First, the U.S. Food and Drug Administration (FDA) issued a safety communication warning consumers about the dangerous side effects of a type of antibiotic known as fluoroquinolones. Aneurysms. Arrhythmia. Inflammation and pain to the joints, muscles and tendons. Permanent damage to the central-nervous system. Type 2 diabetes. All from the little pills intended to clear up infections.
Now, the FDA has required the manufacturers of the drugs sold on the market as Avelox, Cipro, Factive, Floxin and Levaquin to be labeled accordingly, alerting those taking them as to the potential risks. Further, the agency is telling physicians who prescribe them to do so only when there is no other alternative for their patients.
“Fluoroquinolones have risks and benefits that should be considered very carefully,” Dr. Edward Cox, of the Center for Drug Evaluation and Research, said in a press release titled “FDA updates warnings for fluoroquinolone antibiotics.” “It’s important that both health care providers and patients are aware of both the risks and benefits of fluoroquinolones and make an informed decision about their use.”
Doctors are quick to put pen to pad for the medication in cases of bronchitis, sinusitis and urinary-tract infections (UTIs). Not so fast, the agency said. A review by the Antimicrobial Drugs Advisory Committee, formerly the Anti-Infective Drugs Advisory Committee, revealed the dangerous side effects can occur within hours, days or weeks of taking oral – and injectable – fluoroquinolones.
The American Academy of Family Physicians did some research on the topic, too.
“A search of the FDA Adverse Event Reporting System database from November 1997 to May 2015 identified 178 cases in which apparently healthy patients who took an oral fluoroquinolone to treat ABS (acute bacterial sinusitis), ABECB (acute bacterial exacerbation of chronic bronchitis) or uncomplicated UTI developed disabling and potentially irreversible adverse reactions,” the academy said in an article on its Web site titled “Use Fluoroquinolones Only as Drug of Last Resort for Some Infections.”
In reaction to the news, JAMA is offering alternatives to the antibiotics in question. Its recommendations include generic amoxicillin or doxycycline for ABS and Bactim, Macrobid or Monurol for UTIs.
Anyone taking fluoroquinolones who experiences an adverse event is urged to share the incident with the FDA through the MedWatch Online Voluntary Reporting Form. Meanwhile, thousands of lawsuits continue to mount against them, specifically with regard to Johnson & Johnson’s Levaquin.
Miami Beach was the place to be for mass tort lawyers last week, with two drug and medical device conferences as well as a critical hearing before the Judicial Panel on Multidistrict Litigation (also known as the “JPML”). The Judicial Panel, a group of federal judges that meets every two months to consider requests to establish MDLs for pharmaceutical, medical device, environmental, consumer fraud, securities and other mass tort cases, held a hearing on Thursday, January 26, 2017, at the federal courthouse in Miami which included discussion on a potential Eliquis MDL.
One of the most significant arguments heard by the JPML Panel last week was for the establishment of a new MDL No. 2754 for product liability claims stemming from Eliquis. Eliquis is a popular blood thinner drug prescribed to patients who suffer from atrial fibrillation, deep vein thrombosis, or pulmonary emboli. This drug, also known as apixaban, is part of the same class of newer anti-coagulants, which includes Pradaxa and Xarelto. Eliquis is manufactured and sold by Bristol-Myers Squibb and Pfizer.
The manufacturers of Pradaxa and Xarelto have been mired in thousands of lawsuits filed by patients who suffered serious personal injuries or died as a result of taking these drugs. The individual lawsuits focus on the manufacturers’ failure to properly test the medications prior to marketing, irregularities in the conduct of the clinical trials that were completed, failure to properly report adverse events, and inadequate warnings. The lack of a reversal agent and questionable data demonstrating effectiveness of Pradaxa and Xarelto over Coumadin (which has an antidote) are also key contentions in the liability cases against the manufacturers. Similar allegations are now being made as well against the manufacturers of Eliquis.
Eliquis Still on the Market
Eliquis, like Pradaxa and Xarelto, remains on the market, even in the face of the troubling safety issues. Many of the Pradaxa cases were settled a few years ago, while the Xarelto manufacturers will face the first jury trials in the coordinated litigation in 2017. Bristol-Myers Squibb and Pfizer have urged the JPML Panel to establish an Eliquis MDL for the Eliquis cases in the federal court for the Southern District of New York. It is anticipated that hundreds of additional Eliquis lawsuits will be filed in the coming months if an Eliquis MDL is granted.
The dedicated Mass Tort Unit of Searcy Denney Scarola Barnhart & Shipley represents plaintiffs who have been injured by defective drugs and medical devices. The firm filed one of the first lawsuits in the national Pradaxa litigation and has played an active role in litigating Pradaxa and Xarelto blood thinner lawsuits on behalf of a number of injured patients.
Is Sponsor-Submitted Clinical Data Safe?
The U.S. Food and Drug Administration has a tricky task at hand when it comes to reviewing, evaluating, investigating and eventually approving prescription medications. Yes, the agency has a mission to ensure patient safety, and yes, a formal process must be followed before a medication can be marketed, but no, government workers do not conduct the clinical trials whose data leads to the approval process.
Instead, sponsors – also known as pharmaceutical companies and their supporters – pay for the clinical trials, leading to the logical perception that the data might be biased or even tainted. It is a reasonable conclusion that concerns consumers across the country.
In order to make good on its mission of ensuring patient safety, the FDA dispatches the Office of Scientific Investigations to check the accuracy, integrity and quality of all facts and figures. The division’s goals are twofold:
- To verify the efficacy of data submitted in support of new drug applications.
- To protect the rights and welfare of not only patients but also participants in clinical trials.
The OSI also inspects Institutional Review Boards, or IRBs, for compliance with safety standards.
“FDA investigators compare information that clinical investigators provided to sponsors on case report forms with information in source documents such as medical records and lab results,” explains Carolyn Hommel, an OSI consumer-safety officer, in a Living Safer Magazine article titled “The ABCs of the FDA Approval Process.”
Several things are looked at, including whether the clinical trials were run using best practices, whether adverse events were reported and whether the human subjects followed proper protocol. If any errors or falsifications are found, the FDA has the right to issue a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain, or NIDPOE. The warning letter “informs the recipient clinical investigator that FDA is initiating an administrative proceeding to determine whether the clinical investigator should be disqualified from receiving investigational products pursuant to the Food and Drug Administration’s regulations,” states the agency’s Web site.
OSI falls under the FDA’s Center for Drug Evaluation and Research, whose employees conduct as many as 400 inspections every year. Of those inspections, a reported three percent receive a NIDPOE.
Patients additionally are protected by the Drug Safety Oversight Board, or DSOB, also under the umbrella of the Center for Drug Evaluation and Research. The board tackles issues by meeting monthly with eight federal agencies, representatives of which give valuable input and expert advice about emerging problems and possible solutions.
“It’s often a combination of problems that prevent approval,” Dr. John Jenkins, of the Center for Drug Evaluation and Research, tells Living Safer Magazine. “Close communication with the FDA early on in a drug’s development reduces the chance that an application will have to go through more than one cycle of review. But it’s no guarantee.”
Is the road to FDA approval of a new drug as long and winding as it sometimes seems?
The road to U.S. Food and Drug Administration approval of pharmaceutical manufacturers’ medications is a long and winding one. A dynamic process tinged with favorable – and unfavorable – factors can take a drug from lab to label in 10 months or less.
Consumer clarity on how certain products make it to market and whether they are safe is lacking, so much so that some are left wondering whether the FDA is being overpowered by “Big Pharma.” The issue is the focus of a Living Safer Magazine cover story.
“Admittedly, there’s not much in the way of studies to disprove that the FDA is doing its job,” writes Stephanie Andre in an article titled “The ABCs of the FDA Approval Process.” “Yet, one still feels as though the agency could slow down the process, instead of giving way to notions that drug companies can buy their way toward faster approvals, thereby shortening up clinical trials and never fulling understanding the long-term effects of such medications.”
At first, the drug-approval process seems cut-and-dried. Companies developing new prescriptions test them on animals to determine initial efficacy, then conduct clinical trials on humans to measure outcomes relating to specific diseases. The next step involves filing a New Drug Application, or NDA, with the agency. If the drug is made from biological elements as opposed to chemicals, another form called a Biologics License Application, or BLA, is submitted. Both documents contain test results, details on product manufacturing and contents of the label.
“The label provides necessary information about the drug, including uses for which it has been shown to be effective, possible risks, and how to use it,” Andre writes. “If a review by FDA physicians and scientists shows the drug’s benefits outweigh its known risks and the drug can be manufactured in a way that ensures a quality product, the drug is approved and can be marketed in the United States.”
But what about the risks? How much is known about them? Such questions might be prompted by the fact that the FDA does not conduct any testing. The agency instead relies on results from the sponsor seeking approval and occasionally vets the data through its Center for Drug Evaluation and Research, or CDER. The advisory committee is called upon when there are varying degrees of uncertainty about the drug, said Dr. Mark Goldberger, a former CDER director.
“Some considerations would be if it’s a drug that has significant questions, if it’s the first in its class, or the first for a given indication,” Goldberger said. “Generally, the FDA takes the advice of advisory committees, but not always. Their role is just that – to advise.”
Patients have both the responsibility and the right to gauge the safety of prescriptions they take, and the FDA acknowledges that by providing a list of “Frequently Asked Questions about the FDA Drug Approval Process” on its Web site.
A newly published study shows that drugmakers are doing a disservice to patients by inconsistently reporting side effects of medications depending on whether the information is being filed with the U.S. Food and Drug Administration or its overseas counterpart, the European Medicines Agency.
Researchers compared adverse drug-reaction data for anticonvulsants and antidepressants marketed by the same pharmaceutical company in both the United States and Europe and found the results to be counterproductive in protecting the public from injury. Among their findings: 77 more adverse drug reactions were reported to the FDA than the EMA involving 12 brand drugs, which generated 24 documents; in those documents, more background about the sources of the adverse drug reactions was reported to the FDA than the EMA. While America seemingly comes out on top in the analysis, it is bad news for Europeans and the medical community as a whole.
“Publicly available drug product documents have the potential to be valuable and vital sources of harm information, but data included in these were found to be inconsistent and not usefully presented,” concludes the report, titled “Variation in adverse drug reactions listed in product information for antidepressants and anticonvulsants, between the USA and Europe: a comparison review of paired regulatory documents.” “Identifying, selecting, summarising and presenting multidimensional harm data should be underpinned by practical evidence-based guidelines. Prescribers and patients require reliable reporting of pertinent ADRs to enable them to undertake meaningful informed risk-benefit decisions across competing drug therapies.”
Adverse drug-reaction data should not be reliant on location for its accuracy, head researcher Dr. Victoria Cornelius told Pharmalot.
“Without this information, prescribers cannot appropriately inform patients on the totality of the risks of taking a medicine,” said Cornelius, of the Imperial College of London School of Public Health, in an article titled “Drug makers inconsistently report side effects in the US and Europe.”
Thomas Moore, of the Institute for Safe Medicine Practices, agreed.
“This study shows that the reporting of drug adverse effects on product information is fragmentary and inconsistent,” Moore told Pharmalot. “In this sample, neither the FDA nor the EMA versions provided much information about the onset, duration, and severity of drug side effects. Instead they provided just lists that were not necessarily in agreement.”
The U.S. Food and Drug Administration (FDA) received another blow to its ability to regulate pharmaceutical product marketing that was dealt via a court order stating it is not in the agency’s purview to control promotional statements about certain medications’ unintended uses.
In the federal case of Amarin Pharma Inc. et al. v. Food and Drug Administration, it was ruled that officials must abide by the conclusion “that Amarin may engage in truthful and nonmisleading speech promoting the off-label use of Vascepa, i.e., to treat patients with persistently high triglycerides.”
Vascepa is basically prescription fish oil for reducing high triglycerides in adults. While the FDA cleared the drug for patients with triglyceride issues, Amarin has been touting it as the go-to pill for patients with “persistently high triglycerides,” a population for which Vascepa is not cleared.
At issue: the First Amendment. Seven months prior to the current ruling, a federal judge’s decision that Amarin has the constitutional right to make statements – given they are truthful – about Vascepa dealt the initial blow to the FDA.
According to Law360, the judge stated, “There is no basis to fear that promoting Vascepa for this off-label purpose would endanger the public health.”
Amarin had to concede somewhat in the current ruling as the company now is required to keep abreast on the engineering and science of its pill and update its promotional statements to reflect any changes. In addition, the company agreed to a process and timetable by which the FDA can question any promotional statements it deems untruthful and resolve the issue.
A clinical trial to prove Vascepa offers cardiovascular benefits, clearing it for patients with “persistently high triglycerides,” should be completed in 2018.
The lawsuit has been closely watched by the industry and is view as a seminal case when it comes to the oversight of claims by big pharma and also a landmark one involving freedom of speech.