Agenzia Fides, the missionary press agency of the Vatican, has spoken out against counterfeit drugs

Fake tuberculosis and malaria drugs alone are estimated to kill 700,000 people a year. A large part of these victims are African. The World Health Organization (WHO) estimates that up to 30 percent of the medicines on sale in many African countries are counterfeit and have found that nearly half of the drugs sold in Angola, Burundi, and the Congo are substandard.

In 2003, Interpol conducted a survey on the quality of drugs available in Lagos, sub-Saharan Africa's most populous city and found that 80 percent of the drugs available were fakes. In 2008, more than 80 children in Nigeria died after being given medicine for teething pain that was laced with antifreeze.

Fake medicines can be missing key ingredients, use the wrong ingredient, or have insufficient or too much of the active ingredient. In some cases, use of these medicines can increase drug resistance. When there is not enough of the active ingredient, the drug kills some of the parasites or viruses, but the pathogens that are not killed adapt. As time goes on, even if a patent was to be treated with the correct medication, he or she would not be cured.

Agenzia Fides states, “The development of germs resistant to antibiotics and other treatments is a problem that affects all humanity, not just Africans. It is therefore in the best interest of all concerned that smuggling of counterfeit drugs be fought against.”

In an upcoming position paper the Infectious Diseases Society of America suggests that overuse of antibiotics could be controlled via a REMS-like approach – or even an actual REMS.  

Interesting idea, because something new must be done. The problem of antibiotic resistance is a real, urgent, and relatively silent public health crisis.  For those who rant about the influence of DTC advertising on the doctor/patient dialogue -- it doesn't even hold a candle to a parent's plaintive plea for a prescription when their child has an ear ache.

In the past, FDA has worked with the CDC on consumer education programs such as “Cough, Sniffle, Sneeze – No Antibiotics, Please."  But such efforts have met with only modest success (and that’s being generous).

If it takes a REMS to drive the safe and appropriate use of antibiotics, then so be it.  Burdensome on docs, yes – but they have nobody to blame but themselves. 

Counterfeit medicines are a real problem – and quantifying that problem is, well, a real problem.  How do you estimate criminal activity in ways other than a body count? “Show me the dead Canadians” (as Senator Bernie Sanders is so fond of saying) is not an excuse to do nothing. And purposely derailing the international fight against the false profits of fake medicines via the spanner of "definition" is unconscionable. 

Here are four excellent new articles (two from the Wall Street Journal, one from USA Today and the fourth from the Washington Post) that remind us that counterfeit medicines are an important public health issue here at home and around the world.

The first WSJ piece can be found here, the next here, the USA Today story here and the Post’s take here.

While counterfeits are tough to measure, it doesn’t mean that we can ignore the problem.  To belittle the problem because we cannot substantiate the volume is unwise.  If we wait to count the bodies – we have only ourselves to blame.

According to a new study in Health Affairs, more than half of the 354 million doctor visits made each year for acute medical care, like for fevers, stomachaches and coughs, are not with a patient’s primary physician, and that more than a quarter take place in hospital emergency rooms.

The authors of the study pose a significant question about what we’re calling “healthcare reform” --  how can access to primary care be improved when an already stressed system with a dearth of primary care physicians takes on millions of new patients?

More than half of acute care visits made by patients without health insurance were to emergency rooms. That poses a heavy workload and financial burden on the system and means that basic care is provided in an expensive setting.

According to Dr. Stephen R. Pitts (no relation), the lead author and an associate professor of emergency medicine at Emory University, “More and more patients regard the emergency room as an acceptable or even proper place to go when they get sick.”

The study can be found here.

In theory, the new federal law is designed to enhance primary care by increasing reimbursement for practitioners, luring students into the field with incentives.

The real-world reality is, as we know, quite different.  I recently went to my Upper West Side Jewish GP (just to give you an idea of the non-Tea Party demographic).  She asked me, “So, how bad is it?”  When I asked what she was referring to she said, “This new health care law – for me.”  The concept that you can improve primary care by (1) restricting the independence a physician has to practice both the art and the science of medicine and (2) sending very mixed signals about the inevitability of a permanent “doc fix,” (3) increasing case loads, and (4) doing absolutely nothing about tort reform – certainly makes a dubious case for “luring students into the field,” let alone keeping those already in place in practice.

The authors issue a critical warning, “If history is any guide, things might not go as planned.”

And those who do not learn from history ...

And speaking of tort reform, another article in Health Affairs illuminates addresses the issue head on.

The paper by three Harvard professors and a colleague at the University of Melbourne in Australia estimates that the medical-liability system added $55.6 billion to the cost of American medicine in 2008, equal to 2.4 percent of total health spending.

More than 8 of every 10 of those dollars — $45.6 billion — was attributed to defensive medicine by physicians who order unnecessary tests and procedures to protect themselves from malpractice claims. Not decimal dust.

That study can be found here.

Attention must be paid.  Whoever has the gavel for the 112^th Congress has a lot of work to do.

Can consumers really understand what clinical trials have to say about comparative risk and benefit?  And what are the rammifications?

The FDA is studying whether/how to add comparative and numeric information describing benefit and risk data to the brief summary in direct-to-consumer print advertising.

The agency is looking at various presentations of quantitative and qualitative information in a boxed format and determine how consumers perceive drug efficacy and risk as well as measure their understanding of the benefit and risk information.

FDA's summary of the study proposal notes that evidence indicates formatting can impact consumer comprehension of information, and using bullet points or section headings can make the information more readable.

"It is not known whether simply adding efficacy rate information to a consumer-friendly brief summary would be sufficient to enable consumers to understand a product's efficacy, or whether qualitative summations are necessary as well," the agency said in the Federal Register.

Well – duh.  No news there.  All of this is pursuant to the media-friendly (but poorly designed) Dartmouth University study.

One thing that requires no additional study is, shall we politely say, the relative user-unfriendly nature of the current brief summary.  The joke inside the FDA (if a joke it can be called) is that the brief summary is like the Holy Roman Empire – neither brief nor a summary.

Nor of tremendous utility.

According to the FDA’s 2002 study, 65 percent of doctors believed that the DTC ads their patients saw confused them about the relative risks and benefits of prescription drugs—and that is a problem. In a 1999 FDA study, 56 percent of patients who saw a DTC print ad said that they read the brief summary “not at all” or “a little.” In the 2002 study that number jumped to 73 percent—an increase of seventeen percentage points. During that same three-year span, those saying they read “almost all” or “all” fell from 26 percent to 16 percent— these ten percentage points are not decimal dust by any stretch of the imagination.

In the “decimal dust” category, consider this: In 1999, 3 percent said that they weren’t aware that the brief summary even existed. In 2002 that dropped a full decimal place to 0.3 percent. In other words, more people knew that the brief summary was there, but fewer people were reading it.

For more on why the current long format brief summary doesn’t work see this article from Health Affairs.

As to the idea of a risk “window” – it’s already part of the FDA lexicon (see the January 2004 draft guidance on alternative presentations of the brief summary).

For more on that topic (as well as the variable nature of consumer comprehension and alternate solutions) see this paper from the Drug Information Journal.

In otherwords,  the drug is safe and effective as prescribed for the vast majority of patients but since we never know if everyone who gets it will learn about their risk of heart disease we should take the medicine off the market. 

Is it possible that the NEJM thinks doctors who are prescribing Meridia are too stupid or uninterested in potential medical malpractice suits to determine if someone might be at risk?  I don’t think so.  If every medicine that carries a CV risk was yanked from the market for that reason, you would have to take hundreds of drugs out of commission, including every pain killer.      The editorial's authors also assert that "the heart risk associated with Meridia is not justified by the weight loss seen in the study -- about 9.5 pounds (or 4.5 percent of initial body weight) after one year, on average," CNN /Health.com (9/2, Harding) reports.

And of course Steve Nissen has an informed judgment on the issue..

Steve Nissen, MD, "a cardiologist at the Cleveland Clinic Foundation who has been a vocal critic of recent FDA handling of drug safety concerns, agrees," according to Time (9/2, Park). "We've got a drug here that shows little benefit -- a few pounds of weight loss -- and we trade that for a 28% increased risk of heart attack and 36% increased risk of stroke."

Actually the study concluded: "nonfatal heart attacks occurred in 4.1% of sibutramine users and 3.2% of the placebo group, and nonfatal strokes occurred in 2.6% of sibutramine users and 1.9% of the placebo group,"  

That’s actually a relative risk of 22 percent and 27 percent – or increase in risk of about 1 in 100000 --  but who’s counting? 

 http://www.diahome.org/DIAHome/Home.aspx

When you come up with a conglomerate of conclusions that suggest testing is not necessary for different reasons and medicines it would make sense to suggest that you might want to do testing to get it right.   But all studies conclude that genetic testing is not necessary in most cases. 

Let’s take a look at the NEJM article that compared bleeding events in patients treated with  warfarin vs placebo to see why that might not be the best clinical approach:

“Results are presented only for patients of European or Latin American ancestry. Patients with other ancestries were excluded because of small numbers (99 patients in the next largest group) and concern about the potential for population stratification.” 

“Only 18.0% of patients in the CURE population included in our study underwent PCI, and only 14.5% underwent PCI with placement of a stent, as compared with more than 70% in previous studies.”

So the study --  truly a one size fits all approach – excludes African Americans and people undergoing PCI

Further:

"Carriers had a more pronounced reduction in cardiovascular events with clopidogrel treatment as compared with placebo than did noncarriers (hazard ratio with clopidogrel among carriers, 0.55; 95% CI, 0.42 to 0.73; hazard ratio among noncarriers, 0.85; 95% CI, 0.68 to 1.05; P=0.02 for the interaction). A similar interaction was observed with respect to the second composite primary outcome (hazard ratio with clopidogrel among carriers, 0.66; 95% CI, 0.54 to 0.82; hazard ratio among noncarriers, 0.90; 95% CI, 0.76 to 1.06; P=0.03 for heterogeneity)."

Isn’t finding out who  benefits more a good reason for testing?   Eric Topol thinks so:

“Genomics expert Dr Eric Topol (Scripps Research Institute, La Jolla, CA) told heartwire: "Both TRITON and PLATO reinforce the CYP2C19 story . . . that loss-of-function variants lead to diminished clinical impact for clopidogrel. PLATO takes this a step further to now show that the gain-of-function allele *17 is associated with more bleeding."

http://www.theheart.org/article/1114619.do

The rush towards headline grabbing instant analysis undermines a more systematic analysis in the Meridia and genetic testing issues and ignores the fact that RCT’s have limitations.

As another editorial noted with respect to gene testing:

“Besides genetic profiles, the evaluation of the best management should also take into account the clinical determinants of platelet reactivity—from age and sex to body-mass index, diabetes, and inflammation—that modulate platelet function, while also considering the timing from the acute event, she adds. "Prospective studies evaluating different antiplatelet treatments tailored according to the individual characteristics of patients are urgently needed to identify therapeutic strategies that will provide the best benefit for the single patient in this high-risk clinical setting."

Too bad CER funding is not available for such research.

Allergan has agreed to pay $600 million to settle charges that it illegally promoted and sold Botox through 2005 for unapproved uses like treating headaches.

In addition to the monetary fine, Allergan has agreed to a five-year corporate integrity agreement requiring the company to publish information about its payments to doctors.

The agreement also requires Allergan to drop its First Amendment lawsuit against the F.D.A., in which it had claimed free speech protections when giving doctors information about unapproved uses of Botox.

Whether or not DDMAC dodged a bullet on this one is debatable -- but the core issue is clear -- if it's off label you can't promote it. And calling off-label promotion "physician education" is just way too cute.

A new poll shows that public support for healthcare reform dropped sharply in August. 

The Kaiser Health Tracking Poll has support for the bill dropping 7 percentage points in August — down to 43 percent — while opposition rose 10 points to 45 percent.

Respondents listed healthcare as the third most important factor in deciding how they’ll vote this fall — behind the economy and “dissatisfaction with government.”

Forty-two percent of respondents said healthcare reform will play an “extremely important” role in their ballot-box decisions, on par with the 41 percent who said the same thing in June.

A series of insurance industry reforms, including a ban on lifetime or annual caps on insurance coverage and free preventive care on new insurance plans, have proved popular in polls, but the popularity of the overhaul on the whole hasn’t improved. Plus, opposition to other provisions — namely, the requirement that nearly all Americans buy insurance coverage — has increased. The so-called “individual mandate” was opposed by 70 percent of the Kaiser poll’s respondents.

I have to take slight exception to Peter.   I am afraid that while better post market data is needed to inform product development in  ways that accelerate the targeting of treatment and enrich clinical trials, the JANUS warehouse is not the place FDA should go shopping.  

First it is important to know what’s in JANUS and what is not:

“The JANUS warehouse was populated with sample synthesized human trial data related to two oncology studies. This data was furnished in standard STDM format and data load scripts were developed to import the data. A sample caCORE application was developed to demonstrate the analytical capabilities of such an application accessing the underlying JANUS repository. The application was modeled against SDTM domain views of the Janus warehouse instead of the warehouse schema itself to alleviate complexity and improve data access efficiency. The sample application was successful in that you could authenticate the users at signon using CSM authentication and then review the clinical trial data in the following ways:

• View patient enrollment by study
• View patient retention by study
• Efficacy reporting by study
• Safety reporting by study

Note the absence of genomic data.

To be sure, according to HHS, “there is a JANUS pharmacogenomics pilot study to identify gaps in the RIM and suggest further improvement for the import of genomics data into the database. “

But the FDA contract does not fund such research.  Moreover, HHS under the Obama Administration is interested in using personalized medicine to save money above other goals. 

“The molecularly informed comparative effectiveness research (NCI) was set up to determine whether molecular information can inform quality, efficacy and cost-effectiveness in health care…The MI-CER project also requires the integration of health care financial data to examine cost-effectiveness."

SO how does the PACES use of Janus fit into all this?

According the FDA solicitation: “The Contractor shall develop innovative clinical trial design strategies for prospective CER clinical trials and analyses of healthcare data including providing formal recommendations for best practices for submission of studies to the FDA when they involve product comparisons. These strategies and recommendations shall be documented in reports and manuscripts suitable for publication in scientific journals.”

·     Evaluate comparator groups, populations studied, study designs, endpoints, statistical analysis methods, and trial conduct.

·     Include an evaluation of the capability of each study to distinguish differences in effectiveness and safety among different populations, subpopulations and individuals.

·     Provide formal recommendations for best practices for submission of studies to the FDA when they involve product comparisons.  http://tinyurl.com/2fb4fng

 
While a long term goal of analyzing JANUS data is identify robust data standards to capture and exchange clinical genomic data, that goal is not addressed or funded. 

understood.”

Not understood?  Or does he mean not subject to the sort of one size fits all comparison of treatment A to treatment B that he would conduct as a consultant for reimbursement purposes?

Here’s more:

“Many patients, oncologists and other clinicians, payers and policy makers are dependent on these compendia, yet compendia often are viewed as being “too lenient” in terms of the quality of evidence required for compendia listing. Some studies have raised questions about the rigor and consistency of the compendium process. A 2006 analysis of 14 off-label indications concluded that current compendia “lack transparency, cite little current evidence, and lack a systematic method to review and update generated evidence.”

Let’s set aside the fact that the 2006 analysis was conducted by yet another member of the IOM/CER panel (Harold Sox) who is not an oncologist.  Does the fact that the decline in the rate of death and increase in five year survival rates for most cancers matter to Tunis?  Or how about the fact that by definition “off-label” use is based on clinical insights and forms the basis of common use and further research?  Or that research by Frank Lichtenberg shows about “one-fourth of the mortality decline in cancer is attributable to drug innovation, and 40% of the decline is attributable to (lagged) imaging innovation. ( Life expectancy at birth may have been increased by almost three months between 1996 and 2006 by the combined effects of cancer imaging and cancer drug innovation.)”

http://papers.ssrn.com/sol3/papers.cfm?abstract_id=1586687

Not at all. 

Does he really care about personalized medicine?

“Off-label oncology CERs should be designed to be generalizable in that they include sociodemographic diverse patient populations as well as patients with common comorbidities that exist among cancer patients and/or are positively or negatively associated with the use of oncology drug.”

http://www.cmtpnet.org/cmtp-research/Off_label_Overview.pdf

Generalizable.  Common.   But off-label use is treating the patient.  CER is used to make a generalization for purpose of coverage and reimbursement.   Tunis calls for prospective studies using clinical data to compare different drugs, not target treatment.  And he would use the JANUS data to advance his agenda. 

The current PACES project can be skewed to carry out such studies and has the potential to do so because of the lack of specific requirements to advance personalized medicine and integrate genomic analysis with clinical data.  

To give a large contract to an organization that has a vested interest in advancing it’s own approach to CER and has a bias towards using CER and consistently avoids establishing whether CER actually improves clinical outcomes.  Rather,  CER and Tunis focus on process and the creation of “Effectiveness Guidance Documents (EGDs)”  that would become the gold standard for CER research throughout the federal government and would include the FDA.

JANUS should be straightforward, not two-faced about personalized medicine.  Given the potential for bias and manipulation of the existing dataset, the FDA should impose additional requirements and different goals on contractors and itself.