Envisioning 2.0

For years, advocacy groups, physicians, public health officials and others have been crying out about the overuse of antibiotics and the growing threat of drug resistant bacteria. This month, their warnings are being heeded, but at great cost.

Today we learned that a 12-year-old boy died earlier this month from a drug-resistant bacterial infection, methicillin-resistant Staphylococcus aureus or MRSA.

In fact, drug-resistant bacteria has become a major problem in hospitals and nursing homes, where providers and patients exchange opportunistic bacteria. In the past, I’ve been involved with public health campaigns designed to bring home the message that appropriate antibiotic use is a must. This effort was a modest success. The sliver lining to this tragedy is that people are more aware of the dangers of antibiotic resistant bacteria and will take steps to protect themselves and their families.

To read more about this subject on this blog and elsewhere, please click the following links.

Antibiotics, Clinical Trials & More: An Interview With The FDA’s John Powers, MD

Questions and Answers about Methicillin-Resistant Staphylococcus aureus (MRSA) in Schools (CDC.gov)

Antibiotic Roundup: (Fighting drug-resistant bacteria, Michigan Antibiotic Resistance Reduction Coalition)

In 2002, the National Institutes of Health stopped a Women’s Health Initiative (WHI) study because it found that post-menopausal women taking hormones were at higher risk of a suffering from a heart attack. In 2004, another WHI study was halted because it indicated women taking estrogen had an increased risk of suffering from a stroke.

Today, the Wall Street Journal (subscription required) and other publications reported the results of a JAMA study that represents a giant flip-flop by government researchers. New data indicates that hormone replacement therapy is not as dangerous to the heart as earlier research indicated. What?!

Yes, now the Journal is reporting that “women who use hormones in the first five years after the arrival of menopause are not at increased heart risk.” Here’s the catch. While the study meets the normal test of statistical significance (p = .05), it does not satisfy a newer, more conservative standard set after the data was reviewed by JAMA.

According to the Journal: “At issue is something called the P value, an index that measures how strong the evidence really is. Traditionally a P value of 0.05 is acceptable, showing that there is only a 1-in-20 chance that the result isn’t real. That is the standard used in most WHI analyses. The analysis easily met this test of significance, coming in with a P value of 0.02. But once the paper started being reviewed, a decision was made to further lower the standard for statistical significance — to 0.01. ‘Both the internal reviews and the journal reviews drew attention to the need to be cautious and recommended this,’ Dr. Rossouw said. A more conservative approach was needed, he says, because the data had already been subjected to a number of statistical analyses, a process that statisticians agree increases the likelihood of a false positive.”

In this case, researchers were concerned that women could be at increased risk for coronary heart disease when the data indicated they weren’t (under the old standard). Under the new statistical test, they can now conclude that women taking hormones five years after menopause may still be at risk. However, scientists usually set the significance level at the beginning of a study. Changing it mid-stream is very, very unusual and increases the possibility of statistical error.

The ongoing debate about the WHI study illustrates why science is almost never an exact . . . science. Results of clinical trials should be interpreted and communicated with caution. However, because research is always ongoing, we can never be sure if we have the full story.

The Wall Street Journal (WSJ) reports this morning (subscription required) that the New England Journal of Medicine has corrected a study Merck published in the journal on Vioxx titled Approve.  In Merck’s original interpretation of the study, patients taking Vioxx only developed cardiovascular complications after taking the drug for 18 months.  Now a biostatistician hired by NEJM has concluded that patients’ cardiovascular risk could have increased before the 18-month period was up.  (Click here to view the correction.)

According to the WSJ:

“[K]ey results in the New England Journal of Medicine’s original publication of the study . . . were reached by a different statistical method than was described in the article, and that when the data were subjected to the stated method, the contention that risk increased only after 18 months didn’t hold up.”

Earlier this year, Merck admitted to the Food and Drug Administration (FDA) that it incorrectly described the statistical method it used to analyze Approve.

The Implications

Clearly, this correction will be a boon to plaintiffs seeking damages from cardiovascular events potentially caused by Vioxx.  What’s worse is that Merck will likely be accused of “gaming” the data to ensure a more favorable outcome for its embattled drug.  This may lead to calls for pharmaceutical companies to analyze and publish data using a variety of statistical methods to ensure that the results are consistent.

COX-2s Vs. High-Dose Advil

In separate news, the British Medical Journal published a meta-analysis of clinical trials indicating that high-dose Advil increases cardiovascular risk almost as much as COX-2 inhibitors like Vioxx.  Based on the results of this trial, the WSJ’s editorial board has asked the FDA to return Vioxx to the market.

An article by Barry Meier of the New York Times appeared today that provides intriguing details about how medical device maker Guidant responded to a crisis involving one of its products.

Last year, the company considered sending physicians a “Dear Doctor” letter highlighting safety concerns about two models of its implantable defibrillators. According to the Times “at least” seven patients died after the defibrillator failed to work because of an electrical defect. After an internal debate, Guidant decided not to send the letter.

Guidant commissioned an independent investigation of its actions relating to the defective defibrillators. The panel concluded that Guidant’s decision to continue allowing physicians to implant the devices while stopping production was “inconsistent.”

Guidant has admitted that it did not handle the situation appropriately. In a statement, Paul Donovan, a spokesman for Boston Scientific (which recently acquired Guidant), said that the company “understands” that it needs to communicate with patients and physicians in a more “timely and transparent fashion.”

The Decision: Weighing the Benefits Versus Drawbacks Of An Announcement

The Guidant issue highlights the fact that there are no simple answers when healthcare companies are trying to determine how best to address safety concerns relating to a product. In making its decision, Guidant appeared to be weighing three issues:

I - Consequences For Patients: Company documents reveal that Guidant was concerned that patients would have to undergo unnecessary surgeries to remove devices unnecessarily.

II - Financial Implications: The company estimated that it would cost $9 million to destroy its inventory of parts and completed devices.

III - The Technical Assessment: Guidant had its engineers assess the problem. They concluded that the number of deaths associated with the devices was likely low enough to justify continuing to sell them.

Guidant had to make a decision. Do the benefits of full disclosure outweigh the consequences of going public about safety concerns? How big is the problem? Is it significant enough to issue a recall?

The Aftermath: Guidant Facing Legal Scrutiny

An independent panel and the Food and Drug Administration have concluded that Guidant made the wrong decision. In addition, the Minneapolis US Attorney is investigating the company. Clearly, Guidant is facing severe consequences because of its decision.

My point is not to point fingers at Guidant. Rather, I’m interested in what the Times article reveals about the company’s decision-making process.

Dear readers: What do you think motivated Guidant’s decision? If you were providing communications counsel to Guidant what would you have recommended?

Barbara Martinez of the Wall Street Journal dives into the world of pharmacy benefit management (PBM) companies.  PBMs act as the “middle man” between patients and insurance companies, filling the prescriptions that physicians write.  Martinez’s article reveals how PBMs are making lots of money marking up the wholesale price of generic medications.

(Via Fierce Healthcare)

I thought I’d mention that I’ve written an essay on the value of healthcare blogs on HealthCareVox (my other blog).  Click here to read it.

A female African American physician talks about patients’ (Black, White Asian) reaction to her.  A common question is: “Are you a doctor?”

Check out this article from the current edition of Newsweek for more.

(Via Kevin, MD)

Race-based medicine, or the practice of treating people differently based on their racial and ethnic background, has long been a subject of interest to healthcare providers, public health practitioners, communicators and others. Now, with the introduction of Bi-Dil, the first medication approved for the treatment of a condition in a specific race (African Americans), the topic is once again gaining increased attention.

Given the intense interest in this subject, I have decided to conduct a series of periodic interviews with physicians, executives from medical societies, communications experts and others. Each interview subject provides his or her unique perspective on race-based medicine, which I then publish on this blog.

I invite all of you to comment on this issue. If you wish to be interviewed on this subject, please contact me. I can be reached at news at envisionsolutionsnow dot com.

Interview Subject: Sally Guttmacher, PhD

About Dr. Guttmacher: Sally Guttmacher is Professor and Director of the Masters Program in Public Health at New York University. Public health concerns, particularly as they pertain to world health, are at the center of Guttmacher’s research. She has published extensively on the topics of health policy, the prevention of chronic and infectious diseases and the intersection between policy and public health. She has also spent extensive time in South Africa focusing on the HIV epidemic there.

Interview

Q: There has been a lot of discussion recently about race-based
medicine. What are the benefits and/or drawbacks to using race as a means of treating and grouping patients?

A: All humans are identical for about 75% of genetic factors and about 95% of the variation is within racial groups rather than between them. This does not preclude any biological difference between races, but it tells us that the differences are not so great. Therefore, to focus on race as a basis for medical intervention seems inappropriate at best. Much more of the health and disease differences that we see between groups of people are related to socioeconomic status, age, life style, culture, and gender. It would seem to me to be much more productive to base medicine on these factors rather than race.

Q: In your mind, is there a link between race and disease or is
there something else going on?

A: As I just mentioned, there are many other things going on that by far outweigh the difference in health and disease related to race. Almost all disease is class related. Racism in the United States has played a major part in keeping non-whites, especially African Americans or Latinos from moving up the social class ladder. Non-whites are more likely to remain in the lower class and thus are more likely to die at an earlier age than whites from class related disease such as asthma, diabetes, heart disease, cancer, stroke etc..

Q: Pharmaceutical companies, advocacy organizations and others
spend a lot of time and effort attempting to communicate to different groups about diseases that impact them. From what you’ve seen, are these efforts effective?

A: This depends upon how you want to measure effective. I do not believe that secondary prevention is the way to go to decrease the health status difference between whites and blacks in the USA. I think that it is far better to prevent people from getting disease than getting people to use drugs to manage chronic disease once they are afflicted.

Increased education leading to life style changes is the way to prevent disease. Decreasing poverty is a far more efficient way to decrease the burden of disease because living in poverty is frequently associated with poor eating habits, increased use of illicit substances and decreased opportunity for healthy activities.

On the whole, pharmaceutical companies are in the business of selling drugs and making a profit for shareholders. Certainly, they have through advertising managed to reach every group that has access to mass media. Viagra is a good example of this. Sometimes this has been too effective in the sense that many sexually active young men have become careless in their sexual encounters because they now see HIV/AIDS as a chronic disease which can be effectively managed through the use of drugs. I do not think that the problem is that the pharmaceutical companies have been unable to reach people, the problem is that many people in the US lack health insurance and are unable to afford the drugs that they need to have to treat their disease.

Q: What would you do to improve them?

A: I don’t think that the problem is communication. You can not watch TV without seeing drug related advertisements. There are some things that pharmaceutical companies can do to help folks once they have developed treatable chronic diseases. They can work to keep costs down, possibly by spending less money on advertising. They can stop raising prices by bringing “new” drugs on the market that are simply reformulated versions of old drugs in new packaging. They can refrain from creating new markets that don’t necessarily lead to better health. Sleeping pills are a good recent example of this problem. They are currently being aggressively promoted so that their use has skyrocketed.

I believe that pharmaceutical companies have an ethical obligation to see that the drugs that are needed by folks in underdeveloped parts of the world such as sub-Saharan Africa have access to the drugs for major infectious diseases such as HIV/AIDS, TB and Malaria. This means allowing countries to produce these drugs themselves if the companies are not willing to produce them at low cost.

Q: Are there any ethnic/racial groups that are currently being neglected or overlooked in health promotion efforts?

A: I am not aware of any ethnic groups that are being overlooked. Those groups that are being overlooked by the pharmaceutical companies are the ones that do not have the money to pay for drugs.

Q: Have you been following the Jackson Heart Study? If so, what are your thoughts on this effort?

A: I am aware of the study and it certainly looks interesting and I would support such work. But as I have said above, there are many other factors such as class that are more clearly related to disease than race.

Q: Is there anything going on over seas around race-based medicine that disturbs or inspires you?

A: I am not really aware of any work in this area. I work in South Africa for part of each year and I do not know of anyone in South Africa who is focusing on race based medicine. As far as I know such a focus was abandoned when South Africa made the transition from Apartheid to Democracy.

Q: Can you provide any general commentary on this issue?

A: Definitions of race have changed over time and have often been developed uncritically (i.e. skin color). At the turn of the century national origin was thought of as race, i.e. Italians or Irish. The definition of African American has changed from African to Black to African American. Currently ‘ethnicity has been “racialized” to Latinos, Whites, blacks/African American. Certainly the biological meaning of race continues to be refuted by work in population genetics, anthropology and sociology. Do these current concepts of race add anything to our understanding of health and disease? Perhaps a more important question for us in the US is to develop an understanding of how racism contributes to ill health.

I will end my response to your questions with the following quote by Thomas LaVeist:

“Only when we move beyond race as a proxy and directly measure those concepts believed to be measured by race, will we make truly important advances in describing the true nature of racial variation in health. And, only then can we begin what is really the important work: eliminating disparities in health status.”

Many of you may be aware of the recent news coming out of last week’s FDA panel meeting on the heart risk associated with the use of stimulants like Ritalin for the treatment of ADHD. By a vote of 8 to 7, the panel supported placing strong “black box” warnings on labeling for the medications citing the heightened risk of sudden death for children and adults using the drugs. During the panel meeting, FDA officials noted that there were 25 sudden deaths among children and some adults taking the drug. According to the FDA analysis the stimulants might increase the risk of strokes and arrhythmias in children and adults.

Panel members voting for the black box warning said they did so to slow the sales of the stimulants. Dr. Steve Nissen, a member of the panel, said that he wants “to cause people’s hands to tremble a little bit before they write that prescription.” (Thanks to Medpundit for highlighting Nissen’s choice of words.)

With so much attention focused on the FDA, I wondered whether pharmaceutical companies and medical associations were saying anything about this issue. As it turns out, many pharmaceutical companies have been pretty mum.

Novartis, which manufactures Ritalin, simply said that it will cooperate fully with FDA efforts to measure the risk of cardiovascular events due to Ritalin. Johnson & Johnson, which makes Concerta, said the same thing.

Eli Lilly and Company, which makes the ADHD medication Strattera, appears to be in the clear. Strattera is not a stimulant and the panel excluded the medication from its recommendations.

Shire, which makes Adderall and Adderall XR, had the most to say about this issue. The company issued a statement on February 10 in which it asked for additional study before a black box warning is slapped on stimulants’ labels.

“Shire believes that the interests of physicians and patients would be better served by further study to determine whether there is, in fact, a relationship between these medicines and cardiovascular events. Obtaining this information is crucial prior to taking what would be an unprecedented action to include something in a black box that is not been supported by sufficient data.“

Shire also noted that Adderall and Adderall XR already have warnings on their labels regarding cardiovascular risk and abuse.

“Of note is the fact that our Adderall XR and Adderall already include a “black box warning” in their labels for safety concerns related to amphetamine abuse or misuse. The label also warns of the risk of sudden death in patients with structural cardiac abnormalities. We stand behind this labelling and believe that further action is unwarranted.”

Interestingly enough, one of the nation’s leading mental health advocacy organizations, the National Mental Health Association (NMHA) has not yet issued a statement on this issue. However, Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD) has urged parents and children not to be alarmed by the FDA panel’s decision and to continue taking ADHD medications. The group suggests that more study is needed.

Like industry, the American Academy of Child and Adolescent Psychiatry (AACAP) and the American Psychiatric Association (APA) have pledged to work with the FDA to determine the prevalence of adverse events relating to stimulant use.

“The AACAP and APA are committed to working with the FDA to determine the prevalence of rare, unexpected, and serious adverse events to better estimate risk for taking these medications. The Child and Adolescent Psychiatry Trial Network (CAPTN), sponsored by NIMH and AACAP, is a large simple trials network and is one avenue to study these issues. This practice network will provide protocol-driven, postmarking surveillance for youth treated with ADHD medications to track such low frequency adverse events prospectively.”

It will be interesting to see whether Eli Lilly tries to further position Strattera as a safer alternative to stimulants for children and adults with ADHD. If it does choose this strategy, the company might want to be very careful. In the days after Vioxx was removed from the market Pfizer touted the safety and efficacy of its cox-2 inhibitors Bextra and Celebrex. This turned out to be a premature move. Shortly after, Bextra was withdrawn from the market and Pfizer was asked to include a black box warning on Celebrex’s label.

With some critics of stimulant use suggesting that the cardiovascular risk associated with stimulant use is higher than that seen with Vioxx, expect this issue to escalate. It will be interesting to see how industry and patient advocacy organizations respond over time.

For those of you trying to learn more about the ever-growing healthcare blogosphere, you should know about and read Medscape’s Pre-Rounds (registration required). Pre-Rounds is a weekly column written by Nicholas Genes, MD, PhD a resident in emergency medicine at New York City’s Mount Sinai hospital. Each week Genes highlights the author of a well-known healthcare blog who has agreed to host that week’s Grand Rounds, a collection of posts from the healthcare blogosphere.

Various healthcare blog celebrities like Medpundit, Matthew Holt (The Healthcare Blog) and Derek Lowe (In the Pipeline) host the Grand Rounds each week. By reading Genes’ weekly column, you will learn more about the various people that inhabit and contribute to the healthcare blogosphere.

The first Grand Rounds appeared in September 2004. Since then, it has grown into a much-anticipated weekly event that healthcare bloggers ensure they note on their blogs — usually with this simple phrase: “Grand Rounds is up.” For those new to the healthcare blogosphere, this phrase doesn’t mean much. For the initiated, it means a heck of a lot.

Sample this week’s Grand Rounds at Science and Politics.

Intueri will be the site of next week’s Grand Rounds (2/14/06).

To keep track of each week’s Grand Rounds schedule, please visit Genes’ blog.