency began its campaign of electronic snooping after the agency learned that they had written a letter to the president elect, Barack Obama, and his transition team in early 2009 detailing misconduct in approving unsafe medical devices. In that letter, the plaintiffs called the FDA ‘fundamentally broken’, and said its scientific review process for medical devices has been ‘corrupted and distorted’ by managers.

Soon after, the agency installed or activated spyware on the whistleblowers’ work computers and also monitored their private emails, according to court documents. In addition, evidence suggests that the FDA took screen shots of the employees’ computers and also intercepted their emails to and from staff members on key House and Senate oversight committees.

These actions appear to have continued even after the Office of Inspector General (OIG) at the FDA’s parent agency – the Department of Health and Human Services (HHS) – denied the agency’s request to take criminal or administrative action against the individuals. In a May 2010 letter to the FDA, the OIG concluded that the whistleblowers’ communications were legally protected.

Chilling effects

The plaintiffs, who were all heavily involved in the FDA’s safety review process, are seeking an injunction to stop the agency from pursuing what they say is an illegal spying campaign. Two of these whistleblowers still work at FDA and say that they face continued harassment, two were fired and another two did not get their contracts renewed, according to Stephen Kohn, the lead attorney for the plaintiffs.

‘If you can target someone simply because they raise a legal, health or safety concern, that will have a chilling effect on any FDA employee alerting the public or Congress about matters of life and death,’ Kohn tells Chemistry World. ‘There is a lot of pressure on these scientists to approve the devices.’

According to Kohn, the whistleblowers raised major concerns about 20 medical devices that involve, among other things, ultrasound and CT scan technology. Specifically, these reviewers said some of the devices could expose patients to radiation at levels up to 800 times that of a chest x-ray and they found that others couldn’t appropriately detect cancers. Nevertheless, Kohn says the FDA approved 19 out of 20 of these devices that had been flagged.

‘Whistleblowers point out fraud, waste and abuse when no one else will, and while they do so, while also risking their professional careers, they are often treated like skunks at a picnic,’ Grassley wrote in a 31 January letter to Hamburg, asserting that retaliation against whistleblowers ‘should never be tolerated’.

Grassley said that certain employees, including members of the Public Health Service Commissioned Corps within HHS, are not covered under the US Whistleblower Protection Act, which leaves them vulnerable to retaliation. He says that this is a one of several loopholes in current law that should to be closed.

The FDA said it can’t comment on personnel issues or any matters subject to ongoing litigation.

“The consequences are real. The quality of cancer care has been materially impacted. It’s disheartening,” says Susan Schwartz McDonald, ceo of National Analysts Worldwide, a market research and consulting firm that queried 204 oncologists last month. “Unfortunately, the prevalence is not really surprising, because we know the shortages have been severe. But this really brings it home… And it’s particularly painful to think about the factors distorting what’s happening in the supply chain.”

Unless shortages are alleviated, half of the oncologists surveyed expected the situation will worsen, while only 14 percent foresee a reversal. The results come just as yet another bill was introduced on Capitol Hill to combat the problem. The legislation would require the FDA and drugmakers to develop a list of shortages and allow the Drug Enforcement Agency to transfer quotas, among other things.

The survey found little reason for optimism. For instance, 23 percent of oncologists reported that patients were dying a few times a year sooner due to shortages, and 14 percent say this happened every month, while 3 percent claimed this occurred each week. Conversely, 60 percent say they had not seen this happen. Just the same, 40 percent is a big proportion.

Meanwhile, 46 percent of the oncologists report that there were times in the past year when patients were unable to receive timely treatment due to product shortages, and 31 percent report this occurs each month. Another 15 percent said this happens each week and 3 percent lamented that the problem crops up each day.

Equally troublesome, 39 percent of the oncologists reported that patients were unable to receive the best treatment at all and 28 percent this problem occurred each month, while 15 percent complained this happens every week and 2 percent say it occurs every day. This means that just 16 percent of oncologists never encountered this problem.

And 32 percent of the oncologists say their patients experienced a tumor recurrence a few times last year, while 13 percent say this happened each month and 3 percent report the problem arose every week. One percent report the problem was noticed each day. So is the glass half full or half empty? Fifty-one percent reported this was not a problem.

To what extent the legislative efforts will stem the shortages is unclear. The bill that was introduced in the House this week by John Carney, a Democrat from Delaware, and Larry Bucshon, a Republican from Indiana, would require the FDA to take several steps to more aggressively monitor the problem and improve communication within the industry and the medical community. Congressional sources say the bill may be hitched to legislation renewing the Prescription Drug User Fee Act.

Besides developing a so-called critical drug list, which will identify drugs that are vulnerable to shortage, the legislation would require the FDA to notify distributors of an imminent critical shortage, but withhold notification to a distributor if the US Attorney General finds the distributor is involved in gray market shipments (read more here and here).

The bill would also requires the FDA to expedite the review of any application for approval of a drug that is vulnerable to shortage and on the critical drug list, as well as expedite reviews of any request by a drugmaker of a critical drug to approve a change to the manufacturing process or facilities of that drug or to approve an application for an alternate active pharmaceutical ingredient supplier (here is the legislation, which is called the Drug Shortage Prevention Act).

Also, the FDA would be required to notify the DEA of any critical drug on the shortage list and provide info to the US Attorney General to determine whether quotas under the Controlled Substances Act should be increased. This would largely refer to ADHD meds, which have also been in short supply over the past year. Several House Democrats are probing two drugmakers.

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Why the reversal? For months, FDA data has actually shown that the percentage of conflict of interest waivers granted for advisory committee members has remained below targets. At the same time, the FDA vacancy rate for advisory committees has remained low (see here and here). In other words, finding qualified experts is not a problem.

Yet, Janet Woodcock, who heads the FDA’s Center for Drug Evaluation and Research, last year was openly pushing to relax the rules, which include barring participation for any individual who has potentially conflicting financial interests totaling more than $50,000 (you can read more here). Two years ago, the agency tweaked its procedures for granting waivers (see this).

The effort by FDA officials to roll back the rules, which were passed in 2008 after an arduous campaign to promote greater transparency at the agency, alarmed some consumer advocates, who argue that the concerns expressed by Hamburg and Woodcock have more to do with pressure from the pharmaceutical industry than actual difficulties finding unconflicted experts for panels.

Last fall, three US Senators introduced a bill to reverse FDA regs that bar experts with financial ties to drug or device makers from serving on committees without a waiver. The impetus has been a heated debate over the FDA approval process for devices, although drugmakers share the sentiment. “Our view is there a need to improve the process of the advisory committees, particularly in areas where there is a paucity of experts,” Geno Germano, who heads the Pfizer specialty care and oncology unit, told the House Energy & Commerce Committee yesterday.

But in recent months, Hamburg and Woodcock were undermined by their own data, as has been reported more than once (see this and this). Consequently, Hamburg could no longer – at least, not easily – that the FDA was truly having difficulty finding qualified experts.

“At the present time, we are not bumping up against our cap in terms of waivers,” she told the committee. “We don’t, at the moment, see major areas where a legislative fix is required.” Of course, Hamburg would have known this last summer if she had reviewed agency data before issuing her earlier statements.

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Pfizer Inc. is recalling about a million packages of two types of birth-control pills because they might not contain enough pills with active ingredients, Jennifer Corbett-Dooren reports on the News Hub. Photo: AP.

Pulled from shelves were Lo/Ovral-28 pills and their Norgestrel generic versions, which doctors have been prescribing for years to tens of thousands of women. The pills come in blister packs containing a mix of 21 active tablets and seven that are inert. As guided by the packs, women are supposed to take a certain pill each day in order to prevent pregnancy, taking the inert pills at the end of a monthly cycle.

Pfizer said Wednesday that it believes only 30 packs had packaging problems, including having the active and inert tablets out of order, or lacking the proper amount of each kind of pill. The company said it recalled a million packs in the U.S. to be safe.
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The Food and Drug Administration hasn’t received any reports of adverse events, such as unintended pregnancies, and the agency is investigating, according to an agency spokeswoman. Pfizer said it hadn’t received reports either, while noting that it had only just alerted the public.

The pills were made and shipped last year by a Pfizer plant in upstate New York, on the Canadian border. To encourage proper use, active pills in the packs are colored white, while the inert tablets are pink. An alert customer noticed that her pack had a pink pill where a white one should have been, and complained to the company on Oct. 19, a Pfizer spokeswoman said.

Investigating the complaint, Pfizer discovered that some blister packs of pills had an extra active pill at day 22 or 28, one pack lacked an active tablet at day 10 and another pack lacked a placebo tablet at day 24, the FDA spokeswoman said.

Pfizer identified three glitches in its production of the packs that could, on rare occasion, result in improper packaging, a Pfizer spokeswoman said. The problems: The design of the packaging line could allow for incorrect placement of the pills; a mechanical system for detecting defective packs could miss one in “very, very infrequent” times; and plant workers could also miss problem packs. The company said it has since fixed the problems.

Pfizer notified pharmacies and distributors on Dec. 28 that it was recalling the pills, according to an FDA spokeswoman. The company believed, based on the “low defect rate and our health-hazard assessment,” that providing public notice wasn’t necessary, but then went public late Tuesday following an FDA request, a Pfizer spokeswoman said.

Women who miss birth-control pills—say, by taking an inert pill when they should take an active one—are at risk of an unintended pregnancy because they may ovulate in the absence of the hormonal medicines meant to prevent it. Carolyn Westhoff, a professor of obstetrics and gynecology at Columbia University, cautioned that the risk from missing one or two pills is likely low. “Usually the women who ovulate have missed a larger number,” said Dr. Westhoff, who has studied the ovarian effects of missing birth-control pills.
[PFIZER] FDA / Reuters

Lo/Ovral-28 birth-control pills were affected by Pfizer’s recall.

Yet Eve Espey, an obstetrics and gynecology professor at the University of New Mexico, said the risk could be compounded because women also tend to miss pills on their own.

It was unclear how many of the pills were already used and how many remain in the hands of women. Pfizer said it didn’t know. The expiration dates on the affected products range from July 31, 2013, to March 31, 2014. A list of the affected lots is available at www.pfizer.com.

The company is advising women who have used the pills “over the last several months” to consult with their doctors.

“We understand that this news can be very concerning and confusing for any woman who takes birth-control pills to protect against unintended pregnancies. We share their concerns,” the company said in a statement.

Last year, doctors wrote 64,000 prescriptions for Lo/Ovral-28 in 2011, and another 453,000 prescriptions for its generic version, Norgestrel and Ethinyl Estradiol tablets, according to IMS Health, a health-care data firm. The tablets were manufactured and packaged by Pfizer, but are labeled and sold under the Akrimax Pharmaceuticals brand.

“This is one of the pills that are commonly used, and patients depend on it to be efficacious,” said Jennifer Wu, an ob-gyn doctor at Lenox Hill Hospital in New York City. Neither Dr. Wu nor Dr. Westhoff said they had heard from patients taking Lo/Ovral, but would switch their prescriptions to another product and recommend partners use condoms.

Lo/Ovral-28 is a small product for Pfizer, the world’s largest drug maker with $67.4 billion in world-wide sales last year. The product had $7.6 million in sales in 2011, according to IMS Health.

But the recall could dent Pfizer’s reputation for quality manufacturing, a selling point in competing with rival products.

Through Nov. 3 of last year, the FDA had notified Pfizer 12 times of “objectionable” manufacturing conditions requiring correction, up from nine each of the previous two years, according to FDAzilla, a business intelligence firm that analyzes FDA data. Since 2008, Pfizer had received 38 of the letters, which can result in official warning letters if serious problems go unaddressed.

The Pfizer spokeswoman said, “A review of our complete inspection records shows consistently strong performance for the past three years.”

The FDA has been issuing more of the letters. In 2010, it sent 1,500 to pharmaceutical companies, up from 1,068 in 2007, according to FDAzilla.

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A new study suggests that might have been the case. After examining data from FDA advisory committees, a group of researchers from Harvard University, Stanford University and Brown University found that a relationship exists between approvals made closest to deadlines and post-market safety problems, such as drug withdrawals, major labeling revisions or safety alerts issued by the agency.

Although the researchers do not maintain that a strict cause-and-effect relationship has been established, they suggest the implications ran wide and deep. To wit, in the quest to meet deadlines, approvals may have inadvertently led to adverse health outcomes – which raised costs for patients and payers – and caused setbacks for drugmakers that expect predictable financial returns.

The findings, which were published in the American Journal of Political Science, appear as the House Energy & Commerce Committee holds a hearing today on the virtues of the Prescription Drug User Fee Act (you can watch here and see the agenda here). Known as PDUFA, the initiative was first passed in 1992 and ushered in a new era in approvals as drugmakers now pay fees to fund reviews – these cover about 60 percent of the cost- and the agency has specific requirements to meet.

The purpose of the paper was to examine how Congress uses deadlines to control regulatory agencies, and PDUFA offered a useful lesson. “By imposing specific deadlines and linking agency compliance to the agency revenue source – the penalty for not meeting the deadline was not simply embarrassment and congressional pressure, but also the possibility that tens of millions of dollars in user fees would no longer be available for personnel costs – PDUFA represented a significant effort to influence FDA actions,” the researchers write.

To test their hypothesis, they examined the approval process for 1,034 new molecular entities that were approved between 1950 and 2008, when – the Food and Drug Administration Amendment Act – was passed and began to require advisory committee meetings for NMEs. What did they find? Well, the so-called review clock can be problematic. “Our analyses suggest that deadlines have altered the timing of FDA decisions,” they conclude.

For instance, they compared reviews before and after PDUFA began 20 years ago, and found that reviews suddenly piled up in as the six-month deadline neared for those drugs after the legislation went into effect. But there was no such piling in the years before PDUFA. This suggests that deadline pressure altered the timing of reviews and raising the possibility of post-market problems, since this may have compromised the ability of the FDA to gather and distribute info through advisory panels.

Moreover, they assert that, if a drug is approved in the two months before the deadline, then that same drug will, on average, experience higher rates of safety issues in the years after approval, compared both to drugs approved quickly, which was three or more months before the deadline, and to drugs approved more slowly, which would have been after the deadline.

Specifically, they found the probability of a drug approved in the two months before the deadline receiving a new black-box warning is 3.27 times greater than a drug approved at some other time, according to a model used to examine NMEs approved between 1993 and 2007. For NMEs approved between 1993 and 2007, safety-based withdrawal is 6.92 times greater for a drug approved in the two months leading up to its approval deadline than for comparable drugs approved at other times.

“The bottom line is that there remains a relationship between approvals at-the-deadline and the raised incidence of post-market safety problems several years later,” Daniel Carpenter, the Allie S. Freed professor of government at Harvard University and one of the researchers and the author of ‘Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA,’ writes us.

“Although we are still not claiming baldly that the deadlines necessarily cause – in a physics-like notion of causality – these post-market problems, the observational evidence seems to be mounting, and the manuscript uses a variety of statistical controls and tests, including a form of statistical analysis called ‘non-parametric matching,’ to tease out the relationships,” he continues. “And it suggests that one mechanism for this relationship may be compromised consideration of the drug later in the review stage, including occluded or shortened advisory committee consideration.”

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