Latest Drugwonks' Blog
Ah, the brief summary. Inside the FDA many joke that it is like the Holy Roman Empire – neither brief nor a summary. And if you want to throw in “fair balance and adequate provision,” well, go right ahead. Same issue – too much information equals not enough comprehension.
It’s not a new problem. FDA took a crack at addressing it in January 2004 with a draft guidance on new ways to approach the brief summary. (I was proud to have been part of that effort.) Then, in January 2006, came the agency’s New Labeling Rule – an attempt to make the PI more user-friendly (the “user” being the physician). More recently the FDA has launched its "safe use" initiative, trying to reconfigure patient medical information (PMI) in more potent and health literate ways to plural constituencies. To date, all of these efforts met with only modest success.
This is an important public health issue. (In 2006, Dr. Jerry Avorn and Dr. William Shrank of Harvard Medical School wrote a paper in The New England Journal of Medicine calling it “linguistic toxicity.”)
The issue comes front and center again in a short article that appeared in Sunday’s edition of the New York Times, “Side Effects? These Drugs Have a Few.”
Some snippets:
Dr. Jon Duke of Indiana University was trying to figure out why his patient’s blood platelets were abnormal. Could it be a side effect of one of the dozen drugs the man was taking, a number that is not uncommon among elderly people?
He began reading the label of each and every drug. “I was just overwhelmed,” Dr. Duke said. The lists of possible adverse reactions went on and on. Now he knows why. In a new paper in the Archives of Internal Medicine, Dr. Duke and two colleagues report that the average drug label lists 70 possible side effects and some drugs list more than 500. “This was beyond even what I’d expected,” he said.For anyone who has ever had to watch an entire Flomax commercial, the listing of a drug’s side effects is almost a joke. But the question is, why does the list continue to grow?
That same year, the Food and Drug Administration suggested making labels clearer with a new format and advised drug makers: “Exhaustive lists of every reported adverse event, including those that are infrequent and minor, commonly observed in the absence of drug therapy or not plausibly related to drug therapy should be avoided.”
But, Dr. Duke found, instead of decreasing in the years after the agency issued guidelines, the average number of side effects rose to 94, as compared to 67 for those whose labels predated the new format. Some potential complications are weird, like “compulsive gambling.” Others, like “nausea” are so common — it’s listed on 75 percent of drug labels — that they almost seem like a universal issue.
Listing every inkling of an adverse reaction can help drug companies in lawsuits, Dr. Duke said. If someone sues about a side effect that is listed in the drug’s package insert, the company can say patients had been warned.
The Pharmaceutical Research and Manufacturers Association says the companies are just complying with the F.D.A.’s requirement that they reveal all of a drug’s risks, “even if a clear causal connection between the medicine and the observed adverse event cannot be fully established,” a spokesperson for the group wrote in an e-mail.
And the F.D.A., in an e-mail, said “extensive lists of rare and minor adverse events for which there are no data to support a causal relationship” are not useful.
That last statement from the FDA is pretty quixotic when you consider both the volume of warning letters and their content. Perhaps the above e-mail hasn’t yet made it down to DDMAC.
But the big problem is that the current liability system doesn’t reward lawyers who focus on real public health concerns. Instead, the most experienced and well-financed law firms know that the biggest payouts regularly go to those who take advantage of the FDA’s best efforts to promote the safe and effective use of medications and medical technology. More and more often, these “mass tort” firms specialize in taking a new product warning label or withdrawal decision by the FDA, and view it as a signal to go forward with all guns blazing. Their bullets, unfortunately but not unpredictably, hit multiple innocent targets and result in a wounded American health care system.
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Chronic diseases such as cancer, heart disease and diabetes have overtaken infectious diseases as the biggest health problem facing developing countries. While there are many cost-effective ways of tackling these diseases, they often require access to well-trained medical professionals and high quality health infrastructure - something that is sadly in short-supply in many parts of the world.
Please join us in Geneva for an important lunchtime conversation with Eric de Roodenbeke, Chief Executive of the International Hospital Federation. Dr. de Roodenbeke will address the challenges facing developing countries as they adapt to this new epidemiological landscape – and provide some context ahead of the UN Summit on non-communicable diseases in September 2011.
When: Wednesday 13th July, 12:45-2:30pm
Where: Hotel Intercontinental, GenevaBuffet lunch will be included - attendance is free of charge
About Eric de Roodenbeke
Dr. de Roodenbeke is Chief Executive of the International Hospitals Federation, the global association of hospitals and healthcare associations. He has held senior positions in the World Health Organisation, the World Bank, and the French Ministry of Health. He has extensive hospital management experience, gathered both in Africa and France, and has published widely on hospital organisation, health systems reform and health policy insurance and financing in developed and developing countries.
The e-vite (along with RSVP form) can be found here.
“Beware of the tension between CER and personalized medicine.”
-- Francis Collins
Some interesting and thoughtful comments from the interesting and thoughtful Harlan Krumhotz. One thing to note, is that he is a member of the Patient-Centric Outcomes Research Institute (PCORI) board – an organization tasked via the Patient Protection and Affordable Care Act (aka, “ObamaCare,” aka, “healthcare reform”) to study comparative effectiveness research.
No, that’s wrong – what they’ve been tasked to study (by specific legislative language) is comparative clinical effectiveness research. And that’s not rhetoric. Comparative means which treatment (or healthcare technology if you prefer) is “better” (subjective) versus data on real world clinical outcomes. To put it bluntly, “comparative” is subjective. Clinical is outcomes-driven. It’s important to remember both the letter and the spirit of the stature.
And now let's hear directly from Harlan K.
By HARLAN KRUMHOLZ
Comparative effectiveness research — investigations that determine which treatments are best — has attracted attention in the health care debate. Critics charge that these studies are designed to restrict choice. The Center for Medicine in the Public Interest released a report that suggested that they would stifle innovation. Often they are framed as studies to support efforts to keep useful but expensive therapies from patients.
But what if these studies, done well, revealed that some medications were better than others? What if they overturned conventional wisdom about understudied drugs, demonstrating that many patients were receiving ineffective treatments? What if they showed that some patients were actually being harmed? What if more knowledge about the benefit and risk of treatments in medicine, compared with their alternatives, is just what patients need?
His complete comments can be found here – and they’re worth a read.
An amendment to the House Agriculture/FDA appropriations bill that appears intended to block FDA from restricting agricultural use of antibiotics could stymie agency efforts to curtail the use of unsafe products. Farmers and ranchers have been concerned that FDA will limit the use of antibiotics in animals in order to reduce the incidence of resistance to the drugs.
Montana Republican Denny Rehberg insisted his proposal is motivated by interest in the animal sciences. "If I'm looking at it from the perspective of all the rules and regulations I'm required to conform to on my farm and my ranch, it has nothing to do with anything other than trying to make a determination, is the Food and Drug Administration going ... into the social sciences as opposed to the hard science?"
But amendment (approved 29 to 20 by the full House Appropriations Committee as part of the fiscal 2012 Ag/FDA funding package) does not limit its effect to the animal sciences.
Rather, it states that FDA may not spend money from the bill "to write, prepare, develop or publish a proposed, interim, or final rule, regulation, or guidance that is intended to restrict the use of a substance or a compound unless the Secretary bases such rule, regulation or guidance on hard science (and not on such factors as cost and consumer behavior), and determines that the weight of toxicological evidence, epidemiological evidence, and risk assessments clearly justifies such action, including a demonstration that a product containing such substance or compound is more harmful to users than a product that does not contain such substance or compound, or in the case of pharmaceuticals, has been demonstrated by scientific study to have none of the purported benefits."
The latter two conditions would put FDA in the position of examining the comparative harm of two options, or in the case of drugs, having to prove a negative. Further, the amendment would seem to prevent FDA from issuing any regulations or guidances related to REMS.
Oops.
Genentech will be allowed to discuss its proposal for a new confirmatory trial of Avastin in MBC, including reports of its discussions with FDA's Center for Drug Evaluation and Research concerning that study.
Karen Midthun, the hearing's presiding officer, rejected CDER's bid to exclude evidence of its discussions with Genentech on future Avastin studies. The drugs center contended such evidence is irrelevant to its proposal to withdraw Avastin's accelerated approval for MBC.
According to Midthun, "I have concluded, however, that it is not appropriate to exclude this information from the hearing record. It does not appear that CDER disputes the validity of the evidence at issue.”
Genentech recently released on who it will put forward to testify at the June hearing. Chief Medical Officer and Exec VP-Global Product Development Hal Barron will present the overview of Genentech's position, followed by Senior VP and Global Head of Clinical Development for Oncology/Hematology Sandra Horning, who will discuss the clinical data and the proposed confirmatory trial, and James Reimann, global head of oncology biostatistics, who will discuss biostatistics issues.
In addition to the Genentech executives, two oncology researchers will provide "clinical perspectives on the treatment of HER2-negative MBC." Joyce O'Shaughnessy, Baylor Charles A. Sammons Cancer Center, Texas Oncology, U.S. Oncology, has been a lead investigator on a number of breast cancer trials and was formerly a researcher at the National Cancer Institute. Howard A. Burris, III, chief medical officer and director of drug development at the Sarah Cannon Research Institute has published extensively on taxanes.
Finally, Covington and Burling attorney Michael Labson will address regulatory and legal issues.
Here's what the NIH said:
"The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has stopped a clinical trial studying a blood lipid treatment 18 months earlier than planned. The trial found that adding high dose, extended-release niacin to statin treatment in people with heart and vascular disease, did not reduce the risk of cardiovascular events, including heart attacks and stroke.
Participants were selected for AIM-HIGH because they were at risk for cardiovascular events despite well-controlled low-density lipoprotein (LDL or bad cholesterol). Their increased risk was due to a history of cardiovascular disease and a combination of low high-density lipoprotein (HDL or good cholesterol) and high triglycerides, another form of fat in the blood. Low HDL and elevated triglycerides are associated with an increased risk of cardiovascular events. While lowering LDL decreases the risk of cardiovascular events, it has not been shown that raising HDL similarly reduces the risk of cardiovascular events.
During the study’s 32 months of follow-up, participants who took high dose, extended-release niacin and statin treatment had increased HDL cholesterol and lowered triglyceride levels compared to participants who took a statin alone. However, the combination treatment did not reduce fatal or non-fatal heart attacks, strokes, hospitalizations for acute coronary syndrome, or revascularization procedures to improve blood flow in the arteries of the heart and brain...
...The Data Safety Monitoring Board also noted a small and unexplained increase in ischemic stroke rates in the high dose, extended-release niacin group. This contributed to the NHLBI acting director's decision to stop the trial before its planned conclusion. During the 32-month follow-up period, there were 28 strokes (1.6 percent) reported during the trial among participants taking high dose, extended-release niacin versus 12 strokes (0.7 percent) reported in the control group. Nine of the 28 strokes in the niacin group occurred in participants who had discontinued the drug at least two months and up to four years before their stroke. Previous studies do not suggest that stroke is a potential complication of niacin, and it remains unclear whether this trend in AIM-HIGH arose by chance, was related to niacin administration or some other issue. "
Here's what the Prince of Posturing said two years ago...
According to Dr Nissen, ezetimibe "badly failed" the few surrogate outcome studies completed to date. The ENHANCE trial, he recalled, showed a 50 mg/dL greater reduction in LDL-C with simvastatin 80 mg plus ezetimibe 10 mg vs simvastatin 80 mg alone, but no difference in CIMT change. There was even a slight trend toward CIMT progression in the simvastatin plus ezetimibe group. The suggestion that because patients were pretreated with statins, there was too little plaque to observe a differential effect was "nonsense," he said, pointing out that in a similar population in the ASAP trial, a difference of 36 mg/dL in LDL-C lowering was associated with a mean CIMT regression of 0.31 mm.
Dr Brown agreed that ENHANCE was carried out in the wrong population. He noted that many of the patients had been in previous trials for years and had only stopped lipid-lowering therapy for 6 weeks prior to the active phase of ENHANCE, suggesting that they should have had no CIMT to lower. Looking at the same data from ASAP as Dr Nissen, however, he pointed out that all the effect on CIMT was seen in the first year of treatment, which was consistent with the observation that nothing happened in the ENHANCE patients.
According to Dr Nissen, ARBITER 6-HALTS was "equally disturbing, showing a "troubling" decrease in HDL-C and no real change in CIMT with ezetimibe. Again, Dr Brown doubted that the trial was carried out in an appropriate population, since the patients in this trial were at their LDL-C and non-HDL goals at baseline and he would not have chosen ezetimibe for this particular population. He also noted that because the trial was stopped early, some patients (40 on ezetimibe and 35 on niacin) who were still in the study were not analyzed because they had not reached the pre-specified 14-month observation point.
Both presenters noted that there are 2 large trials, SHARP and IMPROVE-IT, underway to examine the effectiveness of ezetimibe in CAD prevention, but neither Dr Nissen nor Dr Brown believes that these are the best trials to answer outstanding questions about ezetimibe. Dr Nissen said he believes that IMPROVE-IT will fail. Dr Brown maintains that a different trial is needed, which he believes would be successful, based on evidence with ezetimibe to date.
Also...
Dr Steven Nissen (Cleveland Clinic, OH), also commenting on the results for heartwire, called ARBITER 6-HALTS a classic "comparative-effectiveness" study and said there have been calls in the US legislature for such trials for the past few years.
"Now, here it is," he said. "Niacin is a 50-year-old drug, and you can buy it over the counter at your local pharmacy. When you have an inexpensive therapy like this—there are issues about being able to tolerate high-dose niacin, but if you get patients to tolerate it—niacin looks to be a better strategy."
www.theheart.org/article/1022265.do
Notably, Nissen touts he results of the first small study as a great example of comparative effectiveness research. Ironically, he's right. Small studies using surrogate measures (most notably the use of ultra-sound to measure thickening of arterial walls, a technique 'invented' and peddled by Nissen) often surprise. But CER community and it's "stakeholders" had all but hailed the ARBITER study as conclusive.
Not that Nissen hasn't engaged in fearmongering based on small studies, meta-analysis, etc only to be rebuked by science. His meta-analysis of CV risk associated with Avandia was undermined by an FDA analysis and the ACCORD study. (Sadly, he was successful in virtually killing off the drug.)
From the Journal of Life Sciences:
SOCIAL MEDIA
Facebook to Pharma: Comments Allowed
Social networking site says its pages must be an open forum for conversation.
MARIE DAGHLIAN
Facebook has told pharmaceutical companies that as of August 15, they will no longer be able to disable the comment feature on their Facebook pages. Until now, to control content on their pages, pharmaceutical brands could ask permission to disable commenting on their Facebook pages, citing compliance and regulatory concerns.
Facebook notes that as a social media platform, it is by definition, interactive. When commenting is not permitted, as on many pharmaceutical brand sites, there is no dialogue, defeating the purpose of social media.
The decision could complicate the pharmaceutical industry’s embrace of social media as companies continue to be cautious because of unintended consequences that could arise from its use.
“Everybody in pharma wants to be in social media—second,” says Peter Pitts, president of the Center for Medicine in the Public Interest [www.cmpi.org] and a former associate commissioner of the U.S. Food and Drug Administration. Many of the regulatory issues that Pharma usually brings up are self-imposed, says Pitts. The FDA has not said that pharma can’t be in social media and recognizes it as an important tool for communication.
Drug companies cite no clear direction from the FDA and say they are worried about conversations about adverse events and off-label uses of drugs, but Pitts believes that these conversations can be handled responsibly. “Blaming the FDA for lack of guidance is an excuse for a lack of understanding or even worse, a lack of courage for being in this space,” says Pitts.
Social media’s marketing use should be secondary to its capability to advance public health. Pharmaceutical companies need to be part of this conversation, notes Pitts.
Although pharmaceutical brand pages will no longer be able to disable commenting on their posts, Facebook will, on a case by case basis, allow disabling of the commenting function on branded pages solely dedicated to a prescription drug.
In an email explaining the policy to pharmaceutical companies, Facebook said it thinks the policy changes “support consistency for the Facebook Pages product and encourage an authentic dialogue between people and business on Facebook.”
Interesting article by Gardiner Harris in today’s New York Times, “As Physicians’ Jobs Change, So Do Their Politics.”
And, although there is a lot of conditional phraseseology (“could mean this,” “could mean that”), it raises some interesting points and is worth some discussion.
Reporters (especially those covering healthcare issues) are keen to say, “The plural of anecdote is not data.” And they’re right. But after leading off with, well, an anecdote, the story continues:
There are no national surveys that track doctors’ political leanings, but as more doctors move from business owner to shift worker, their historic alliance with the Republican Party is weakening from Maine as well as South Dakota, Arizona and Oregon, according to doctors’ advocates in those and other states.
No surveys or facts or figures but, nevertheless, some telling anecdotal trends worth reporting.
Mr. Harris continues,
That change could have a profound effect on the nation’s health care debate. Indeed, after opposing almost every major health overhaul proposal for nearly a century, the American Medical Association supported President Obama’s legislation last year because the new law would provide health insurance to the vast majority of the nation’s uninsured, improve competition and choice in insurance, and promote prevention and wellness, the group said.
Please note the word “would.” The new law “would provide” among other things improved competition and choice. Well, to put it mildly, that remains to be seen.
With the politics out of the way, the article hits the crux of the matter:
Because so many doctors are no longer in business for themselves, many of the issues that were once priorities for doctors’ groups, like insurance reimbursement, have been displaced by public health and safety concerns, including mandatory seat belt use and chemicals in baby products.
Even the issue of liability, while still important to the A.M.A. and many of its state affiliates, is losing some of its unifying power because malpractice insurance is generally provided when doctors join hospital staffs.
But the issue isn’t just money – it’s also physician disempowerment. With first insurance companies and now (and increasingly) Uncle Sam telling doctors how to practice medicine (step therapy, restrictive formularies, an increasing reliance of questionable comparative effectiveness research and more strident and cumbersome preauthorization requirements). It’s no wonder that physicians are leaving private practice.
So it’s highly questionable that physicians (their political affiliations notwithstanding) are going to be fans of the Patient Protection and Affordable Care Act.
And to that point, the article ends … with an anecdote:
Dr. Kevin S. Flanigan, a former president of the Maine Medical Association, described himself as “very conservative” and said he was fighting to bring the group “back to where I think it belongs.” Dr. Flanigan was recently forced to close his own practice, and he now works for a company with hundreds of urgent-care centers. He said that in his experience, conservatives prefer owning their own businesses.
“People who are conservative by nature are not going to go into the profession,” he said, “because medicine is not about running your own shop anymore.”
So, consider the Irish proverb, “Every disease is a physician” – and then consider what disease we’re addressing.
And, according to the Federal Register, Jupiter aligns with Mars.
It seems that peace, love and happiness have broken out.
As BioCentury reports:
BIO and PhRMA have reached a final agreement with FDA on terms for reauthorizing PDUFA, according to sources involved with the negotiations. The final element of the deal, language committing FDA to "promoting innovation through enhanced communication" with sponsors during drug development, was agreed upon this week. Previously agreed elements of PDUFA V include two-month extensions on standard and priority PDUFA review goals, and user fee funding for 119 new FDA staff for regulatory science projects. The five-year PDUFA V cost is expected to be about $3 billion, up from about $2.8 billion for PDUFA IV.
FDA has agreed to adopt a "philosophy statement" committing the agency to "timely interactive communications with sponsors during drug development." A PDUFA V goals letter commits FDA to develop, by the end of FY13, a dedicated staff to liaise with sponsors during the IND process and to train CDER staff on best practices for enhanced communication with sponsors.
The two-month extensions of review goals will provide time for FDA to incorporate two new elements: a status update for sponsors in the middle of a review, and a late-cycle meeting in advance of any advisory committee meeting to present a comprehensive report on the agency's review.
FDA is expected to publicly release the PDUFA V agreement following review by HHS and the Office of Management and Budget, and to hold a public hearing in October. The House Energy and Commerce and Senate Health, Education, Labor and Pensions committees have tentatively scheduled hearings on PDUFA in June.
And in other news of mutual admiration and respect:
Midthun to allow discussion of future Avastin studies at hearing
CBER Director Karen Midthun indicated she will allow Genentech Inc. to present information about future studies of Avastin bevacizumab at a June 28-29 hearing on FDA's proposed withdrawal of metastatic breast cancer from Avastin's label. In a letter to the Roche unit and CDER, Midthun said it is not appropriate to exclude the information since CDER does not dispute the validity of the evidence, only its relevance. She added that she is not prepared to rule at this time on whether or not the information is relevant to the hearing.
Last week, CDER said in a letter to Midthun that it did not believe future studies of Avastin were within the scope of the hearing.
Harmony and understanding?
Is this the dawning of a regulatory Age of Aquarius?
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
