Latest Drugwonks' Blog
That’s one question we can be sure Jenny McCarthy and other anti-vaccine adherents will never answer.
Terrific review of PDUFA V (via BioCentury’s always insightful Washington Editor, Steve Usdin), “PDUFA: A lot of talk.”
The selected verbiage below is from Mr. Usdin’s article – the subheads are not.
Thy rod and thy staff, they comfort me
High quality reviews performed on a predictable timetable has been the industry’s primary objective for PDUFA since the program’s inception in 1992. But as user fees have exploded over the decades and have been allocated to a widening range of activities, success in achieving their principal goal has been elusive. FDA has consistently managed to approve about 60% of priority NDAs for new molecular entities (NMEs) and original BLAs within a single review cycle, but has done so only by pulling staff away from standard reviews.
The 33 1/3rd % Solution
Although about 80% of all NDAs and BLAs are eventually approved, there has never been much more than a one-in-three chance that a standard NME or BLA would be approved in the first cycle.
Subjective Meeting Objectives Meetings
To increase first-cycle approval performance, the PDUFA V agreement adds a two-month “filing period” to the start of the review process for NME NDAs and original BLAs, establishes a mid-cycle meeting to allow sponsors to attempt to get errant reviews back on track, and sets up a late-cycle meeting to smooth any advisory committee meetings or negotiations over labels or risk evaluation and management strategies (REMS).
In addition to improving communications with sponsors, the agency plans to create new fora for patients, along with formal procedures for integrating patient perspectives into review criteria.
According to CDER Director Janet Woodcock, “I would like to pursue patient-centered drug development where the regulators and the developers really understand where the patients are coming from in that disease,” She said that “no one, the medical profession or the FDA, has done a good enough job listening from the patients how drugs feel to them and how they feel about benefits and risks.
The BRAT Pack
Woodcock added that FDA is developing a semi-quantitative benefit-risk framework that will “standardize how we think and talk about benefits and risks and residual uncertainty,” and that the agency plans to make it part of the review process during PDUFA V.
Begging the question – or just begging?
The industry also has agreed that FDA can use PDUFA money to hire over 10 staff to bring new scientific expertise into the agency. Nevertheless, the total tab for PDUFA V over five years is expected be about $3 billion, compared to $2.9 billion for PDUFA IV. Thus the begging question will be whether the added review time and communications commitments, rather than money, will achieve the kind of agency performance that has not been reached in prior user fee agreements.
Unpresent Danger
Moreover, the agency’s Office of Surveillance and Epidemiology (OSE) has not been present in the negotiations, which could be a sign the agreement will not resolve poor coordination and bureaucratic in-fighting.
A Mighty Minyan
Industry agreed to pay for 10 FTEs to implement the enhanced communications program, as well as $100,000 annually for internal training and industry outreach. FDA has agreed that the “liaison staff. The new liaison staff will “serve as a point of contact for sponsors who have general questions about drug development or who need clarification on which review division to contact with their questions,” according to the goals letter.
Better Late Than Never
PDUFA V also will add a late-cycle meeting for new molecular entity NDAs and new BLAs that is intended to be a comprehensive assessment of the agency’s review, including descriptions of issues that might be raised at an advisory committee meeting.
The late-cycle meeting addresses complaints from sponsors that they have learned about critical issues FDA will raise with an advisory committee only a few days before the meeting, and that often companies learn about agency concerns for the first time in a complete response letter.
For applications that will be discussed by an advisory committee, the late-cycle meeting will occur at least 12 calendar days before the panel meets. FDA will provide the sponsor with a draft of the questions the agency plans to ask the committee.
The Lords of Discipline (Letters)
FDA has stated it will provide the briefing package at least 20 calendar days prior to a scheduled advisory committee meeting and at least 12 calendar days prior to the late-cycle meeting if a panel meeting is not planned. FDA told industry it aims to have “discipline review” letters ready in advance of the late-cycle meeting. Discipline review letters note any deficiencies in specific sections of applications, such as the clinical, chemistry, manufacturing and controls, non-clinical pharmacology and toxicology, and the human pharmacokinetics and bioavailability sections.
A New Broom?
In the end, FDA and the industry groups agreed on a sweeping policy that applies to all companies and is intended to make the drug review culture more interactive and collaborative.
Amen.
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.)
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.
