Testosterone Replacement Trials Proceed Slowly

(part 2 of 2 posts)

Alerting men to screening and treatment for low testosterone may get them in to their doctors faster, but they may be astounded to learn that the science in the field is wanting. The National Institute of Aging only enrolled its first patient in a testosterone replacement trial a little over a year ago, according to Peter Snyder, MD, principal investigator of the trial, and endocrinologist at the University of Pennsylvania, Philadelphia.”You can’t make any conclusions about whether it does any good,” said Snyder, who added that in 2003, an Institute of Medicine Panel urged systematic study in older men and recommended against “widespread, generalized use to prevent possible age-related diseases or for enhancing strength or mood in otherwise healthy older men.”

On the day that the report was released, a New York Times editorial titled “The Testosterone Gamble” opened with this question: “Can American men be rushing into the same reckless use of hormones that brought grief and anxiety to so many unsuspecting women?”

Although proponents of testosterone liken testosterone levels declining in a similar fashion to female menopause and refer to “male menopause” or “andropause,” the IOM Committee concluded that there is “scant evidence” for a shutdown like there is among women. In fact, the Committee concluded that supplements “are only appropriate for indications approved by the FDA (the primary indication is hypogonadism in men who make little or no testosterone.)”

The Committee is not alone in this assessment: many physicians told me that they worry that men will use testosterone replacement therapy before studies of effectiveness, benefits, and any problems are known.

Research Priorities

The wheels of science proceed slowly, perhaps too slowly for those who want to try the latest drug. Without rigorous study, there could be harm. In fact, some research has raised concerns about testosterone accelerating prostate cancer and an enlarged prostate (BPH); one  study was halted because of heart effects.

The IOM Committee pressed for studies that would show whether testosterone is an effective treatment in men with low testosterone levels. Unless a clear benefit is demonstrated, the Committee urged not proceeding to studies of long-term risks.

A top priority is to test testosterone replacement among men age 65 and older whose testosterone levels are below the physiologic levels of young adults. These would be randomized, short-term, placebo-controlled randomized trials. Outcomes should be measured in four areas, weakness/frailty/disability; sexual dysfunction; cognitive dysfunction; and well-being/quality of life. If clinically significant benefit is demonstrated in the early trials, long-term studies should follow,according to the Committee. Safety should be assured in all the trials. Further study of age-related changes in testosterone levels should also be done.

The Testosterone Trial

A coordinated set of six trials is being done at 12 sites around the country, under the direction of the National Institute of Aging, according to Snyder. “We are selecting men age 65 and over with unequivocally low testosterone, 275 ngs on two separate early mornings because these are the men we would anticipate might get the most benefit,” said Snyder. Overall, 80 percent of men have values over 275 at 2 separate times.

Testing testosterone replacement in men age 65 and over is in contrast to the advertising, which focuses on men age 45 and over. “We have strict entry criteria so that men have a very low risk for prostate cancer and at least one of the following conditions: anemia, decreased physical function, low vitality, impaired cognition, or reduced sexual function,” Snyder added. Men in the study either get a testosterone gel (AndroGel/Abbott) or placebo gel to be applied to the torso, abdomen, or upper arms. The testosterone is given first as a loading dose and then adjusted so that the gel brings testosterone into the normal range.

“Of every 100 men who call into our sites, one ends up satisfying enrollment criteria and gets enrolled.” In contrast,  advertising suggests that as many as 38 percent of men age 45 and over have low testosterone and may benefit from treatment.

Caveat Emptor: Direct-to-Consumer (DTC) Ads for Testosterone Replacement Therapy Soar

Sebastian Botero in the 2005 Tour de France. By J.P. Partland.

“Ted,” a 50-year-old bicycle racer from Philadelphia, saw his primary care doctor for the last time several months ago– when he was advised to start testosterone replacement therapy. “Your labs are excellent,” said Ted’s doctor. “I’d like to frame them.” The lab values included a normal range testosterone level. Ted was there for a regular check-up and he had no particular complaints, except that he was struggling through the after-effects of a motorcycle accident.

Ted’s doctor told him that even though his testosterone level was normal, with testosterone replacement, Ted might be able to build more muscle mass and go all night. It was not as if Ted indicated he was having any trouble on either of those fronts.

“Nah, that’s okay. I don’t think I need it.” Until this episode, Ted had no real complaints about his doctor and found him pretty knowledgeable. Yet the only pamphlets that Ted saw in his doctor’s office were about testosterone. Ted suspects that his doctor, a solo practitioner, may be trying to hit a volume target:  if his doctor prescribes a certain amount of testosterone replacement therapy, he may get rewarded financially by pharma in what Ted calls a “payola” type arrangement.

While the FDA has cracked down on some promotional activities, it’s still probable that doctors are rewarded for just talking up a product. The placards around the office can open a discussion that might never happen otherwise.

Ted became disgusted when he watched the front office staff ask his doctor what code to put testosterone replacement therapy under for an elderly man seen right before him. “My reaction was ‘the bucket must be pretty big if both of us are candidates for hormone replacement therapy’.”

Ad campaigns on television, newspapers, and the internet urging men age 45 and over to get screened for low testosterone and consider long-term testosterone replacement therapy (TRT) are everywhere. It is hardly surprising: hormone replacement therapy (HRT) for women was a blockbuster drug category long before randomized controlled trials went forward. It was not until the Women’s Health Initiative was stopped early because it showed a link between HRT and both cardiovascular disease and breast cancer that this trend reversed itself. The hypothesis that HRT might help avert dementia did not pan out. That marketing is far from over; journal supplements and continuing medical education programs are devoted to highlighting the limitations  of the  Women’s Health Initiative (for example, claiming that the women were not representative) and maximizing any studies suggesting that even a little hormone replacement therapy given with caution is not so bad after all. Now, as pharmaceutical companies take their turn with men, the marketing is proceeding ahead of rigorous scientific study.

Ads Tackle Aging, Low Libido,  and Low Energy

The ads use macho imagery: cars, computers, and racing prominently. Men look moderately overweight in many ads. Some of the information on testosterone replacement on the web targets men with high cholesterol, diabetes, COPD, and asthma, suggesting that testosterone replacement therapy could reverse low libido, a bummed mood, and low energy in men age 45 and over. The catch-phrase “is it low T” appears in several Abbott ads. Abbott makes the testosterone gel AndroGel and Auxilium the testosterone gel Testim. So far, these are the two products in the US market; more are in the pipeline.

Public opinion on these ad campaigns runs the gamut of people who view it as potentially harmful disease-mongering and medicalization of aging to the point of view that testosterone could confer positive anti-aging benefits.

In June, an event was held in New York City’s Times Square, on what is known as Military Island (a military recruiting station has been there for many years), asserting that men care more about cars than they do about their health.The event featured a young race car driver, a race car, and old vintage cars. Now on the Internet, the ad plainly says it is from Abbott. The Times Square event may have been unbranded. It states that the race car driver had his testosterone checked, that it was fine, and he was relieved. if you maintain a high testosterone, you can still drive fast cars and perform like you did 20 to 40 years ago. (Too bad that the event coincided with the Anthony Weiner twitter fiasco –-hardly the optimal time for a big splash for testosterone therapy.)

One television ad shows a robust man slamming a laptop shut, walking across the screen, with the message: “Stop living life in the shadows.” An ad in the Boston Globe ran a few months back showing a healthy looking man in his forties, reading: “Has he lost that loving feeling? He may have low testosterone (lowT).” Frequently men are shown with their female partners who want the guys upstairs in the sack. The men look distracted and disinterested in sex.

In May,  Pharmaceutical Executive gave Heartbeat and Auxilium Pharmaceuticals (Testim) top billing for “rich media ads that helped dispel common misunderstandings of low testosterone symptoms and increase awareness of the condition and its treatment, while keeping a sense of humor about the potentially sensitive medical issue. The unbranded ads were accompanied by the www.lowtfacts.com website and directed users to additional information on symptoms and treatment.

Some low testosterone awareness ads on the Internet that I viewed in May or June had links to the American Diabetes Association (ADA), implying that ADA must espouse the point of view that diabetes is associated with low libido, low energy, and low testosterone; hence, screening for low testosterone in men with diabetes is sensible and safe.  However, such links came up empty—just bringing you to the generic ADA website. This link has since been removed, perhaps because the implication that ADA has guidelines on testosterone screening for men with diabetes is indeed a stretch.

Around the world,  the United States and New Zealand are the  only countries that permit DTC drug marketing, according to Barbara Mintzes, PhD, assistant professor of anesthesiology, pharmacology and therapeutics initiative, University of British Columbia, Vancouver, Canada. If you turn on television during prime time in the US, you are bound to see ads for a multitude of drugs, so much so that it is daunting. In much of the world, DTC drug marketing is illegal. Although DTC drug marketing has been illegal in Canada, the law is not enforced in Canada, Mintzes explains. “This is in part because of the large influence of US media (nearly all Canadians can see US television), and partially because of specific steps that the Canadian government has taken to re-interpret existing laws in a more permissive way,” says Mintzes. Part of this involves the definition of ‘information’ versus ‘advertising,’ another part branded ‘reminder’ ads with no health claims,” said Mintzes. “In both cases Health Canada (federal regulator) has put out advertising policy briefing papers explaining the way the law is being interpreted, and advising industry of what would and would not be considered legal,”stated Mintzes in an email. “It’s a stretch in both cases to connect what’s in those policy papers with the actual words in the law or how it was interpreted previously.”

Canada has a self-regulatory Pharmaceutical Advertising Advisory Board, which can provide opinions on direct-to-consumer ads, and report back to Health Canada. Barbara Mintzes, University of British Columbia. However, as many as 30 percent of Canadians view American television through cable and satellite.

Testosterone Promotional Marketing Questioned

In June, Mintzes and 23 physicians, researchers, and ethicists around the world, including experts at Harvard, Oxford, in Germany, Australia, lodged a formal written complaint with the Pharmaceutical Advertising Advisory Board regarding an ad campaign by Abbott in the June 6 to July 12 Globe and Mail, accompanied by a promotion to physicians, and a Canadian-based website: www.lowT.ca. The ad had been reviewed by PAAB and its logo appeared on the ad, according to Mintzes. The complaint concerns a Canadian ad. It is still pending.

The letter argues: “Not only is the message in this advertisement in contravention of the Food & Drugs Act, it has serious potential to lead to harm to public health, it provides misleading and inaccurate information that would not withstand any serious test of truth in advertising, and it is likely to lead to unjustified increases in health care costs, the latter by promoting testing of men unlikely to be suffering from hypogonadism [the technical term for having a low testosterone]. By redefining this condition to include signs of normal ageing, Abbott is promoting this product for an unapproved use – normal age-related changes in testosterone levels.”

The letter takes issue with promoting testosterone to treat lack of energy, low sex drive, loss of that loving feeling, and urging men to see their doctors for a testosterone test if they experience these things. The low T website also features a 10-question quiz that suggests complaints such as “falling asleep after dinner” or “deteriorating work performance” may be symptomatic of low testosterone.” The email to doctors suggests that 38 percent of men over age 45 could have low testosterone, which the authors contend is inflated.

Also at issue, the authors write, is targeting this to overweight men and those with diabetes, who may be at risk for heart disease. The authors point to a study in the New England Journal of Medicine of testosterone replacement therapy that was halted early because of excess cardiovascular events. (The letter did not address concerns that testosterone is ill-advised in men with prostate cancer or at elevated risk for it, but that has been a concern raised by many physicians.)

The authors of the letter to Canadian authorities also take issue with the “unbranded”campaign, which disguises that it is really from Abbott; this is not in alignment with the WHO Ethical Criteria for Medicinal Drug Promotion, signed onto by all UN Member states. The US ad campaign by Auxilium was similarly unbranded, as was the Times Square/Military Island event.

Testosterone replacement therapy could gain a foothold in markets around the world through aggressive direct to consumer drug advertising and physician incentive programs. Just like hormone replacement therapy for women, it seems to go be going forward with limited science to back broad use.

Later this week: The Science (or lack thereof) to Back Testosterone Replacement Therapy