Censorship causes Blindness: A Valuable Public Servant has been Silenced

I was shocked to learn that one of my favorite cyberfriends, René Najera, aka “EpiRen,” has received a gag order, prohibiting him from tweeting or blogging about public health issues, after a complaint by an aggressive anti-vax tweeter, “cigaRhett,” Rhett Daniels. I won’t rehash the whole unfortunate drama, as the back story is well-described by Liz Ditz, with many subsequent flavorful comments.

I did, however, want to call my reader’s attention to this, particularly since there is currently a heated debate about the value of anonymity on-line. EpiRen’s harassment is a perfect example of the benefits of anonymity—more poignant since he blogged under his own name. Ren was careful to “clarify that none of the views presented in this blog (or anywhere else, really) represent the views of any of Ren's employers. Got it? Good.” Yet cigaRhett complained to Ren’s superiors, prompting them to threaten his continued employment.

It makes me feel ill that Rene has been bullied into silence. Maybe it’s sort of PTSD from similar past events in Cumberland. As I posted in Liz Ditz’s comments, Ren’s Epi Night School has taught me more about epidemiology than anything I learned either in med school or during my Infectious Diseases fellowship. He has a fine gift as a teacher, and the rare talent of being able to explain difficult topics in an engaging manner. The Daily Ren is a valuable news source and helps me keep up to date in my practice. EpiRen’s tweets are similarly an ongoing, real-time source of public health information, and he curates information from multiple sites I would otherwise overlook. Ren writes with humor and with passion about public health. He has been an ardent proponent of vaccinations. I have grown to find a sense of community as he and I and the #HandHygeine Team joust with the #pathogenposse. From my perspective, EpiRen and “The Germ Guy,” JATetro are the lynchpins of my staying current on public health, and this team is much more engaging than just reading CDC or CIDRAP reports.

Yesterday, the new EpiRen posted,

“Last day to print out or cache your favorite posts of the Epi Times. It goes down permanently at midnight tonight.”

As of last night, EpiRen has closed his sites. What a shame.

The response from Ren’s cyberfriends has been heartwarming, and perhaps good will come of this travesty:
anarchic_teapot provided further background perspective with Malevolent stupidity never sleeps.

The Skeptical Lawyer has joined the fray with an excellent post, “Lessons from EpiRen: do public employees have free speech rights?

PZ Myers, “Pharyngula,” has characterized cigaRhett’s posts as those of a litigious bully, who now, having been confronted, is attempting to erase his tracks on the internet. But the best characterization of the bullying behavior comes from Rhett Daniels' own threatening words.

A seasoned veteran of similar wars, Orac, has written about the consequences of blogging under one's own name. This is a timely issue, given the move by Google+ and ScienceBlogs to prohibit anonymity.Before “#Epigate” happened, the need for anonymity was carefully explained by Skepchick in her post, Does Google+ hate women? I highly recommend her article for valuable perspective.

My initial reaction to the breaking news was to want to enlist William Raillant-Clark and Kyle VanderBeek to help, given their recent success with getting internet troll David Mabus’ violent threats to scientists and atheists to be taken seriously by Montreal police. But EpiRen asked to not have a large internet outpouring to his employers and discouraged action.

I’ve been heartened by the support for EpiRen and free speech. I hope that EpiRen’s employers take to heart Skeptical Lawyer’s comments about transparency. And I would tell them that René Najera’s posts as EpiRen are not just frivolous social banter. EpiRen provides important, real-time news and an outstanding tutorial series on epidemiology.

As I was rereading the Epi Times last night, I noted an apt quote. To paraphrase Cesar Chavez, “Let us remember those who have been silenced by injustice; For they have given us life.

How I Spent My Summer Vacation…or Adventures Teaching Undergrads in India

As my Twitter followers know, I just returned from an eye-opening trip to India, where I was part of a faculty team for U Maryland undergrads. I was too busy and exhausted prepping, teaching, and studying there to blog, but want to relive and share some of this trip via my tweets, photos, and jotted notes of impressions.

Prelude…or why am I doing this?

When daughter, Heather, was 15, she persuaded me to take herand my son on a volunteer trip to India. It was transformative for all of us, fueling my interest in tropical infectious diseases and social justice issues, as well as my kids’ later career interests.

Heather has continued her interest in global and public health, and is now pursuing an MPH at U MD. As part of her work there, she put together this comprehensive summer program for undergrads, “Summer India: Global Health & Development,” and I was drafted as one of the faculty members, appointed “Visiting Senior Research Scientist” at the university, given my background in Infectious Diseases and clinical research, and that I had previously been to India. The other faculty were Mili Duggal, a PhD candidate and wonderfully down to earth, kind person, and Lis Maring (who was not able to join us until later into the trip), faculty in Family Life Sciences at U MD, and who has worked and taught in Varanasi, India.

The trip was logistically quite complex for a number of reasons. In addition to the didactic coursework—Heather put together an amazing syllabus—there were experiential and research components. The students were divided into three groups and rotated each week: observing at Lady Willingdon Hospital in Manali, joining village health care workers in assessing children’s health, or spending time at a rural health clinic in Jibhi, 3-4 hours from Manali. The final week was devoted to each student working on a research project of their choosing.

I helped arrange the research component, working with Dr. Philip Alexander, the director of the LWH, and Jayanth Devasundaram, an epidemiologist I recently met here in the states. Dr. Philip had asked for help in addressing their problem with tuberculosis, with many patients with drug-resistant (MDR) TB. We had only a sketchy plan before we left the states, and modified our approach as we went along, based on conditions we encountered there.

We set off!

The trip started a bit tenuously. I didn’t even get my visa until the day before, when my brother, aka St. George, was kind enough to wrest it out of Travisa’s clutches and deliver it to Mili.

I met the kids at BWI and was initially struck by their enthusiasim, and how YOUNG they all appeared, feeling OMG, what am I getting into? They were remarkably good sports on the trip though, which included the long flight, followed by a 9 hr wait in the Delhi airport, then a puddle-jumper to Kullu, which flew through a beautiful valley at the base of the Himalayas. We had to wait for some time in Kullu for Sunny and Heather to meet us—I guess there were more sheep blocking the road than they had counted on. (Sunny is a wonderful young man we met in Dharamsala 7 years ago, and he handled the logistics on the ground for all of us. We could never have done this trip without his guidance). But Sunny had a friend, Srita, who worked for Kingfisher and who was kind enough to ply us with chai while we waited.

There is a “taxi mafia” at the airport, and transportation has to be made using their services. Four taxis and a hair-raising 2 hour drive later, we arrived in Manali and settled in for the duration...(to be continued)

FDA Clears First Test To Quickly Distinguish MRSA And MSSA

There is good news today from the medical device section of the FDA, with the approval of the first test to quickly distinguish MRSA from MSSA (HT @EyeOnFDA). This new test, the KeyPath MRSA/MSSA Blood Culture Test, is said to differentiate between the two in about five hours after growth is detected in blood cultures.

So how much difference will this make in patient care and the MRSA epidemic? I suspect not much…

First, the test detects MRSA in blood cultures. While handy, most patients with MRSA do not have blood stream infections. Instead, they are colonized (just have it happily coexisting with them) or infected in wounds, sputum or, less commonly, in urine. Many people simply carry Staph, including MRSA, in their noses. This asymptomatic carriage and shedding of MRSA is what leads to outbreaks, and why many hospitals now screen high-risk patient admissions for the organism, or isolate such patients presumptively. So this test is unlikely to lead to much change in isolation practices. It might be quite useful, however, if it can rapidly detect MRSA in wounds.

If someone is seriously ill, most physicians will now empirically treat for MRSA, along with giving other broad-spectrum antibiotics, since the mortality of septic patients is quite high. Generally, after 24-48 hours, when culture results are initially available, an attempt is often made to narrow the spectrum to use more specific drugs. This reduces side effects and emerging antibiotic resistance.

Where the KeyPath MRSA/MSSA test reportedly has significant value is in its ability to do rapid susceptibility testing, important because there are major differences between many of the “community-acquired” MRSA and “hospital-acquired” strains. They report using a “Bacteriophage Amplification Technology,” which is well described by Drew Smith.

I will likely find this test of some use, as it will guide my therapy and lead me to narrow the spectrum of antibiotics I am prescribing up to a day earlier. I am a narrow-spectrum antibiotic kind of Infectious Disease physician. Some of my colleagues, whether because of their training or by having been burnt by experiences, tend to use very broad-spectrum drugs. This is especially likely to occur with more severely ill patients—even if there are no positive cultures—both because of genuine concern and because of fears of malpractice suits.

I don’t believe having this test will dramatically change practicing patterns, however. There is ample evidence that physicians don’t change their prescribing habits in response to data. In one widely cited study, 47% of docs made changes in response to susceptibility test results, but “but only 50% of the changes were considered appropriate.” In contrast, Berild, et. al. found 88% of their docs adjusted antibiotics, resulting in narrow spectrum use in 80% and a 23% cost savings. The findings of this 2006 Norwegian study were much more positive than others I have seen reported, or seen in my practice.

But the other factor arguing against this new rapid diagnostic test’s having great impact is the psychological need of the doc—a need that often seems to overcome reason. If a patient is better, many are loathe to change course—just in case, or “not wanting to argue with success.” Magical thinking, perhaps?

I can certainly see many uses for this new Bacteriophage Amplification Technique for antibiotic susceptibility testing. We can use all the help we can get in the fight against antibiotic resistance, and rapid diagnostics would be a big help. What kind of impact do you think this new KeyPath MRSA/MSSA test will have?

#ahcj11 Report: Food Safety, or Lack Thereof?

I was reminded last week of the Tom Lehrer admonition, “just don’t drink the water and don’t breathe the air.” That lead to the other Lehrer song, “Who’s next?”

In this week’s episode, the doom and gloom comes from food safety, brought to you by #ahcj11. The first panelist, Michael Taylor, deputy commissioner for food, Food and Drug Administration, set the stage, explaining the magnitude of the problem. The U.S. has 12 million shipments imported from150 countries. He explained that the FDA's role is to set standards to ensure accountability for both domestic and international products, but he placed the primary responsibility for ensuring safety squarely on industry. Unfortunately, the FDA’s efforts to improve safety standards are being stymied by budget cuts, as well as politics and the bizarre fragmentation of responsibilities.

Scott Faber, J.D., vice president, federal affairs, Grocery Manufacturers Association, countered that the new Food Safety bill provides some increased protection for consumers—for example, by giving the FDA access to industry records as well as the authority to require 3^rd party auditors. The bill also gives the FDA the power to issue mandatory recalls.

Erik D. Olson, director, Food and Consumer Product Safety Programs, The Pew Charitable Trusts, stole the show, however, with his clear outline of the problems and the mixed improvements coming via Food Safety Bill:

1. Inspections now only occur ~every 10 years. The frequency is to increase to every 3 years. (This seems unlikely to occur, given the budget cuts, and still leaves huge gaps).
2. Appallingly, the FDA has not previously had the authority to issue mandatory recalls.
3. 80% of our seafood is imported. While the FDA was only checking 1% of imports, they only now are being given authority to block imports at the border.
4. There is no requirement that industry test their products for contaminants; this is still a gap despite the new bill.
5. Historically, the FDA has been almost entirely reactive. Under the Food Safety Bill, the focus will be prevention based.
6. U.S. food legislation has changed little since 1906, when it was revised after Upton Sinclair’s “The Jungle” exposed the unsanitary meat packing industry; there was a small update—most recently—in 1938.
7. Why change? There are ~48 million foodborne illnesses in U.S. per year—about 1 per 6 people, with 127,000 hospitalizations and 3,000 deaths.
8. FDA previously was not able to see any internal industry records; now they can.
9. There have been no rules regarding produce safety—e.g., water quality or contamination by manure. Proposals to address this will now be required in 2012 (but who knows how long industry will have to implement changes after that).
10. The FDA will still not have any enforcement of penalties without going to court. (and look at BP’s penalties—tax breaks and bonuses to execs).

Similarly, schools have somehow seemed oblivious to many recalls, and not complied, per GAO reports.

Taylor, the FDA deputy commissioner for food, spoke positively of Administration support for food safety in the budget; unfortunately, some in Congress—you can guess who—want to unimplement the Food Safety bill.

There are still many logistical hurdles to be overcome including better ability (let alone, authority) to conduct tracebacks. They are cumbersome and time-consuming, but have worked for items with one ingredient, like produce or meat. But there is no good system for tracking products with multiple ingredients. This is giving more impetus for food manufacturers to work with the FDA more cooperatively, a risk sharing arrangement.

One of the most shocking things I learned—there is huge hole in the system—meat and poultry are regulated by the USDA, not the FDA, and therefore are not included in improvements in the Food Safety bill. How irrational is that?

And 60% of produce and 80% of seafood is imported, with little oversight.

I’ve always enjoyed the CDC outbreak investigation reports and marveled at the ability to do tracebacks. Given the magnitude of the problem, their success is even more amazing.

I’ve reassured myself somewhat about food safety from the early polio studies, that showed that children from more affluent families were disproportionately affected.

Unlike many other illnesses, David M. Oshinsky notes “in the past, polio had been a disease of cleanliness.” Poor kids, from less sanitary environments, actually fared better, presumably from having built up some immunity.

(Photo by Judy Stone; Luang Prabang, Laos--suggest you enlarge)

So, while the Food Safety bill offers some hope, there are still huge gaps, especially with such a fragmented system. What’s a mother to do? I guess I’ve gotten much more fatalistic. Try to eat organically, at least where the most pesticide-laden crops are concerned. If you can, support local farmers who don’t use antibiotics or hormones, and who support free-range animals. Otherwise, if you think it will help, pray or lobby, whichever suits your beliefs, or assume an ostrich-like stance.

#ahcj11

This past week I attended my first conference of the Association of Health Care Journalists, aka #ahcj11. I was initially drawn to the meeting by seeing that some of my favorite bloggers—Maryn McKenna, Pharmalot, Scott Hensley—were moderating panels. The conference far exceeded my expectations. While neither my fingers nor my mind have the agility to live tweet, here were some of the highlights for me:

Workshop: Mapping and charting health in your area

Introduced me to neat mapping that can be done with Google’s Fusion Tables. I’m a visual person, so love the ability to display reams of data visually, such as global patterns in TB. Later, I was also impressed by esri’s GIS mapping capabilities.

Workshop: What are your criteria in reporting on health care research?

This session, on critically reviewing stories, was excellent. Th-e session and the accompanying book, “Covering Medical Research,” taught more about how to evaluate articles than I received throughout my medical training, sadly enough. Gary Schwitzer’s Health News Review uses this approach, and is a valuable resource. Schwitzer’s point about differentiating stenography from journalism is broadly applicable and well taken.

Later sessions included a briefing by Donald Berwick, an overview of nanotechnology in cancer, and Francis Collins’ perspective on NIH research. Given my own clinical research background, I found the talks on problems in drug development, detecting fraud in medical research, and James Wilson’s lessons from gene therapy trials (Jesse Gelsinger) gave valuable perspectives.

Overall, the knowledge of many of the speakers and of the journalist questioners was impressive, with many perceptive, pointed questions being addressed to the panelists.

I even felt comfortable enough with the group to raise questions of my own.

One of the most provocative sessions was that on food safety. I’ll have more on that in my next post.

Photo courtesy Pia Christensen, ahcj

Like horror flicks? Read this…

I used to worry about MRSA…then I started seeing multi-resistant Gram negative bacteria in the hospital, like the carbapenem resistant (KPC) Acinetobacter I mentioned in my last post, usually infecting nursing home or chronic ventilator patients. That pales in comparison to the impending wave of infections caused by bacteria carrying the NDM-1 gene. NDM-1 stands for New Delhi Mettalo-beta-lactamase, an enzyme that chews up the “beta-lactam” ring, which is the backbone of many antibiotics, rendering them useless. NDM-1 was first described in a patient from India in 2008. Last year, a cluster of cases was described in 180 patient isolates. A common denominator was that most of the patients had received medical care in India or Pakistan.

As I’m preparing to go to India with a group of students next month who want to study public health, I was particularly struck by this week’s unsurprising news that the NDM-1 carrying bacteria had been identified in Delhi tap water and in standing water in the city—I said unsurprising, having seen some of the lack of sanitation first-hand.

What makes NDM-1 scarier than other recent superbugs is its ability to transfer its genetic material more readily. Part is because the transmission occurs via plasmids, small extra-chromosomal bits of DNA. Another part is that the transmission between bacteria can occur at water temperature, facilitating the spread in sewage-contaminated water. India also has a high rate of people without access to good sanitation or clean water, diarrheal disease, and access to over-the-counter antibiotics, all of which serve as enhanced breeding grounds for transfer. Even worse, the NDM-1 resistance gene is able to transfer to common bacterial pathogens there, such as cholera, typhoid, and the ubiquitous E. coli.

On my first trip to India, as the train approached the station in Delhi, I was rather shocked to see men lined up along the river like this:

Now take a look at this graph of antibiotic drug development from IDSA, to commemorate World Health Day:

Scary, isn't it?

Until CA-MRSA (community acquired MRSA), superbugs were fairly predictably associated with ill people and healthcare associated infections.

But now, this NDM-1 has now been isolated throughout the environment in one of the world’s most densely populated cities...and will soon spread globally.

Add to that the way antibiotics are squandered, irresponsible detailing by pharma and misuse by agribusiness…and you understand the insomnia...

A minor hope—may the student’s trip remain academic, and not become an experiential study.

(photo from drmuir.wordpress.com)

Superbugs and Seasons

Besides MRSA, other superbugs are now vying for our attention. A few months ago, NDM-1, from India, was creating a furor. A new article, by Maryn McKenna, focuses attention on Carbapenem resistance in Klebsiella pneumonia and clearly outlines how this form of resistance occurs. But there is one element fueling this growing problem of resistance that is not often touched upon—that of the public’s unreasonable expectations about care.

For example, I saw another patient last month who was minimally responsive, with little likelihood of recovery. This patient was colonized with a carbapenem resistant Acinetobacter baumanii which, like the KPC, was susceptible only to colistin, a highly toxic antibiotic. Years ago, when I started practice, families understood when doctors said, “Nothing can be done.” Patients were allowed to die in peace, with the emphasis being on comfort. Now, many families appear to believe in the immortality of their loved one and want “everything” done—no matter the cost in money, pain for the patient, or the danger to others. In the current U.S. environment, families have a sort of magical thinking in the ability of technology to prolong life, and an inability to accept death as a part of life. This leads to their demands for care beyond what seems reasonable for both the patient and from a public health perspective. And all of this is fueled by conservative religious groups. These demands—based on wishfulness—contribute to the increasing bacterial resistance to antibiotics, which in turn is putting the viable segment of our population at risk for unnecessary death from multi-resistant bacteria.

While some might be shocked at the idea of “rationing” antibiotics, or feel that we might head down a slippery slope to euthanasia, I would suggest that consideration be given to the public health aspects of squandering antibiotics on what is widely agreed to be futile care. Is it reasonable to continue antibiotic treatment of such end-stage patients, who have no likelihood of recovery, knowing that they are a breeding ground for multi-resistant organisms that threaten the community? How else might this be addressed? Keep in mind that there are almost no antibiotics in development; many pharmaceutical companies, such as Pfizer, have forsaken antibiotic research as not being adequately profitable. After all, who needs antibiotics when you can have Latisse or Viagra?

Drugs in Search of a Disease

The conclusion in the NY Times op-ed today, “Better Drug Ads, Fewer Side Effects,” raised my hackles a bit. Ian Spatz raises the innocent and  reasonable sounding idea of “legislation that would allow drug companies to cooperate with one another, and with physician and patient organizations, to develop joint ad campaigns that are specific to certain diseases and conditions but not to any particular drug.” While this may be an improvement over the current plethora of erectile dysfunction drug ads, the proposal skirts an important issue.

Spatz optimistically concludes, “Instead, we’d get unbiased information about the medical conditions we care about, and encouragement to seek out the medicines and vaccines that can help us maintain and improve our health.”

Two problems are immediately evident. The first is that the emphasis remains on medicines. While I certainly value drug therapies, we would have a far healthier population if there were a more holistic approach and emphasis on nutrition, exercise, preventive care, and personal responsibility. Instead, patients are encouraged to seek instant gratification for any minor complaint, rather than taking any—let alone difficult—steps to alter their behavior or be an active, responsible participant in their well-being.

Secondly, this fuels disease mongering and the idea of some new drugs being in search of a disease. A fine example of this was the NPR story, "How A Bone Disease Grew To Fit The Prescription," which vividly described osteopenia having been created as a new disease. Not only was there a new need for a drug, but an entire industry rose up around special new x-ray machines, called densitometers, to diagnose osteopenia, and repeated diagnostic tests to monitor therapy. Then the “Bone Measurement Institute”, created by Merck, successfully lobbied Congress to pass the Bone Mass Measurement Act, which required Medicare to cover the costs of the scans. This biography of osteopenia and its multi-billion dollar industry is a must-read. It also makes me wary of the claim that this new model of patient education won’t just be a repeat of the same successful—for pharma—approach.

Note: Clinical research has shown that drugs for osteoporosis are effective are valuable and may be life-saving. Drugs for early osteopenia have not shown such benefit, and have many serious side effects).

This innocent sounding proposal to educate patients about diseases is promising—but only if it is not instead twisted into a tool to create new diseases and lucrative drugs.

Being open to opportunities

A few days ago I had the pleasure of attending Bill Tobia’s class on New Drug Development at Northeastern University. Bill was a cyberfriend I met a few years ago after he had contacted me about my textbook, "Conducting Clinical Research." When it came time to develop topics for the 2^nd edition, he generously shared useful suggestions. So when I went to Boston last week, I e-mailed Bill and asked if he had time for a cup of tea. Instead, he invited me to speak to his class about a smorgasbord of topics, including globalization of clinical trials, career opportunities for these regulatory affairs students, and my favorite—ethics of clinical research.

While being a guest speaker was fun, it was fascinating to watch Bill weave seemingly disparate topics into a practical framework for these international students to use later in their careers—including our chance meeting being an example of being open to possibilities, which we then tied into the career talk. I was impressed, too, with how he plans a research assignment for his students, and then links that to a brief presentation to their peers, an experience on their CV, and a useful talking point in future interviews. I received a valuable lesson that night from an excellent teacher. Thank you, Bill.

Back to—and from—the books

Some of you might have been wondering about my uncharacteristic silence since the 2^nd edition of my book was born. No—it’s not from post-partum depression. From June until Thanksgiving I have either been working caring for patients or been immersed in the ritual hazing known as preparing for the “Boards.” I am now coming back to my usual self and a more normal life. I have just taken the ABIM’s Infectious Diseases computer-graded subspecialty examination, yet won’t know the results for months. While recovering from this miserable rite of passage, I thought I would get back to commenting on recent notable events.

Two of my favorite pharma scandals to follow have been intermittently in the news. First is the ongoing saga of Pfizer’s Trovan trials, now of Wikileaks fame. Guess apologies are due for my previous guarded defense of Pfizer. Sorry…

Genzyme is often in my thoughts. Perhaps their story reminds me of karma. They were one of the darlings of biotechs. First, they had great respect, having developed life-saving drugs for orphan diseases, Gaucher’s, Fabry’s, and Pompe’s disease, each caused by in-born errors in metabolism.

Then the company’s avarice caught up with them, and they exploited their position as the sole provider of treatment, as I’ve written about here, both in the US and in Latin America, where courts have upheld the constitutional right of access to medication, regardless of the cost.

Last spring, Genzyme’s products were found to have viral contaminants and even bits of trash, prompting a shutdown of its plant and rationing of the life-saving drugs. This has led to the FDA’s issuing a costly consent decree and fast-tracking a rival’s drug. The rationing has gone on for 18 months (for Fabrazyme) and no end is in sight.

Genzyme has also been the target of a takeover bid from Sanofi Aventis in recent months.

So, patients petitioned the NIH and DHHS to override Genzyme’s patent exclusivity, given that the NIH funded the research at Mt. Sinai, which then licensed Fabrazyme only to Genzyme. Last week, NIH turned down this appeal for licensing rights.

Given that patients have no other source of vitally needed medicines, that the drug development was funded by the public, and that Genzyme has not been a good steward of its patent monopoly, do you think pro-business laws like the Bayh-Dole act should be reconsidered? Should NIH now reject patent exclusivity in favor of patient access? What do you think?

Birthing a New...Book!

Longer than the usual gestation, the 2^nd edition of Conducting Clinical Research just came into being. A bit overdue, the past 10 months have been an immersion of reading, research, and writing to bring you an expanded, revised, and fully updated edition.

CCR 2^nd shares the basic genetic makeup of its older sibling—a pragmatic, step-by-step, how-to manual for both experienced medical professionals and newbies, and shares the dominant wry humor gene.

There are notable differences, with many updates including recent regulations affecting research, subject injury clauses, tips on surviving audits and legal landmines. New topics include the unique needs of device and vaccine trials, perspective on the globalization and outsourcing of clinical trials, cultural competency and health literacy—keys to understanding and succeeding with the changing dynamics of the industry.

My first-born was greeted with much critical acclaim:

"Successfully covers . . . clinical trials. Practical considerations, substantial background and resource information. The text is well written . . . fills an important need."

—Annals of Internal Medicine, April 2007

“5 Stars! (100 out of 100)… This is a must have for novice or experienced clinical researchers.”

Doody's Review: Expert Review 2007

Sibling rivalry portends even greater success for the new addition.

0 0 0

To find out more, click here for an excerpt, table of contents, and complete description.

Please share our joy with your friends.

The Rise of the Superbugs

0 0 0

This week has brought news of new superbugs--daptomycin-resistant VRE (Vancomycin-resistant Enterococcus) isolates and linezolid-resistant MRSA.

I've cared for patients this week with MRSA, VRE, and ESBL gram-negative rods resistant to almost every antibiotic.

Many factors fuel the rise in resistant organisms. Some that are not often addressed include inadequate education (e.g. that asymptomatic Foley catheter related cultures should not be treated);

fear of peer review or legal liability for not treating a culture;

the demands of family or religious groups that “everything be done” even when the patient is clearly terminal and the treatment is futile—and where the treatment of one such patient puts many others at unnecessary risk.

A excellent overview of some of the other issues can be found at the Center for Global Development’s drug resistance site.

As an Infectious Disease physician who has been involved in clinical research for new antibiotics as well as patient care, I am very familiar with the difficulties of bringing a new drug to market. In fact, I participated in early clinical trials for both Daptomycin and Linezolid. It angers and saddens me to see these valuable and critical resources squandered by irresponsible detailing and prescribing patterns and because of liability concerns. We need serious guidelines and restrictions on antibiotic use if we are not to soon enter the post-antibiotic era. There is no time to wait for new drugs to be developed.

Rare Diseases Day

Just a quick note to remind you today is Rare Diseases Day. A rare disease is one that affects less than 1 in 2000 people. Because of the infrequent occurrence, these diseases tend to be overlooked by many, including Pharma, as there is generally no financial incentive, as the potential market is so limited (Genzyme is an exception--see the previous posts about Gaucher's disease and orphan drugs).

You can learn more about this from the European Organisation for Rare Diseases, EURORDIS, an umbrella group of organizations addressing problems of specific rare diseases and encouraging research in these areas. Check it out. They have great information./a>

Clinical Trials of Obese Patients Lacking

There are huge numbers of markedly obese patients in the US. While I have seen little literature on this topic, I am acutely aware of in my own practice is the lack of data on treating the morbidly obese.
For example, a weight >300 pounds is a common exclusion on many clinical trials. The result is that there is little evidence-based medicine, and considerable problem knowing how to dose patients with a variety of medications. Little pharmacokinetic or pharmacodynamic information is available, and much of that is limited to healthy volunteers. Accurate physical examination is near impossible at times. Many patients are too obese to have diagnostic imaging studies, especially CAT scans or MRI scans, reducing us, it seems, to veterinary medicine. There are various recipes for drug dosing in obese patients—some based on ideal body weight (IBW), some on actual body weight, or some based on witchcraft (somewhere in the middle between IBW plus a percentage of the excess weight). The concern about the lack of evidence is particularly timely now, given that serious illness and deaths from Influenza A H1N1 are disproportionately affecting the obese. Some studies are proposed, as Oseltamivir Pharmacokinetics in Morbid Obesity (OPTIMO), but are just getting started (November 2009). Given the unfortunate change in patient demographics in the US and the epidemic of obesity here, clinical trials focusing on this population would be timely and most welcome.

Hurricane Katrina Revisited...and Likely Consequences

If it is hurricane season, you can count on someone dredging up the story of Dr. Anna Pou and her nurse colleagues, who had been been accused of homicide for the deaths of some patients under their care during Hurricane Katrina. The New Orleans D.A. asked a grand jury to indict them; the grand jury declined. This year's second guessing begins with a disappointing ProPublica/New York Times joint exposé that really adds nothing enlightening to the debate and neglects important considerations.

In the aftermath of Katrina, these devoted healthcare workers stayed to care for their patients as best they could, despite searing temperatures and extreme humidity, lack of supplies, exhaustion, and considerable risk to themselves. As part of their care, they prioritized allocating their limited resources. “Triage” --this process of allocation-- is a long-standing practice in medical care, and will be more visible when we are faced with the next disaster or epidemic. The concept of triage, which has it's roots in battlefield medicine, in it's simplest form involves sorting patients into three groups – those who are likely to survive with no medical care, those that are unlikely to survive given the level of care available at the site, and those that likely will survive if treated at the site. The limited care that is available is then provided first to the group that is deemed most likely to benefit from it, and only when that group has been treated, is it provided to the others. Dr. Pou and her colleagues were faced with a situation that was, in many ways, similar to a battlefield situation, in that their resources were extremely limited, to the point where they couldn't save everyone. Thus it seems that the most sensible thing for them to have done was to focus their efforts on those who were likely to survive, and do whatever they could to make those who were unlikely to survive as comfortable as possible in their remaining hours.

There are unintended consequences of the homicide accusations that were not addressed by this article. For example, many patients currently receive inadequate pain medications because of physicians' concern about criminal liability and accusations against them of crossing the line between comfort care and euthanasia. My elderly mother was one such victim, and I am still haunted by her death last year. After a number of admissions over a period of a year during which time her quality of life continued to decline, she had elected to be removed from a ventilator, knowing that she would die. The hospital's ICU physician did not explain to her or me that they were going to insist on a “breathing trial” rather than sedating her with morphine or other drugs before they removed the breathing support. After their trial failed, as expected, they began to titrate morphine intended to “keep her comfortable.” When, after hours of watching her twitch while waiting at her bedside for her to die, I called the doctor in and asked him to increase the morphine as she appeared aware and uncomfortable to me, he refused, saying that he did not want the appearance of having hastened her death. What if someone audited her chart? This, even though mom was 95, had a living will, had granted me medical power of attorney, and had requested being removed from life support and allowed to die in peace. While I would argue that any physician's first duty is to his patient, this physician chose to put himself first and my mother second. His behavior, allowing my mother to experience unnecessary pain for a period of several hours as she lay dying, was despicable and inexcusable... yet sadly still somewhat understandable given the justified fear medical professionals have of being second-guessed by “reviewers” after the fact.

Another pressing concern is health care workers' potential response to future disasters. We are currently faced with the influenza season approaching and the continued concerns about a severe “swine flu” epidemic. I am an Infectious Diseases physician and likely will be working long, hard hours should an influenza epidemic occur. This week, I received an e-mail from my state's medical association asking me to register as a volunteer in case of a bioterrorism or natural disaster emergency. I reflexively signed up. After all, I was raised to help others, and chose to enter a “helping' profession. Now, reminded of the persecution of this fine physician and two nurses, I feel ambivalent.

Dr. Daniel Sokol discussed the ethics of healthcare workers “duty of care” in responding to virulent epidemics. While no clear conclusion can be made, I appreciate Dr. Sokol’s discussing the multiple roles that physicians have that may be in conflict. For while a doctor has an obligation to patients, they also have:
“a duty to care for their own children by protecting them (and hence themselves) from infection. So a further problem with the duty to care, aside from its vagueness, is that it fails to consider the holder of the duty as a multiple agent belonging to a broader community. Doctors and other medical professionals, in such situations, play several incompatible roles—health care worker, spouse, parent, for example—and they must deal with them as best they can. The limits of the duty of care are thus also defined by the strengths of competing "rights and duties.”

Add to that burden of responsibility the possibility of criminal prosecution for triaging patients and allocating the scarce resources that are likely to be available, be it medication or access to ventilators and ICU care, and you can anticipate the most likely outcome.

The irresponsible charges brought against Dr. Pou and her colleagues will have a chilling effect on other health care workers in the future, who will be loathe to respond to disasters. First, there is the risk of malpractice for caring for patients outside our specialties or beyond our experience. Now there is the risk of the destruction of one's reputation and career, not to mention crippling legal defense bills and even prison from attacks from Monday morning quarterbacks.

Enough of the attacks from the protection of the sidelines. Their attackers are, in effect, tying to impose 21st Century legal, moral and ethical obligations on a staff that was forced to operate for several days under 16th Century conditions. Dr. Pou and her nurse colleagues should be hailed for their heroism and devotion to their patients.

Given the conditions that are likely to exist during the next emergency, be it a natural disaster, an epidemic or an attack – limited or no power, lack of equipment and supplies, shortage of staff and no relief staff – would you want to stay and help? Who will be willing to risk his or her career and incur thousands upon thousands of dollars in legal fees defending herself? Who will care for you during the next disaster or epidemic?

Let us put this entire story into perspective by recalling that the true guilty parties in the Katrina debacle were the incompetent and irresponsible officials—most notably Bush and his “Heck-of-a-job, Brownie” FEMA head who failed to protect New Orleans and then further betrayed it's citizens with falsehoods – and not the healthcare workers who devotedly stayed and provided the best care they could under almost unimaginable conditions.

Comparative Effectiveness Research-Rational Healthcare or Healthcare Rationing?

I've been reading about the comparative effectiveness research debate and found my understated quote of the week in the normally staid New England Journal: "Developers face few incentives to conduct active-comparator superiority trials and understand that they benefit from the unacknowledged deficiency of evidence. The development or marketing of me-too drugs and devices may provide a greater return on investment than research aimed at true clinical innovation."

For those who might not have been able to keep up, the focus on comparative effectiveness became more urgent, given soaring healthcare costs, enormous budget deficits, and the strained economy.

While traditional trials usually centered on establishing the efficacy of a drug or device compared to a placebo (a non-inferiority trial), the new focus is on comparing the effectiveness between available therapies. This research is a congressional mandate as part of the American Recovery and Reinvestment Act (ARRA) of 2009. The law provided that the Institute of Medicine (IOM) should make recommendations for national priorities for CER funding—which they did in remarkably short time.

Not surprisingly, the CER plan has come under attack by pharmaceutical companies, despite the assurance, for now, that the research will not be used to restrict physician prescribing choices based on cost-effectiveness data. Others are concerned that, rather than supporting rational healthcare decision-making, the CER initiative is the first step down the slippery slope towards healthcare rationing. An interesting proposal—intended to close the evidence gap and more directly benefit prescribers and consumers—is to have the FDA require comparative effectiveness labeling on their products, to make the benefits and risks of each product clearly evident.

While the two sides are not evenly matched, making the likely outcome predictable, barring an upset, it will be interesting to watch this debate evolve.

Genzyme's Business Model-You've Got to Read This!

An excellent, thought provoking article by Stephen Heuser, "One girl's hope, a nation's dilemma," appeared in the Boston Globe on June 14. Mr. Heuser details the appalling, rapacious approach Genzyme takes to marketing orphan drugs. A guest response, detailing some of the lesser known implications of Genzyme's predatory practices, follows:

"The Boston Globe article about Genzyme’s business tactics is quite alarming.
Nearly every country in Latin America has incorporat ed a legal guarantee to the "right to the highest attainable standard of health" (a.k.a. right to health) in their constitutions. This judicial language has been enforced in a number of countries.

The right to essential medicines is defined by WHO as “those that satisfy the priority health care needs of the population," with the caveat that they “are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality, and at a price the individual and the community can afford."

Recent court cases, particularly in Brazil (initially surrounding access to ARVs) have increasing granted the right to access to essential medicines in Latin America, insisting that the government provide the drugs, no matter the cost. In the past this has led to successful cost-lowering mechanisms which both made the drugs available and didn't run the health budget completely dry. For instance, Brazil put significant pressure on international pharmaceutical companies to lower the prices on anti-retrovirals by developing the pharmaceutical capacity to produce their own generic forms as well as fighting heavily in the World Trade Organization. They also focused attention on prevention efforts, as a way to curb the number of people who would eventually need the drugs.

However, the same leverage does not necessarily apply to a small country like Costa Rica. The pharmaceutical capacity is probably not there, and it is too small a population for market interest in many circumstances.

But this particualar case raises a interesting and less discussed issue--- are drugs for rare diseases considered essential medicines, and does the government have the responsibility to provide them to any affected citizens, no matter the cost? In some ways the problem is ultimately about the ability of the pharmaceutical country to charge any amount, unrelated to a reasonable assessment of the costs of production and a marginal profit.

The U.S. has dealt with the issue of rare diseases by creating special incentives for companies to develop drugs for these diseases, on the assumption that there will be no market for profits. This has been moderately successful.

But Genzyme, is breaking the rules (at least in a moral sense). They are using very dirty tactics and enormous resources to engage governments in a questionable manner. While the right to health is open to interpretation, I find it hard to justify such enormous expenditures for so few individuals. That being said, it is not inconceivable for the drug to be viewed as essential.

The problem really lies in the fact that the company is charging such an enormous price, with a huge profit margin, and very little threat of competition in the form of generics, and they stay below the public health activists radar to a great degree.

While pharmaceutical companies have the right to make a profit, just like any other corporation, they should not be allowed to intentionally drain the already strapped resources of the Ministries of Health of developing countries."

Heather Stone
Founder, President of G.A.A.P.E.:
Global Action Against Poverty Everywhere!
Smith College

International Clinical Trials Day

Tomorrow, May 20, is International Clinical Trials Day.

This annual event was established by the European Clinical Research Infrastructures Network, a group formed to help interconnect national networks of clinical research centers across the European Union and to help streamline multi-national studies.

ECRIN launched the International Clinical Trials Day in 2005 to educate the public about clinical trials and to further discussion amongst various interested parties, including clinicians, industry sponsors, ethics committees, regulatory agencies, and patients.

May 20th was selected as the appropriate date for this celebration in honor of James Lind who in 1747 conducted a six-way comparison of cider, elixir of vitriol, vinegar, sea water, oranges and lemons, and a purgative mixture of spices, garlic and mustard seeds on sailors suffering from scurvy. Each treatment group had 2 men. Within 6 days, the two men receiving citrus fruits were well--such a dramatic improvement compared to the other groups that it made the statistical analysis unnecessary. His descriptive treatise was published in 1753 and makes for interesting reading.

When less than 5% of patients with cancer participate in clinical trials, it is clear that a bit more outreach still needs to be done, to educate physicians and patients—and insurance companies, who often have archaic rules that preclude participation. The Public Library of Science (PLOS) is trying to do its part and launched its open access clinical trials journal, also on May 20th.

Some other efforts are not quite as supportive. It probably doesn’t help when a mascot is proposed, “Clint,” the clinical trials guinea pig …nor when a celebration includes discussion of heart-warming topics like “inspections.”

What would you suggest as an enticing celebratory event? How do you encourage participation in, and support of clinical trials?

AccessCR-a Great Source of Infomation

A few months ago I discovered AccessCR, an Australian company with expertise in clinical research. Janelle Bowden, PhD, AccessCR's Managing Director, has a wealth of experience in clinical research and an obvious passion for making research accessible to and more accepted by the public. She also aims to improve communication and partnership between all involved in the clinical research process, from patient to researcher to government to industry. Her website and newsletter reflect that and are a terrific source of frequently updated information.

I’ve been following Dr. Bowden’s site avidly for several months and recently had the pleasure of speaking with her about some of the problems confronting clinical trials both in the US and abroad. I look forward to exploring this with her more in the future.

I highly recommend the AccessCR site and newsletter for interesting updates on clinical trials. Check it out here!