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I’ll bet all those pols and pundits who naively call for a “conflict-free code” for FDA advisory committee members don’t realize that such a zero-tolerance policy would lead to the destruction of the most open, transparent — and successful programs of clinical review in the world.
Consider Canada and Europe where advisory committees meet in secret, deliberating behind closed doors, commenting publicly only after they have reached a decision.
During my tenure at the FDA I was the senior official in charge of advisory committees. I recollect a meeting with officials from Health Canada — the FDA’s equivalent in Ottawa — who were aghast that our adcomm meetings were regularly attended by members of the media, financial analysts, patient groups, politicians — and that the meetings were recorded for public consumption.
I explained that such transparency was what made the meetings so valuable. At an FDA adcomm the agency is put to the test, to explain and defend its scientific thinking in public, before a panel of experts with the breadth and depth of experience to dissect the results, to challenge conclusions, and to make sure that no clinical stone goes unturned.
And the cornerstones of every adcomm are the clinical experts who serve on them. The best and the brightest our nation has to offer.
But Dr. Scott Gottlieb (the FDA’s Deputy Commissioner for Medical and Scientific Affairs) is worried (and rightfully so) that the value of these committee meetings could be eroded, “if current legislative proposals become law, and FDA is hampered in its ability to put experience and expertise as the paramount criteria when recruiting members to serve on these committees.” Gottlieb is concerned “by some who want appearance to trump acumen — who want the lack of private sector work to trump a plethora of scientific experience as a criterion when we are selecting who to put on our committees.”
In order to increase public confidence in the integrity of the advisory committee process, the FDA plans to take the following steps to help ensure advisory committees continue to be scientifically expert and independent and that the advisory committee process is transparent:
* Issue a guidance identifying more clearly the conditions under which conflict of interest waivers are granted. Currently, for example, waivers can be granted to committee members under certain circumstances for participation in scientific endeavors related to the work of the committee, as well as for certain unrelated activities.
* Issue a guidance specifying when waivers of conflict of interest will be disclosed to the public and what information will be made available.
* Issue a guidance specifying when briefing materials used at advisory committee meetings will be made publicly available.
* Provide greater public dissemination of advisory committee schedules through increased mailings to public groups, and providing electronic notifications through an FDA advisory committee list serve and posting on the FDA web site.
* Implementation of a more streamlined approach to the appointment of members to the agency’s drug-related advisory committees.
At a panel discussion today on government-sponsored advisory committees organized by the Center for Science in the Public Interest (a group whose regular criticism of the agency makes Charles Grassley’s aureate prattle look meek by comparison), Gottlieb is expected to say that it “would be a significant step backwards if our primary criterion for selecting members to our committees becomes their lack of private sector work, if we exclude people for deep experience rather than embrace them for it. The public health will not be served if we’re no longer able to attract the kind of very active medical practitioners and clinical trialists who are able to inform our meetings with some very unique medical insights that only comes from years of experience both seeing patients and developing and looking at clinical data, sometimes in some very narrow fields or for specific indications.”
Yet pols and pundits continue to ask simplistic questiones, phrased more as accusations than inquiries. For example — “Why can’t the FDA just appoint panels with experts who don’t have conflicts and, therefore, won’t need waivers?”
It sounds good as a soundbite, but even a little homework shows the ignorance inherent in the question. FDA doesn’t appoint adcomm members meeting-by-meeting, case-by-case, action-by-action. FDA adcomms are standing committees, with members recruited and appointed sometimes years in advance, and who serve for defined terms of up to four years. And, according to Gottlieb, “This serves us well, since there is a value from having people who have institutional experience from serving on these committees. It is similar to the way the Senate works, where you don’t want all the members being brand new each year, or appointed just to vote on each individual issue.”
Gottlieb continues, “And this leads me to the heart of the problem: When we appoint these committee members, it is impossible to tell who is going to have relationships that could present the potential for an appearance of a conflict around a specific issue, and therefore require them to get a waiver, since we don’t know what issues are going to come up a year or two in advance. If we err on the side of caution, and only appoint members who have had absolutely no associations of any kind with any regulated products or industries, then we’re going to be hard pressed to find people that have also been engaged in relevant and unique scientific endeavors, since a lot of medical product research is done in collaboration, at least in part, with sponsors.”
“If we were prevented from being able to grant waivers in the first place, we’d have to recruit people who had no such associations, and were unlikely to develop them for the length of their tenure on our committees. I’m not only worried that such people would be very hard for us to find, especially since it’s sometimes not obvious to researchers themselves that their institution might have received a grant for research they had no involvement in, or a clinical trial they are working on might have received partial funding from a private source.”
Might we really pass legislation that bans the best and the brightest from serving the public health by disallowing their service on advisory committees because their preeminent expertise has also been viewed as valuable by the pharmaceutical industry?
Well, maybe not outright ban, but a codicil tucked in at the very end of the Enzi/Kennedy bill (page 98 for you really dedicated drugwonks out there) would make the process seem like persecution. The bill calls for the HHS Inspector General to review “on an on-going basis” the financial interests of a representative sample of individuals who have served on an FDA advisory committee.
I can attest, as a former senior FDA official, that it is very difficult to recruit the best and the brightest. This would make it almost impossible. After all, who would want to serve on an advisory committee when you’re viewed as a potential criminal before the ink on your appointment is even dry? Independent-thinking adcomm members will feel threatened and suffocated by the unspoken threat of federal investigators knocking at their clinic doors. Such legislation amounts to adcomm Lettres de Caches for folks like CSPI, posturing pols and Page One hungry reporters.
Ad captandum vulgus.
Our friend, Minnesota Governor Tim Pawlenty, just called pharmaceutical advertising “silly” and said that Congress should enact a two-year moratorium … if it would hold up in court.
Nice two-step Tim.
Coincidentally, Governor Pawlenty is in a tough reelection battle with Minnesota Attorney General Mike Hatch, author of the infamous 51-page, “Follow the Money: The Pharmaceutical Industry — The Other Drug Cartel.”
Silly? Only if getting more people to visit their physicians is silly. Silly? Only if earlier diagnosis of diabetes and heart disease is silly. Silly? Only if the distigmatization of depression and, yes, even erectile dysfunction, is silly.
Governor Tim also repeated the anti-pharma NewSpeak that drug ads raise drug prices. Sorry Gov — not so. When you compare all the drugs in any given therapeutic category, the ones that advertise the most do not always cost the most. In short, no correlation between ad spending and product cost.
To further flex the Governor’s pecs, Brian McClung, Pawlenty’s spokesman, noted that Pawlenty took on the White House early in the administration with a “first-in-the-nation” proposal to facilitate the buying of less expensive drugs in Canada.
But, according to the Minneapolis Star-Tribune, “… only about 18,000 prescriptions were ever obtained under the program, despite Pawlenty’s prediction that 700,000 Minnesotans would benefit.”
Silly indeed.
May 10, 2000: Senator Byron Dorgan co-sponsors the following amendment:
“NONINTERFERENCE. — In administering the prescription drug benefit program established under this part, the Secretary may not — (1) require a particular formulary or institute a price structure for benefits; (2) interfere in any way with negotiations between private entities and drug manufacturers, or wholesalers; or (3) otherwise interfere with the competitive nature of providing a prescription drug benefit through private entities.”
Six years and 180 degrees later …
July 2006: Senator Byron Dorgan plans to offer the following amendment:
“REQUIREMENT TO NEGOTIATE PRICES WITH MANUFACTURERS. — In order to ensure that each Part D individual who is enrolled under a prescription drug plan or an MA-PD plan pays the lowest possible price for covered Part D drugs, the Secretary shall negotiate contracts with manufacturers of covered Part D drugs, consistent with the requirements of this part and in furtherance of the goals of providing quality health care and containing costs under this part.”
Yep — Senator Dorgan was for it before he was against it.
As Lord Byron wrote, “I’ll publish right or wrong. Fools are my theme, let satire be my song.”
Here are the facts behind the posturing:
The CMS chief actuary has already rejected the idea that Federal “interference” will save money:
“In considering these issues, we believe that direct price negotiation by the Secretary would be unlikely to achieve prescription drug discounts of greater magnitude than those negotiated by Medicare prescription drug plans responding to competitive forces.”
And the CBO has made a similar determination:
“We estimate that striking [the non-interference] provision would have a negligible effect on federal spending because CBO estimates that substantial savings will be obtained by the private plans and that the Secretary would not be able to negotiate prices that further reduce federal spending to a significant degree.”
The fact is that robust competition among Medicare Drug Plans continues to drive down costs for beneficiaries and taxpayers, while stimulating enrollment.
* According to CMS, the net total cost of the drug benefit to the federal government over the next decade is about 20% (or $180 billion) lower than the total cost estimated last year.
* The vast majority of this reduction is the result of lower-than-expected drug costs and higher-than-expected price breaks negotiated by Medicare drug plans. According to CMS, data from Part D plans demonstrate that rebates and discounts on drugs are much larger than originally projected.
When’s the last time a government-negotiated program delivered such numbers?
(Hint: Never.)
According to government experts, eliminating “noninterference” won’t save money, but it will lead to government price controls and a government controlled benefit.
CBO has found that multiple, competing private sector plans contain costs more effectively than a government-controlled benefit through competition and plans’ use of price discounts, rebates, and other tools. (Surprise! Everything you learned in Econ 101 was right.) The noninterference provision protects this approach by preventing government bureaucrats from getting in the way of these negotiations.
Repeal of the noninterference provision would also repeal the prohibition on the government setting a national, one-size fits all, formulary. Yikes!
According to CBO, allowing the government to negotiate prices may not result in current VA prices for Medicare Part D — The VA Health Care System is a public health system with statutory price controls and other special arrangements representing a very small share of the market.
For more on why VA is not a better way, please see my previous blog (“VA is not the way,” 3/13/06).
Bottom line? The Medicare Drug Benefit gives Medicare beneficiaries the same negotiating power that works for Members of Congress and 190 million other Americans.
Federal interference was a bad idea when Senator Dorgan was against it in 2000. And it is still a bad idea now that he is for it in 2006.
Competition works. Politics gets in the way.
To once again quote Lord Byron, “Always laugh when you can. It is cheap medicine.”
And, methinks, Lord outranks Senator.
NPR’s Joanne Silberner has an informative and compassionate look at the progress — so far — of the use of pharmacogenomics in improving drug prescribing in her broadcast today. The link to the podcast and excellent FAQ about personalized medicine is posted below. She, along with Cathy Arnst of Businessweek and Anne Underwood of Newsweek have provided solid coverage of this field.
http://www.npr.org/templates/story/story.php?storyId=5568710
Remember the Madonna video?
Vogue. Strike a pose.
That’s what’s behind the ill-considered and dangerous Vitter amendment that would neuter US Customs and Border Protection from actually protecting US citizens — by removing their authority to seize illegal, potentially unsafe and counterfeit prescription drugs that Americans import “from Canada.”
“From Canada?” Not necessarily.
All of the large Canadian internet pharmacies openly admit that the drugs they send to unsuspecting Americans are not “the same” drugs that Canadians get at their local pharmacy. They’re from other places — many from Europe. So what’s wrong with that? Two words — parallel trade — the term Europeans use for drug importation. Senator Vitter may only want drugs “from Canada” — but that’s impossible — because EU law makes it so. According to the Treaty of Rome, parallel trade is completely legal and Articles 30 and 36 prohibit manufacturers from managing their European supply chains in their own or patients’ interests.
Sorry Senator, the truth is inconvenient.
Last year 140 million individual drug packages were parallel imported throughout the European Union — and a secondary wholesaler repackaged each and every one. (The same type of secondary wholesaler that we are trying to eliminate in the US because of their role as “weak link in the chain” — the chain of custody that is.)
This means that, literally, parallel traders in Europe open 140 million packets of drugs, remove their contents and repackage them. But these parallel profiteers are in the moneymaking business, not the safety business. And mistakes happen. For example, new labels incorrectly state the dosage strength; the new label says the box contains tablets, but inside are capsules; the expiration date and batch numbers on the medicine boxes don’t match the actual batch and dates of expiration of the medicines inside; and patient information materials are often in the wrong language or are out of date. Oops.
Vogue. Strike a pose.
This means that drugs purchased from a British pharmacy to an unknowing American consumer (or a blissfully ignorant United States Senator) could come from European Union nations such as Greece, Latvia, Poland, Malta, Cyprus, or Estonia. In fact, parallel traded medicines account for about 20% (one in five) of all prescriptions filled by British pharmacies. In the EU there is no requirement to record the batch numbers of parallel imported medicines, so if a batch of medicines originally intended for sale in Greece is recalled, tracing where the entire batch has gone (for example, from Athens to London through Canada to Indianapolis) is impossible. Caveat Emptor is bad health care practice and even worse health care policy. Safety cannot be compromised, even if the truth is inconvenient.
Stubborn facts.
No time to Vogue.
From today’s Washington Times…. The Vitter amendment is a shameful reflection on the political instincts of the Senator who sponsored it. But it also reflects poorly on the collective judgment of those members who voted for it without considering the signal it sends our enemies and more importantly, those courageous law enforcement agents who have risked their lives to make America and the medicines they take safer.
Counterfeit drugs and border security
The Washington Times
USA, 7/19/2006 - On March 29, the federal Joint Terrorism Task Force unsealed an indictment charging 19 persons with operating a global crime and terrorism ring spanning Lebanon, Canada, China, Brazil, Paraguay and the United States. The ring sold counterfeit drugs and other contraband materials, largely through direct consumer shipment from Canada, to Americans seeking cheaper drugs. It, in turn, directed its profits to support of the criminal terrorist group Hezbollah.
Less than four months later, as Hezbollah rockets rained down on Israel, the Senate voted for an amendment offered by David Vitter of Louisiana to ban U.S. Customs and Border Protection agents from seizing prescription drugs that Americans import from Canada. For Mr. Vitter, the passage was a defeat of sorts: He wanted to ban Customs agents from seizing medicines imported from anywhere, which suggests that the politicians who voted for the measure knew that dangerous people were trying to sell fake drugs in America.
How they deluded themselves into thinking that banning law enforcement from seizing drugs purchased from Canada would not be like creating a safe haven for terrorists is another question. Indeed, Canada is already the favorite port of call for fake medicines. According to customs, most of these drugs are not shipped through wholesale distribution channels but are shipped directly to consumers, with Canada being the major transshipment point because of its access to the U.S. market
In 2003, the FDA and Customs confiscated thousands of drug shipments headed for the United States. When opened, nearly half claimed to be of Canadian origin, but, according to FDA and Customs officials, 85 percent of them were from 27 other countries, such as China, Iran and Ecuador. And 30 percent of the drugs were counterfeit.
Banning Customs enforcement is tantamount to giving terrorists a free pass to flood America with fake and dangerous drugs. Customs and Border Protection is the largest investigative arm of the Department of Homeland Security. It plays the leading role in targeting criminal organizations that produce, smuggle and distribute counterfeit pharmaceuticals. Hence, Mr. Vitter and the Senate are handcuffing Customs from policing the very trafficking corridors that Hezbollah and gangsters use to penetrate our borders.
According the NY Times today, David Graham who is to rational evaluation of the risks and benefits of medicine what Hezbollah is to advancement of peace in the Middle East, called for the withdrawal of Ketek based on the fact that others in the FDA’s infectious disease division relied on post market data from Europe submitted by the company. That’s pretty funny considering Graham has called for the removal of Crestor, Celebrex, Accutane, Rice Krispies and tap water based on post market data.
Graham is not alone is his obsessive pursuit of Ketek. He is joined by an FDA staffer who wondered in a memo whether the risk of liver failure was worth one less ear infection in regards to a Ketek trial. Well, as I wrote before, if that is the benchmark, we shouldn’t give anyone tylenol for a fever.
“David Shlaes, an expert in infectious disease and antibiotic research with the development of a new medicine under his belt has sent this email to me in response to the recent articles about Ketek’s “dangers”
Recent press reports on the development, approval and subsesquent reports of toxicity of the antibiotic Ketek have me concerned. … The implicit (if not explicit) message was that the evil pharmaceutical company submitted flawed data to the FDA who, admitting the study was flawed, still approved the drug in spite of serious safety concerns. Now patients are dying because of the greed of Sanofi and incompetence or worse at the FDA.
.. Ketek, an antibiotic developed by Aventis, now Sanofi-Aventis, was reviewed by the FDA in 2001. They noted safety concerns, partly around the potential for liver toxicity, and requested additional safety data. Aventis then carried out an extremely large study of over 24,000 patients using more than 1800 different investigators worldwide. This was the study (no. 3014) where the FDA noted that the study was so flawed that they could not rely upon its data. Nevertheless, the FDA noted that in the post-marketing experience with Ketek worldwide during the intervening years until 2003, almost 4 million courses of therapy had been prescribed with no clear safety concern, plus there was a general lack of a safety signal in the 24,000 patients in the flawed study. Therefore, the FDA approved the antibiotic.
FDA conducted a thorough review of adverse events related to Ketek in the post-market setting. They were able to identify 12 cases of acute liver failure of which four were fatal among 10 million prescriptions. There were 23 cases of liver toxicity overall in the data set. As a result of these findings, the FDA approved label for Ketek has been changed to note in bold letters the possibility of severe liver toxicity â a reasonable approach based on the data.
Congress, specifically representatives Markey and Waxman, both democrats, and Senator Charles Grassley, a republican, have sent inquiries to the FDA regarding the approval of Ketek. Apparently, they believe that Ketek should never have been approved, and that the FDAâs approach to the entire problem has been flawed. Some have demanded that Ketek be withdrawn.
I would like to try and put all this in some perspective. To me, Ketekâs story is one of risk and benefit and the risk tolerance of American society and the FDA. Let us take an old reliable antibiotic or even two or three â penicillin, amoxicillin and augmentin. These antibiotics are very closely related, generic, inexpensive and are taken by many more millions of patients, including and especially children, than take Ketek. Augmentin, a combination of two penicillin-like drugs, had peak year sales of well over $2B at one point and may be the biggest blockbuster antibiotic in the history of the pharmaceutical industry. Penicillin is thought by most physicians to be the most safe and effective antibiotic ever to be developed and marketed. Yet the penicillin drugs can be expected to cause a fatal allergic reaction once in every 35-100,000 courses of therapy. Therefore, among the 10 million courses of therapy as surveyed for Ketek and for which 4 fatal cases of liver toxicity were identified, we could expect 100 to 285 deaths if the prescriptions had been for any of these penicillin drugs. In the FDA approved labeling for the penicillin drugs, the possibility of serious or even fatal allergic reactions is noted, just like the possibility of liver toxicity is noted in the Ketek label. Aspirin probably causes 7,000 deaths and 76,000 hospitalizations a year in the United Sates.
I wonder if, given our concern over Ketek, penicillin would even make it to the marketplace today, or if it were approved, whether it would be withdrawn shortly afterwards as reports of fatal anaphylactic reactions started to arrive at the FDA. Could we register asprin? Or, would we rely on the information already included in the approved product label noting a risk of rare but serious allergic reactions? Is Ketek different from penicillin? Would there be congressional hearings pillorying the FDA for approving or not forcing the withdrawal of penicillin?
I think its time for all of us, the press, Congress and the American public to take a step back from this brink â for the brink it is. More large pharmaceutical companies have halted their antibiotic research efforts than the number that still continue working in the area. Among a large number of reasons for this pullback is the increasing stringency and cost of clinical trials required for registration â of which Ketek is an example. If we want to have continued new and beneficial therapies from the pharmaceutical industry, in particular, if we want to have new antibiotics that fight infections resistant to the old antibiotics, we need come to a realistic understanding of the risk we are willing to accept.”
Covering less effective drugs
USA TODAY’s story implies that because most new drugs don’t “cure” cancer for most patients, they shouldn’t be so expensive. In fact, from 1975 to 1995, new cancer drugs increased the life expectancy of people diagnosed with cancer by about one year. From 1995 until today, death from cancer has been declining faster than at any other time in history.
USA TODAY bases its assertion that most new drugs don’t extend life on studies that tested drugs designed for specific groups from the results of one-size-fits-all studies. But lives are extended and enhanced by matching the right drug to the right patient well before the disease advances.
Maybe someone should have looked at an earlier USA TODAY story titled “Experimental drug stuns cancer doctors” (News, May 16, 2005). It describes Revlimid, which costs thousands a month and is a drug that targets a certain genetic mutation that causes a hitherto incurable blood disorder more common than leukemia is. Revlimid is nearly 100% effective in two-thirds of patients with the disease. It eliminates ineffective, equally expensive and debilitating blood transfusions.
USA TODAY wonders why people have to shell out money for cancer drugs. It should have asked why health plans cover the entire cost of cheaper and less effective drugs but not Avastin.
Robert Goldberg, Vice President
Center for Medicine in the Public Interest New York
William Tucker today has a great column in OpinionJournal discussing an interview with Andy Kessler, the author of The End of Medicine, with a particular emphasis on the amazing impact of advancing technology in terms of early diagnosis of disease and chronic conditions. Not emphasized heavily—-but clearly implicit within the topic—-is the complementary role of pharmaceuticals in the early treatment and cure of such diseases and conditions discovered early. It does not take a rocket scientist to foresee a large component of medical care as early diagnosis and then cure by pharmocology. Nor does it take a genius to see the dark clouds hovering over that bright landscape as a result of price controls, bureaucratic footdragging, and other such policy impediments, yet another shining achievement of Beltway magic.
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.
