Pharmaguy's Insights Into Drug Industry News
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Pharmaguy's Insights Into Drug Industry News
Pharmaguy curates and provides insights into selected drug industry news and issues.
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EpiPen Failures on the Rise Just Like Its Price

EpiPen Failures on the Rise Just Like Its Price | Pharmaguy's Insights Into Drug Industry News |

EpiPens, which contain the hormone epinephrine (also known as adrenaline), are used to stave off allergic reactions that can in some cases kill. Failure of EpiPens to deploy correctly have been cited in seven deaths this year through mid-September, according to reports by patients and physicians made to the U.S. Food and Drug Administration and obtained by Bloomberg News. The FDA received a total of 228 reports of EpiPen or EpiPen Jr. failures during the same time period, according to documents made available as a result of a Freedom of Information Act request. In addition to the deaths, 35 people were hospitalized, according to the reports.


Until now, the medical device has been the subject of controversy for a different reason. EpiPen is sold by Mylan NV, a drugmaker legally based in the Netherlands but run from Pennsylvania, that was under fire last year for significantly raising the price of the allergy shot, from about $50 for a single pen to more than $600 for a two-pack. Congress held hearings, government agencies began inquiries, and rival Sanofi sued. The Paris-based competitor claimed Mylan sought “to preserve the monopoly position of their $1 billion crown jewel” by engaging in anti-competitive conduct. Mylan has denied any wrongdoing.


EpiPen and EpiPen Jr. failures, meanwhile, resulted in a recall of some units in March by the company that makes the device for Mylan, Pfizer Inc.’s Meridian Medical Technologies. Mylan, which sells the drug-device combo using Meridian’s “pens,” called the defect “extremely rare” (read “A Pfizer Company that Makes EpiPen Devices Failed to Investigate Patient Deaths Says FDA”;


Reports submitted by users to the FDA, however, show broadening accounts of malfunctions dating as far back as 2014.


More About EpiPen:

  • “Letters to "Pharma Sis" to Cut EpiPen Price to Improve Goodwill Will Fall on a Tin Ear”;
  • “Mylan CEO Bresch, aka "Pharma Sis," Defends Price Gouging, Tax Evasion as Job Savers”;
  • “FDA is Cause of Mylan's Monopolistic Pricing of EpiPen, Says WSJ. Allergist Has Cure.”;
  • “Mylan's Patient Assistance is a "Convoluted Scheme," Says Public Citizen”;
  • “Sarah Jessica Parker to Stop Shilling for Mylan Because of EpiPen Pricing: What Did She Expect?”;
  • “Awash in Criticism, Mylan Has Decreased its Fearmongering Awareness Advertising”;
  • “Mylan, EpiPen Price Gouger, Ranks No. 2 in U.S. #Pharma Exec Pay!”;
  • “Is There No End to Mylan's Shenanigans? Paying Off Patient Groups to Lobby!”;
  • “Mylan CEO's Mom Used Position with Education Group to Boost EpiPen Sales Nationwide”;
  • “Yes, Mylan DID "Misclassify" EpiPen as a Generic, Says Medicaid”;
  • “Mylan "Gamed the System" and Refuses to Testify at Senate Hearing About EpiPen Costs to Medicaid”;
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558 Pharma Funded Post-Marketing Drug Studies and Not a Single Adverse Event Reported – Sounds Too Good to be True

Studies drug companies fund after medicines go on sale may be too small to detect rare side effects, a recent German study suggests.


Even if these so-called post-marketing studies do uncover previously undetected adverse events, physicians conducting the trials are often required to keep results confidential, limiting the potential for regulators or patients to learn about safety issues, according to the study in The BMJ.


When drugs are approved based on tests in only a few thousand patients, very little is known about long-term safety or the potential for rare side effects to occur when tens of thousands of people take the medicines, said lead study author Dr. Angela Spelsberg, medical director of the Comprehensive Cancer Center in Aachen, Germany.


"The fact that many physicians are obliged by contracts to handle adverse drug reactions as confidential business information rather than reporting them is very disturbing," Spelsberg added by email. "In light of the indispensable role of general practitioners and clinicians in detecting, diagnosing and publicly reporting adverse drug reactions, this means a very big threat to public safety."


For the study, Spelsberg and colleagues made freedom of information requests to three regulatory authorities responsible for registering post-marketing studies in Germany and obtained data on 558 studies.


Not one adverse event report could be identified from any of the 558 post-marketing studies.


Still, the study offers fresh insight into several potential shortcomings of post-marketing drug studies, said Dr. Barbara Mintzes of the University of Sydney in Australia.


"When a drug first comes to market it has been tested on average in 2,000 to 3,000 people, too few people to uncover most rare serious harmful drug effects," Mintzes, who wasn't involved in the study, said by email. "Often, patients at greatest risk of harm like the frail elderly or people with several serious health conditions are excluded from the trials, so post-marketing safety studies are very important."


[What’s even worse is the fact it takes many years to complete these studies (see here) while the drug is on the market.]

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Everyone Loses When Doctors Trust Pills Over Patients. Implications for Adherence.

Everyone Loses When Doctors Trust Pills Over Patients. Implications for Adherence. | Pharmaguy's Insights Into Drug Industry News |

Treating pain is a notoriously tricky business. But it’s even harder if the medications on which we rely are inappropriately marketed. Last month, a Los Angeles Times investigation of Purdue Pharma asserted that for years, the company falsely elevated the efficacy of its twice-daily OxyContin, a powerful opioid pain reliever. The L.A. Times’ review of evidence—including three decades of court cases, investigations, patient and sales rep testimonies—provides good data that the drug's effect may not, as claimed by Purdue, last for 12 hours across the board (read “OxyContin's 12-hour Problem: Misrepresentation of Efficacy Leads to Addiction & Purdue Knew It”; ).


In other words, OxyContin may not be the magical drug that provides longer-lasting pain relief than all other oral opioids. Purdue has argued that the L.A. Times’ claims are not valid, and it remains to be seen whether there will be federal investigations into this claim as recommended by Massachusetts Sen. Edward Markey.


In the meantime, as a doctor who bought the hype about OxyContin’s twice-daily efficacy for decades, I’m frustrated. While my gut sense that someone was pulling the wool over my eyes was correct, I was casting blame in the wrong direction—toward my patients.

Pharma Guy's insight:

When drugs don't work as advertised - especially if they have side effects that are downplayed by sales reps - it impacts what the drug industry terms the "problem" of lack of adherence. Patients will stop taking drugs that don't work or have side effects and thus they will be labelled as non-adherent and seen as the problem that has to be solved by more advertising or by more adherence apps and programs, when in fact it is the drug that is the problem. That's why I say “Medication Adherence Won't Get Better Unless Pharma Marketers Accept Some Blame”;

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The Dog - i.e., RA Contractor - Ate Our Adverse Event Data. FDA Doesn't Buy the Excuse, Sends Letter

Blame it on the contractor.

That’s the reason Heritage Pharmaceuticals gave the Food and Drug Administration after an agency inspector found 10 instances in which the generic drug maker failed to convey side effect reports about its medicines, which is required by law.

Between 2010 and 2014, the company did not submit an unspecified number of side effect reports concerning an undisclosed number of its drugs, according to a Nov. 5 warning letter that the agency sent to the drug maker.

Such violations are rare.

Whenever a drug maker receives a side effect report about one of its medicines, the information is supposed to be conveyed periodically to the FDA. This is standard procedure, but one that is taken seriously by regulators, since they must detect troubling trends with drugs.

By and large, drug makers are keen to comply with this requirement. Not only do companies fear the wrath of FDA officials, they want to avoid the suggestion they are unwilling to disclose side effects. In fact, only once during the past four years has a company not filed required reports, according to the FDA database. And there have only been eight other instances during the past decade.

But in its annual reports filed with the agency between 2010 and 2014, Heritage noted that there were no side effect reports. Yet, an agency inspector found at least 10 such instances. So what was the problem? When confronted with the discrepancy, Heritage blamed a regulatory affairs contractor for the failure, according to the warning letter.

Pharma Guy's insight:

Gee, I wonder who the contractor was?

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OpEd: FDA's Antiquated Drug Safety Program is "Obscene"

OpEd: FDA's Antiquated Drug Safety Program is "Obscene" | Pharmaguy's Insights Into Drug Industry News |

There was quite a bit of news coverage recently about a study published in JAMA Internal Medicine that documented delays in the disclosure of serious adverse events to FDA (read "Pharma Delays Reporting Adverse Events to FDA").

But that's not the real problem. Not by a long shot.

The first real problem is the much more extensive delay FDA has in releasing these data to the public. Currently, the most recent publicly available FAERS data includes case reports received by FDA through December 31, 2014. That means that critical, potentially life-saving, data is currently 7 months out of date. And we're not talking about 10% of the data being late. We're talking about 100% of the data being late. While pharmaceutical companies have a requirement to report adverse event cases to FDA in a timely manner, FDA has no such obligation to release those data to the public in a timely manner.

Some could argue that the delay in public data release is critical so that FDA can examine the case reports, perform analysis and issue relevant warnings and label changes. And in fact that does happen from time to time. But not nearly the way it should.

Which leads to the second real problem. An analysis of our safety signaling system shows that it takes on average a full 5 years for FDA to issue a label change after a safety signal is detected from FAERS. We know this because we track active safety signals from FAERS data and record the delays in FDA labeling changes. Why does the issue of label changes matter? Specifically because of the reasons Dr. Redberg cites -- patients and physicians need to understand the real world risks. And in the current healthcare system they simply won't know until FDA issues a label change.

So, is the fact that pharmaceutical companies fail to report 10% of serious and unexpected adverse events within the 15-day window a problem? Sure. But it's a little problem.

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Overuse, Safety Questions Cloud Advair’s Ascent to Asthma Blockbuster

Overuse, Safety Questions Cloud Advair’s Ascent to Asthma Blockbuster | Pharmaguy's Insights Into Drug Industry News |
Millions of Americans use GlaxoSmithKline's purple inhaler. But whether Advair poses a higher risk of asthma-related death remains uncertain 15 years after regulators approved the drug.

On an April day in 2001, more than 2,000 Glaxo salespeople flocked to the Paris Las Vegas hotel for events to launch Advair. Spotlights swirled and the room glowed purple, matching a giant replica of the drug's inhaler.

Jim Daly, the Glaxo manager nicknamed "Mr. Advair," took the stage sporting a purple tie. "There are people in this room who are going to make an ungodly sum of money selling Advair," he told the cheering throng.

The 50 salespeople who persuaded physicians to prescribe the most Advair would get $10,000 bonuses on top of healthy commissions.

"I think we can make some millionaires out there," declared Glaxo's then-president of pharmaceutical operations, David Stout.

Stan Hull, the company's senior vice president at the time, rhetorically asked the crowd, "What patient is not appropriate for Advair?"

Pharma Guy's insight:

An interesting story, especially regarding how difficult it is for patients to learn about drug safety issues. While every drug has side effects, patients need to be aware of emerging safety issues of the drugs they are prescribed - doctors too. Patients can no longer depend on their doctors to know all the facts.

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Mirapex, ReQuip, Etc. Should Have Prominent Black Box Warnings About Serious "Psychotic-like," Compulsive Behavior

Mirapex, ReQuip, Etc. Should Have Prominent Black Box Warnings About Serious "Psychotic-like," Compulsive Behavior | Pharmaguy's Insights Into Drug Industry News |

For several years, a group of drugs used to treat Parkinson’s disease has been blamed for various unusual addictive behaviors, such as pathological gambling, compulsive shopping and sudden sexual urges. Sensational stories occasionally appeared in the media and lawsuits were filed by patients who blamed the drugs, such as Requip and Mirapex, for wreaking havoc on their lives.

Now, a new analysis suggests in JAMA Internal Medicine finds these widely used drugs. known as dopamine receptor agonists, are more closely associated with these impulse control disorders  than has been demonstrated. Consequently, the study authors are calling for stronger warnings – specifically, so-called Black Box warnings, which are the most serious type of warning – to be added to product labeling.

In reaching their conclusions, the researchers analyzed 2.7 million domestic and foreign side effects for all drugs reported to the FDA between 2003 and 2012. 

Using a statistical analysis they found the proportion of side effects involving impulse control behaviors was 277 times higher than other central nervous system drugs, such as those used to treat depression, schizophrenia and epilepsy. 

“The associations were significant, the magnitude of the effects was large and the effects were seen for all six” of the dopamine receptor agonists, they wrote. And they conclude by noting that none of these six drugs currently have boxed warnings about impulse control disorders, but that such warnings should be added based on their findings, as well as small studies indicating the reasons for the side effects may go unrecognized.

“This is a striking example of an unusual and very specific set of psychiatric side effects linked to drugs that effect a specific neuroreceptor,” lead author Thomas Moore, a senior scientist at the Institute for Safe Medicine Practices, a non-profit, writes us.“In some patient groups, 10% to 15% may experience this potentially catastrophic side effect, a rate of injury that is extremely high.”

The association was strongest for the dopamine agonists pramipexole [Mirapex] (n = 410; PRR = 455.9, P < .001) and ropinirole [ReQuip] (n = 188; PRR = 152.5, P < .001)

Pharma Guy's insight:

"Our findings confirm and extend the evidence that dopamine

receptor agonist drugs are associated with these specific impulse control disorders," say the authors. "At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings."

The same companies that market these drugs -- e.g., GSK for ReQuip -- also want to market drugs that treat some of the side effects such as "Hypersexuality." GSK, for example, at one point wanted to market Paxil for Persistent Genital Arousal Disorder or PGAD (see story here: PGAD. EGAD! Another Syndrome/Disorder, Whatever!).

Somewhere way down in the ReQuip official FDA labeling, you'll find this:

"Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with REQUIP or after starting or increasing the dose of REQUIP. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium."

Pretty serious. This information should, IMHO, be placed in a black box instead of being hidden within the other side effects and often the LAST side effect mentioned! 

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Why is Questcor’s Disclosure on Acthar Side Effects News?

Why is Questcor’s Disclosure on Acthar Side Effects News? | Pharmaguy's Insights Into Drug Industry News |
The failure to allow post-approval adverse event data to be used by non-pharmacovigilance experts, as in the Acthar case, may be a very expensive lesson for Questcor and Mallinckrodt.

A month ago, the New York Times ran a front-page business section story on Questcor and its primary revenue producing drug Acthar. In that article, the NYT reported on a bevy of previously undisclosed side effects linked to Acthar and the report highlighted the related risks – both patient safety risks, and the risks to Questcor’s future earnings potential should the FDA take action on the drug as a result of those side effects. The revenue risk was particularly troubling for Questcor because they are in active discussions to be acquired by another large pharma company, Mallinckrodt, for over $5 billion dollars. The vast majority of that purchase price is attributable to the success of Acthar in the marketplace and if that revenue were to decrease – or dry up entirely – it might scuttle the deal (or, at least, result in a very uncomfortable discussion on revised valuation).

To those of us used to working with the FAERS data from which the NYT article was derived, there was nothing new or particularly interesting about these disclosures. In fact, we regularly find major undisclosed safety concerns in our monthly data updates and make that information available to our clients.

So, we didn’t think too much about this article. We didn’t see it as news. Until this week.

On Wednesday, Questcor filed an 8-K – a public disclosure document – that included the side effect information that had already been detailed in the NYT article, along with some very interesting analysis.

Clearly, someone over at Questcor made the realization that these safety issues were, in fact, a big problem. In order to: a) salvage any possible deal with their pending acquirer; and b) not run afoul of federal securities laws, Questcor needed to get out in front of this story and publically disclose what has been reported.

The key disclosures made in that 8-K filing, as noted in a follow-up New York Times article this morning, were that “the number of patients reporting a so-called adverse event while using the drug last year represented almost 5 percent of prescriptions dispensed. The total number of events in 2013 reported by patients, who can experience multiple ill effects, was almost 14 percent of prescriptions, up from 9.1 percent in 2011.” Among the reported adverse events driving the spikes in reporting, according to the article, were abdominal pain, increased in blood sugar, and renal failure.

In an effort to better relate what those adverse event risks actually mean to the company and its pending deal, Questcor heavily beefed up its “Risks Associated With our Business” section of its public disclosures to include gems like this:

"Such events could subject us to costly litigation, delay, negatively impact or end our opportunity to receive or maintain regulatory approval to market Acthar, or materially impact our commercialization efforts,”

Wow. When 95% of your revenue is derived from a single drug and that drug’s revenue stream is coming under fire from previously undisclosed safety risks, you better believe that you should be disclosing that information to your public shareholders and your potential acquirer.

Pharma Guy's insight:

It does seem that more dangerous drugs are being approved by the FDA. As shown in the chart above/left, DEATHS reported to the FDA via its adverse event reporting system have increased dramatically in the last few years for which data is available.

Between 2003 and 2012, FDA received 588,000 death notices via Adverse Event Reports (AERs). This is scary considering that FDA's adverse event reporting system is notoriously inefficient. I've heard that FDA captures only about 10% of drug adverse events.


Are FDA's Efforts to Improve Adverse Event Reporting Being Hobbled by Pharma?

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FDA Makes Side-Effect Database Searchable

FDA Makes Side-Effect Database Searchable | Pharmaguy's Insights Into Drug Industry News |

If you had a bad reaction after taking a medicine, there’s now an easy way to find out whether others experienced the same.

The U.S. Food and Drug Administration improved its online database of reports about side effects filed by patients and doctors, making it easily searchable by product, patient age, type of side effect or year it occurred.

It means that, for the first time, the public will have access to data it can make sense of. Previously, inquiring minds needed to know a little about coding to figure out the FDA’s adverse-reaction database. And even then, they had to file a Freedom of Information request with the government to get the actual reports and check the information’s accuracy.

The FDA said it hopes that the increased transparency will spur patients and doctors to submit more detailed and complete reports. Many patients don’t even know they can submit adverse-event reports to the agency.


Further Reading:

  • "Institute for Safe Medicines Practices Calls for a Full-scale Modernization of FDA’s Adverse Event Reporting System";
  • “So Far, FDA’s Sentinel Drug Safety Monitoring Initiative Has Not Delivered as Hoped”; 
  • “OpEd: FDA's Antiquated Drug Safety Program is ‘Obscene’"; 
  • “Another Aspect of Patient Power: Making It Easier to Report Adverse Events!”; 
  • “More Than 1 Million Adverse Event Reports Were Sent to FDA in 2015 – Only the Tip of the Iceberg”; 
  • “Deregulation and Budget Cuts Likely to Lead to Increased Adverse Event Reporting”; 
  • “FDA's Dependence on User Fees & ‘Institutional Corruption’ Blamed for Dramatic Increase in Drug Adverse Events and Deaths”; 
  • “#FDA Blames Computer Glitch for Hundreds of Errors Found in Essure Adverse Event Reports”; 
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Much of the Information on Adverse Events Remains Unpublished

Much of the Information on Adverse Events Remains Unpublished | Pharmaguy's Insights Into Drug Industry News |


We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events.

Methods and Findings

Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status.

The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies.

A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases.

The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published.


There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events.

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#Pharma Companies Don't Report the Full Story of Drug Side Effects to FDA

#Pharma Companies Don't Report the Full Story of Drug Side Effects to FDA | Pharmaguy's Insights Into Drug Industry News |

The regulatory system for reporting side effects caused by prescription drugs is producing its own kind of side effect — incomplete information about injuries that patients may have suffered. And the reason for the lack of data is that many drug makers are filing patchy reports, according to a new analysis published in the Pharmacoepidemiology and Drug Safety.


At issue is the Adverse Event Reporting System maintained by the Food and Drug Administration. The database is the key method for collecting side effect data. Both doctors and consumers can voluntarily report problems to the agency or a drug maker. But drug companies are also required to investigate and report side effects that may be attributable to their products.


Drug makers typically file the vast majority of reports of a serious or fatal outcome to the FDA. Yet compared with the side effect reports turned in by physicians and consumers, drug makers generally fail to include key data that the FDA might use to assess future warnings. For this reason, one of the study authors contends there are still wider implications.


“With increasing pressure for the FDA to approve drugs fast but with less clinical testing, it is a major concern that postmarket surveillance has major problems that are not being addressed,” said Thomas Moore, a senior scientist the Institute for Safe Medicine Practices, a nonprofit that tracks drug safety issues. “It is time for the FDA, the medical community, and industry to start work on a badly needed modernization” of this “critical tool” for monitoring safety.


The analysis found that in 2014, the FDA received 528,192 new reports of a serious or fatal side effect, of which 4.7 percent were filed with the agency directly by doctors and consumers. Of those, 86 percent included complete information about four important data points – patient age and sex, the date the side effect occurred, and a specific medical term to describe the problem.


By contrast, drug makers filed 95.3 percent of side effect reports, but most were incomplete. For instance, 40 percent of so-called expedited reports — those that must be filed within 15 days of learning of a serious side effect — were incomplete. And 51 percent of periodic reports, which drug companies generally file up to 90 days later, were similarly incomplete.

Pharma Guy's insight:

Also read: "Are FDA's Efforts to Improve Adverse Event Reporting Being Hobbled by Pharma?"; 

Pharma Guy's curator insight, March 28, 2016 8:04 AM

Also read: "Are FDA's Efforts to Improve Adverse Event Reporting Being Hobbled by Pharma?"; 

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Relaxing Rules for Off-Label Prescribing: "Akin to Crying 'Fire!' in a Crowded Theater?"

Relaxing Rules for Off-Label Prescribing: "Akin to Crying 'Fire!' in a Crowded Theater?" | Pharmaguy's Insights Into Drug Industry News |

In the Amarin court case, the court ruled that the company has the right, under the First Amendment, to promote information to health-care professionals about certain uses of the drug Vascepa that aren't covered by the drug's FDA-approved labeling -- as long as the information is true and not misleading (read "Amarin Wins Off-Label Case Against FDA"). This case is likely to influence new guidance from the FDA regarding off-label drug promotion by pharma marketers. 

"Might changes in rules for promotion of off-label indications based on free speech arguments lead to a situation akin to crying fire in a crowded theater?," asks authors of Commentary published in the recent issue of JAMA Internal Medicine. The authors of the commentary -- Chester B. Good, M.D., M.P.H., and Walid F. Gellad, M.D., M.P.H., of the Veterans Affairs Pittsburgh Heathcare System -- referred to "compelling evidence" that "off-label prescribing is frequently inappropriate and that prescribing in these circumstances increases the risk for an adverse event substantially."

That evidence was presented in a study published in the same issue of the journal titled "Off-label Prescription Drug Use and Adverse Drug Events" (JAMA Intern Med. Published online November 2, 2015. doi:10.1001/jamainternmed.2015.6058).

What is the "compelling evidence?" Find out here.

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Pharma Delays Reporting Serious Drug AEs (i.e., Death) to FDA

Pharma Delays Reporting Serious Drug AEs (i.e., Death) to FDA | Pharmaguy's Insights Into Drug Industry News |

Federal regulations define adverse drug events as those “associated with the use of a drug in humans whether or not considered drug related”. Health care professionals and consumers can voluntarily report adverse drug events directly to the US Food and Drug Administration (FDA) or the drug manufacturer. Serious adverse events (AEs) are defined by the regulation as those involving “death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.”

Our analysis provided evidence that drug manufacturers delay reporting of serious AEs to the FDA. Strikingly, AEs with patient death were more likely to be delayed. It is possible that manufacturers spend additional time in verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.

Our findings are likely an underestimate of overall underreporting or misreporting, given the anecdotal evidence of FDA warning letters to manufacturers alleging downward misclassification of serious AEs. While increased enforcement may decrease violations, a simple alternative would be to recommend direct submission of reports to the FDA rather than via the manufacturer. Further research is needed to better understand the mechanisms behind the manufacturers’ delayed reporting and the optimal regulatory policy toward mandatory disclosures of AEs.

Pharma Guy's insight:

"A larger fraction of these serious and unexpected events that involved a patient death were delayed -- about 12 percent of events with patient death, compared to 9 percent of events without patient death," senior study author Karaca-Mandic said.

I guess "patient centricity" doesn't matter once the patient is dead!

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FDA's Reprint Distribution Guidelines are "Counterintuitive" & "Indecent"

FDA's Reprint Distribution Guidelines are "Counterintuitive" & "Indecent" | Pharmaguy's Insights Into Drug Industry News |

The consumer watchdog group Public Citizen garnered significant attention this week when it raised an alarm against an FDA proposal that would enable pharmaceutical companies to distribute new drug safety data from clinical trials directly to doctors, prior to FDA review for a potential label change. Its concern is that this proposal would allow pharmaceutical companies to publicize medications as "more safe" than what the FDA approval process had previously revealed.

As noted in a Reuters article covering Public Citizen's protest, "Last June the Food and Drug Administration proposed allowing the distribution of new risk information about approved drugs, saying that a drug's safety profile "evolves" as exposure to the product increases." And yet the article states, "Companies would not be allowed to distribute literature about newly identified risks or information that shows an already identified risk is more serious than stated on the label. Such information would need to be reviewed by the FDA and potentially included in the label."

Huh? Why would FDA acknowledge that as new information emerges it changes the safety profile of a drug (which it does -- see Table 1), but that those data should only be conveyed if drugs are presenting as more safe than expected? Isn't that totally counter-intuitive. More safe is like an added bonus, a surprise treat in the cereal box. Less safe? As in new, unanticipated side effects, isn't that what people really need to know about? And quickly? Isn't the FDA's primary goal to ensure the safety of the public at large? How could keeping dangerous side effects a secret be a good thing for anyone?

Pharma Guy's insight:

I believe the FDA is tipping the balance in favor of commercial "free speech' and away from drug safety. For more on that read and a review of the FDA guidelines, read this Pharma Marketing News Article:  "More FDA Guidance on Distribution of Reprints." 

Topics include (partial list):

  • Some Off-Label Litigation History
  • A String of Off-Label Guidances
  • WLF vs FDA
  • Criteria of Approved Off-Label Studies
  • Sidney Wolfe Cries Foul!

Download the full text PDF file here:

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Consumer Groups Petition FDA to Keep Black Box Warning for Pfizer’s Chantix

Consumer Groups Petition FDA to Keep Black Box Warning for Pfizer’s Chantix | Pharmaguy's Insights Into Drug Industry News |
Several consumer groups have petitioned the FDA to increase the warnings about the controversial Chantix smoking-cessation drug, which has been linked to risks of suicidal behavior and hostility, based on new scientific information they say has become available since a serious warning was placed on the product labeling five years ago.

In their petition, the groups cite fresh analyses of studies and side effect reports to argue the pill causes distinct psychiatric side effects – suicidal ideation and behavior, aggression and violence, psychosis, and depression – which should be more clearly spelled out in the product labeling.

The move comes one week before an agency advisory panel will review whether some of the existing warnings on the Chantix labeling should be removed, a step that Pfizer, which sells the drug, has requested based on the results of several studies. Last month, in fact, the FDA updated the labeling to indicate the drug may not carry the risks of suicidal behavior.

Pfizer maintains that change was warranted based on a meta-analysis of five studies involving nearly 2,000 patients that did not show an increase in suicidal thoughts or actions among those who took Chantix compared with a placebo. The drug maker also pointed to four observational studies of thousands of patients that did not find differences in risk between its pill and other nicotine treatments.

The petition, however, also argues that those recent studies had methodological flaws and other limitations. “None of the studies are of sufficient quality to establish a convincing estimate of incidence, provide a valid comparison to other treatments, or have the scientific weight to refute evidence from other scientific methods,” the groups wrote.

Pharma Guy's insight:

In a comment to this post a certain Dr. Epi wrote:

The comment by Pfizer is amusing to any scientist, unless the scientist is taking Chantix. None of the research that the company cites re Chantix is any better at proving causation (or lack of causation) than adverse reaction reports. All most of those studies can show is association, not causation. That’s why replication in science is so important — as is close examination of individual patients. Adverse event reports can tell you if the patient experienced the side effect after taking the drug and it went away when they stopped. The more dramatic the adverse reaction — and the Chantix reports are very dramatic — and the more they show a pattern (ditto re Chantix reports) the more likely they are to show causation.

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