Jenny’s Vaccine Fearmongering

06/08/2011 02:54 AM |

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A Mighty Minyan and the Lords of Discipline (Letters)

06/07/2011 08:47 AM |

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 1/3^rd % 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.

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When PMI is TMI

06/06/2011 08:48 AM |

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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Push Peggy's Buttons!

06/03/2011 10:07 AM |

What Are Your
FDA Hot Buttons?

Help BioCentury
tell Commissioner Dr. Margaret Hamburg
what's important to you.

In an Exclusive Interview
on
"BioCentury This Week" TV
 

Email your comments or questions
to viewercomments@biocenturytv.com
(sender identity will not be disclosed)

Your questions/comments must be received
by Tuesday, June 7

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Join us in Geneva

06/03/2011 08:52 AM |

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, Geneva

Buffet 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.

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Harlan Speaks!

06/02/2011 09:18 AM |

“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.

Five Lessons From Niaspan’s Disappointing Study

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.

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Comparative Harmfulness?

06/02/2011 08:56 AM |

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.

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Mistress and Commander

06/01/2011 01:46 PM |

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.

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Nissen Keeps Missing With Drug Safety Scares

05/31/2011 06:37 PM |

Steve Nissen was hiding under a rock after a study of the protective effects of niacin not only failed to reduce risk but also was associated with a slight increase in CV events.

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. "

www.nih.gov/news/health/may2011/nhlbi-26.htm


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.)

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Let's Facebook the Music and Dance

05/31/2011 08:29 AM |

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.”

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Remember the Maine (Medical Association)

05/30/2011 09:46 AM |

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.

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PDUFA Update: Moon in Seventh House

05/27/2011 07:53 AM |

And, according to the Federal Register,  Jupiter aligns with Mars.

It seems that peace, love and happiness have broken out.

As BioCentury reports:

PDUFA V deal done

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?

  Read More & Comment...

Jerry Rigged

05/26/2011 12:29 AM |

Per yesterday’s post (“Academic Retailing"), here’s a comment from a highly respected and high priced Inside the Beltway FDA/Regulatory Affairs attorney:

Dude, great piece.  How about a follow up describing the incredible resource intensity of the copy review process and calling on Avorn to have the same thing?  He would need economists, physicians, regulatory people, medical information, and lawyers.  My rate is $850/hr but I might knock off ten percent.  Seriously, I'm sick of critics pretending there's no rigor to company promotion.  They spend hundreds of thousands of hours a year scrutinizing promotional programs and detail aids and ads.  That's not the issue.  The issue is that the government refuses to provide clear rules because it would rather play gotcha.

Indeed.

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Counterweight to CER From Across the Pond

05/25/2011 04:48 PM |

CER advocates and even Patient Centered Outcomes Research Institute committee members push the healthcare system to embrace data-dredging of the lowest form.  See the article from Drug Benefit News where the one size fits all CER crowd extols the virtues of poorly powered head to head studies included in FDA submissions as a 'treasure trove' of data for driving prescribing decisions and guidance.  A study by Joshua Gagne ,Sebastian Schneerweis ( a member of the PCORI methodology committee) are drooling over the possibility of using such data to shape what drugs we can use and when.

The Harvard researchers were taken aback, he says, to discover so many drugs had CER on file. “We were also surprised by how many actually had defective comparator data,” Gagne says. “So even though our study suggested that 70% actually had data available, it doesn’t necessarily guide coverage decisions for 70% of the drugs.”

Note to Gagne and PCORI committee  member Schneerweis: CER is not supposed to be used to guide coverage decisions.  Or maybe they didn't read the statute.

aishealth.com/archive/ndbn051311-04

By contrast the Association of the British Pharmaceutical Industry has published a document for using real world data to guide treatment selection that the PCORI and CER crowd should pay attention to.

www.youtube.com/watch

It takes up to three years after a drug gets approved by Britian's Medicine Agency to get through CER review and onto market.  Are we willing to make such delay part and parcel of health care reform?
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Academic Retailing

05/25/2011 07:18 AM |

“Harvard Academic To Organize Insurance Industry CER Detailing Program” gushes the headline of the article on academic detailing:

 

“A prominent academic at the forefront of comparative effectiveness research pharmaceutical detailing efforts will soon begin seeking support for the establishment of a third-party payer non-profit organization to help physicians receive information on medical therapies from a wider group of experts -- including insurance companies -- as opposed to predominantly from drug manufacturers.”

The “prominent academic?” Why it’s non other than Harvard Medical School researcher Jerry Avorn – the same high-minded and unbiased man of science who said, “Marketing departments of many drug companies don’t respect any boundaries of professionalism or the law.”

 

Untrue and unfair. That’s a pretty broad brush – but Dr. Avorn has never worried about the unintended consequences of hyperbole.

 

(Avorn already established two non-profit groups supported by government funding that help disseminate CER information to doctors. The National Resource Center for Academic Detailing obtains funding from HHS' Agency for Healthcare Research and Quality to help train academic detailers, while the Independent Drug Information Service compiles CER information and is supported by some state government agencies, including the Pennsylvania Department of Aging.)

"I'll be, basically, phoning contacts that I know in the private sector and asking if they would like to engage in this bold adventure together," he told FDA Week.

Well, “bold” may be one word for it.  Another, less flattering adjectival phrase, “intellectually dishonest” – may be more applicable.

(This is the same Jerry Avorn who tried to claim that there was a higher incidence of black box warnings around drugs approved right before user fee deadlines but got caught when Bob Temple and FDA economists found significant, uh, omissions in his database and "rounding" errors that, when accounted, for essentially eliminated any difference in the number of black box warnings.) 

There is little information on why so few AD programs attempt to measure overall healthcare cost reductions.  This is likely due to the fact that measuring changes in prescription drug costs is a more manageable analysis than determining changes in overall healthcare spending. It also (in the calling a spade a spade department) fits into the general cognitive mapping of those who believe that pharmaceutical costs are the main driver of health care costs. (FYI – on-patent drug costs represent less than a dime on the American healthcare dollar.)

I’ve said it before, but it’s worth repeating -- the worst part about rushing headlong into academic detailing is that there is no clear articulation or transparency regarding the specific rules and regulations that will govern the behavior and activities of AHRQ-funded detailers.

Some of those unanswered (and, alas, unasked) questions:

Q: What safe guards are in place to certify that physicians are being presented information that is unbiased? Previous government detailing efforts have often focused on demonstrating their own value by highlighting the cost effectiveness of initiatives through savings generated from the increased utilization of generics and other low cost therapies.

Asked another way – how can an “academic detailing” program funded by our nation’s largest payer be considered neutral? Just like detailing programs run by pharmaceutical companies, there is an inherent “interest.” And that’s okay – as long as that “interest” is transparent.  But “academic” it ain’t.

Q: What information is worthy of being detailed by these programs?  Who decides and on what basis?

Q: What can they say or not say?  Who decides? Will they have to play by the same rules as pharmaceutical representatives?  And, importantly, what is the oversight mechanism?  If academic detailers stray into off-label conversations, to whom does DDMAC send a letter?  Whom does the Department of Justice investigate? Who pays the fine?

All this to say that, if academic detailing is the answer – what’s the question?

As the old Crazy Eddie commercial asked, “What’s the story, Jerry?”

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Information is in the eyes of the beholder

05/24/2011 08:24 AM |

What’s the difference between “advertising” and “information?”

Consider the interesting (but somewhat byzantine) decision from the Court of Justice of the European Union (CJEU) on the “advertising” of medicines.

The Pink Sheet reports that the ruling in MSD Sharp & Dohme GmbH v. Merckle GmbH, handed down on May 5, “seeks to define the boundaries of acceptable information provision so that compliant manufacturers of prescription medicines can avoid accusations of engaging in direct-to-consumer advertising. DTC is both illegal and unwelcome in the EU, the European Commission has time and again stressed.”

The decision is restrictive -- allowing companies to provide objective information that will in no way lead directly to a decision to purchase, leaving firms with few options beyond essentially providing the labeling online.

 "A different classification must, however, be adopted where the information relating to the medicinal product is selected or rewritten by the manufacturer, since such manipulation of information can be explained only by an advertising purpose," the court said.

MSD had put information on its website concerning its prescription-only products Fosamax (alendronate), Singulair (montelukast) and Vioxx (rofecoxib). (Vioxx was withdrawn worldwide in 2004; the product's presence in the case stems from the long-simmering nature of the dispute.)

MSD's site included images of the product packaging, the therapeutic indication and the leaflet containing instructions for use of the product. This is essentially information contained with the Summary of product Characteristics (SmPC), which a company must file when applying for a marketing authorization.

Merckle complained that this constituted advertising to the public, as the site was not password-locked, and was anti-competitive. The CJEU, to whom the case was referred by the German Federal Court of Justice, dismissed the suggestion behind Merckle's complaint that simply communicating this information was inherently promotional.

Indeed, "the possibility for the patient to access in advance, before a medical examination, objective information from reliable sources could, in some circumstances, contribute to the prescription of appropriate treatment, in so far as there may be a more fruitful dialogue between the doctor and the informed patient," the court wrote.

The European Parliament adopted a position on a Directive on Information to Patients on November 24, 2010. It went before the Council of Ministers' Employment, Social Policy, Health and Consumer Affairs Council on December 6-7, 2010. The Council has asked the Commission to amend parts of the proposal, and the next stages of the political debate will take place after those changes are complete.

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Personalized Medicine Advances

05/23/2011 04:53 PM |

Could it be that the pessimism about the biopharma pipeline is overstated.  In two weeks we had the approval of two new drugs that are effective cures for Hepatitis C and reduce the need for other medicines.   At the same time, a whole slew of new targeted cancer therapies were unveiled at ASCO.   And two new drugs to stop the replication of HIV were approved.

Increasingly, drugs that are approved have the following qualities:  they address an unmet and complex medical need; they are targeted drugs that use diagnostics to identify people who will benefit the most; and they highly effective. 

Meanwhile, members of Congress cannot stop flogging the same silly issues:  Herb Kohl wants all information in drug liability trials to be made public and Jo Anne Emerson and Peter Welch have launched the Congressional Affordable Medicines Caucuc in the House, designed to undermine legal and regulatory framework that still in some fashion support innovation. 

Innovation will prevail but not without help.  R and D productivity needs to be much higher.  And given the important products that are emerging from companies large and small, it would make sense to develop policies to promote better medicine.  But maybe that's too much too ask...


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Our Very Own Thunder from Down Under

05/23/2011 08:47 AM |

It seems that one size does not fit all – even Down Under.

From The Australian and the pen of CMPI Senior Fellow Tim Wilson:

Private health accounts may solve looming health crisis

Structural reform of Australian healthcare financing can cut inequity and promote universal choice as well as universal service delivery.

In a society as wealthy as ours it's understandable that Australians support universal access to healthcare.

But accepting this principle and the current one-size-fits-all structure of Medicare are different.

Under the current structure only those who can voluntarily afford to opt out of the system have real choice.

For the rest of us the government predominantly picks up the tab through wholly taxpayer-funded visits to local GPs and hospitals with restricted choices.

With only some services requiring co-payment most Australians have no real understanding of how much healthcare costs, armed only with anecdotal stories of nightmare scenarios faced by travelers in the United States' messy pseudo-public/private system.

But healthcare in Australia is expensive as well. And it’s going to become more so.

According to the latest Treasury Intergenerational report based on 2009/10 dollars the government’s expenditure on total healthcare provision is set to increase three and a half times by the middle of the century.

Considering research consistently finds health expenditure is concentrated in the final months and years of life the looming acute pressure on taxpayers with a dramatically ageing population is quite horrifying.

Today's taxpayers are paying for the managed departure of their grandparents, and there's about to be a lot more of the latter proportionate to the former.

Without reform universal healthcare cannot continue to enjoy funding consistent with current levels of care. As a consequence individuals will either have to pay more or there will be rationing of services universally enjoyed.

It’s essentially the same challenge government faced with the pension resulting in the introduction of compulsory superannuation.

Instead of continuing to provide universal health financing through a top-down government-knows-all-model the government should use the opportunity of this temporary resources boom to restructure our health system toward a bottom-up individual health account system.

Put simply every Australian would have an individual health account that they contribute to on a periodic basis from their income, like superannuation. That savings account would then be used to pay for healthcare services as required throughout their lifetime.

As outlined earlier, considering the bulk of people’s health expenditure occurs at the end of their life people should easily be able to accumulate savings for their final health bill over a lifetime.

The scheme would also need to be complemented with progressive tax cuts as the transfer of the health financing burden shifted from government to individuals.

Healthcare financing accounts for children would need to remain wholly government subsidised since they will not have had the chance to contribute to their own accounts. 

Equalisation subsidies would also be needed for welfare recipients, low-income earners and people with specific diseases to ensure universality and that no one is disadvantaged because of socio-economic status or because they were born with a particular disease.

According to Monash University Academic Just Stoelwinder’s research the Dutch system has working equalization subsidies supporting their compulsory health insurance scheme.

While the intent of health accounts is for individual management through appropriately regulated financial products, the scheme could be designed to allow Australians the choice to take up an insurance alternative to increase service access and pool risk.

The benefits of individual of restructuring Medicare around individual health accounts are manifest.

By engaging patients more directly with the management of their health they’ll come to appreciate healthcare is expensive and discourage inefficient, costly behaviours like the current problems of people using hospitals for primary care.

Individual accounts would also increase private sector involvement to compete with the public sector and create a generally higher level of competition improving patient value.

In his autobiography A Journey Tony Blair identified the essential challenge that "health care systems in which there was a mixed public/private provision, of which at least demand some individual commitment and gave some individual choice, did best".

Choice isn’t always the first priority in healthcare delivery, but it can be relevant in non-emergency situations.

Accounts would discourage information asymmetry between the medical profession and patients because the latter is empowered with choice necessitating greater responsiveness from service providers.

Importantly individual accounts would remove the need for a private health rebate which could instead be redirected to helping healthcare provision for the poor.

Individual accounts would also address through ‘carrots’ the growth in health costs associated with longer lives and lifestyle diseases by promoting preventative healthcare rather than cures.

As the Federal government’s commissioned National Preventative Health Taskforce identified every dollar spent on community-based preventative health delivers a $5.60 "return on investment" within five years and is a no brainer for keeping costs down.

But instead of restructuring the design of our health system as part of the solution they proposed nanny state taxes and regulation 'sticks' to direct consumers away from fast food, alcohol and tobacco consumption.

Under individual health accounts individual choice would be preserved without the need for a nanny state as patients take financial responsibility for the consequences of their behavior.

A well-designed scheme could allow for compulsory contributions to exhaust if an individual’s account reached a certain level where it far exceeded a reasonable projection for a lifetime health costs.

Doing so creates tax cuts for those who actively seek healthy lifestyles.

Structural reform toward individual accounts would be expensive initially to ensure everyone continued to have access to healthcare, but it would be coupled with government savings in the long-run.

More importantly it would drive productivity improvements in healthcare by injecting competition and universal choice that benefits patient outcomes.

Tim Wilson is Director of the IP and Free Trade Unit and Climate Change Policy at the Institute of Public Affairs and a Senior Fellow at New York’s Centre for Medicine in the Public Interest and co-author of The Impact and Cost of Health Sector Regulation.

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Cookbook Karma

05/23/2011 08:19 AM |

First weigh the considerations, then take the risks.

-- Helmuth von Moltke

For you PDUFA junkies, some important reading prior to the upcoming E&C and HELP hearings.

Some snippets from a pre-publication copy …

A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration

Committee on Ranking FDA Product Categories Based on Health Consequences, Phase II, Board on Environmental Studies and Toxicology Division on Earth and Life Studies, National Research Council, Institute of Medicine

FDA and the Department of Health and Human Services (DHHS) asked the National Research Council (NRC) to develop a conceptual model that could evaluate products or product categories that FDA regulates and provide information on the potential health consequences associated with them. As a result of that request, NRC formed the Committee on Ranking FDA Product Categories Based on Health Consequences.

Difficult decisions are common for the Food and Drug Administration (FDA). Whether it is allocating scarce resources, deciding how to mitigate newly found risks, or deciding what investments in human capital, facilities, data, or analytic methods would be most useful, decision-makers in the FDA often need to integrate data of varied quality, recognize uncertainties, and make trade-offs to arrive at a decision. Public-health and public-safety concerns must be balanced with the economic realities of budgets and the political constraints of imposing new regulations.

How a program is presented by the media and understood by the public is an important determinant of the acceptance and success of the program. Science and public preferences and perceptions must be considered if one is to understand the potential outcomes of different decision options. To inform the decision-making process, data of differing degrees of quality and robustness must be used and sometimes fed through an array of models of varied sophistication. Expert opinion must be used to interpret the relevance of available data and to solve problems on which available data are weak or nonexistent. Immovable deadlines can thwart uncompromising reliance on the most thorough analysis based on detailed quantitative data for a given decision.

To succeed in such an environment, FDA needs a framework within which alternatives can be defined and evaluated systematically. Although it is beyond the scope of the present study to provide a comprehensive decision-making procedure for FDA, the committee proposes a general framework for thinking about and characterizing the human-health dimensions of FDA decisions. Health consequences are only a subset of the large array of factors that must be considered for any given problem. However, they constitute a reasonable place to start the process of developing a decision framework inasmuch as such factors loom large in most FDA decisions and substantial work has already been done on methods for estimating the human-health consequences associated with various risks, hazards, and decisions.

The framework offered here provides a common language for describing potential public-health consequences of decisions, is designed to have wide applicability among all FDA centers, and draws extensively on the well-vetted risk literature to define the relevant health dimensions for FDA decision-making.

This chapter first provides a brief description of the proposed framework and the risk and decision contexts that influenced the committee’s approach. Next, the basis and definition of the risk attributes that characterize the framework are provided, and then some approaches for estimating the outcomes of decisions using the risk attributes are described. The chapter concludes with a discussion of how the output of the framework can be used to support decision-making.

THE FRAMEWORK

The risk-characterization framework is designed to be as general as possible while providing consistent risk information in a way that can be used to support the wide variety of decisions that FDA faces. It is intended to supplement and augment other risk-based and risk-informed approaches that are in use and under development by FDA, not to be a replacement or a one-size-fits-all prescription for conducting all risk-informed decision-making.

Indeed, the committee recognizes that the public-health consequence factors highlighted in this framework will seldom be the only important considerations in the decision-making process, but they are almost always some of the key considerations. The U.S. Nuclear Regulatory Commission has also recognized that risks are not the only factors that must be taken into account in regulatory decision-making. It recently embraced the concept of risk-informed decision-making, which it defines as “the use of risk insights, along with other important information, to help in making decisions” (USNRC 2008, page 1-1). The committee’s framework focuses on risk information but also recognizes that other information will be relevant for most FDA decisions.

The process is straightforward and involves three steps:

Step 1. Identify and define the decision context: What decision options are being considered? What are the appropriate end points to evaluate and compare?

Step 2. Estimate or characterize the public-health consequences of each option by using the risk attributes that are described below. The values of the risk attributes should be summarized in a table to facilitate comparison of the options.

Step 3. Use the completed characterization as a way to compare decision options and to communicate their public-health consequences within the agency, to decision-makers, and to the public; use the comparison with other decision-relevant information to make informed decisions. Although the steps can be easily articulated, they involve thought and effort to complete.

The framework is not a cookbook and will require FDA to exercise judgment in how it is used.

The full report can be found here.

The policy of being too cautious is the greatest risk of all.

Jawaharlal Nehru

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Center for Public Integrity Smear 2

05/20/2011 03:57 PM |

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