Tell the FDA +/- 20% Is Not "Good Enough" ... Today!

Great minds must think alike! Kelly Kunik wrote about this very same topic as I was going to publish this posting. Read her post here.

Last June, the U.S. Food and Drug Administration's new Commissioner Dr. Margaret A. Hamburg wrote a formal letter of response to the American Association of Clinical Endocrinologists (AACE), which had formally asked that the regulatory agency act on the issue of clinical accuracy of home blood glucose testing supplies. The New York Times reported that the group had requested the FDA to push for greater accuracy in a letter sent to the FDA in May 2009.

The standards used in the U.S. (and elsewhere) today for blood glucose tests were actually established in 2003 by the Switzerland-based multinational organization known as The International Organization for Standardization (ISO), and those standards permit manufacturers +/- 20% deviation from actual clinical laboratory tests for blood glucose levels. (The formal document number is ISO 15197:2003 entitled "In vitro diagnostic test systems - requirements for blood-glucose monitoring systems for self-testing in diabetes mellitus", but be advised that the organization will charge you a hefty 130 Swiss Francs to download a copy of the lengthy document, or about $122 U.S. based on current exchange rates).

The AACE was prompted, in part, to ask the FDA to step in to tighten standards when a study undetaken by government researchers actually revealed when comparing tests from 5 different brands of widely-used blood glucose meters/test strips showed the results varying from lab values by as much as 32%. What's more, the study controlled for a number of different factors that might impact readings in a real-world clinical environment, such as ensuring that subjects washed and dried their hands before each test, for example.


Dr. Hamburg asked the FDA's Center for Devices and Radiological Health, the unit of the FDA responsible for reviewing, approving and establishing standards for blood glucose self-testing supplies sold in the U.S., to respond to the AACE. In their response, the Center for Devices and Radiological Health did cite a number of different statistics that seemed to suggest tighter standards were probably appropriate, including the number of adverse events attributed inaccurate blood glucose test readings from these devices, a number to FDA readily acknowledges is most likely under-reported because reporting is voluntary. Then, in June 2009, the FDA formally pressed ISO to tighten the standards for self-monitoring devices for blood glucose, believing that ISO has the ability to act much more quickly and broadly than the FDA does all by itself, although the FDA did hint that if ISO refused to act on the request, then the FDA "may instead recognize other (higher) performance standards" on its own. For the FDA to act on it's own would likely be more time-consuming because Federal regulations mandate that the Agency must have a formal public comment period announced in the Federal Register, a minimum period of time to collect responses, followed by a formal review of the comments gathered before even reaching a conclusion. Collectively, the process can take well over 18 months at a minimum, which would then need to be followed by a sufficient time period to enable manufacturers to comply with tighter new standards.

At a two-day meeting held to review blood glucose meters held by the FDA on March 16-17, 2010 (see here for the FDA's notice on that meeting) held at a Hilton Hotel located the Maryland suburbs just outside of Washington, DC, the FDA solicited input from a number of relevant stakeholders including: physicians, nurses, healthcare providers who work in intensive-care settings, industry representatives, diabetes educators, professional societies, consumers and even patient advocate groups to determine whether FDA review criteria for these blood glucose meters/strips devices should be changed "in order to promote greater public health". Among the attendees representing the industry was Alan Cariski, MD of Johnson & Johnson's LifeScan, Inc. unit and Mike Flis of Roche's home diagnostics unit.

Although the manufacturers claim to support tighter standards in much the same way as the tobacco industry supports smoking "prevention" programs and education, the industry tried to suggest that changes to tighten standards to within 15% were technologically feasible, while tighter standards were not. However, if one reads the FDA-mandated inserts included with a vial of test strips, the literature in a number of popular brands suggests those products are already compliant with +/- 15%, therefore such a mandate would require the manufacturers to do absolutely nothing! Meanwhile, the industry claims that reducing the variance from lab values to a margin of +/- 10% (or even +/- 5% as some would like to see) is not possible using current technology. Of course, that argument is a tad ironic considering at least one manufacturer, in this case AgaMatrix, Inc. already meets the Consider the following statement given at the meeting by industry-consultant Barry Ginsberg, MD, PhD, (from the firm Diabetes Consultants, based in Wyckoff, NJ)<10 actually="" although="" and="" at="" based="" benefits="" br="" buyers="" can="" comment="" deviation="" do="" groups="" i="" insurers="" know="" least="" less="" managers="" manages="" much="" on="" other="" pay="" pharmacy="" price-competitive="" prices="" really="" remaining="" retail="" say="" so="" standard="" still="" t="" than="" that="" those="" to="" typically="" we="" while="" wholesale="">:

"How much accuracy you need depends on who you are. Those with type 2 diabetes who treat their condition with diet changes and oral drugs don't need to monitor their blood levels as closely as those with type 1 diabetes who take insulin", he said.

What does Dr. Ginsberg's statement mean, exactly? Allow me to translate:

In effect, he's saying "Look, 90-95% of patients have type 2 diabetes and they don't require insulin, so the current standards are more than adequate for the vast majority of users".

That's a lame excuse. Why should anyone with diabetes, regardless of type, have to deal with such inaccuracies? The industry has repeatedly suggested that more stringent mandates will result in higher prices. To some extent, that's true, and we need to realize that retail prices for testing supplies are higher than most payers (meaning insurance companies, and/or Medicare) actually pay. The FDA estimates the pricing differential to range from 20-40%, depending on the drug or device.

All I can say in response to Dr. Ginsberg is: "Oh my God, the industry is claiming that the minority should not be dictating tighter standards for everyone else and threatening that doing so will possibly raise Medicare costs!" Sorry, but that smells like an excuse to avoid doing anything more. As they say "Why buy the cow when you can get the milk for free?" This business is a cash cow, plain and simple.

Reuters reported (see here) on the meeting phrased it a bit differently:

"At issue is whether incorrect meter readings stem from problems with the technology or other issues such as patients or doctors and nurses not using the devices properly. Other problems can include trouble with test strips, blood samples, hand washing and other factors that can impact results."

Unfortunately, my impression is that representatives with a direct, vested financial interest in the fortunes of the blood glucose self-monitoring device and supply industry seemed to rely on an all-too-common yet pathetic practice that has always existed in diabetes care: to try and deflect any criticism away from the treatment (or in this case, the device/strip manufacturers) and instead shift the blame to the end-users of their products, notably patients and to a lesser extent, doctors, nurses and hospitals which now routinely use the devices even if they are not formally approved for clinical use in those non-individual settings. The industry does claim to support the FDA in establishing standards to for blood testing devices that are used by doctors and nurses, but FDA regulators should be asking: "why wouldn't they?" Support for that effort translates into more users and buyers of their products, thus more earnings for their shareholders!

Claims that users aren't washing hands which can indeed impact test results was, from a patient's perspective, a pretty lame effort to suggest user error is the biggest issue, when the fact is, it isn't. This is a less-than-blatant attempt to discredit a legitimate need for greater precision even while claiming that they really "support" greater precision, but the FDA shouldn't buy it!!

Fortunately, Ellen Ullman actually attended the FDA meeting, and was there to represent the needs of patients and/or their caregivers (such as parents of children with diabetes), rather than the more typical style of FDA meeting where there's a conference room full of "experts" consisting of scientists, doctors, nurses and industry reps basically discussing the issues amongst themselves because it's required by law, but then do pretty whatever industry wants anyway. That helps explain why the diabetes industry, especially under the previous Commissioner, usually got what it wanted from the FDA. For those of you who don't know Ellen, her son Zach was diagnosed as an infant less than 2 years old if memory serves me correctly (he's now in college), and she has long been very actively involved in the online diabetes community, including the Children with Diabetes website, DiabetesTalkFest and many others. Ellen sat on the far right-hand side of the panel table for the DRI's Diabetes 2.0 Conference in Miami last November (see here for the video of that panel discussion). Ellen presented the results of a survey she conducted (Kelly Kunik of Diabetesaliciousness(TM) wrote about the survey here), and although Ellen told me she felt she could have done a better job than she did at the meeting, I really think she did very well! More importantly, I believe her mere presence there was far more important than what was actually included in her presentation.

The FDA notes that transcripts of the workshop may be requested in writing from the Freedom of Information Office (HFI-35), Food and Drug Administration, 5600 Fishers Lane, rm. 6-30, Rockville, MD 20857, approximately 15 working days after the public workshop (on or around March 29, 2010) at a cost of $0.10 cents per page. In your request, you should specify the docket number for the event (which is "FDA-2009-N-0604") and the title "FDA/CDRH Public Meeting: Blood Glucose Meters - March 16-17, 2010". A transcript of the public workshop will also be available (which should be free, if I'm not mistaken) on the Internet at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm187406.htm. There you'll be able to read all of the details from this important meeting, including the formal positions expressed by the various parties in attendance. From what I can discern, it appears that most practicing doctors and patients were on the side of tighter standards for BG meters and strips (the tighter the standards, the better as far as I'm concerned, although I do not want this the manufacturers to use it as an excuse to jack up prices, which they likely will).

Submit Your Own Comments on Whether You Think Current Accuracy Standards for BG Meters are Sufficient -- Online!

There's a BIG opportunity for the Diabetes O.C. (Online Community) to take part in this discussion even if we could not attend the meeting. First, I should note that the FDA has been migrating to the Federal Dockets Management System, which is a U.S. Government-wide system for posting documents, arranging meetings and seeking public commentary on issues such as accuracy standards for blood glucose monitoring systems. According to the Federal Register, the deadline for submitting comments regarding this public meeting is Tuesday, April 20, 2010 by 5:00 PM EST (about 2 1/2 weeks from today), so do not delay ... Act Now!! Click on the FDA Comments Docket for details! (If the link is not working, visit: www.regulations.gov, and search for Docket No. FDA-2009-N-0604)

The Business of Diabetes: FDA Delays Afrezza, Byetta LAR (now Bydureon)

The U.S. Food and Drug Administration, now under new leadership, appears to be taking the agency's role as protector of the U.S. public health more seriously instead of being viewed as a "partner" to the pharmaceutical industry. On Monday, March 15, 2010, the FDA delayed decisions on two diabetes medicines now pending approval. In a dramatic break from practices that had been underway for the past decade or longer, the FDA did not simply rubber-stamp approve two new diabetes treatments, instead, it asked the applicants for additional information before reaching a final decision.

The two medicines impacted are MannKind Corp's Afrezza inhalable insulin for type 1 and type 2 diabetes, which would compete with injectable, rapid-acting insulin formulations such as Lilly's Humalog (insulin lispro), Novo Nordisk's Novolog (insulin aspart) and Sanofi Aventis' Apidra (insulin glulisine). The other is Amylin Pharmaceuticals' Byetta LAR (which means "Long-Acting Release") which has now branded as Bydureon -- using Alkermes technology to extend the release of the drug, and is seeking approval only as a type 2 diabetes treatment. Bydureon is an extended-action version of Byetta, an already FDA-approved drug available today. Because both of these drugs are for modified forms of already FDA-approved medicines, both were submitted via the the 505(b)(2) process, which is usually regarded by the investment community as very likely to be approved, often with few (if any) expected delays.

Under the new Obama-appointed FDA leadership of Dr. Margaret Hamburg and her chief deputy, Dr. Joshua Scharfstein, the FDA has worked very hard to restore public trust and confidence in the FDA, which had been beset by one safety scandal after another in food, drugs and medical devices during the preceding 8 years. While numerous reforms have yet to be implemented, these delays are viewed by many healthcare professionals that the FDA is not simply there to serve the needs of the industries (namely, pharmaceuticals, biotechnology, medical devices and certain areas of food production) it is there to regulate, but to ensure public safety as the primary goal of the agency.

Consider this scathing commentary on the FDA under previous leadership as a sad example of exactly what the new leadership walked into.

This is really a dramatic change from the recent culture at the FDA under the previous leadership of Dr. Andrew von Eschenbach, who implemented a culture of fear among FDA staffers were made to feel accountable to the very industries the FDA regulates because of user fees mandated by Congress in a budget deal under the leadership of Newt Gingrich but signed into law by President Clinton back in 1992. These were often implemented with threats of job termination to whistle-blowers.

It should be noted that although the user-fees have saved taxpayers a tremendous amount of money, there were no user fees required of generic drugmakers, and the impact had the unintended impact of shifting staff towards new drug applications, while staff for generics, enforcement and post-market analysis were overburdened more work than they could effectively handle. Although the the FDA can theoretically demand post-market analysis from the very same user fees that fund the new drug applicants, practically speaking, the FDA should have been mandating those fees at the time approvals were granted, so the Agency has struggled to restore the agency's credibility among lawmakers.

Indeed, this year, Dr. Hamburg stated "We very much want to work with you to see generic drug user fees enacted this year" and has indeed asked Congress to pass legislation to enable the agency to hire staff to address the massive backlog these functions (generics and enforcement) now face.

Rather than provide written details, you may watch the following two short news summaries (albiet with commercials) on these decisions below.

FDA Delay #1: MannKind's Afrezza

First, the move on MannKind's Afrezza inhalable insulin, which can be viewed here:



The U.S. Food and Drug Administration sent MannKind a so-called "complete response letter" Friday requesting additional information. The fact remains that the FDA could have simply declined the insulin, but the agency instead asked about the medication and the inhaler patients will use, MannKind said on Monday in a statement. The regulators didn't cite any safety concerns as many analysts had expected, but they did request updated safety data. MannKind said it had not planned to launch a commercial version of the device in its current form, and had hoped to follow-up with a supplemental new drug application (NDA) to market a next-generation version of the inhaler device known as Dreamboat instead.

MannKind was planning to submit a new drug application for the Dreamboat inhaler in Q2 2010. But at the urging of the FDA, the company will now request an "end-of-review" meeting with the agency in an effort to hopefully resolve the regulator's concerns.

In particular, the FDA questioned whether the inhaler used by MannKind in clinical trials was comparable to a newer one the company has developed and wants to market with the drug, MannKind's chief financial officer, Matthew Pfeffer said. The FDA letter also requested changes to the proposed labeling of the cartridges, foil pouches and cartons. MannKind also said that the FDA was concerned about Afrezza's clinical utility, which a number of analysts reacted very negatively to.

Indeed, MannKind's eagerness to introduce a slightly modified version of the inhaler device can be viewed as an "amateurish" mistake due to it's lack of experience in working with the FDA. The company probably should have waited for an approval on the drug before even trying to modify the device it planned to bring to market, which would almost certainly would have been the approach taken by any experienced pharmaceutical company such as Novo Nordisk or Eli Lilly & Co., whose experience in working with the FDA and many other regulators around the world is far lengthier than is MannKind's.

But in spite of yesterday's delay, MannKind's senior management team remain upbeat about Technosphere insulin's prospects.

"We think the issues raised by the letter are completely addressable," company CFO Pfeffer said in a telephone interview.

"If we are allowed to incorporate this information on the inhaler in our response, we can stay on schedule for the commercial launch," Pfeffer said. He said the FDA would take 6 months to respond to new information from the company once it is submitted, so this particular inhalable insulin has suffered a lengthy delay, realistically, it may be postponed until 2011.

As a result of this delay, the reaction among the investment community on Wall Street was mostly pessimistic. The news sent MannKind shares tumbling nearly 25% Monday, on fears that the FDA might not actually approve the product.

"The fact that the FDA wants more data supporting clinical utility is not good for Afrezza," said Jon LeCroy, an analyst at the New York office of the Israel-based bank Hapoalim Securities. "We have always questioned the need for a new inhaled insulin and it looks as if the FDA may have similar questions."

A few other analysts echoed LeCroy's opinion.

JPMorgan Chase analyst Cory Kasimov said "The complete response letter in our view is an onerous one."

But whether Wall Street responds positively is really only a minor consequence.

To date, MannKind has been kept afloat with the help of its founder and CEO, Alfred Mann, who has poured millions of dollars of his own money into the company.

Mann, who owns roughly 46% of MannKind's shares, is one of the world's richest men, ranking No. 721 on Forbes' list of the world's billionaires. He built his fortune as an entrepreneur who helped develop solar cells, cardiac pacemakers, insulin pumps and implantable technology designed to restore hearing and sight.

Mann remains convinced that Afrezza can have the same revolutionary impact on the treatment of diabetes as cardiac pacemakers had on the treatment of heart disease.

To address the investment community, MannKind scheduled a conference call on Tuesday (March 16, 2010) morning to discuss the FDA's requests.

"We will discuss with the FDA whether it is appropriate to use what would otherwise have been a supplemental NDA submission, which we had planned to make during the second quarter of this year, to address the agency's requests," Mann said in a statement. "If this approach is acceptable, we believe that this regulatory action will not have a significant impact on the timing of the commercial launch of Afrezza."

"At this point, we have no reason to believe that our plans to launch in 2011 are adversely impacted by issues raised in the ... letter," CEO Alfred Mann said.

But whether doctors and patients are anxiously awaiting Afrezza's approval remains to be seen, especially given the competition expected to emerge in the coming years (see my previous post here for more details).

FDA Delay #2: Amylin's Bydureon (formerly known as Byetta LAR)

Second, the FDA's delayed its decision on Amylin Pharmaceuticals' (along with partner Eli Lilly & Co. and using Alkermes technology) for a drug formerly dubbed Byetta LAR (which means "Long-Acting Release") -- now branded as Bydureon -- which is seeking approval only as a type 2 diabetes treatment. Bydureon is an extended-action version of Byetta, an already FDA-approved drug available today. Again, rather than providing complete details in writing, you may watch the following short news summary for the basic information. The FDA's decision on Amylin's Bydureon can be viewed here:



Byetta already has annual sales of $700 million, and the long-acting release version would only have to be injected once weekly instead of daily for Byetta. But a similar drug just approved by the FDA, Novo Nordisk's Victoza (liraglutide) was approved, albiet with noteworthy delays and an FDA-mandated black-box warning over pancreatitis, suggesting far more caution from the FDA than Wall Street analysts gave the Amylin/Lilly drug on March 15, 2010. Bydureon is also delayed, though the reaction on Wall Street was mostly more positive than the news on MannKind, perhaps given the relative experience in resolving issues with the FDA on issues raised.

Conclusion

My take on both news releases is pretty much the same: the newly, more-cautious FDA is asking for more information, rather than simply awarding approvals and asking questions later. These are delays for both, although due to the nature of MannKind's letter, if I had to guess, that drug will be delayed longer than Amylin's Bydureon.

"The Doctors" Features JDRF's Artificial Pancreas

As some of you may know, the syndicated television show "The Doctors" features four practitioners with four different specialties. The show aims to share medical knowledge and by utilizing the hosts' collective hands-on experience to help educate TV viewers and also provide some valuable resources.

The daytime television show's primary host is an E.R. physician named Dr. Travis Stork, who is at least partially responsible for the show's ratings success among daytime viewers, who are disproportionately comprised of stay-at-home housewives.


Ladies' Home Journal magazine referred to Dr. Stork as the "hunky host" of the show and he's regularly featured wearing hospital scrubs in spite of the fact that he's in a television studio, nowhere near an emergency room. Dr. Stork's presence on the show no mere accident; TV viewers may remember Travis Stork as the star of the ABC reality show "The Bachelor" back in 2006. Dr. Stork doesn't do the show completely by himself, the show also features obstetrician and gynecologist Dr. Lisa Masterson; plastic surgeon and reconstructive surgery expert Dr. Andrew Ordon; and pediatrician Dr. James Sears.

Maybe it's just me, but I cannot help but recall the FX cable television show "Nip/Tuck" when both of the lead characters pack up and move their entire plastic surgery practice from Miami Beach to Los Angeles, as if that happens all the time. Upon settling in L.A., one of the show's lead characters, Dr. Sean McNamara (played by Dylan Walsh) ends up getting his own reality TV series. Whenever I have watched "The Doctors", with hosts that look like soap opera stars, Nip/Tuck always comes to mind, which sort of diminishes its credibility (at least a little) from my perspective. Then again, I'm not exactly the show's target demographic.

In any event, today's (March 11, 2010) episode of "The Doctor's" is entitled "Futuristic Medicine that Can Change Your Life" which, according to the show's website explores "bionic limbs, robots and advanced biotechnology ... the fantastical designs of science fiction are fast becoming a life-saving reality. See a robotic breakthrough for the treatment of autism. Defy gravity with a hyperbaric oxygen chamber for pets [using NASA technology]!" The promotional clip (for the moment) can be viewed here:



One particular segment of this episode features the Artificial Pancreas project. JDRF's Aaron Kowalski is featured and interviewed (remotely) and talks about the effort, how it would work and how it could potentially impact the lives of people with type 1 diabetes. Of note: the show does caution viewers that the artificial pancreas is still in development.

I've downloaded the segment clips for future reference (and viewing) and feature that segment below, but you can also visit the show's website here or the actual clip from the show here. At the show's website, you can find links to the episode's summary, order a copy of the show's transcript, as well find links to the episode's summary, visit the message board and more.