For the last four years I have served in a volunteer capacity among a panel of pharmacotherapy experts queried regularly by the ABC News Medical Unit about breaking or upcoming news involving the efficacy and safety of drugs and supplements. Where appropriate, I provide background information that informs the story. My incentive is largely to put my time where my mouth is when I say that scientists need to take a more active role in making sure medical stories are reported accurately. An additional dividend is paid to my students who then benefit from my presentation of the science behind timely medical developments.

On occasion, perhaps once or twice a year, I’ll be asked for an on-camera interview. Even when this occurs, the resulting story will contain no more than 15 seconds of the interview and some summary by the reporter of other issues we discussed. I take this responsibility very seriously and prepare as much as I can given the deadlines of the press and my daily education and research schedule. But given airtime constraints, much of what I prepare would normally end up in the abyss of my files and come out in the classroom when I lecture about that particular topic. However, blogging now allows us to expand further on stories where we are consulted, giving us an opportunity to air, albeit to a smaller audience, the information we found important from our perspective. Authoring a blog, therefore, takes away the excuse some scientists and physicians have in not wanting to talk to the press: “There’s never enough airtime to tell the whole story the way I would tell it.”

This post was informed by one of those brief appearances, this time on ABC World News Sunday with Dan Harris. The interview was solicited last weekend following the release of information obtained during the execution of a search warrant in lodging occupied by the self-help guru, James Arthur Ray, who led an Arizona sweat lodge ceremony last October where three people ultimately died and almost two dozen were hospitalized. The segment was not archived to the World News website but some ABC affiliates subsequently aired truncated versions of the story.
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On October 8, 2009, paramedics responded to a 911 call at a mystical retreat being held at Angel Valley Spiritual Retreat Center in West Sedona, Arizona, a stunningly beautiful area known widely as a mecca for New Age enthusiasts. Eyewitness accounts compiled in this October 21 New York Times article describes what medics encountered upon arriving at a 415-square-foot “sweat lodge” on the center’s grounds:

Midway through a two-hour sweat lodge ceremony intended to be a rebirthing experience, participants say, some people began to fall desperately ill from the heat, even as their leader, James Arthur Ray, a nationally known New Age guru, urged them to press on.

“There were people throwing up everywhere,” said Dr. Beverley Bunn, 43, an orthodontist from Texas, who said she struggled to remain conscious in the sweat lodge, a makeshift structure covered with blankets and plastic and heated with fiery rocks.

Dr. Bunn said Mr. Ray told the more than 50 people jammed into the small structure — people who had just completed a 36-hour “vision quest” in which they fasted alone in the desert — that vomiting “was good for you, that you are purging what your body doesn’t want, what it doesn’t need.” But by the end of the ordeal on Oct. 8, emergency crews had taken 21 people to hospitals. Three have since died.

Participants paid $9,695 each to attend a “Spiritual Warrior” retreat led by Mr. Ray, an event whose next offering continues to be advertised on the website for James Ray International, Inc.

Yes, the 2010 event is still scheduled for September 18-23, 2010 and registration remains open.

But I wouldn’t put up my ten grand just yet because an investigation of Mr. Ray is ongoing and the Yavapati County Sheriff’s Office has recently released the affidavit from a search warrant executed shortly after this tragedy.

This December 30 New York Times article displays the 33-page search affidavit and this January 3 Prescott News article has several photographs and an excellent distillation of the affidavit.

Many other news sources will provide you with details on the circumstances of the tragedy with eyewitness reports and you can read elsewhere of Mr. Ray’s appearances on The Oprah Winfrey Show associated with the book, The Secret by Rhonda Byrne.

But here we would like to discuss some of the pharmacology associated with the Sedona tragedy. Lynne LaMaster in the Prescott News notes that according to the search warrant documents, investigators were originally looking for:

“A saleable/useable quantity of unlawful drugs including but not limited to marijuana, methamphetamine and peyote, paraphernalia for packaging, manicuring, weighing, distributing, including but not limited to scales, baggies, grinders, bindles, envelopes, seals paraphernalia used to administer the drug, i.e., syringes, cotton swabs, alcohol swabs, spoons, razor blades, tubes.”

While investigators did not appear to find any overtly psychoactive substances, they did find a veritable cornucopia of prescription drugs, dietary supplements, and syringes, with prescriptions in the name of Mr. Ray. But it wasn’t the supplements that caught my eye. It was this letter from a Michigan doctor of osteopathy:

Dr. Crisler operates the website, allthingsmale.com, and offers in-clinic and online consultations. The frontpage of his site argues strongly that he is in the business of anti-aging therapies as shown lecturing to the American Academy of Anti-Aging Medicine and offering subscriptions to Life Extension Magazine. Further exploration of his website reveals that he specializes further in assessment of low testosterone levels, or hypogonadism.

Testosterone cypionate, hGH, hCG, Arimidex (anastrozole) and finasteride (sold previously as Propecia or Proscar, but now available generically). OK, that’s starting to make sense. Testosterone and human growth hormone (hGH) are anabolic agents. That is, they enhance the development of lean, skeletal muscle mass. The larger cocktail is a typical bodybuilding/anti-aging regimen that is also purported to enhance sex drive. But you might have some questions at first glance.

(For pharmacology students and professors, dissecting the endocrine pharmacology of this combination would make a great comprehensive qualifying examination question for graduate candidacy.)

Arimidex/anastrozole? Isn’t that used to treat estrogen-dependent breast cancer?

Finasteride? Isn’t that used to treat prostate cancer?

Let’s take a closer look at some of these drugs.

Testosterone cypionate is known as a “depot” form of testosterone that has a half-life of 5-8 days, sold as DEPO®-Testosterone in the US. Testosterone, the steroid hormone primarily responsible for secondary sex characteristics in men, is not active when taken orally because it is rapidly metabolized by the liver. Therefore, if one wishes to boost testosterone, it is commonly formulated into a gel or patch that slowly releases the hormone across the skin. But it is more effectively delivered by injection, usually into muscle. When combined with a fat-soluble compound like cypionic acid, the testosterone is slowly released from the injection site. According to a PowerPoint presentation available at Dr. Crisler’s website (here, 4.5MB), his regimen employs weekly injections of 100 mg testosterone cypionate, about double the manufacturer’s recommendation for treating clinical hypogonadism.

When I was interviewed by Dan Harris for ABC World News Sunday last weekend, we discussed in footage that did not appear whether testosterone qualified as an “anabolic steroid.” The public normally thinks of ultrapotent, clandestine compounds as being the anabolic steroids used by athletes. But in purely pharmacological terms, testosterone is a steroid based on its chemical structure and it has anabolic, or tissue-building, activity. However, testosterone is an anabolic steroid that we make naturally, men and women.

Hence, testosterone is an endogenous anabolic steroid. When injected as testosterone cypionate, this would be called the exogenous supplementation of an endogenous steroid. But true bodybuilders wouldn’t bother with something like testosterone when more potent and effective synthetic anabolic steroids are available on the clandestine market.

Arimidex (anastrozole) is classified as an “aromatase inhibitor.” You may not know that testosterone is the starting material for estradiol, the steroid hormone primarily responsible for secondary sex characteristics in women. Testosterone, which we all make from cholesterol as the starting material, is converted to estrogen by aromatase or CYP19, an enzyme that is highly abundant in the ovaries. When a woman is diagnosed with a form of breast cancer that required estrogen to grow, aromatase inhibitors are given to prevent the ovaries from making more estrogen from testosterone (Older drugs such as tamoxifen can also be given as they directly block the effects of estrogen on breast cancer cells themselves.)

We do not know if Mr. Ray was among the approximately 1% of breast cancers that occur in men. Former drummer of the rock band KISS, Peter Criss, is the most recently public of male breast cancer patients in the US.

However, it does not appear that Dr. Crisler is a board-certified oncologist, so there must be some other reason that he prescribed Arimidex to Mr. Ray. Men have some testosterone that gets converted to estrogen but usually it’s not enough to cause estrogenic side effects such as gynecomastia and testicular shrinkage. But when taking supplemental, supraphysiological doses of testosterone, the small amount of aromatase that men have will convert enough of it to estradiol such that they may experience some feminizing effects.

Interestingly, Dr. Crisler notes on slide #66 of his aforementioned PowerPoint presentation that anastrozole’s #1 use worldwide is in testosterone replacement therapy regimens. Unfortunately, a citation is not available to support that statement.

Finasteride prevents conversion by 5-alpha-reductase of testosterone to dihydrotestosterone or DHT, a form of the hormone that can cause benign prostatic hypertrophy, can promote prostate cancer, and is also partly responsible for hair loss. Hence, finasteride combats several side effects of testosterone supplementation. So, these testosterone injections can be combined with anastrozole and finasteride to maximize testosterone’s anabolic effect while minimizing “unsightly” side effects.

Human growth hormone (hGH) is a peptide normally produced in the pituitary gland that is also anabolic on its own and augments the muscle-building effects of testosterone.

Human chorionic gonadotropin or hCG is normally the hormone produced by the placenta during pregnancy and is the hormone detected in the urine by home and clinical pregnancy tests. Yes, men taking this hormone would give a positive pregnancy test.

Understanding why hCG might be given in this cocktail requires that we revisit the hypothalamic-pituitary-gonadal axis (HPGA). Gonadotropin-releasing hormone, or GnRH, is produced in the hypothalamus of the brain and signals that pituitary gland to synthesize and release several peptide hormones that each share a common subunit: LH, FSH, TSH, and hCG. LH, or luteinizing hormone, when released from the pituitary gland and causes the testes to create mature spermatozoa and release testosterone. However, when too much testosterone is produced, or too much is available from external injection, a negative feedback loop suppresses LH secretion. Suppression of LH over time will cause testicular atrophy. It is thought that providing hCG will provide more of the subunit shared with LH, restoring LH levels. I am not convinced that this actually occurs. Restoring LH also is purported to increase the conversion of cholesterol to pregnenolone, a precursor or building block of testosterone. Believe it or not, this is an oversimplification of the pathway but I hope that gives you an idea of the rationale behind hCG use.

There were also some other drugs found in Ray’s room at the lodge prescribed by other physicians that included Diovan (valsartan), an antihypertensive of that competitively binds receptors for an endogenous vasocontrictor, angiotensin II, and an injectable relative of vitamin B12 called methylcobalamin. Although we don’t know for certain if Ray was taking the drugs prescribed by Dr. Crisler, investigators did at least find anastrozole and genotropin brand of hGH, Propecia brand of finasteride, together with pregnenolone, the testosterone precursor. Also found were bags, suitcases, and pill boxes of energy supplements and amino acids. The complete litany of objects confiscated from his possession are detailed at the Prescott News website.

As mentioned at the outset, one of the biggest reasons investigators were interested in any drugs that might have been in Ray’s possession was that there may have been psychoactive substances that could have impaired his judgment or that of followers/clients in the sweat lodge at the retreat. Ray was reported by several eyewitnesses as being aggressive and aloof, and even unhelpful when medics arrived at the sweat lodge. Dan Harris at ABC News asked me if I thought that Ray’s pharmacopeia might have contributed to his state of mind.

This is very difficult to do for a plethora of reasons, not the least of which because I am not a physician nor am I privy to what drugs he was actually taking or his basal personality characteristics. However, I am a pharmacologist and did train in endocrinology during my postdoctoral fellowship and can make some general comments.

A person taking an anabolic steroid regimen (recall that testosterone is a natural anabolic steroid) is prone to mood swings, anxiety, and aggressive behavior. In “TRT: A Recipe For Success,” a Word document available at All Things Male, Dr. Crisler apparently makes note that the intent is not to create an anabolic steroid cycle but rather testosterone replacement therapy, where testosterone levels are targeted to the upper-level of a normal range. Unfortunately, we cannot be sure if Mr. Ray was taking the drugs as directed or at doses greater than those recommended.

A physician colleague also reminded me that some of the drugs on the search warrant could alone cause electrolyte disturbances that could be exacerbated by being in an enclosed area with hot stones where other people were vomiting and begging to get out after fasting for 36 hours. Specifically, testosterone can cause sodium retention and Diovan/valsartan can cause potassium retention. These ionic imbalances can certainly influence one’s state of mind and one can speculate that these imbalances would be made worse by fasting and dehydration.

Off-label drug prescribing
This case also raises some questions as to how these drugs were prescribed in the first place. Sources close to Ray told ABC News that the “practical mystic” was being treated for a hormonal imbalance.

It is peculiar why a man of Ray’s means living in Carlsbad, CA, would be prescribed drugs by an internet physician in Michigan rather than seeing a board-certified endocrinologist or urologist at one of the outstanding medical centers in southern California.

Nevertheless, there are no laws that would have prevented Dr. Crisler from prescribing this regimen to Mr. Ray. To the contrary, physicians in the United States, whether they are MDs or DOs, are granted the latitude to prescribe any FDA-approved medicine for any indication they see fit. While it is illegal for drug companies themselves to promote “off-label” uses of drugs (i.e., indications for which the company has not received explicit FDA approval), a physician can legally prescribe a breast cancer drug to a man wishing to build lean muscle mass. I will leave it to my physician colleagues to comment on whether this falls under the standards of medical practice. In fact, the ethics of off-label prescribing would be an excellent separate issue to discuss in another post.

But let us not forget that this is a very sad case where three people lost their lives and nearly two dozen people were hospitalized. Press accounts of the sweat lodge incident and subsequent investigation suggest that blame and potential criminal penalties will fall where they may. The Camp Verde Journal noted in its 2009 roundup that:

Lawsuits have been filed by survivors, victims’ families and the Black Hills Sioux Nation, alleging Ray “committed fraud by impersonating an Indian,” thus violating the 1868 Treaty of Fort Laramie.

What we have offered here is a perspective on the pharmacology and toxicology of prescription hormone products and considerations of issues raised in publicly available documents and questions posed of us by the press. It is likely that several factors conspired to end up with this loss of life. As always, tragic events are what drive changes in laws and regulations.

The following is a collaborative effort by Peter Lipson, MD, a usual contributor to Science-Based Medicine, and Ames Grawert, JD, a soon-to-be-sworn-in attorney working in New York City.

Proponents of science-based medicine have always had one major problem—human beings are natural scientists, but we are also very prone to cognitive mis-steps. When we follow the scientific method we have developed, we succeed very well in understanding and manipulating our environment. When we follow our instincts instead, we frequently fail to understand cause and effect. This is how people on the fringes of medicine and science survive—intentionally or otherwise, they exploit our natural tendency to have too much faith in our own non-systematic observations.

One of the most important examples of this is the anti-vaccination movement (hereafter called the “infectious disease promotion movement” or IDPM). There have always been those suspicious of medicine and science, but the IDPM has taken this a step farther. They encourage people to “go with the gut”, ignoring centuries of science and public health data in favor of superstition. It’s not hard to exploit a parent’s fears. But exploiting these fears leads to real harm as many of us in the blogosphere have documented (and documented, and documented).

The IDPM is so fixed on their false beliefs that vaccination causes some sort of serious harm that they cannot be swayed by evidence. As each piece of their hypothesis is disproved, they move on to the next. Thimerosal doesn’t lead to autism? Then maybe it’s “the toxins”. Once the idea is fixed, there is no way to dislodge it. It simply shifts around a bit.

Since there is no science to lend legitimacy to the infectious disease promoters, they must rely on appeals to emotion. Most of their websites are full of testimonials, misinformation, and outright hostility. And when they really get backed into a corner, rather than hunkering down to do some real science, they sue.

Dr. Paul Offit is a nationally known expert on vaccination. He was featured in an excellent article by WIRED reporter Amy Wallace in which he said, among other things:

She lies.

The “she” in this instance is Barbara Loe Fisher, one of the leaders of the infectious disease promotion movement. She didn’t like this at all. Among her complaints she alleges the following:

The purpose of the Wired article was to create the impression that anyone not in support of universal and mandatory vaccination is irrational, uneducated, unscientific, controlled by fear and a danger to the public health. Wallace and Offit combined in an effort to defame and discredit those not in favor of universal and mandatory vaccination and singled out Plaintiff Fisher, whom the article describes as the “movement’s brain,” and the “media’s go-to interview for … ‘parents [sic] rights’” for condemnation as a liar.

To many physicians and scientists, this type of claim is hard to understand. Science is a process for finding and understanding facts. People can become emotionally tied to their work but science doesn’t care, and scientists often have vigorous debates about their work. Real scientists and real doctors must have thick skins.

So when someone is so attached to their own scientific opinion that they feel a need to use the legal system to protect their beliefs, many of us are left scratching our heads. Why wouldn’t she just try to find evidence to support her beliefs? How can a court possibly have something useful to say about a scientific question? What the Hell?

If you’re thinking that the law shouldn’t work this way — that angry combatants in the battle of ideas shouldn’t be able to leverage defamation law into silencing their more strident critics — you’re right. And it doesn’t. For better or worse, the American first amendment is a vigorous creature. Where other countries would hold defendants liable for negligently false and offensive speech, American law prefers that ideas be spoken, and their value decided by informed citizens, rather than lawyers and judges. This is actually a relatively novel topic in conflict of laws jurisprudence, and regardless of whether its assumption about the intellectual capacity of our public is accurate, it’s a uniquely American approach to the law, and one that Fisher completely ignores.
(FYI — all cases noted below in parentheses are Supreme Court cases, and therefore circumscribe any state defamation law. We don’t even need to reach beyond federal constitutional law to show where Fisher goes wrong.)

Virginia’s defamation laws follow the traditional American model, (although it eliminates the slander/libel, or speech/print distinction). Virginia therefore requires a showing of objective falsity, and a degree of malice, before defamation can be proven. The latter is keyed partially to whether the person pleading defamation is a “public person.” Because citizens should be free to question their leaders, as a matter of free speech, courts will only hold a defendant liable for defaming a public figure if the defamation occurs with actual “Sullivan” malice (referring to a famous Supreme Court case).

Accordingly, it becomes important to define a “public person.” While a private person speaking on a public matter — e.g., a small-time attorney commenting on a high-profile case — counts as “private” (Gertz v. Robert Welch), someone who voluntarily inserts herself in the role of shaping public opinion is a public person (Curtis Publishing v. Butts).

This distinction exists precisely because of people like Fisher. While she’s not a household name, she styles herself an opinion-maker, and has taken the requisite actions to make herself just that.

Critically, when it comes to public figures, the first amendment protects hyperbole, and some pretty wicked satire, too (N.Y. Times v. Sullivan; Hustler Magazine v. Falwell). A statement about someone’s character and honesty — “she lies” — may be offensive. But it’s this kind of vigorous dialogue that the first amendment not only protects, but encourages. Any conclusion to the contrary would hold our capacity for public debate hostage to a few sensitive players who “can’t take the heat.”

If you want a poignant example of just what Fisher’s argument would deprive us of, look no farther than her complaint. While talking about alleged distortions in the Wired interview, she writes:

Although before the Wired article appeared Defendant Wallace interviewed Plaintiff Fisher at length and derived substantial information from her concerning the risks and rights issues that mandatory vaccination begets, she chose not to include content reflecting that information in her article. (emphasis ours)

Give her credit for honesty: Fisher isn’t hiding the fact that, if we accept her argument, the editorial decisions of newspapers are now suddenly subject to judicial review. It may be that American defamation law is too generous, providing too much room for offense. But the line for which Fisher advocates would change one problem for a far more grave one.

In critiquing Fisher’s decision to “lawyer up,” we might also consider her choice of forum. Why federal court? First, note that the sole basis for federal jurisdiction in Fisher’s complaint is “diversity of citizenship.” She’s not pleading a violation of federal law; she’s pleading state-law defamation, but because the Constitution’s framers imagined federal court as a neutral ground between citizens of different states, federal jurisdiction is proper.

In diversity cases, federal courts apply state substantive law (there is no federal common law*). So she’s not trying to avoid state law. I suspect this is a prestige thing. Suing in federal court sounds better than suing in state court, requires better lawyers, and therefore costs more. Call it the Birther/Orly Taitz instinct. Even though litigating in federal court is impossible given the nature of her claim, she’s spurned the (slightly) more plausible venue of state court for the glory of federal court. It’s not gone well. Count this as still further prove that Fisher’s real desire is publicity, and the slim chance of vindication — not the redress of any real legal grievance.

Fisher’s actions betray a fundamental misunderstanding of both science and law. Science requires conflict, and the law does not protect us from the consequences of our ideas or the negative opinions of others. A free society cannot thrive on suppression of conflict, and science cannot progress without an atmosphere that allows vigorous, sometimes painful, debate.

Even before knowing the outcome (which is almost certainly going to sting for Fisher), this case is a major victory for those who favor free speech and the role it plays in science. It highlights the desperation of those whose cult-like beliefs are being discarded by the reality-based community. As the foundations of their beliefs rot, they cling to the hope that the law will save them from the onslaught of science. But they are likely to discover a painful fact: just as you have a right to your own beliefs, others have the right to remark on their arbitrariness and idiocy. Science, like the law, allows us to have our own opinions, but not our own facts.

For further analysis:

• Neurologica Blog
  
• Respectful Insolence
• Terra Sigillata

Imagine if we could save lives from a dread and often fatal disease simply by performing a minor surgical procedure. People would hail this simple victory and rush to adopt it… Not exactly. The disease is HIV and the simple surgical procedure is circumcision and anti-circ activists oppose it under almost any circumstances.

In this month’s edition of the Archives of Pediatrics and Adolescent Medicine, Tobian, Gray and Quinn present a compelling case for neonatal circumcision. The paper is entitled Male Circumcision for the Prevention of Acquisition and Transmission of Sexually Transmitted Infections. The authors report:

The American Academy of Pediatrics (AAP) male circumcision policy states that while there are potential medical benefits of newborn male circumcision, the data are insufficient to recommend routine neonatal circumcision. Since 2005, however, 3 randomized trials have evaluated male circumcision for prevention of sexually transmitted infections. The trials found that circumcision decreases human immunodeficiency virus acquisition by 53% to 60%, herpes simplex virus type 2 acquisition by 28% to 34%, and human papillomavirus prevalence by 32% to 35% in men. Among female partners of circumcised men, bacterial vaginosis was reduced by 40%, and Trichomonas vaginalis infection was reduced by 48%. Genital ulcer disease was also reduced among males and their female partners. These findings are also supported by observational studies conducted in the United States. The AAP policy has a major impact on neonatal circumcision in the United States. This review evaluates the recent data that support revision of the AAP policy to fully reflect the evidence of long-term health benefits of male circumcision.

The AAP had long recommended male circumcision for prevention of urinary tract infections in young boys, but backed down in 1999, partly in response to pressure from anti-circumcision activists. According to circumcision.org:

Based on a review of medical and psychological literature and our own research and experience, we conclude that circumcision causes serious, generally unrecognized harm and is not advisable.

Anti-circ activists have employed inflammatory language to express their opinion. Circumcision is “mutilation” and parents who choose to circumcise their sons are “mutilators”. But the benefits of circumcision are real and clinically important. As Tobian, et al. explain:

The biological mechanisms whereby circumcision could reduce viral STIs may be due to anatomic and/or cellular factors. The foreskin is retracted over the shaft during intercourse and this exposes the preputial mucosa to vaginal and cervical fluids.61 It has been hypothesized that viral infections may enter the mucosa through microtears in the preputial mucosa. The moist subpreputial cavity may also provide a favorable environment for viral survival. The inner mucosa of the foreskin is lightly keratinized compared with the epithelium of the shaft, coronal sulcus, and glans, which may facilitate mucosal access of HIV, HSV-2, or HPV. The mucosa of the foreskin also contains a high density of dendritic (Langerhans) cells, macrophages, and CD4_ T cells, which are all targets of HIV …

Anti-circ activists are convinced that circumcision reduces sexual satisfaction. Until recently, it was difficult to study that claim because very few men were circumcised after becoming sexually active, making it almost impossible to determine the sensory effect of circumcision. But recent studies make it clear that sexual satisfaction is not affect by circumcision:

… [T]here were no reported differences in sexual satisfaction in the randomized study arms in either the Ugandan or Kenyan male circumcision trials or among men before and after they were circumcised. In addition, it has been hypothesized that behavioral disinhibition may counteract any protective effects of male circumcision. However, there was no consistent or substantial evidence of change in sexual behavior after circumcision in the Kenyan or Ugandan randomized controlled trials.

Tobian et al. call on the AAP to revise its policy to reflect the latest scientific evidence:

The World Health Organization/Joint United Nations Program on HIV/AIDS has concluded that “the research evidence that male circumcision is efficacious in reducing sexual transmission of HIV from women to men is compelling … and has been proven beyond reasonable doubt.” In 2007, the American Urological Association revised their policy to state that “circumcision should be presented as an option for health benefits.” However, the AAP, American College of Obstetricians and Gynecologists, and American Medical Association are likely to have the greatest influence on parental decisions and insurance coverage for neonatal circumcision in the United States. With the mounting evidence that male circumcision decreases viral STIs, genital ulcer disease, and penile inflammatory disorders in men, and bacterial vaginosis, T vaginalis infection, and genital ulcer disease in their female partners, it is time for the AAP policy to fully reflect these current data.

The AAP should heed the authors’ call.

In the most recent issue of The Journal of clinical Oncology is a study comparing acupuncture to Effexor in the treatment of vasomotor symptoms (hot flashes) in women with breast cancer who cannot take hormone replacement therapy. The study found that the two treatments are equivalent, with longer duration and fewer side effects from acupuncture. However, the study is designed as a pilot study (very preliminary) and therefore the conclusions are highly unreliable – given prior research, this raises the question as to why the study was performed at all.

The study included only 50 women, which is a small number for a clinical trial and alone means this is at best a preliminary study. There were 25 women randomized to one of two arms – either acupuncture or Effexor (which is standard treatment for vasomotor symptoms in women with breast cancer). However, the two arms were not blinded in any way, and there was no acupuncture control group – no sham or placebo acupuncture.

It is unclear why the researchers undertook a small unblinded study such as this, given that previous studies were better designed.

Acupuncture for Hot Flashes in Other Conditions

The largest literature for acupuncture and vasomotor symptoms is not in cancer patients, but in post-menopausal women. It is unclear if these two groups are comparable for treatment effects, but at least acupuncture for any vasomotor symptoms touches on the plausibility of this treatment in any context.

A recent systematic review of the literature included six trials in which acupuncture was compared to sham acupuncture – 5 of the 6 studies were negative. The reviewers concluded:

There is no evidence from RCTs that acupuncture is an effective treatment in comparison to sham acupuncture for reducing menopausal hot flashes. Some studies have shown that acupuncture therapies are better than hormone therapy for reducing vasomotor symptoms. However, the number of RCTs compared with a nonpenetrating placebo control needle or hormone therapy was too small, and the methodological quality of some of the RCTs was poor. Further evaluation of the effects of acupuncture on vasomotor menopausal symptoms based on a well-controlled placebo trial is therefore warranted.

This would seem to be sufficient evidence to conclude that acupuncture lacks efficacy. For those who believe that further research is required, it only makes sense to perform larger and more rigorous studies.

Acupuncture has also been studied for the treatment of hot flashes in men being treated for prostate cancer. A systematic review of this research concludes:

The evidence is not convincing to suggest acupuncture is an effective treatment for hot flush in patients with PC. Further research is required to investigate whether acupuncture has hot-flush-specific effects.

There was much less literature to review in this case, and there were no large blinded studies.

Acupuncture for Hot Flashes in Breast Cancer

A recent systematic review of studies looking at acupuncture for breast cancer side effects concluded:

In conclusion, the evidence is not convincing to suggest acupuncture is an effective treatment of hot flash in patients with breast cancer. Further research is required to investigate whether there are specific effects of acupuncture for treating hot flash in patients with breast cancer.

There were only three controlled trials comparing acupuncture to sham acupuncture, one positive, and two negative. The review also included some studies of electroacupuncture – but I maintain that electroacupuncture, which uses electrical stimulation through acupuncture needles, is not acupuncture (it’s electrical stimulation) and should not be considered in the same therapeutic category.

Conclusion

The history of acupuncture research in general has been that the technology of performing acupuncture studies and properly blinding them has actually improved. At first blinded sham acupuncture was the standard, but that was improved by sheathed non-penetrating acupuncture needles allowing for double-blinding.

Also, the general trend within clinical research of any question is to progress from small unblinded pilot studies to progressively larger and more rigorous studies, if warranted, until there are a few large well-designed trials that together sufficiently settle an issue.

Overall, the results of acupuncture for any indication are very similar to the results I outline above for hot flashes – small studies with mixed results, followed by better-designed studies that are mostly negative. For any indication the evidence is either inadequate or shows that acupuncture does not work.

This study is therefore of dubious utility. It is a very preliminary study in an area where there is already several more rigorously designed studies, trending negative. Given the overall acupuncture research, and the minimal prior plausibility, in my opinion there is already sufficient evidence to conclude that acupuncture probably does not work for hot flashes in patients with breast cancer. However, if researchers feel that there is some potential to acupuncture and more research is deserved, the only utility would be from a large rigorously designed trial – which this study definitely is not.

In short, this study changes nothing and is a step backwards. It does, however, result in another round of press releases with the very misleading title that acupuncture works for hot flashes.

A recent story on NPR accused the drug manufacturer Merck of inventing a disease, osteopenia, in order to sell its drug Fosamax. It showed how the definition of what constitutes a disease evolves, and the role that drug companies can play in that evolution.

Osteoporosis is a reduction in bone mineral density that leads to fractures. The most serious are hip fractures, which require surgery, have complications like blood clots, and carry a high mortality. Many of those who survive never walk again. Vertebral fractures are common in the osteoporotic elderly and are responsible for dowager’s hump and loss of height. There is also an increased risk of wrist and rib fractures.

Bone density tends to decrease with age. Postmenopausal women are particularly susceptible to osteoporosis when their production of estrogen declines. The risk is increased in people taking corticosteroids and in people with certain diseases like rheumatoid arthritis. Other risk factors are European or Asian ancestry, smoking, excess alcohol, a family history of fractures, vitamin D deficiency, too much or too little exercise, malnutrition, and low body weight.

When a measurement like bone density varies widely in a population and decreases with age, how can we decide where to draw the line and call it abnormal? When does it become a disease requiring treatment?

For a long time, the diagnosis of osteoporosis depended on the occurrence of a fracture. In 1992 a group of experts convened by the World Health Organization agreed to define osteoporosis as a bone density 2.5 standard deviations below that of an average 30 year old white woman. They defined osteopenia as a bone density one standard deviation below that of an average 30-year-old white woman. The decision to use one standard deviation and 2.5 standard deviations was arbitrary, and it was meant as a tool to measure the emergence of a problem in a population rather than to have precise diagnostic or therapeutic significance for an individual. Nevertheless, these criteria were widely interpreted to mean that half the population has a disease they need to worry about.

Bisphosphonate drugs like Merck’s Fosamax and Sally Field’s beloved Boniva were intended to reduce the risk of fractures in patients with osteoporosis. They are effective in reducing spine fractures and in increasing bone density measurements, but some studies have shown no reduction in non-spine fractures, which are more common, and in the case of hip fractures, more significant. A British Medical Journal article pointed out,

Two thirds of vertebral fractures are subclinical or asymptomatic and may not affect quality of life. As a consequence showing that drugs reduce vertebral fractures may not be as important to patients as it seems.

According to a table published by the USPSTF (US Preventive Services Task Force), among women aged 50-54, 60 women need to be treated to prevent one vertebral fracture and 227 to prevent one hip fracture. Among women aged 65-69, 30 must be treated to prevent one vertebral fracture and 88 must be treated to prevent one hip fracture. Sally is 63: the numbers for her age group are 30 and 121. One wonders if she is aware of these numbers.

These drugs are not benign. To prevent ulceration of the esophagus, for 30 minutes after taking Fosamax patients must avoid eating or drinking anything but plain water; they must not lie down or recline, or take any other medications during that time. Bisphosphonates have been linked to osteonecrosis of the jaw. There are as yet no long-term studies. Case reports suggest the possibility that they might paradoxically increase fractures in the long run. By one estimate, the NNH (Number Needed to Harm) is 16 as measured by discontinuing treatment due to adverse effects.

When Merck started marketing Fosamax, not many women were being screened for osteoporosis because the standard DEXA (dual energy x-ray absorptiometry) test required expensive equipment and was not readily available. They thought if they could increase the rate of diagnosis they could sell more pills. Merck promoted the development of small, less expensive scanners that could be used on a heel or wrist in a doctor’s office. Merck even set up a nonprofit organization called the Bone Measurement Institute, which worked to spread the use of these machines and bring down the price of bone exams. Unfortunately, the results of those scans did not correlate well to the results of the gold standard DEXA scan.

A doctor quoted by NPR said,

The problem with the smaller peripheral machines is that taking a measurement of someone’s heel or forearm isn’t going to tell you what you need to know about the bones in the parts of the body that, if fractured, increase a woman’s risk of death — the hip and spine.

Who should be screened? The USPSTF found that, for women 55 to 59 years of age, the number needed to screen (NNS) over five years was more than 4,000 to prevent one hip fracture and 1,300 to prevent one vertebral fracture. The NNS to prevent one hip fracture over five years declines with age, to 1,856 for women 60 to 64 years of age, 731 for women 65 to 69 years of age, and 143 for women 75 to 79 years of age.

The USPSTF currently recommends that women aged 65 and older be screened routinely for osteoporosis. It recommends that routine screening begin at age 60 for women at increased risk for osteoporotic fractures (there is a handy online FRAX tool for estimating an individual’s risk of osteoporotic fractures). It found insufficient evidence to make any recommendations for younger women or for men. Meanwhile, direct-to-public ultrasound screening companies have jumped on the bandwagon and are offering poor quality osteoporosis screening to men and women of all ages, with innumerable false positives requiring further testing and unnecessary worry.

The results of the scans promoted by Merck were reported either as normal bone density, osteopenia, or osteoporosis. Osteopenia carries only a small increased risk of fractures, but the assumption was that left untreated it would progress to osteoporosis. It is really more of a risk factor for osteoporosis than a disease in its own right. Some women diagnosed with osteopenia may not even have bone loss; they may just be at the low end of normal on a wide spectrum. But osteopenia sounds abnormal, and it sounds like a diagnosis, and it sounds to a lot of people like it needs treating. A new disease was born with a ready-made treatment.

There are other pharmaceutical options for osteoporosis. Estrogens reduce osteoporosis risk but carry too many other risks to be used for that indication alone. Raloxifene is a selective estrogen receptor modifier that has estrogenic effects on bone but anti-estrogenic effects on the uterus and breast. It reduces the risk of vertebral fractures but not other fractures. It increases the risk of thromboembolism and fatal stroke although it does not reduce the overall death rate. Another option is calcitonin, but it is less effective.

Pharmaceutical treatments are not the only option. Weight-bearing exercise, prevention of falls, quitting cigarettes, curtailing alcohol, and ensuring adequate intake of calcium and vitamin D are all beneficial. A recent study showed that higher doses of vitamin D supplements (over 400 IU a day) reduced fractures by 20%.

Merck’s actions may have been misguided, but I don’t see this as a scam. Merck employees were trying to make money for the company, but that doesn’t mean they weren’t also genuinely trying to do the right thing to help patients. They had a product that they thought would prevent fractures and save lives, and they wanted to get it to everyone who could benefit. In their enthusiasm, they overshot and went beyond the science.

The NPR article admitted that there are two sides to this story.

…drug companies produce incredible drugs that can greatly relieve suffering. But one way they profit from those drugs is to extend their use to as many people as possible, which frequently means that medications are used in populations with milder and milder versions of a disease, so that the risks of medicating can come to outweigh the benefits.

Big Pharma advertises but it is doctors who write the prescriptions: when drugs are over-prescribed, only the prescribers are to blame. What should doctors do? In the first place, they should be recommending preventive lifestyle changes to all their patients. They should stick to the best science-based practices and evaluate the evidence for themselves rather than being influenced by Sally Field or by Big Pharma propaganda. They should prescribe drug treatments only when fracture risk is significant, when a fracture has already occurred, or when they think bone density is significantly low (still a judgment call). They should explain the gray areas to their patients and involve them in the decision to treat. They should think in terms of number needed to treat and number needed to harm. And they should be aware of the games Big Pharma plays.

In my five years in the blogosphere, two years blogging for SBM, and over a decade in Internet discussion forums about medicine and “alternative” medicine, I’ve learned a few things. One thing that I’ve learned is that one of the biggest differences between those whose world view is based on science and who therefore promote science-based medicine and those promoting pseudoscience, quackery, and anti-science is that science inculcates in its adherents a culture of free, open, and vigorous debate. Indeed, to outsiders, this debate can seem (and sometimes is) vicious. In other words, if you’re going to be a scientist, you need to have a thick skin because you will have to defend your hypotheses and conclusions, sometimes against some very hostile other scientists. That same attitude of a Darwinian struggle between scientific ideas, with only those best supported by evidence and with the most explanatory power surviving, is a world view that those not steeped in science have a hard time understanding.

Among those who don’t understand science, few have a harder time with the rough-and-tumble debate over evidence and science that routinely goes on among scientists than those advocating pseudoscience. Indeed, in marked contrast to scientists, they tend to cultivate cultures of the echo chamber. Examples abound and include discussion forums devoted to “alternative” medicine like CureZone, where never is heard a discouraging word — because anyone expressing too much skepticism about the prevailing view on such forums invariably finds himself first shunned by other members of the discussion forums and then, if he persists, booted from the forum by the moderators. In marked contrast, on skeptical forums, most of the time almost anything goes. True, the occasional supporter of woo who finds his way onto a skeptical forum will face a lot of criticism, some of it brutal. However, rarely will such a person be banned, unless he commits offenses unrelated to his questioning of scientific dogma, such as insulting or abusive behavior towards other forum participants or trolling. Such people may annoy the heck out of us skeptics sometimes, but on the other hand, they do actually from time to time challenge us to defend our science and prevent us from becoming too complacent. Indeed, that’s what I like about skeptics and being a scientist. Nothing or no one is sacred.

In marked contrast, supporters of pseudoscience are very much characterized by their aversion to scientific debate. The reason is obvious. They don’t have the goods. (If they did, what they’re advocating wouldn’t be pseudoscience.) They can’t win on science, reason, and evidence. The result is that they often end up forming communities that exist more to support their pseudoscience than to discover what does and does not actually work. Indeed, Prometheus describes this phenomenon well as he’s seen it in “autism biomed” discussion forums.

The same sort of group dynamics occurs in forums like CureZone and many others. Those who try to apply science and skepticism to the prevailing dogma of the group usually end up banned or give up in disgust. Indeed, at the anti-vaccine crank blog Age of Autism, comments are ruthlessly censored, and anyone who disagrees too strongly with the prevailing “wisdom” that vaccines cause autism will soon find himself or herself permanently banned. One consequence of this can be that the adherents of such views become progressively less able to defend their views in an evidence- and science-based argument, because they simply aren’t used to having them challenged based on evidence and science. Indeed some no longer even know how to react to criticism other than by lashing out. We’ve seen this before on this very blog, where anti-vaccine activist J.B. Handley lashed out at Steve Novella, while from time to time various anti-vaccine activists, J.B. Handley included, and promoters of pseudoscience and quackery periodically launch prolonged ad hominem attacks on me^{1,2,3,4,5,6,7,8,9,10}.

Another consequence is that promoters of unscientific and anti-scientific “medical” modalities have a tendency to be lawsuit-happy. We at SBM have written about this time and time again, both here and on individual bloggers’ blogs. The most recent and famous victim of this tendency is Simon Singh, who is being sued by the British Chiropractic Association for pointing out that there is no evidence behind their claims to be able to treat allergies and colic and quite correctly characterized such claims as “bogus.” Thanks to Britain’s notoriously plaintiff-friendly libel laws, Singh is fighting an uphill battle, too, and may very well lose. Fortunately, his case has become a cause célèbre, and Sense About Science has rallied public opinion in his favor and, more importantly, of reforming the U.K.’s antiquated anti-free speech libel laws — please sign the petition. However, Singh’s case is simply the most famous current example of how promoters of pseudoscience try to suppress criticism with legal threats or action. There have been several others before, including Andy Lewis of Quackometer, whose ISP caved in to legal threats from the highly dubious Dr. Joseph Chikelue Obi (who bills himself as the “world’s top expert in nutritional immunomudulation“). This came on hot on the heels of legal thuggery directed against him by the Society of Homeopaths. In both of these cases, the attempted legal action backfired spectacularly, as dozens, perhaps hundreds, of bloggers republished the posts verbatim that the Society of Homeopaths and “Dr.” Obi had successfully suppressed. Another example includes Kathleen Seidel, who was subject to a frivolous and punitive subpoena by lawyer Clifford Shoemaker, who is well known for bringing lawsuits based on the pseudoscience that vaccines cause autism. Fortunately, Shoemaker overreached and was forced to retreat in shame.

And I haven’t even mentioned über-quack Matthias Rath trying to silence Ben Goldacre through litigation

The most recent flavor of anti-science groups using the law to silence critics seems to be anti-vaccine activists. And, I’m sad to report that this time around it is Barbara Loe Fisher of the organization with the most Orwellian name, the National Vaccine Information Center (NVIC), who is suing Dr. Paul Offit; Amy Wallace, who quoted him in her excellent article published in WIRED Magazine in October (for which J.B. Handley launched misogynistic attacks on her); and Condé Naste, WIRED’s publisher. Here is the legal complaint (scrubbed of home addresses of the private parties involved).

This is not the first time an anti-vaccine activist has sued Dr. Offit. Just last year, Handley sued Dr. Paul Offit for a passage in his 2008 book Autism’s False Prophets, which included highly unflattering portraits (and, in my opinion, justifiably so) of anti-vaccinationists like Mr. Handley, including a discussion of a threatening post by Handley posted to an anti-vaccine mailing list, in which he said to the “neurodiverse folks monitoring this list”:

We will bring the full resources of myself and Generation Rescue to stop this. We will sue you for libel and we will go after your homes and assets. My lawyers live to investigate and sue people like you.

This, of course, sums up the attitude of all too many anti-science activists. They can’t win on the science; so they try to suppress criticism through legal action. Sadly, it’s their most potent weapon, certainly far more potent than any scientific argument they can come up with, given that even in the relatively defendant-friendly U.S. libel suits can be so intimidating that they will effectively silence criticism.

I don’t know enough of the details of the suit to determine whether Handley’s case had any merit or not, and I’m not a lawyer anyway. I tend to doubt that it did. Regardless of the merit of his suit (or, more probably, the lack thereof), I am pretty sure I have deduced Handley’s intent, as his e-mail and postings on AoA certainly leave no doubt as to his attitude. I also know that it’s very interesting that, as Squillo points out, Handley’s lawsuit was not filed on the basis of libel, but rather on “false light invasion of privacy” rather than for libel (a form of defamation), probably because false light is less well-defined than libel and easier to prevail on, perhaps as a result of Dr. Offit’s lawyer’s response. Whatever the case, Dr. Offit and his lawyers decided to settle rather than fight, with the settlement being an apology, an agreement to correct the passage in dispute, and a $5,000 donation to one of Jenny McCarthy’s favored autism charities, all of which to me sounds very much like a token settlement. I may be totally wrong about this, but my guess is that Dr. Offit just didn’t want to go through the pain of a full trial, which is, of course, the point of such legal actions; being sued is painful for anyone, and many decide it’s easier to cave than to fight, even when they have a strong case. My second guess is that Handley may have had just enough of a case plus a set of pockets deep enough to make a lot of trouble but probably not a good enough case to have had a high likelihood of prevailing if it had gone to trial. Otherwise, given his visceral hatred of Dr. Offit, I highly doubt that Handley would have agreed to such a tiny token settlement. (Another possibility to be considered is that Handley didn’t really want Generation Rescue and himself to be subject to discovery regarding the incidents at the heart of the disputed passage had the legal case moved forward.) On the other hand, Offit’s settling is a huge propaganda victory for Handley, which he has been trumpeting on his blog.

Unfortunately, Handley’s apparent success appears to have emboldened other anti-vaccine activists, and this, I suspect, is why Barbara Loe Fisher likely decided that she might be able to cause Dr. Offit some trouble. So cause him trouble she did by suing over this passage from Amy Wallace’s article:

Paul Offit has a slightly nasal voice and a forceful delivery that conspire to make him sound remarkably like Hawkeye Pierce, the cantankerous doctor played by Alan Alda on the TV series M*A*S*H. As a young man, Offit was a big fan of the show (though he felt then, and does now, that Hawkeye was “much cooler than me”). Offit is quick-witted, funny, and — despite a generally mild-mannered mien — sometimes so assertive as to seem brash. “Scientists, bound only by reason, are society’s true anarchists,” he has written — and he clearly sees himself as one. “Kaflooey theories” make him crazy, especially if they catch on. Fisher, who has long been the media’s go-to interview for what some in the autism arena call “parents rights,” makes him particularly nuts, as in “You just want to scream.” The reason? “She lies,” he says flatly.

“Barbara Loe Fisher inflames people against me. And wrongly. I’m in this for the same reason she is. I care about kids. Does she think Merck is paying me to speak about vaccines? Is that the logic?” he asks, exasperated. (Merck is doing no such thing). But when it comes to mandating vaccinations, Offit says, Fisher is right about him: He is an adamant supporter.

Regular readers may have noticed that I almost never accuse anyone of lying. The reason is that I tend to believe that most anti-vaccine activists really and truly believe in their pseudoscience. Consequently, when they spread misinformation and outright nonsense, they are not technically lying, at least not most of the time, because they have no clue that what they are saying is false. Indeed, although I do not know the specifics upon which Dr. Offit based his claim that Loe Fisher “lies” (although having read some of the vitriolic attacks on Dr. Offit by members of the anti-vaccine movement I can certainly understand why he might come to that conclusion), I do know that she is profoundly wrong about the science of vaccines and, utterly impervious to any science contradicting her viewpoint, spreads misinformation, so much so that whether Loe Fisher believes what she says or knows it to be false almost becomes a moot point when so much egregious misinformation and pseudoscience is spread against the backdrop of mountains of evidence showing that they are not scientifically valid. The end effect is more or less the same in a practical sense, although whether it is in a legal sense I do not know.

Even so, in her complaint Loe Fisher takes takes Jenny McCarthy’s disingenuous claim that she is “not anti-vaccine, but pro-safe vaccine” to whole new heights of bizarre contortion. I’ve written about this technique before. Fisher is very clever and couches her views in rhetoric of freedom and “informed consent.” Yet, it is very clear from the NVIC website what its true agenda is. For instance, there is a “memorial” for “vaccine victims,” which states:

They are the men, women, and children who have died or been injured by vaccines in nations around the world for the past 200 years. This is a virtual Memorial dedicated to those whose lives have been forever changed by vaccines they were often required by law to use.

And concludes:

Our hope is that, by honoring those who are casualties of mass vaccination policies, there will be greater public awareness of the need to value and care as much about those who are harmed by the complications of vaccines as we care about those who are harmed by the complications of infectious diseases. This International Memorial for Vaccine Victims is offered to the world as testimony of the need to protect the biological integrity of life on this planet.

The NVIC also runs a website called Stand Up! Be Counted!, which states: “No Forced Vaccination. Not in America.” It also uses common anti-vaccine tropes, such as confusing correlation with causation for the “autism epidemic.” Meanwhile the NVIC page about the H1N1 vaccine cites dubious studies on mercury in vaccines, in particular the discredited Hewitson study that I blogged about here and here. Then there’s the Vaccine Law Firm Directory she maintains of lawyers ready to sue for vaccine injury. But perhaps most telling of all is the recent NVIC conference, in which luminaries of the anti-vaccine fringe presented their views and “data,” and in which the man who started the fear that the MMR vaccine causes autism based on the shoddiest of science and whom Barbara Loe Fisher herself has vociferously defended, namely Andrew Wakefield, was given NVIC’s Humanitarian Award. The conference also included total cranks such as Gary Null, who is anti-vaccine to the core, an HIV/AIDS denialist, coffee enema advocate, and supporter of cancer quackery, and David Ayoub, whose claim to fame is that he thinks that mass vaccination programs are a plot by the Illuminati, complete with black helicopters. Quite frankly, from my point of view, if Barbara Loe Fisher isn’t anti-vaccine, she sure has an amazingly odd way of showing it. It would be very interesting to ask her whether there is anything or any evidence that could ever persuade her that vaccination is far safer than the diseases vaccinated against. I tend to doubt it, although I have no doubt, given her silver tongue, that she’d dance around the question quite skillfully, move the goal posts, or propose impossible-to-meet (in the real world, at least) standard of evidence.

My guess is that Loe Fisher’s lawsuit has very little to do with her reputation. After all, among real scientists knowledgeable about vaccination (as opposed to anti-vaccine “scientists” like Andrew Wakefield) her reputation is that of a promoter of pseudoscience; in other words, her only scientific reputation is a bad one. Moreover, among Loe Fisher’s core constituency, I highly doubt that Dr. Offit’s saying “she lies” about her would have any effect whatsoever on its opinion of her veracity, other than, perhaps, to make her fans love and believe her all the more. After all, in the circles that she travels, Dr. Offit is viewed as practically akin to Satan himself and routinely castigated as “Dr. Proffit.” However, having her veracity called into doubt by a real vaccine scientist could potentially hurt Loe Fisher in her efforts to win mainstream acceptance, and that is probably the real concern driving the lawsuit.

Another reason that Fisher’s frequent, impassioned, indignant denials that she is anti-vaccine are hard to believe is that she is very one-sided in her application of her appeals to freedom. She states over and over again that she is for “informed consent” and the right of parents to express “philosophical exemptions.” No doubt a libertarian argument could be made on political and philosophical grounds to support such a position. But, as PalMD shows, when a private institution decides that it will require that students be fully vaccinated according to the recommended schedule before they can attend school, suddenly Fisher isn’t so supportive of the whole freedom thing anymore. For example, when a Jewish school in Pittsburgh decided that it would not accept philosphical exemptions, would require that its students, other than those with legtimate medical exemptions, be fully vaccinated, and would not accept a letter from anyone other than a child’s primary care physician in order to grant a medical exemption, Fisher was most displeased:

According to Loe Fisher, the federal vaccine injury compensation program, established by the National Childhood Vaccine Injury Act of 1986, has paid more than $2 billion to families of children who have been injured or died as a result of vaccination.

“Vaccination should not be separated out from the informed consent paradigm,” she said.

Since the establishment of the CDC and American Academy of Pediatrics recommendations regarding vaccination requirements, Loe Fisher continued, families seeking medical exemption from vaccination have found it rough going.

Because it’s hard for a family to find a physician to provide a medical exemption, Loe Fisher said, many must rely on the religious or philosophical exemption, available in almost all states, to avoid vaccination.

She is not in favor of a private school refusing to accept those exemptions which are provided for by state law.

“It is questionable for a school to narrow those exemptions and not allow a parent who believes a child is at risk to take an exemption,” Loe Fisher said.

In other words, Fisher is against the government’s mandating vaccination before a child can attend school, public or private, but if the administration of a private school voluntarily decides without any government laws or pressure that it is going to require vaccination of its students before admission and not accept philosphical exemptions, she thinks that the government should have the power to enforce philosophical vaccine exemptions on it. Her advocacy of freedom with respect to vaccination is rather one-sided, don’t you think? After all, I bet Loe Fisher supports the right of private schools, such as Waldorf Schools, that do not require vaccination, often have high percentages of unvaccinated children, and, of late, have become incubators for outbreaks of vaccine-preventable diseases, not to require that her students be vaccinated. Thus, her support for “vaccine choice” except when it is the choice of a private institution to mandate vaccines casts her assertion in her complaint that she “does not seek to prohibit or advise against vaccination but to ensure that vaccination is voluntary and that it proceeds following fully informed consent” in a rather dubious light and contributes to the overall impression that she is in reality not a “vaccine safety” activist, but an anti-vaccine activist.

In my opinion, after having read her website and seen her quoted in many interviews, the bottom line is that Barbara Loe Fisher is anti-vaccine. True, she’s good at cloaking what I consider to be her anti-vaccine views in rhetoric of “freedom” and “informed consent,” but whenever push comes to shove, she’s against vaccines and clearly thinks that they do more harm than good. Nowhere have I ever seen her say that she supports a single vaccination as routine. Not one. Her entire organization supports the scientifically discredited notion that vaccines cause autism and holds conferences with anti-vaccine speakers. It’s hard not to conclude from this that she is anti-vaccine. Moreover, Barbara Loe Fisher is one to talk about libel, after what she said about Dr. Offit the very article by Amy Wallace over which she is suing:

Against this backdrop, Fisher, a skilled debater who often faces down articulate, well-informed scientists on live TV, mentioned Offit frequently. She called him the leading “pro-forced-vaccination proponent” and cast him as a man who walks in lockstep with the pharmaceutical companies and demonizes caring parents.

Maybe Dr. Offit should countersue for libel. It sounds as though he may have a case. After all, on the NVIC website, there is this little tidbit as well:

Offit’s attempt to exonerate DPT is part of a larger effort to convince the public – and drug company stockholders – that most vaccines, including his own, have no risks whatsoever.

I’d love to see Loe Fisher present evidence that Dr. Offit has ever said that most vaccines, including his own, have no risks whatsoever. But attacking Dr. Offit in such terms is not enough for Loe Fisher. As Kim Wombles points out, Loe Fisher sees her fight against vaccine mandates in apocalyptic terms, as she describes on the NVIC website:

The discrimination begins, always, with the majority in a society pointing the finger at a minority for somehow endangering the public health and welfare. Individuals in the minority group are singled out as different – ethnically, biologically, spiritually, morally – from the majority. The human impulse to fear, judge, marginalize or eliminate those different from the rest has left a blood soaked trail winding throughout the entire history of man from the Great Inquisition to the Holocaust; from the killing fields of Cambodia to Rwanda, Serbia and Tibet; while the persecution of those with leprosy, TB, AIDS, mental illness, and handicaps continues in every society.

Later in the same article, I found this quote by Loe Fisher likening Andrew Wakefield to a victim of the Inquisition:

I thought of the persecution of Andrew Wakefield, M.D., who is being punished by his British colleagues for daring to report an association between the MMR (measles-mumps-rubella) vaccine and neuroimmune dysfunction, including inflammatory bowel disease and autism. Like when the heads of heretics were impaled upon stakes on the Tower of London as a warning for all to see, the Wakefield inquisition is a spectacle designed to persuade all doctors contemplating questioning the safety of current mass vaccination policies to remain silent.

And this allusion to the Holocaust:

Holocaust survivor Elie Weisel has said “When you take an idea or a concept and turn it into an abstraction, that opens the way to take human beings and turn them, also, into abstractions.”

Individuals harmed by vaccines are not abstractions. They are human beings who deserve to be spared a lifetime of suffering rather than being thrown under the bus to prop up forced mass vaccination policies that fail to acknowledge biodiversity within the family of man.

When Barbara Loe Fisher likens the supporters of vaccination programs who correctly criticize her and those holding views similar to hers as “anti-vaccine” to Nazis or the Inquisition and their criticism to what the Nazis did to the Jews during the Holocaust or the Inquisition did to heretics, when she likens criticism of her stance on vaccines to the genocides in Cambodia and Rwanda, she shouldn’t be too surprised when a lot of people conclude that she is anti-vaccine, not pro-safe vaccine.

Just like those of the Society of Homeopaths, “Dr.” Obi, the British Chiropractors Association against Simon Singh, or Matthias Rath against Ben Goldacre, Loe Fisher’s lawsuit is also likely more about shutting up critics than it is about protecting her reputation. Clearly, Wallace’s article hurt the anti-vaccine movement. Moreover, if there’s one good thing about 2009, it’s that more and more mainstream media outlets stopped portraying the anti-vaccine movement as poor, persecuted parents and more and more portrayed it as a threat to public health based on pseudoscience, which it is. Yes, it’s true that individual stories from the movement can be very sad and compelling; many of these parents and their children have had a horribly rough time. However, we do not have to downplay their difficulties or insult them personally to point out that they are profoundly wrong based on science when they blame vaccines for their children’s autism and that their activities do represent a serious threat to public health. More and more reporters, like Trine Tsouderos and Amy Wallace, have come to realize that. Such reporters represent a threat. Moreover, demonizing these journalists online, as the anti-vaccine movement tried to do with Amy Wallace and Trine Tsouderos (the latter of whom was included in a Photoshopped collage with Steve Novella preparing to make a Thanksgiving feast of a baby), doesn’t work very well. That leaves lawsuits to intimidate those who would speak out and discourage other media outlets from writing similar stories.

I wonder. Sense About Science did a fantastic job of publicizing the Simon Singh libel case and using it to promote the need for reforming the U.K.’s libel laws. I wonder if it’s time for a similar movement right here in the U.S. to prevent promoters of pseudoscience from using the law to intimidate and harass defenders of science-based medicine. Although Dr. Offit probably has the financial means to defend himself, there are a lot of writers and bloggers who do not, should someone with deep pockets decide to try to silence them with a frivolous lawsuit. We definitely have a problem here, and I predict it’s going to get worse as pseudoscience movements like the anti-vaccine movement rightly become more and more marginalized.

I’m a translational researcher. To those of you who aren’t familiar with what that means, it means (I hope) that I study potential therapies in the lab and try to translate them into actual therapies that will cure patients of breast cancer — or, at the very least, improve their odds of survival or prolong survival when cure is not possible. Translational research is extremely important; indeed, it is the life blood of science-based medicine, with basic science producing the discoveries and clinical research the applications of these discoveries. When it works, it’s the way that science leads medicine to advance. However, sometimes I think that it’s a bit oversold. For one thing, it’s not easy, and it’s not always obvious what basic science findings can be translated into useful therapies, be it for cancer (my specialty) or any other disease. For another thing, it takes a long time. The problem is that the hype about how much we as a nation invest in translational research all too often leads to a not unreasonable expectation that there will be a rapid return on that investment. Such an expectation is often not realized, at least not as fast and frequently as we would like, and the reason has little to do with the quality of the science being funded. It has arguably more to do with how long it takes for a basic science observation to follow the long and winding road to producing a viable therapy. But how long is that long and winding road?

A lot longer than many, even many scientists, realize. At least, that’s the case if a paper from about a year ago by John Ioannidis in Science is any indication. The article appeared in the Policy Forum in the September 5 issue and is entitled Life Cycle of Translational Research for Medical Interventions. As you may recall, Dr. Ioannidis made a name for himself a couple of years ago by publishing a pair of articles provocatively entitled Contradicted and Initially Stronger Effects in Highly Cited Clinical Research and Why Most Published Research Findings Are False, which Steve Novella blogged about a couple of years ago.

Dr. Ioannidis lays it out right in the first paragraph:

Despite a major interest in translational research (1-3), development of new, effective medical interventions is difficult. Of 101 very promising claims of new discoveries with clear clinical potential that were made in major basic science journals between 1979 and 1983, only five resulted in interventions with licensed clinical use by 2003 and only one had extensive clinical use (4). Drug discovery faces major challenges (5-8). Moreover, for several interventions supported by high-profile clinical studies, subsequent evidence from larger and/or better studies contradicts their effectiveness or shows smaller benefits (9). The problem seems to be even greater for nonrandomized studies (9).

In order to figure out how long translational research can take to come to fruition, Dr. Ioannidis looked at some fairly high profile therapies (defined as therapies claimed to be effective in at least one study about it that has been cited 1,000 or more times) between 1990 to 2004. The reason that this particular definition was chosen is to use studies for which a milestone at which a therapy is widely recognized to be effective and safe. That, by the paper’s definition, is the point at which a basic science finding has finally been completely “translated” into an accepted therapy. The problem then becomes to identify exactly when such therapies began as a grain of a basic science finding or an idea based on basic science observations. This is not always easy to identify. In the case of one of my major areas of research interest, tumor angiogenesis, it’s relatively easy to cite Dr. Judah Folkman’s famous 1971 paper proposing the targeting of tumor angiogenesis as a therapy for cancer. Oh, we could quibble over whether that was truly the beginning. After all, it was hypothesized that angiogenesis was important to tumor growth decades before. However, the 1971 paper was the first explicit proposal to develop strategies to target tumor angiogenesis to treat cancer. Be that as it may, I’ve mentioned before that it was thirty years before an actual therapy used in humans was developed as an example of just how long it can take.

Dr. Ioannidis has tried to quantify this gap in a more general manner, which he refers to as the “translation lag.” What he found is quite sobering for people who are anxious for the rapid translation of basic science:

To place each discovery in time, we identified the year when the earliest journal publication on preparation, isolation, or synthesis appeared or the earliest patent was awarded (whichever occurred first). Overall, the median translation lag was 24 years (interquartile range, 14 to 44 years) between first description and earliest highly cited article (see the chart). This was longer on average (median 44 versus 17 years) for those interventions that were fully or partially “refuted” (contradicted or having initially stronger effects) than for nonrefuted ones (replicated or remaining unchallenged) (P = 0.004).

In a secondary analysis, we defined the time of discovery as the first description (publication or awarded patent) of any agent in the wider intervention class (those with similar characteristics and mode of action). Early translational work may be performed with different agents in the same class compared with those that eventually get translated into postulated high-profile clinical benefits. Analyses using information on the wider class of agents showed even longer translation lag, with median of 27 (interquartile range, 21 to 50) years and similar prolongations of the translation lag for refuted interventions.

This is represented in this table:

One thing that you may notice on the table above that Dr. Ioannidis also did was that he also looked at some treatments or interventions that had been highly cited and were later refuted. What makes this interesting is that therapies that were never later refuted by clinical trials after the highly cited clinical trial that was used to support their use had a markedly shorter translation lag, 16.5 years (range 4 to 50 years) in the main analysis and 22 years (range 6 to 50 years) if the wider class of drugs is considered. In contrast, for remedies whose efficacy was later refuted, the translation lag was 44 years, as mentioned in the passage cited above. What could be the explanation? Dr. Ioannidis speculates:

We observed that most highly cited claims that were eventually refuted had a very slow translation history preceding them [e.g., flavonoids, vitamin E, and estrogens were already available for many decades before observational (nonrandomized) studies claimed implausibly large survival benefits in the 1990s]. We conclude that claims for large benefits from old interventions require extra caution as they are likely to be exaggerated.

I’m half tempted to mention that there is a bit of an elephant in the room here in that it makes one wonder about complementary and alternative medicine, and how the existing studies would fare in this sort of analysis. Of course, one would be unlikely to find a paper on a CAM intervention cited 1,000 times showing efficacy. (In fact, for some it would be hard to find a paper strongly demonstrating efficacy of most CAM therapies.) But think of it this way: Many of these therapies have been around for hundreds of years, and there hasn’t been compelling evidence of their efficacy. Think of homeopathy, for instance. Samuel Hahnemann thought of it over 200 years ago, and we still don’t have evidence of its efficacy.

I know, I know, I’m dragging one of my personal peeves into this, and it is ridiculous to use the term “science” or “translational research” in referring to something like homeopathy, but I couldn’t resist. Mea culpa.

We can quibble about whether his methodology was the most appropriate or whether he picked the correct milestones to compare, but what Dr. Ioannidis shows is that, in essence, a lot of “translational” research takes close to two decades to bear fruit, and it’s fairly uncommon for it to take less than a decade. Moreover, as Dr. Ionnidis points out, less than 5% of promising claims based on basic science ever come to fruition as actual therapies. In other words, translational research is hard. Few promising ideas make it to therapies, and it takes a long time for those that do. Indeed, Dr. Ioannidis makes this recommendation:

Our analysis documents objectively show the long length of time that passes between discovery and translation. As scientists, we should convey to our funders and the public the immense difficulty of the scientific discovery process. Successful translation is demanding and takes a lot of effort and time even under the best circumstances; making unrealistic promises for quick discoveries and cures may damage the credibility of science in the eyes of the public.

His other recommendations are rather obvious: multidisciplinary collaborations with focused targets, incentives for testing claims in high quality, unbiased research, and the that large clinical trials with repeatability are required to demonstrate the efficacy of therapies. One recommendation, however, caught my eye:

New drug discovery is probably essential for common diseases where the existing drug armamentarium has been already extensively screened. Conversely, for uncommon and neglected diseases, the existing drug options may remain largely untested, and old drugs may find interesting new uses (12-14).

Actually, that’s a recommendation that’s been pretty obvious for a long time. For common diseases, existing drugs and related drugs have been tested and retested, and many, many variations on the old have been tried. For substantial breakthroughs, something new is required. Unfortunately, the profit incentive in drug manufacturing tends too much towards “me-too” drugs. The second part is actually very relevant to what I do. Testing such “off-label uses” of drugs can yield surprising results. Indeed, one of my two research projects is based on exactly such an off-label use. However, ironically it is a treatment for a very common disease, breast cancer, that I am testing; so Dr. Ioannidis is not entirely correct. Interesting new uses for drugs do not always make themselves known in uncommon and neglected diseases.

Regardless, however, what the public needs to understand is that translational research takes a long time. What they also need to understand is that the foundation upon which translational research rests is a strong core of basic science research. Without a wide variety of basic science findings upon which to base treatments, translational research has little to choose from in moving such findings to the next step. Contrary to popular belief as well, when there are robust basic science findings upon which to base a potential therapy, the road from laboratory bench discovery to usable therapy is long and winding.

REFERENCE:

D. G. Contopoulos-Ioannidis, G. A. Alexiou, T. C. Gouvias, J. P. A. Ioannidis (2008). Life Cycle of Translational Research for Medical Interventions Science, 321 (5894), 1298-1299 DOI: 10.1126/science.1160622