The life cycle of a medical advance usually goes something like this: from discovery at the research bench and replication of findings, to translational research and clinical trials, to implementation. The bottleneck can be at any one of these stages, and often it is in the discovery one; we just haven’t yet found the thing that works.
But other times, we have – the intervention works, we have shown and confirmed that it works, and yet for some reason, it just hasn’t caught on.
In medicine, we talk a good deal about overuse and misuse of resources leading to waste. But once in a while, we face the opposite problem.
Here are three stories of amazing medical advances that remarkably have not spread.
Less sickling, less being sick
Sickle cell disease is a disorder in which hemoglobin – the part of red blood cells that carries oxygen to body tissues – has difficulty doing its job. It is the most common inherited blood disorder in the United States, affecting 70,000 to 80,000 people. Patients are vulnerable to repeat “pain crises” when red cells sickle, or distort their shape. These episodes are typically treated with fluids, painkillers, and, in severe cases, exchange transfusion, where patients receive working red blood cells and swap out the dysfunctional ones.
The only known cure is a bone marrow transplant – a very intricate and risky procedure and thus usually reserved for a select few. Yet for the many individuals who don’t undergo curative transplant, there is another excellent option. There exists a single medication that leads to significantly fewer hospitalizations, reduced pain crises, fewer episodes of acute chest syndrome (a painful complication when lung vessels become clogged with sickled cells), and even longer lifespans. If that’s not enough, this one medication has also been projected to save the United States 26 million dollars annually if used in every eligible patient.
That wonder drug is called hydroxyurea. It works by increasing what is known as hemoglobin F, which is actually the form of the molecule we have as fetuses. More production of this type of hemoglobin leads to less assembly of the damaged version, resulting in less cell sickling and better oxygen delivery.
The FDA approved hydroxyurea for sickle cell patients in 1998, and their decision was based on a powerful randomized trial showing that taking the drug nearly halved all complications in adult patients. Patients had fewer pain crises (2.5 per year compared to 4.5), longer times to first pain crisis (3 months compared to 1.5 months), fewer acute chest events (25 compared to 51), and fewer transfusions (48 versus 73). The drug was relatively well tolerated, with no “important adverse effects.” The main side effect to watch out for is decreased blood cell counts, which can be effectively monitored with regular blood draws.
A second prospective non-randomized study evaluated the long-term efficacy and safety of hydroxyurea and found that after eight years, all the above benefits were maintained. Moreover, the probability of 10-year survival was significantly longer for those treated (86% vs 65%), even though those taking the drug may have been sicker overall. The same bump in survival was seen for patients with variants of sickle cell disease combined with thalassemia. Because of these findings, hydroxyurea is currently recommended in patients with frequent pain episodes, vaso-occlusive events such as acute chest syndrome, or severe anemia. It is the sole effective disease-modifying therapy currently approved for sickle cell disease.
Despite these striking findings, since 1998 the drug has been astonishingly underused. In 2008, a panel convened by the NIH shone a spotlight on its gross underutilization. One study found that despite three quarters of physicians agreeing with recommendations on hydroxyurea use in adult patients, only 45% reported prescribing it for all their eligible patients. Pediatric sickle patients fared no better; in 2009, a survey of hundreds of pediatricians caring for sickle cell revealed that only 8% reported that at least half of their patients were on the medication. Meanwhile, nearly two-thirds said 30% or fewer of their patients were taking the drug.
So what is the hold up? Dr. Courtney Thornburg at Duke Children’s Hospital has a fantastic presentation available online on just this topic. Barriers to more widespread use exist from both doctor and patient vantage points, she points out. On the patient side, one study found that major barriers among non-users were beliefs that the drug wouldn’t work, general lack of awareness of what it is or that it even exists, and concerns about safety (“I was told that HU causes birth deformities”; “My concerns are that it could lead to cancer”). From the doctor’s perspective, major obstacles include concerns about patient adherence with taking the meds, following up with lab work to monitor for side effects, or remaining on contraception while taking the drug to prevent potential risk of birth defects.
Interestingly, one study found that black physicians prescribed hydroxyrurea at better rates than non-black physicians. Ninety-four percent of black versus 73% of white versus 40% of other race respondents thought that hydroxyurea was effective or very effective in sickle cell treatment. With the majority of sickle cell patients black, this finding may signal a possible role of racial divides between caregivers and patients contributing to worse outcomes.
Dr. Thornburg’s presentation called for clearly delineated guidelines and increased education to combat some of these obstacles. Hopefully the drug will soon be brought to the forefront of the doctor-patient interaction where it belongs.
The strange case of the vanishing vaccine
Anyone who lives in an endemic area knows to watch out for ticks. Lyme Disease is the most common vector-borne disease in the United States, with approximately 300,000 cases each year. There is no vaccine to prevent it.
Except that there was, at one point. As Dr. Gregory Poland from the Mayo Clinic describes it, the rise and fall of the Lyme vaccine marks:
“...the first time in the modern era that an FDA-licensed vaccine in the United States was withdrawn because of low public demand and class action lawsuits, despite the context of a high background rate of disease and a continuing, if not increasing, significant public health burden of morbidity.”
The vaccine known as LYMErix was developed in 1998 by SmithKline Beecham (now GlaxoSmithKline). A randomized, placebo-controlled study published in the New England Journal of Medicine found its efficacy to be 76% for symptomatic disease and 100% for asymptomatic disease after three doses. Though more people who received the vaccine experienced soreness, redness, or swelling at the injection site in addition to broader symptoms such as fever or chills, the risk of these symptoms is common to all immunizations; and all self-resolved without treatment. Of particular note, there was no difference in joint symptoms between the vaccine and the placebo groups. Based on these outcomes, the Advisory Committee on Immunization Practices (ACIP) of the CDC gave a permissive recommendation for the use of LYMErix in people aged 15 to 70 who lived in Lyme endemic areas.
Yet within its first year of use, vaccine recipients began speaking out about perceived side effects. By and large the most common was arthritis, and their voices gained a national spotlight. “Vaccine victims” were covered extensively in the media and on the Lyme Disease Network, a non-profit citizen action group. In 1999, the manufacturer of the vaccine was faced with a class action lawsuit.
Were these effects really due to the vaccine? It was an extremely important question worth studying. Fortunately, we had the data to do so.
In the beginning stages of vaccine administration, doctors reported all adverse events to the Vaccine Adverse Events Reporting System (VAERS). By 2001, over 1,400,000 doses of the vaccine were distributed, and the VAERS database listed 905 adverse events. Joint pain was the most common (with 250 reports), and there were 59 reports of arthritis. However, when the data was examined further, it was found that just as many vaccine recipients reported arthritis as those in a comparison of unvaccinated people. There was also no increase in arthritis after the second and third doses of the vaccine, which would be expected if it were causative.
In 2001, after examining all the evidence and hearing testimonies from those affected, a panel convened by the FDA decided that there was no evidence that the vaccine was responsible for joint symptoms. For continued safety, they required the manufacturer to collect more data through its ongoing phase IV clinical trial.
But every day publicity took a hit, with the power of public mistrust gaining traction against the power of what the data actually showed. In the face of class action lawsuits, decreasing sales, and diminishing doctor support, the manufacturer finally decided to withdraw the vaccine from the market. Moreover, the public backlash against SmithKline Beecham was a big reason why competing manufacturer Pasteur Mérieux Connaught decided not to push forward with their own Lyme vaccine – even after it had already demonstrated efficacy in phase III clinical trials.
Sadly, the vaccine never made a comeback. According to Dr. Polack: “Since 2002, there has been no active, sustained interest in developing or licensing a Lyme disease vaccine in the United States.” A few have spoken out against the absurdity of this, including Dr. Stanley Plotkin in a 2013 op-ed in the New York Times.
Yet as we enter 2015, we remain essentially where we were before 1998.
If breast cancer runs in your family, you might want to ask about this
Did you know there is a medication to help prevent breast cancer in high-risk patients?
Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are better known for their use in breast cancer treatment. But now these drugs, which operate by interacting with estrogen receptors in breast tissue, have been shown to work for primary prevention, too.
In 2013, the U.S. Preventive Services Task Force (USPSTF) recommended that doctors should offer tamoxifene or raloxifene to women at increased risk. It is a Grade B recommendation, meaning there is “high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.”
The idea that SERMs could prevent cancer was sparked by the finding that women who received treatment for cancer in one breast also had lower rates of cancer development in the non-affected breast. A large randomized trial known as the Breast Cancer Prevention Trial was initiated in 1992 to test the hypothesis. The outcomes on over 13,000 women were impressive: five years of tamoxifen treatment reduced the relative risk of developing invasive breast cancer by 49% and non-invasive breast cancer by 50%. In absolute terms, this meant average annual rates of breast cancer were 3.43 per 1000 women in the tamoxifen group, compared to 6.76 per 1000 in the placebo group. Over 5 years, the absolute risk decreased from 2.6% for 1.3%. Moreover, women with a history of a type of precancerous condition known as atypical hyperplasia showed an 86% reduced relative risk – an absolute decrease from 10.11 cancers per 1000 women to 1.43.
Was this too good to be true? Use of tamoxifen did not come without risk: as it works by interacting with estrogen receptors, it can also affect tissues outside the breast. One of these susceptible tissues is the endometrium of the uterus. The rate of endometrial cancer was increased in the tamoxifen group (with a risk ratio of 2.53) and occurred mainly in women over 50. Still, all endometrial cancers were stage I (localized disease), and no endometrial cancer deaths occurred. A second adverse event was increased risk of blood clots, which also occurred mainly in women over 50. However, despite the increased relative risk, the absolute risk remained quite small.
But what if we could use another SERM that interacts more exclusively with breast tissue? Another large randomized trial focused on tamoxifen’s sister drug raloxifene, and found that 5 years of treatment reduces invasive breast cancer risk in high-risk women by about 38 percent. Here, raloxifene was statistically as effective as tamoxifen in reducing the risk of invasive breast cancer – and it came with significantly less risk of endometrial cancer and blood clots. A longer-term analysis confirmed the reduced risk for at least 5 years after treatment as well.
As a result, both tamoxifen and raloxifene were approved by the FDA in 1998 for the primary prevention of breast cancer. Guidelines from the American Society of Clinical Oncology (ASCO) and the USPSTF discuss their role in certain high-risk populations, including those with BRCA1 or BRCA2 mutations who do not undergo prophylactic mastectomy, women over 35 with a personal history of certain pre-cancerous breast lesions, women between 35 and 59 who meet a certain risk score, and women over 60. The bottom line is that while the risk-benefit calculation varies for individual women, the conversation should absolutely be had.
Yet in spite of the recommendations, the use of SERMs for prevention has remained staggeringly low in practice. Among 50,884 women in the Sister Study, where participants had at least one sister diagnosed with breast cancer, only 2% (1,046) reported ever taking tamoxifen for prevention. Overall, in 2005 0.08% of US women were found to be on tamoxifen for breast cancer prevention. And the US is not alone; one 2011 study in Australia found that less than 3% of 3788 high-risk women had used SERMs for prevention.
In an excellent cover story of HemeOnc Today, several experts weighed in on why this may be the case. A major barrier could be reluctance to prescribe or take a medication with potential side effects when the patient is otherwise healthy. With the exception of vaccinations, the act of intervening to prevent future illness is actually still quite unique in the medical world. When someone is ill, it is easier to swallow starting a medication. When a person appears totally healthy, however, starting something with potential adverse effects – even when the absolute risk of those adverse effects is small – is a harder sell.
A recent perspective piece by Wickerham and Vogel, however, is hopeful the lag can be improved by attacking it on several fronts. The National Cancer Institute can take a lead in promotion on both doctor and patient fronts, they argue; professional organizations can develop training for the next generation of residents and fellows; and breast cancer advocacy groups can push even harder for this underused, effective course of action.
Last year, Dr. Atul Gawande published a fantastic piece in The New Yorker called “Slow Ideas.” His premise was simple: why do some innovations in medicine spread, while others are slower to catch on?
I’d recommend reading the whole thing. But some highlights include recognizing that ideas spread more slowly when the problems are more invisible, along with realizing how change is fundamentally a social process.
“Simple ‘awareness’ isn’t going to solve anything,” Gawande asserts, and I agree.
Here’s to the start of something more.
A special thank you to the many outstanding physicians and researchers without whom these advances – and this article – would not be possible
 This paper by LE Nigrovic and KM Thompson has an excellent summary of what the basic science world was saying in response to the clinical suspicion. In short, it was theoretically plausible that a subset of individuals with a certain genotype (known as type DR4+ of the human leukocyte antigen (HLA)) could experience a greater risk of developing arthritis after the Lyme vaccine due to a cross-reactive autoimmune response. As the authors explained: “Differential genetic susceptibility applied to immunization risk represents a new concept. Although the clinical importance of the DR4+ genotype to a person receiving an OspA Lyme vaccine remains incompletely understood, some suggest screening recipients for HLA type DR4+ and vaccinating only non-carriers.”
 Aromatase inhibitors are also a burgeoning field of interest in primary breast cancer prevention, and these may someday be an alternative to SERMs. Their promise was shown in the International Breast cancer Intervention Study (IBIS-II), which randomized approximately 4000 postmenopausal women to the drug or a placebo. Women who received the drug had a 50% reduction in invasive breast cancer. Aromatase inhibitors have not yet been approved for primary breast cancer prevention.