Investigating Compounding Pharmacies
The saga began just a few days after the tainted steroid-induced fungal meningitis outbreak started in October 2012. Because I’m writing a book about the back pain industry, it was a story I followed closely. The medication in question, methylprednisolone acetate, is commonly used in epidural steroid injections administered to reduce the inflammation associated with herniated discs and other spine pathology.
This supposedly sterile solution was produced by a compounding pharmacy in Framingham, MA. Some 18,000 vials had been shipped to hospitals and pain clinics in 23 states, starting in the spring of 2012. By the next spring, 749 patients had fallen ill, and 63 people had died. The FDA regulates pharmaceutical companies, but state pharmacy boards regulate compounders, and these agencies have been known to look the other way in the face of substantial trespasses.
For many compounding pharmacies, the big business is not sterile preparations. It’s custom-compounded hormone therapy, used by millions of women, and hyped by Suzanne Somers, who has written a stack of enthusiastic books on the subject. My editor at More magazine wondered whether custom-compounded hormones might pose a risk to women’s health.
Starting in the late 1990s, 160,000 post-menopausal women aged 50–79 years were enrolled in the Women’s Health Initiative (WHI) trial, funded by the National Institutes of Health, designed (among other endpoints) to assess if hormone treatment offered them any cardiovascular benefit. That trial was halted prematurely in 2002, because the outcomes suggested that among post-menopausal women, Prempro, which combined conjugated equine estrogen and a synthetic progestin, (the only drug used in one arm of the large-scale Women’s Health Initiative) was linked with serious medical problems -- such as an increased risk of heart attack, stroke, blood clots and invasive breast cancer. The risks, therefore, exceeded the benefits.
The media largely misinterpreted the published outcomes, setting off a panic, and causing younger women, who were actually in menopause, and their doctors to eschew hormone products made from pregnant mare’s urine. Many hot and sleepless women looked for “safe,” “natural” alternatives, turning to custom-compounded bioidentical hormone therapy (BHT). Compounding pharmacies claim these “bio-identical” hormones are exactly the same as what a woman’s body produced in her more fertile years.
At More, we wanted to better understand what such compounding pharmacies were offering, since without FDA regulation of their business practices, that remained unclear. We knew that the FDA had dismissed “bioidentical” as a meaningless marketing term. Mexican yams provide the molecules for all bioidentical hormone products, whether they are made commercially or formulated in a pharmacy’s back room. From a pharmacological standpoint – at least at the molecular level – there was no difference. But our main focus of the article was: Would the capsule contents reflect what the doctor had prescribed? We developed a study design to see what was inside the pills and a plan for a story that we hoped would help a lot of women and alter public policy.
The magazine would order independent laboratory analysis of a compounded BHT product. A well-known academic physician would provide 12 copies of a single prescription, which we would distribute to 12 compounding pharmacies across the country. Once the prescriptions were filled, they’d be shipped to reporter Jillian Keenan, who would log them as they were received. Finally, we’d ship the prescription vials to Flora Research Laboratories in Oregon, where they would be analyzed, first to see if the ingredients were what we had ordered, and second, to determine if the specimens had been contaminated by foreign substances or bacteria.
There was one problem: Independent laboratory testing is expensive. More's deputy health editor Nancy Stedman suggested getting a grant, which we ultimately received from The Fund for Investigative Journalism (FIJ), to the tune of $5,000.
Together, Stedman and I developed the study design, aware all the while that this project engaged us well beyond our pay grade. In the course of my 35-year career, I have never worked as closely with an editor on a story as I did with Stedman on this one. I think we recognized that neither of us could do it alone.
Meanwhile, the prescriptions made their way across the country, first to Keenan in New York and then to Flora. Several pharmacies bungled the job and shipped the prescriptions to incorrect addresses, which sent Keenan on a wild goose chase to various strangers’ apartments.
When she wasn’t chasing down prescriptions, Keenan took care of filing a FOIA request with the FDA to obtain the agency’s reports of adverse events resulting from compounded and FDA-approved hormone therapy. I hoped I’d find some good leads in these documents – perhaps the names and addresses of compounding pharmacies that were repeat offenders. When the documents finally arrived, after weeks of nagging the agency, virtually every piece of useful information had been redacted.
Meanwhile, I dove into the medical literature describing bioidentical hormone therapy, simultaneously hitting the drug policy white papers. Arlene Weintraub’s meticulously researched book, Selling the Fountain of Youth, helped tremendously.
Once I’d read almost every article written about bioidentical hormone therapy, the ill-fated Women’s Health Initiative study, and subsequent investigations revealing that hormones weren’t nearly as dangerous as WHI had suggested, I began contacting OB-GYNs. Most of them were affiliated with the North American Menopause Society (NAMS), and they were furious about the way in which Somers had brainwashed their patients, who walked in waving print-outs from the Internet, determined to get the “safe” and “natural” hormones they were certain would restore them to premenopausal pizazz.
Many women had already visited clinics whose sole purpose is hawking hormones. Physicians at these establishments are rarely board certified as OB-GYNs or endocrinologists, or even equipped with useful expertise. Still, they order expensive blood hormone level tests and, on the basis of those largely irrelevant results, prescribe large doses of compounded bioidentical estrogen, progesterone and testosterone at a cost of several thousand dollars a year –- none of which is covered by health insurance.
According to the OB-GYNs I spoke with, few patients understood that plant-based (“natural”) bioidenticals were not the sole province of compounding pharmacies, but could also be obtained from commercial pharmaceutical manufacturers. In the latter incidence, the drugs, would be FDA-approved, uniform in dosage, and covered by health insurance.
I interviewed multiple NAMS doctors, helpful and smart people who also happened to be “key opinion leaders.” That sounds like a welcome status for an expert source, but those of us who write about health care know what the term signifies –- that the expert likely has consultancy arrangements with pharmaceutical companies, and possibly, conflicts of interest. I asked for their disclosure statements, which inevitably listed a string of such corporate entanglements.
The market for hormones in the U.S. is huge -- about 40 percent of the 33 million menopausal women in the U.S. will use these drugs at some point in menopause. Before WHI scared women off, the entire market belonged to Big Pharma. Wyeth Pharmaceuticals’ revenues from Prempro –- the hormone product that combines estrogen and progestin –- dropped from $2 billion in sales 2001 to just under $240 million in 2012. Many of those dollars drifted into compounders’ cash registers
With so much money at stake and abounding corporate relationships among the “experts,” I needed lab results to confirm I wasn’t being taken for a ride –- a thinly veiled effort by physicians to help Big Pharma get its money back. If the content of the capsules wasn’t significantly different than what was written on the prescription, our hypothesis wouldn’t hold up.
As I waited for Flora to submit its results, I contacted pharmaceutical experts who were aware of the questions surrounding custom hormone compounding. They agreed to study the lab report and tell me what was significant.
As the lab suffered further delays, I spoke with hormone clinic patients. Some women had used testosterone to enliven their sexless marriages and subsequently grown hair where hair shouldn’t be or developed alarming clitoral changes. Other hormones may have caused women to gain or lose significant amounts of weight, develop breast cancer or endometrial hyperplasia, or suffer liver failure.
One of my pharmaceutical experts told me to call the attorney general’s office in Tennessee. Something nefarious had occurred in the state, involving a company called HRC. Digging through that mess, I found that perhaps 30,000 women had been treated with hormone pellets at HRC’s affiliated clinics across the U.S. Patients had filed so many reports of malfeasance that the AG had shut the Tennessee clinics down, and the company’s physician proprietor –- who had already been sanctioned and lost his license in other states –- had fled.
I had court transcripts. I had potent patient interviews. But almost none of this would make it into the piece, and not only because of the word count. As is their responsibility, More’s lawyers would veto actionable material, which meant that I’d be saying very little about Suzanne Somers or HRC. I couldn’t even mention the name of another massive franchiser of hormone clinics.
Finally, I received the lab results, and passed them quickly to my pharmaceutical experts. The outcomes were appalling: The 12 prescriptions -- that should have been identical -- demonstrated gross differences in weight and potency.
The pharmaceutical experts, whom I sorely wished had been involved in the original study design, were not satisfied. The data we had gathered was a start, but it wasn’t enough. We needed additional analysis, and FIJ agreed to give us $2,000 more.
Within 24 hours of the printer’s deadline, we got the additional data. And what data it was! Nearly every prescription was substantially short of the prescribed quantity of progesterone, the hormone that balances estrogen and is required to prevent women who use estrogen from developing uterine cancer. The OB-GYNs were correct: Women who relied on “custom” compounded hormones had no idea what they were getting and were taking a huge risk. From what Flora Labs could tell us, the ingredients were not contaminated with foreign substances or bacteria, but subsequently I learned that the high-powered equipment required to assess such factors accurately is typically not something a commercial lab will have on hand.
When the article was published in the October 2013 issue of the magazine, I was raring to send it out through social medial channels, but More has a policy of delaying the posting of article links on its website for a couple of months. I understood the intent –- to sell the most newsstand copies. But the piece had the potential to influence legislation intended to crack down on compounders that at that moment was on the move through Congress.
The day before the article was posted online, Congress passed The Drug Quality and Security Act, which mildly restricts the activity of large-scale compounders that produce sterile drugs. However, it will hardly affect pharmacies that compound bioidentical hormones.
Slowly, news of the Hormone Hoax rolled out, with reports on Huffington Post, the website PharmWatch, and in a number of other health-related publications. From the annual NAMS meeting in Dallas in October, one physician, Lauren Streicher, MD, sent me a note to say that the article had hit the conference like “a very large wave.” Another doctor noted that this was perhaps the first time that independent laboratory research published in a woman’s magazine became the main topic of discussion at a medical conference.
Still, I kept looking at the overstuffed file box that More’s talented fact-checker, Aliyah Baruchin, had returned to me. Although the new legislation would impose some control on compounders who make sterile drug products, hormone compounders had walked away virtually unscathed. In any event, the FDA was dependent on sterile compounders’ voluntary registration with the FDA, which was like suggesting that your ten-year-old enlist to tell you before he hit a baseball through the living room window.
Fat chance, I thought.
As it stands, the ball’s fair game. Who among us is going to pick it up and run with it?
Image by Robson# via Flickr