The FDA Flexes Its Muscles on Testosterone

by Karen Solomon, Bioethics Program Student

In 2002, Solvay Pharmaceuticals developed a new marketing strategy that characterized the natural decline in testosterone production associated with normal male aging as a medical problem, termed low-T. The ultimate objective was to encourage physicians to prescribe testosterone to otherwise healthy patients to combat the effects of normal male aging, such as low energy and libido.

This marketing strategy worked. In the last decade, testosterone use in men has increased by over 300%. Over 2 million men are now being treated with testosterone in the US, earning pharmaceutical companies a great deal of money. In 2012, US testosterone sales hit $2 billion, up from a “mere $324 million” in 2002. Although the US leads the world with testosterone prescribing, a significant and steady increase in testosterone use has been seen across the globe.

However, safety concerns over testosterone use by otherwise healthy men are mounting. One observational study revealed that within three months of starting testosterone, heart attacks doubled in men over 65, and in younger men with heart disease. Another study found that among older men with low testosterone undergoing coronary angiography, many with heart disease, there was a 30% increase of “stroke, heart attack, and death” among those being treated with testosterone.

Earlier this year the FDA took notice, asking an Advisory Committee to provide recommendations on licensing and use of testosterone as an anti-aging panacea. That committee has since recommended that the Agency place additional restrictions on the ability of pharmaceutical companies to promote testosterone for low-T. The panel also recommended that researchers conduct additional clinical trials designed to better understand the frequency and severity of side effects associated with testosterone use.

It is encouraging to see an FDA Advisory Panel argue for greater caution with the use of prescription drugs in otherwise healthy individuals. As demonstrated with testosterone, FDA drug approval does not mean that all potential safety issues had been vetted. When drugs are prescribed with larger and more diverse populations than those studied in clinical trials, new safety concerns can arise. Once physician prescribing habits become established for off-label uses, drug manufacturers may not have an incentive to pursue additional studies to demonstrate whether such use is effective or safe.

Hopefully this will change. Until recently, manufacturers profited from increased sales while questions about whether off-label use was safe or effective were left unanswered.

In 2007, however, the FDA was given new authority under the Food and Drug Administration Amendments Acts (FDAAA), to require manufacturers to conduct post-marketing studies, as new safety information becomes available. The FDA now has the option to flex new regulatory muscles, as they have done with testosterone manufacturers, instead of negotiating for voluntary action with little promise of an end game. This can only be a win for patients.

[The contents of this blog are solely the responsibility of the author and do not represent the views of the Bioethics Program or Union Graduate College.]

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Big Bad Ebola

by Theresa Spranger, Bioethics Program Alumna (MSBioethics 2012)

Last week Ebola came to the United States, it came on a specialized plane in the form of two medical missionaries. The conversation since has revolved around whether or not bringing them home for treatment was wise and/or just.

First, let’s talk about the risk of Ebola transmission, this seems to be the main concern for those who object to the patients being transferred to the U.S. As a nation we are at far greater risk from travelers not yet showing signs of the disease. The two missionaries are being well isolated and every precaution has been taken to ensure the virus does not escape the containment unit. The risk of contamination, transmission, etc. is very low from these patients. It is certainly not zero, a lie I have heard too many times from the media, but it is extremely low.

An argument I simply can’t stomach is: If the missionaries caught Ebola while using the appropriate personal protection equipment (PPE) isn’t the American medical staff at the same risk? Absolutely not. In Africa Ebola is rampant, patients are kept in large wards, the disease is in the communities, and there is no possible way the healthcare providers could have kept their guard up at all times. The risk of contracting the disease while in Africa is high, no matter the protection they used.

Argument 2: They knew the risks and went over anyway, just leave them in Africa to suffer the consequences of their decision. True, they knew the risks and this a viable, though not-so-compassionate response to the problem. Honestly, I think either decision could have been rationalized though I am sure the families of the missionaries appreciate the choice we made to bring their loved ones home and if it had been your family member you would have wanted them home too.

Now that we have unpacked the risk of Ebola spreading in the U.S. I want to talk about the experimental Ebola antiserum. It is reported in the media that the two American missionaries have received this experimental antiserum and I have heard calls to release the drug to all those suffering in Africa. Advocates for release of the drug are particularly intent that it be given to the medical staff who has become infected while treating Ebola patients, since they were infected in the same way as the Americans. I understand the desire and it “feels” compassionate to fight to send this antiserum to Africa. However, there are some very important reasons why this should not happen:

First of all, we don’t know that this drug even works, it’s experimentation in humans is extremely limited, and for all we know it could cause more harm than good. It may seem like the simple solution in an emergency to toss protocol out the window. However, for the safety of the trial participants studies need to be limited in scope and as controlled as possible. If released to the general public or even the medical staff of Africa there would be no way to appropriately monitor for side effects and safety issues. Furthermore, to get the drug to the population as quickly as “demanded” would necessarily violate all study regulations and proper procedure in Africa. This is a huge risk, and if anything were to go wrong with the drug or study who would be blamed? Certainly America and the scientists. It simply isn’t a wise move.

Secondly, the supply of antiserum is extremely limited, there would be no way to make an acceptable amount of antiserum to treat those infected, presuming of course that the drug does what it is intended to do without major side effects.

The scientists have been painted as the bad guys by many of those pushing for the drug’s release and this is simply not true. Those scientists have committed their lives to finding a cure for Ebola and just because they are bound to a process you don’t like right now doesn’t mean that they are evil. If the process is followed and the trial successful perhaps we can have a long term cure for Ebola. Pushing to exempt this project from the scientific process will not help long term progress and could result in short term disaster.

It is easy and feels right to act on emotion, but it is rarely the wise choice.

[The contents of this blog are solely the responsibility of the author and do not represent the views of the Bioethics Program or Union Graduate College.]

The Botched Execution of Clayton Lockett: Is Lethal Injection Painless and Humane?

by Sean Philpott-Jones, Director of the Center for Bioethics and Clinical Leadership

Clayton Lockett died last week, but few will mourn his death. A four-time convicted felon, Mr. Lockett was executed by the State of Oklahoma for shooting and then burying alive a 19-year-old girl. Following his death, Oklahoma Governor Mary Fallin proudly stated that, “justice was served”.

Justice indeed was served, at least if you believe in the Biblical principle of an eye for an eye and a tooth for a tooth, for Mr. Lockett suffered greatly during the 43 minutes it took him to die by lethal injection.

Twenty minutes into the execution — during which Clayton moaned, writhed and gritted his teeth — correction officials discovered that the vein used to deliver a lethal cocktail of drugs had collapsed. Instead of entering his bloodstream, drugs that were meant to render Mr. Lockett unconscious, paralyze him, and stop his heart leaked into the surrounding tissue. He was partially awake and in considerable pain.

State officials called off the execution, but it was too late. Forty-three minutes after the execution began, Mr. Lockett suffered a heart attack and died.

Although a majority of Americans support the death penalty, capital punishment remains a controversial topic. Should our system of justice be based on rehabilitation or retribution? Can a society condemn the wanton taking of life by individuals like Clayton Lockett and yet sanction the same act by government officials? Is this penalty fairly applied to all of those accused of capital crimes or do racial and ethnic minorities bear a disproportionate burden of punishment?

No matter where you fall in this debate, the horrific manner in which Mr. Lockett died should raise serious concerns about our current method of execution by lethal injection.

Execution by lethal injection was first proposed in the 19th century. It came into widespread use in the 20th century, initially as a cost-effective means of involuntary euthanasia under the Action T4 program in Nazi Germany.

It wasn’t until the latter part of the 20th century that lethal injection became a common method of execution in the United States. Oklahoma was the first state to legalize the use of lethal injection, and other states quickly followed suit. It is the preferred method of execution in the 32 states that allow the death penalty.

Until recently, the approach used in the United States has remained largely unchanged from the lethal injection protocol first proposed by Oklahoma’s state medical examiner, Jay Chapman. Known as the Chapman protocol, it involves the use of three drugs: a barbiturate like sodium thiopental to render condemned prisoners unconscious and insensate, pancuronium bromide to cause paralysis and suppress respiration, and potassium chloride to trigger cardiac arrest.

But despite claims that this approach is more humane and less painful than other execution methods, this has never been demonstrated. Chapman himself did no research in designing the lethal injection protocol that bears his name. Similarly, no one has ever collected data that shows that lethal injection prevents the “unnecessary and wanton infliction of pain” required by the Eighth Amendment to the US Constitution.

Worse yet, states that allow execution by lethal injection are now forced to deviate from the Chapman protocol due to drug shortages. Several of the drugs used to execute condemned prisoners are in short supply, largely because imports from manufacturers in Europe have stopped.

The European Union limits the manufacture and export of drugs that can be used for capital punishment under its existing Torture Regulation. Many European drug companies no longer produce and sell these compounds. Of those companies in Europe and the US that do still manufacture these drugs, most are reluctant to sell them to state Departments of Corrections.

In states like Texas and Ohio — where lethal injection is the only execution method allowed by law — this shortage has left corrections officials scrambling to find alternative sources of these drugs or to devise alternative means to carry out state-sanctioned executions. Rather than use sodium thiopental, for example, some states have started using varying doses of a different drug — sodium phenobarbitol — alone or in combination with pancuronium bromide and potassium chloride as their lethal injection cocktail.

States are also calling upon small companies known as compounding pharmacies to provide the drugs required, as Oklahoma did for Clayton Lockett’s execution. But compounding pharmacies are not FDA-regulated. Sometimes, they are even not licensed or qualified to mix these particular drug combinations. States are thus using drugs of unknown quality and potency as part of the lethal injection protocol.

Our increasingly random approach to executing prisoners via lethal injection, using drugs obtained from poorly regulated sources, raises any number of questions about the constitutionality of this method of capital punishment. Regardless of what you might think about men like Clayton Lockett, they too have certain inalienable rights. One of these is the right to be free of “cruel and unusual punishments,” which includes guaranteeing that state-sanctioned executions are free of unnecessary and wanton pain.

There should be immediate moratorium on the use of the death penalty until we can prove that our current methods of lethal injection are indeed humane and pain free. Otherwise we are condemning thousands of inmates to a fate worse than death.

[This blog entry was originally presented as an oral commentary on Northeast Public Radio on May 8, 2014, and is available on the WAMC website. Portions are also adapted from an article written by Dr. Philpott-Jones and published in the March-April 2014 Issue of the Hastings Center Report (Philpott S. 2014. Execution by Lethal Injection: Illegal Research? Hastings Center Report 44(2): 11-12). The contents of this post are solely the responsibility of the author alone and do not represent the views of the Bioethics Program or Union Graduate College.]

Punishing the Promoters

by Sean Philpott, Director of the Center for Bioethics and Clinical Leadership

Earlier this week, the US Justice Department announced that pharmaceutical giant Johnson & Johnson agreed to pay more than $2 billion in fines and penalties for illegally marketing the drug Risperdal to doctors and patients.

For nearly seven years, pharmaceutical reps pushed this drug as a way to manage some of the behavioral issues, such as agitation or hostility, that are often seen in patients with dementia or developmental disabilities. Those problems make caring for these patients difficult, particularly in a nursing or group home setting.

The company also pushed the drug to treat some of the symptoms associated with attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) in children.

However, the US Food and Drug Administration (FDA) only approved Risperdal for use in patients with schizophrenia and bipolar disorder. It was not approved for use in demented or developmentally disabled patients. Moreover, despite knowing that older patients were at increased risk of stroke when using the drug, Johnson & Johnson aggressively marketed the drug to gerontologists — doctors who treat the elderly. The cardiovascular risks to patients, and the very fact that the drug was only approved to treat schizophrenia, were downplayed.

The $2.2 billion dollar settlement is, surprisingly, not the largest of its kind. In 2009, for example, the pharmaceutical company Pfizer was fined $2.3 billion for improperly pushing the painkiller Bextra. That drug was removed from the market when it was found to increase a user’s risk of stroke nearly three-fold.

Similarly, just last year British drug maker GlaxoSmithKline (GSK) paid the US Justice Department $3 billion to settle allegations that it illegally promoted drugs like Paxil and Wellbutrin for unapproved uses. GSK also hid the fact that its anti-diabetes drug Avandia was linked to heart attacks.

In the last decade alone, over two-dozen such cases have been settled and nearly $15 billion in criminal fines and penalties paid. One might hope that substantial penalties like these would dissuade pharmaceutical companies from inappropriately marketing drugs for unapproved and potentially dangerous uses.

Nothing could be further from the truth. A $2 billion settlement is simply seen as the price of doing business, and it barely makes a dent in drug companies’ bottom line. In one year alone, Risperdal brought in over $3 billion in sales. Given that blockbuster drugs like Risperdal can dominate the market for a decade or more, the financial incentives to commit wrongdoing are immense.

Don’t get me wrong. I am a strong supporter of the pharmaceutical industry. I believe that companies like Johnson & Johnson have every right to earn a profit by developing and distributing new drugs. It is that very incentive that leads to improvements in medical care and treatment, improvements that benefit all of us. But drug manufacturers should be allowed to put profits before patients.

As I have argued in the past, pharmaceutical companies have a legal and moral responsibility to ensure that their drugs are safe. This requires that they not only seek FDA approval to sell these drugs, but also that they abide by that Agency’s rules for marketing these drugs to doctors and patients. Moreover, it also requires that they inform physicians and consumers about the potential risks associated with their use, rather than downplay or hide them as so often happens.

Although the US Supreme Court ruled in Citizens United v. Federal Election Commission that corporations are people too, companies like Johnson & Johnson are not people. They have no moral compass. In order to ensure that they meet their ethical obligations to patients, we as a society thus need to impose some form of conscience on these companies.

Despite what I implied earlier, financial penalties are the way to go. The problem is that the penalties imposed to date are not nearly enough. A $2 billion penalty is merely a slap on the wrist. We need to encourage the Justice Department to demand increasingly larger penalties — in the range of $20, $30 or even $40 billion. These fines must substantially affect, or even eliminate, the profit that these companies earn from promoting inappropriate or unsafe use of drugs like Risperdal. Until then, it will simply be business as usual.

[This blog entry was originally presented as an oral commentary on Northeast Public Radio on November 7, 2013. It is also available on the WAMC website. Its contents are solely the responsibility of the author alone and do not represent the views of the Bioethics Program or Union Graduate College.]

Drug Pushers

by Sean Philpott, Director of the Center for Bioethics and Clinical Leadership

Like many academics — and contrary to the image of college professors as lazy scholars that take sabbaticals every other year and have their summers off — I about have four or five full-time jobs. I direct a graduate program in bioethics, teach six courses (including two summer courses), and supervise four students each year as they complete their Masters projects.

I also oversee an international training program, write and review federal grants, publish scholarly papers, record commentaries like this, edit a professional journal, and chair several institutional, professional and government committees. My colleagues do the same.

One of these colleagues, a professor at a prestigious university in Australia, just lost one of his five jobs. The Royal Australasian College of Physicians disbanded its ethics committee last week, which he chaired. It was disbanded just days after producing a report that criticized Australian doctors ties to drug companies. Release of the report was also quashed, leading many to speculate that the pharmaceutical industry strong-armed the College of Physicians to prevent a public denunciation of its drug marketing practices.

Drug companies spend over $10 billion a year to influence physicians and patients using a variety of techniques. They hire physicians as spokesmen and advisors, pay clinicians to recruit patients for clinical trials, sponsor professional conferences and training programs at luxury resorts, and send a bevy of attractive salespeople bearing drug samples and gourmet sandwiches to doctors offices.

Over 95% of American physicians have some sort of relationship with drug and medical device companies, ranging from paid consulting gigs to receiving food in the workplace. While taking a slice of pizza or a free coffee mug might not seem like a big deal, it is an incredibly effective marketing tool.

Of dozens of studies looking at physician prescribing habits, every one found that doctors are more likely to prescribe heavily promoted drugs to their patients even when there were cheaper and more effective treatments available. A gift as small as a ballpoint pen was found to affect treatment decisions.

Because of this, many medical schools, hospitals and clinics now prohibit their staff from taking gifts or accepting meals from drug company representatives. Most medical societies have also developed strict guidelines designed to reduce pharmaceutical industry influence on clinical practice. Finally, as part of the Affordable Care Act (or Obamacare), Congress passed the Physician Payment Sunshine Act.

The Sunshine Act requires drug companies and medical device manufacturers to report any payments — be they consulting fees, gifts, or sponsorship of training programs — they make to doctors and teaching hospitals. These records will be publicly available starting in 2014, allowing you to check how much money your physician received from Pfizer before you fill that prescription for Lipitor.

This sounds like a great idea in practice, but it probably won’t make a damn bit of difference. Money and gifts aren’t the only way that the pharmaceutical industry influences treatment decisions.

Consider, for example, free drug samples. These samples are excluded from the reporting requirements of the Sunshine Act, and doctors and patients love them. Free drug samples let doctors and patients see if a particular course of treatment is effective at little to no cost, and can be used to provide care to poor patients that lack prescription coverage.

But pharmaceutical companies don’t provide free samples of low cost generic drugs, only the latest and greatest (and most expensive) new treatments. Once these samples run out, a patient is unlikely to request and a doctor unlikely to recommend cheaper alternatives. In the long run, patients end up paying more with the free samples than they would if they’d be prescribed a lower cost but equally effective drug.

This isn’t to say that your doctor is in the pocket of the drug companies, even if she consults for Eli Lilly and has a closet full of Pfizer-branded swag. But her prescribing practices may be influenced in subtle ways that she is unaware of.

This also isn’t to demonize the pharmaceutical industry. Drug companies produce valuable lifesaving medicines. But these companies are beholden to corporate shareholders. It makes sense that they want to maximize profits while easing patient suffering. The easiest way to do that is to convince you that you need the latest and greatest drug, even if cheaper alternatives exist.

There’s nothing inherently wrong with this, even though it contributes to the escalating cost of medical care in the US. It is that very profit that provides the incentive for these companies to develop the dozens of miracle drugs that have come on the market over the last thirty years.

So how can you be sure that the drug your doctor just prescribed is the right one for you, both in terms of cost and effectiveness? The answer is quite simple: stop being so naive. Stop asking for the latest and greatest drug simply because you saw a commercial for it while watching the evening news: newer doesn’t always mean better. And stop assuming that the drug your doctor recommends is the best choice: inquire about alternatives, including low-cost generics, and ask why they are or are not right for you.

[This blog entry was originally presented as an oral commentary on Northeast Public Radio on October 24, 2013. It is also available on the WAMC website. Its contents are solely the responsibility of the author alone and do not represent the views of the Bioethics Program or Union Graduate College.]

Look Before You Leap

by Theresa Spranger, Bioethics Program Alumna (MSBioethics 2012)

Last week a US Food and Drug Administration (FDA) Advisory Committee recommended that restrictions on the diabetes drug, Avandia, be lessened.  The restrictions were originally placed in 2010 because of concerns that the drug caused an increased risk of heart failure.  The increased risk of heart failure was originally suggested by a researcher at the University of Cincinnati, he performed a study compiling data from several old Avandia trials.  His work suggested a 43% increased risk of heart attack in diabetic patients taking Avandia.  GlaxoSmithKline, the developer of Avandia, insisted that they had a study being performed that showed no increased risk of heart failure and had a superior design to the data analysis study.

At the time of the 2010 decision, Avandia was the most popular diabetes drug on the market, its popularity instantly dropped and the pharmaceutical company was accosted with lawsuits.  Settling these lawsuits and dealing with other issues from the FDA’s decision cost the company a small fortune.

The re-review we saw at the FDA last week is extremely rare.  The committee was called because of an analysis performed by Duke University.  Duke re-analyzed the data from the original study by GlaxoSmithKline.  This is a study that was specifically designed to show cardiac risk and that the company had stated showed no increased risk of cardiac event in patient’s taking the medication.

Duke’s analysis matched that of GlaxoSmithKline and because of this the board reversed their initial decision and recommended that restrictions be lessened. They have also asked that additional studies be performed to confirm this result.  It is important to note that the advisory board decision is only a recommendation to the FDA, so no formal lessening of restrictions has been made at this point.

If this reversal is formally made by the FDA it won’t erase the damage done.  Millions of Americans were using Avandia and were forced to change drugs because of these restrictions; they were told that the drug was dangerous to their health, which may not have been true.  Avandia’s stock plummeted, the company lost millions on penalties and legal cases, and the drug’s reputation is forever tarnished.

GlaxoSmithKline is certainly not a hapless victim. They had a history of data integrity issues with other drugs that led to a mistrust of the Avandia data.  However, when making decisions like this it’s a fine line between being cautious for reasons of patient safety and jumping to unfair conclusions about the risks of an experimental drug or treatment.

Pharmaceutical companies are often placed in a bad light by our society.  We view them as power hungry, money grabbing machines that have little or no regard for the people they claim to help.  This is a gross misinterpretation.  Certainly, they are companies and therefore concerned with profit margins, but our American market system is based on a big risk/big reward theory.

These companies risk billions of dollars on drugs that have a limited chance of ever getting to market. Clinical trials are hugely expensive and placed under heavy scrutiny along the way.  This is not to say that data cannot be manipulated.  However, even the most cynical among us should admit that a pharmaceutical company would be concerned about the safety of their drug, if for no other reason than that being repeatedly sued is an expensive endeavor.

It is important in a situation like this, with so much at stake, to have all of the facts before making a decision.  It’s nice that the advisory committee has corrected their mistake, but it would have been nicer to have avoided the error in the first place.

[This blog entry was originally posted in a slightly edited form on Ms. Spranger’s blog on June 14, 2013. Its contents are solely the responsibility of the author alone and do not represent the views of the Bioethics Program or Union Graduate College.]