All posts by CPTFadmin

New Drugs So Pricey They Need New Payment Plans

Sarah Owermogle, Politico: August 13, 2018.


[…] FDA LOOKS TO MODERNIZE CANCER TRIALS — The FDA issued guidance on Friday intended to speed up certain early and mid-stage clinical trials for oncology drugs by merging elements typically found in phase 1 and phase 2 trials. Studying multiple patient groups separately for criteria like safety and efficacy has the potential to lower costs and add efficiency, Commissioner Scott Gottlieb said in a statement.

Initial reviews were positive: “There is no tablet that got handed down from God to Moses that said drug trials must be conducted in three conventional phases,” said Dana-Farber’s George Demetri, who chairs the American Association for Cancer Research’s government affairs committee. The new approach, known as expanded cohort trials, could allow researchers to be more nimble, Demetri said — more easily spotting a drug’s effect on specific cancers or realizing earlier that it isn’t working.

Vanessa Lucey said the Cancer Research Institute, where she directs the venture fund and clinical accelerator, has itself moved toward these kinds of studies.

The costs: But while the proposed changes could streamline certain cancer trials — the guidance is limited to cases in which a drug’s benefits justify an increased risk, like for cancers that have no cure — there still could be additional costs. In the guidance, the FDA warned that trial sponsors would need to streamline logistics and data collection, and incorporate plans to assess data in real time.

“What’s important about this guidance is it’s trying to come to some kind of political compromise,” said Diana Zuckerman, president of the National Center for Health Research. “It’s trying to do two things that usually conflict — speed and safety don’t go together, usually.” She added: “It’s OK to say they’re going to do this to speed up drug development, but some patients are definitely going to get harmed.” […]

Read the full story here.

NCHR Testimony of TIRF REMS

Stephanie Fox-Rawlings, National Center for Health Research: August 3, 2018


Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.

Our Center worked with Congress to create the REMS [risk evaluation and mitigation strategy] program in legislation that became law quite a few years ago.  The goal always was to enable FDA to approve effective drugs even if they had worrisome risks. The REMS were intended to lower those risks as much as possible, so that patients taking the drug were most likely to be helped and least likely to be harmed.

A major shortcoming of these risk mitigation strategies has always been ensuring that they are effective in lowering risks.  It is difficult to evaluate the effects of the REMS on prescribers, pharmacists, patients, and others who accidentally or intentionally misuse the drugs.

The data before you today that evaluated these REMS are limited.  However, we commend the efforts of TRIG [TIRF REMS Industry Group] and the FDA to assess these REMS and to improve the data as well as the effectiveness of these REMS. We strongly urge that TRIG implements the FDA recommendations in a timely and complete manner to more fully understand to what extent the REMS are or are not working, so that they can increase the benefit to risk ratio of their products.

The data are especially limited regarding the proportion of prescriptions for cancer pain or other indications.  That is a big problem since this product is only approved for cancer pain.

And, also like the FDA reviewers, we are very concerned about the increased rate of adverse events after implementing REMS.  Even though the reports are voluntary and therefore could be biased, the increase after REMS is very disturbing. The quality of the REMS data are also low because only a subset of potential events are evaluated.  This makes the data very difficult to interpret. However, other sources of data also suggest that there are concerning numbers of therapeutic errors, misuse and exposures with severe consequences.

Congress supported REMS because they were intended to reduce the risk of serious harms, while continuing to make the product available to those who need it. The data indicate that these REMS need improvements. For example:

  • 42% of new users were not opioid-tolerant. That is not the indication, so that means at least 42% are prescribed off label.  This increases the risk for central nervous system and breathing problems.
  • Relatively high proportion of survey respondents did not know the correct indication or that TIRFs need to be stopped if around-the-clock opioid medication is stopped.  They learned this in the training, but could not remember it when surveyed later.

Changes to the REMS should be designed to make them more effective at protecting patients. Changes in REMS should not be aimed primarily at increasing the number of prescriptions.  An increase in prescriptions without ensuring appropriate prescribing, dispensing, use, and disposal increases the risk that more patients will be harmed, and that the drugs will be used accidentally or misused by individuals who were not prescribed the drug.

Bottom line: TIRFs [transmucosal immediate-release fentanyl] provide important options for cancer patients dealing with pain. However, we all know that they carry very serious risks and that’s why we need REMS that protect patients’ these risks.  These REMS are not working as well as the should to protect patients and need to be improved.

 

The Human Tragedy of Poorly Regulated Medical Devices Gets the Spotlight in a Netflix Film

Amy Martyn, Consumer Affairs: July 27, 2018.


The motel where Ana Fuentes arrives one evening with her young daughters charges $110 for a single night and doesn’t offer weekly discounts. Fuentes asks the cashier for a moment so she can think about it.

Outside, the camera captures an anguished look on her face. It’s clear she can’t afford the expense. She books the room anyway. “Do you like it?” she asks her girls as they excitedly unpack their bags.

The family used to have an apartment, but Fuentes had to visit the emergency room so often that she lost her job, her daughters explain on camera.

Such situations aren’t rare in the United States, where experts have repeatedly warned that millions of Americans have almost nothing in savings and are a single medical disaster away from financial ruin. The problem is compounded nationwide by costly healthcare, lack of access to paid sick leave in the workforce, or a combination of the two.

But Fuentes’ story, like dozens of others featured in an upcoming expose about the medical device industry, has a particularly cruel twist. She says in the film that she was healthy until a doctor convinced her to undergo what was supposed to be a routine, non-surgical medical procedure — getting small birth control implants permanently embedded into her fallopian tubes.

The $155 billion medical device industry has mostly avoided the type of scrutiny that drug companies and health insurers sometimes face from elected officials and others. On Friday, a documentary about the device industry and patients like Fuentes called The Bleeding Edge is set to go live on Netflix, bringing what advocates hope will be widespread attention to an industry increasingly characterized by lax safety standards, enormous power in the operating room, and horrific side effects.

“If you’re going to have something implanted in your body for potentially the rest of your life, wouldn’t you like it to be really well-tested beforehand? Is that really too much to ask?” says Dr. Diana Zuckerman, a health policy analyst who has worked in the White House and as a staffer in Congress.

The current president of the National Center for Health Research, Zuckerman and the other researchers at her non-profit are among the few to have taken interest in faulty medical devices.  

Diving into the medical device industry

Hollywood directors Kirby Dick and Amy Ziering knew they wanted to make a documentary film about preventable medical injuries, Dick tells ConsumerAffairs, but that was about it.

Sitting in on one patient advocacy meeting for research, they caught a presentation that Zuckerman gave about the medical device industry and the ease with which questionable products get on the market. They decided that they had found their story.

The team interviewed approximately 70 patients to make their film, Dick tells ConsumerAffairs. The film also includes interviews with numerous whistleblowers, such as doctors, former Food and Drug Administration (FDA) researchers, and one medical device sales rep who requested anonymity in exchange for speaking on camera.

Dick and Ziering were previously nominated for an Oscar for The Hunting Ground, their documentary about sexual assault on college campuses. Another earlier film, The Invisible War, is an expose about sexual assault in the military.

But persuading people to speak out against the device industry made for the most challenging interviews they’ve done, Dick tells ConsumerAffairs. (A medical device industry lobbyist touts in one scene that the industry is more powerful than some national governments.)

The “E-sisters”

As the film and the research it is based on shows, the problem is bigger than any single device. The Bleeding Edge captures the story by focusing  on four implants — three of which were used exclusively women’s reproductive organs.

The narrative is driven forward by the story of the “E-sisters,” or the activists who say that they suffered debilitating side effects after receiving the permanent birth control implant Essure.

For years, the “E-sisters” have organized a grassroots campaign to convince regulators to ban Essure from doctors’ offices. That goal seemed like an uphill battle until last week, when Bayer suddenly released an announcement that Essure will no longer be sold in the United States by the end of the year.

Bayer frames the move as a “business decision.” The announcement came one week before the Netflix documentary was scheduled for release.

“I’m very glad that these issues are getting this kind of attention, and I hope that Bayer’s decision to take Essure off the market won’t take away from the bigger message of the film,” says Zuckerman, “which is the whole process for devices that makes no sense at all.”

“Why in the world would you want to have a regulatory agency in our government, the FDA, having much lower standards for devices than they do for prescription drugs?”

Essure implants

The story of Essure, in particular, only saw the light-of-day thanks to the “E-sisters,” who count 30,000 people in their Essure Problems Facebook group and have convinced numerous elected officials, doctors, and even early clinical trial participants to join their cause.

“One of the things that is disturbing to me is that these issues only came to light because of the work of victims,” former Representative Mike  Fitzpatrick (R-Pa.) said in an interview several years ago.

Women who agreed to participate in clinical trials for Essure in the late 90s have said that they there were sold on a pitch to get a free, non-hormonal, and permanent birth control that was already proven safe.

A nickel coil, the size of a ballpoint pen, would be placed in each fallopian tube. That was designed to create an inflammatory response so that the coils would become permanently encased in the resulting scar tissue.

Regulators with the FDA approved the device in 2002, despite admitting that they knew little about the long-term side effects of such a procedure, as footage that the E-sisters had obtained captures. What’s more, numerous clinical trial participants later said that their painful side effects were not included in the company’s official data.

Doctors not long after began using the devices without questioning potential risks. “For some reason we did that to women. And I did that, too,” Dr. Shawn Tassone, an Austin-based gynecologist, tells ConsumerAffairs.

Insurance and profit margins

The sales representatives who taught doctors how to place the devices — something that Bayer has defended as a common industry practice — offered no instructions on how the device should be removed if there were side effects.

“We were just told from the very beginning that even if they’re misplaced, you don’t have to remove them,” Tassone remembers.

The role that insurance coverage may have played isn’t examined specifically in The Bleeding Edge, but testimony from patients and doctors suggests that getting insurers to cover Essure proved much easier than getting them to cover removal.

Tassone remembers that both private plans and Medicaid paid fairly generously for the Essure procedure, especially considering that inserting Essure was much cheaper and less labor-intensive than tubal surgery, the older sterilization procedure.

“If you think about a tubal ligation where you go to the operating room, it’s $400 [in profit] give or take,” he say. “Essure in the office, after you subtract the amount of the device, it’s probably $1100.”

Treating any resulting side effects proved impossible for women navigating unfamiliar territory. Angie Firmalino, the New York City mail carrier who founded the E-sisters network, initially seeked help from a doctor who morcellated the coils into small pieces — sending the nickel elsewhere in her body.

Connecting patients with doctors who are willing and able to properly remove the devices, as well who are able to code it correctly so that insurance will pay, has since become one of the E-sister’s major tasks.

Tassone, for his part, implanted his last Essure device in 2013. He says it was a call from another doctor who convinced him not to perform the procedure anymore; a woman with Essure apparently had gotten pregnant, he was told, which can be extremely dangerous for both the baby and the mother. One researcher has counted 303 fetal deaths linked to the device.

Tassone has since switched sides, counseling the E-sisters online and in the operating room. He estimates that he has conducted 600 Essure removal surgeries.

Trust remains despite ban

In recent years, the advocates have convinced the FDA to add a black box warning to Essure. Later on, they were able to help pass a rule which requires doctors to give patients more detailed warnings about the product.

But that didn’t appear to stop most doctors from trusting the device. The American College of Obstetricians and Gynecologists continues to say on its website that lasting pain from the procedure is “rare.” By contrast, nearly 27,000 reports have been filed to the FDA’s “adverse event” report database describing health problems caused by Essure and 16,000 lawsuits have been filed here. An estimated 750,000 women worldwide have undergone the procedure.

Now that Essure is off the market, doctors may be more willing to attempt removal surgery, Tassone says, something he thinks is necessary but frightening

“They’re going to think its not a big deal to take out,” he worries. (More detailed advice about removal surgeries is offered on the Essure Problems page).

Generally, before any major surgery involving a permanent implant, researchers advise patients to press doctors on the specific devices that will be used. Zuckerman, the health policy analyst who helped inspire the Netflix film, recalls that even she struggled to get specific answers when she asked a doctor what brand of hip he would choose for her own surgery.

The procedure ultimately went well, she says, but trying to search for good data comparing brands beforehand was nearly impossible.

“In the vast majority of cases, the surgeons are still quoting the company data,” Zuckerman says. “The company’s data on humans is nonexistent —  at least publicly.”

FDA Expedited Approval Process Raises Concerns About Risks

Roxanne Nelson, Medscape: July, 20, 2018


The Breakthrough Therapy designation created by the US Food and Drug Administration (FDA) expedites the approval of drugs intended to treat serious or life-threatening conditions, thus allowing patients quicker access to therapies. But the shorter approval process leads to great uncertainty about safety and efficacy. Are the risks greater than the benefits?

These concerns have been raised again in a new study published online July 17 in JAMA and in an accompanying commentary in the JAMA Forum.

The findings from this study “suggest that the FDA’s expedited review programs may invite greater risks than benefits,” writes Austin B. Frakt, PhD, director of the Partnered Evidence-based Policy Resource Center, Veterans Health Administration, Boston, Massachusetts, in the commentary.

“The idea that doing something more quickly means it is not done as well has considerable face validity,” he comments.

Shorter Trials Lacking Controls  

The new study reviewed all FDA approvals given Breakthrough Therapy designation from 2012 through 2017 and found that the pivotal trials used as a basis for these approvals more often than not lacked randomization, double-blinding, and control groups. They also tended to use surrogate markers as primary endpoints and had small patient cohorts.

In addition, over half of the approvals were based on the results of a single trial.

This leads to greater uncertainty, say the authors, led by Joseph S. Ross, MD, MHS, an associate professor of medicine at Yale University School of Medicine, New Haven, Connecticut.

It is not known whether the effect observed in the single small trial will be observed in a larger population or replicated in another trial, or whether the effect observed over the short term will persist over the longer term.

“There is also uncertainty over whether the effect observed on the outcomes used in these shorter trials, such as surrogate markers of disease, will be confirmed by eventual demonstration of benefit and safety based on clinical outcomes like improved mortality or improved symptoms,” Ross told Medscape Medical News.

Ross said that the FDA “is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions.”

“My expectation is that this is what the public and clinicians — and Congress — want,” he told Medscape Medical News. “More novel therapies coming to market as quickly as is reasonably possible, while still assuring drug safety and efficacy.”

But their research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non–breakthrough therapy drugs.

If this “trade off” is going to be made, with novel drugs entering the market on the basis of evidence that is generally accompanied by greater uncertainty, “we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarket trials are conducted within a reasonable period of time,” he added. “This will resolve some of this uncertainty and ensure that the drugs are associated with the benefit/safety profile that we expect based on the initial clinical studies, allowing clinicians and patients to make fully informed decisions about whether to use these novel treatments.”

Minimal Evidence

In this study, Ross and colleagues reviewed all new FDA approvals that had been granted Breakthrough Therapy designation, looking at the pivotal clinical trials that serve as the basis for approval as well as pre-market development and review times.

They identified 46 agents that had received Breakthrough Therapy designation between 2012 and 2017, based on 89 pivotal trials. Of these, more than half were for oncologic indications (n = 25 [54.3%]), followed by infectious disease (n = 8 [17.4%]); just over half the drugs (n = 25 [54.3%]) were considered to be first in class.

In addition, nearly two thirds of these agents were designated as orphan products (n = 30 [65.2%]) and qualified for Fast Track review (n = 24 [52.2%]) and Accelerated Approval (n = 18 [39.1%]).

Many of these drugs had only one clinical trial (median, 1; interquartile range [IQR], 1 – 2), while the median number of patients enrolled in these trials was 222 (IQR, 124 – 796). Roughly half of all approvals were made on the basis of a randomized trial (n = 27 [58.7%]), while 21 studies used double-blind allocation (45.7%), 25 had an active comparator or placebo control group (54.3%), and 10 had a clinical primary endpoint (21.7%).

Clinical trials that supported breakthrough approvals with Accelerated Approval status were less likely to be randomized than those without Accelerated Approval (3 trials with Accelerated Approval [16.7%] vs 24 trials without Accelerated Approval [85.7%]; P <  .001).

The median time to FDA approval was 4.9 years (IQR, 2.7 – 7.6 years), and all eight agents (100%) that received accelerated approval had at least one clinical safety or efficacy-focused postmarketing requirement, as did 18 (64.3%) without Accelerated Approval designation.

Information Lost

Approached for comment, Diana Zuckerman, PhD, president of the National Center for Health Research, noted that historically, the FDA required two clinical trials with clinically meaningful endpoints, and for cancer, that was survival.

“That was the standard, and it did result in complaints,” she told Medscape Medical News. “There were complaints that trials take too long and are too expensive, and complaints from patients and physicians that the drugs weren’t available.”

“This research letter in JAMA is important, as it is a very well done reminder what you lose when you speed things up,” Zuckerman added.

The FDA required two studies because the second study shows replication of the results, and that is the keystone to research. “You need to replicate the results,” Zuckerman commented.

“This paper also shows that we have lost double-blinding and active comparators and placebo groups half of the time,” she said. In addition, “very few trials had a clinical endpoint.”

“We lost a lot of information, and this means that patients are using drugs that may not be as effective as older treatments, but yet are much more expensive,” she said.

Zuckerman pointed to a study that she coauthored in 2016, which found that many new cancer drugs approved on the basis of surrogate endpoints retain their approval status and remain available to prescribing physicians even though postmarketing studies show no survival or quality-of-life (QoL) benefit compared with placebo or observation groups.

Of 36 drugs that were approved between 2008 and 2012, 18 did not significantly prolong overall survival in postmarket studies. QoL information was available for 7 drugs, and compared with placebo or observation groups, 2 drugs demonstrated worse effects on QoL, 4 drugs showed no statistical difference, and 1 drug had mixed results. In addition, 1 drug reduced overall survival and 6 offered no survival benefit compared with placebo or observation groups.

“These drugs are very expensive,” Zuckerman explained, noting that they ranged in price from $20,237 to $169,836 per year. “There is no relationship between cost and evidence.”

The FDA does allow access to experimental drugs, and with the Right to Try law, it is now easier for patients to gain access, she said. “At least patients know that they are getting an experimental treatment, and that long-term safety and efficacy are unknown. But with expedited approval, they believe they are getting something backed by evidence.”

Right now, the model is “unsustainable,” she said.

Zuckerman also added that the FDA is not responding to these concerns by enforcing requirements for postmarketing studies, and those that are completed are not giving useful results.

Greater Risks Than Benefits?

In the related commentary, Frakt says the findings suggest that the FDA’s expedited review programs may invite greater risks than benefits.

He notes that most of the new drugs are approved even though information concerning long-term outcomes is limited, and more than two thirds are approved on the basis of clinical trials lasting under 6 months.

In addition, the median approval for cancer drugs in the expedited process is 6 months, which is much quicker than in Europe and Canada.

However, it remains an “empirical question” as to whether the drugs that receive an expedited approval have a worse or better benefit/risk balance compared with drugs that receive standard approval.

Frakt points out that over time, safety concerns may arise for drugs with expedited approval. “Drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings,” he says. “We should therefore continue to monitor these drugs and update the performance of expedited approval programs as more information is available.”

But another concern, he adds, is that from 2009 through 2013, only a minority of drugs with expedited approval had their efficacy tested in a postmarket trial within 3 years, as previously reported by Medscape Medical News.

Accepting greater risks may be “reasonable and consistent” with patient preferences, as the expedited review programs are for new agents designed to treat serious conditions and address unmet medical needs. But because many of these new drugs are quite costly and are paid for with public funding through Medicare, Medicaid, and other programs, Frakt notes that “the patients’ point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers.” […]

Read the original article here.

To Improve Treatments, Researchers Want To Hunt For Clues In Medical Records

Richard Harris, NPR: July 16, 2018


When you go to your doctor’s office, sometimes it seems the caregivers spend more time gathering data about you than treating you as a patient.

Electronic medical records are everywhere – annoying to doctors and intrusive to patients.

But now researchers are looking to see if they can plow through the vast amount of data that’s gathered in those records, along with insurance billing information, to tease out the bits that could be useful in refining treatments and identifying new uses for drugs.

For instance, when the Food and Drug Administration approves a new drug, doctors often don’t know the optimal dose, the ideal length of treatment or who is most likely to benefit – or be harmed – by the medicine.

Especially when it comes to drugs fast-tracked through the process, “there are so many questions that remain when a drug is approved,” says Dr. Janet Woodcock, who heads the FDA’s drug-approval branch. “Many of the questions are not interesting to academics so they’re not done in the academic setting, and companies are not compelled to do them… so nobody does them. I’ve been raving about this for years!” she said Wednesday at a meeting on the subject convened by the Friends of Cancer Research, a nonprofit organization that builds collaborations between government, industry and advocacy groups.

Relevant information is buried – somewhere – within medical records and billing information. The question is whether it’s practical to extract it from these systems, which weren’t designed to be used for research.

It’s an uphill climb. Researchers involved in an experiment to explore medical records to study cancer treatment discovered that these data sources lack some very basic information.

For example, these records don’t typically even show whether a patient is alive or dead.

“Physicians are spending a tremendous amount of time entering information into electronic systems to the point they can hardly find time in their day to look patients in the eye,” says Dr. Andrew Norden, chief medical officer of Cota, a company that crunches digital medical data gleaned from these records. “Yet to date, we’ve not been able … to drive knowledge forward much from that information.”

Cota joined five other organizations recently in an experiment to explore the value of electronic medical records to improve cancer treatment. Friends of Cancer Research asked these six firms to plumb their databases to see what they could conclude about the value of various treatment options for a type of lung cancer.

The results of this pilot study, unveiled at the Friends of Cancer Research meeting, showed that the six independent dives into the data came up with roughly consistent answers. That suggests that this information gathered about patients, dubbed real-world data, is potentially useful for research.

But there are plenty of challenges. Take death. Doctors and insurers rarely add this information into the record of a patient who has died. Researchers have to find that critical piece of information elsewhere.

“We do have a national death index,” says Nancy Dryer, at the medical data firm called IQVIA. “It’s phenomenal, but it’s slow.” It can take more than a year for a death to be recorded there, which means people trying to study medical records have to deal with a difficult time lag. There are other faster ways to glean this information – for example from credit bureaus. “They actually know if you’re dead!” Dryer says. But medical researchers can’t readily access that information because of privacy concerns.

Another challenge is using medical records to measure whether a disease has progressed. Researchers who run formal clinical trials of a potential new drug define disease progression carefully. But that’s not usually the case in medical records. Researchers have to figure out ways to infer that from the medical records and in billing information, and that’s dodgy.

Sometimes it’s even hard to tell a patient’s exact diagnosis from an electronic medical record. “Apparently that’s a very big barrier, to get the diagnosis correct in the patient’s own chart!” Woodcock says. “So you can see how far we have to go.”

Nevertheless, Woodcock says this is an avenue well worth exploring. Much of medical research now depends on formal clinical trials – typically tests that pit a new treatment against a placebo or one that is already on the market.

The traditional system provides the most reliable data, but “it’s incredibly, ridiculously and unsustainably expensive,” Woodcock says. She laments that clinical trials operate largely in isolation from routine clinical care, “and we must bring them back together if we’re going to investigate interventions rapidly and thoroughly.” Figuring out how to use real-world evidence “is the key to making that happen,” she says.

But data from individual patient records is never going to be consistent or error-free. The balancing act is to figure out when a finding extracted from this noisy information is good enough to make judgments that affect clinical practice.

Insurers and drug companies are already interested in using this information to help establish the value of a particular treatment, which can affect whether a new treatment is covered, and at what price. But drug companies would also like to use this information to identify new or expanded uses for drugs already on the market.

Diana Zuckerman, president of the National Center for Health Research, is concerned about that use of real-world data. “You can pretty much make the data show whatever you want it to show,” she says in a telephone interview. So if you put the data into the hands of drug companies, who have a financial incentive to find new uses for their drugs and improve their market share, “you can’t expect they’re going to be conducting unbiased research if nobody’s monitoring that.” […]

Read the original article here.

Letter from Nonprofits to DC Mayor and Other Officials About Dangers of Artificial Turf and Playgrounds


Identical letters were sent to members of the DC City Council, the DC superintendent of schools, and other DC officials.

July 10, 2018

Dear Mayor Bowser:

We, the undersigned organizations and businesses, are writing to strongly urge that the District government stop installing synthetic turf and poured in place (PIP) playgrounds in Washington, D.C.  There is a growing body of evidence that these synthetic surfaces endanger children’s health, are harmful to our environment, and are very expensive to install and maintain compared to natural grass.1,2,3,4

  • In the District, children have been endangered by surface temperatures that have been measured in excess of 160 degrees Fahrenheit.5,6,7,8
  • For years, children in the District have been endangered by playing fields that are excessively hard, far out of compliance with any safety standards.  Until last year, the District did not correctly monitor Gmax testing of field hardness (called impact attenuation) to ensure even a minimum safety standard to prevent injuries when children fall.  A score of 165 or higher is considered too dangerous for children by the Synthetic Turf Council.  Dozens of DCPS playing fields exceeding that 165 score remain in service with no remediation at all.8,9,10,11

When products with known risks of injuries from infection, high temperature and hardness are installed, the District has an obligation to provide monitoring and safety standards.  That hasn’t been done in a timely manner,12 and students have been harmed.13,14,15

We oppose the District’s plans to install more synthetic turf of any type on playing fields or playgrounds. These plastic carpet systems and infills are exposing our children and environment to harmful toxicants, as documented by independent researchers at Yale,1  Mount Sinai Children’s Environmental Health Center,16,17 and the National Center for Health Research.18  

Synthetic rubber playground materials (often called PIP) that are used under slides, swings, and other children’s play areas contain similarly harmful toxicants.19

  • Claims from vendors or industry-funded scientists that the materials are proven safe are inaccurate.  Misleading claims that there is “no evidence” of harm does not mean that the synthetic systems are proven to be safe.  On the contrary, concerns about safety have been documented by independent scientists noted above, and were examined during the Obama Administration by the Consumer Product Safety Commission (CPSC) and the Environmental Protection Agency (EPA).20  The CPSC and EPA reviews were not completed as expected in 2016 or 2017, and it is not clear whether those reviews are held to the scientific standards that had previously been established.
  • In addition to the health risks to school children and athletes, approximately three tons of infill materials migrate off of each synthetic turf field into the greater environment each year.  About 2-5 metric tons of infill, such as tire crumb, must be replaced every year for each field, meaning that tons of the infill have migrated off the field into grass, water, and our homes,21 and the fields also continuously shed microplastics as the plastic blades break down.22,23 These materials may contain additives such as PAHs, flame retardants, UV inhibitors, etc., which can be toxic to marine and aquatic life; and microplastics are known to migrate into the oceans, food chain, and drinking water and can adsorb and concentrate other toxins from the environment.24,25,26
  • Synthetic surfaces also create heat islands.27,28  In contrast, organically managed natural grass saves energy in urban areas by dissipating heat, cooling the air, and reducing energy to cool nearby buildings.  Natural grass and soil protect groundwater quality, biodegrade polluting chemicals and bacteria, reduce surface water runoff, and abate noise and reduce glare.29

We urge your support for the installation of organically managed natural grass fields and Engineered Wood Fiber (EWF) playgrounds that are properly engineered, installed, and maintained for ADA compliance.  It is incumbent upon the District of Columbia to:

  1. Halt all installation of synthetic playgrounds and playing fields.
  2. Remove synthetic playgrounds and playing fields instead of renovating them or replacing with new synthetic materials.
  3. Prioritize proper installation and maintenance of ADA compliant natural surfaces.
  4. Solicit public ideas for increasing the inventory of playing fields and recreation opportunities.

We endorse the January 2018 policy recommendations made by DC Safe Healthy Playing Fields, which provide a measured and reasonable approach to phasing out of synthetic fields and playgrounds in DC and replacement with natural surfaces.

As noted above, there is well-documented evidence on the environmental and health dangers of synthetic fields and playground surfaces.  The scientists and consultants denying these risks to the DC Government have financial and other ties to the companies that manufacture and install synthetic turf or to the recycled rubber industry.

Tax dollars should not be spent on products that endanger children’s health and harm our environment.

Sincerely,

DC Safe Healthy Playing Fields

Alliance of Nurses for Healthy Environments

American Academy of Environmental Medicine

Audubon Naturalist Society

Beyond Pesticides  (October 2017 Testimony to DC City Council)

Cedar Lane Unitarian Universalist Church Environmental Justice Ministry

Center for Environmental Health

Children’s Environmental Health Network (October 2017 Testimony to DC City Council)

Kids in Danger

MOM’s Organic Market

Maryland Public Interest Research Group

Maryland Environmental Health Network

Moms Clean Air Force

National Center for Health Research

Neighbors of the Northwest Branch of the Anacostia River

New Hampshire Safe Water Alliance

Non Toxic Communities

Public Employees for Environmental Responsibility (Statement on EPA Study)  

Safe Grow Montgomery

Safe Healthy Playing Fields Coalition

Sierra Club DC

Trash Free Maryland

Toxics Action Center Campaigns

Women’s Alliance for Democracy & Justice

 

CC:

City Administrator Rashad Young

Department of Energy & the Environment Director Tommy Wells

Deputy Mayor of Education Ahnna Smith

Deputy Mayor for Health and Human Services HyeSook Chung

Department of Parks and Recreation Director Keith Anderson

Department of General Services Director Greer Gillis

DCPS Chancellor Amanda Alexander

Interagency Synthetic Turf Task Force

Evan Lambert, Fox5

Mike Ozanian, Forbes

Rachel Sadon, DCist

 

PDF Copy: July 10 Safe Healthy Playing Fields to Mayor Bowser et al

References:

  1. Benoit G, Demars S. Evaluation of organic and inorganic compounds extractable by multiple methods from commercially available crumb rubber mulch. Water Air Soil Pollut 2018. 229(3): 64. https://doi.org/10.1007/s11270-018-3711-7
  2. Llompart M, Sanchez-Prado L, Pablo Lama J, Carcia-Jares C, Roca E, Dagnac T. Hazardous organic chemicals in rubber recycled tire playgrounds and pavers. Chemosphere. 2013. 90: 423-431. http://www.elcorreodelsol.com/sites/default/files/chemosphere_maria_llompart.pdf
  3. Massachusetts Toxics Use Reduction Institute. Sports turf alternatives assessment: Preliminary results: Cost analysis. September 2016. http://www.turi.org/Our_Work/Home_Community/Artificial_Turf/Cost_Analysis
  4. Ozanian M. How taxpayers get fooled on the cost of an artificial turf field. Forbes. September 28, 2014. https://www.forbes.com/sites/mikeozanian/2014/09/28/how-taxpayers-get-fooled-on-the-cost-of-an-artificial-turf-field/#ea43caf5db28
  5. Images of the high temperatures recorded at Janney Elementary on June 12, 2017. On a day when the ambient air temperature was 96°F, poured-in-place surfaces were 164°F and 165°F, artificial turf field was 162°F, while mulch and concrete were 122°F and 127°F, respectively.
  6. Image of the high temperature of an Envirofill field at Janney Elementary on October 1, 2017. The field was 136°F when the ambient air was 64°F.
  7. As temperatures increase, surface hardness also increases: Vidair C, Haas R, Schlag R. Testing impact attenuation on California playground surfaces made of recycled tires. Int J Inj Contr Saf Promot. 2007. 14(4): 225-30. https://www.ncbi.nlm.nih.gov/pubmed/18075871
  8. National Center for Health Research. Letter to the DC City Council on Artificial Turf. October 26, 2017. http://www.center4research.org/nchr-letter-dc-city-council-artificial-turf/
  9. Evaluation of D.C. testing results found that dozens of DCPS playing fields exceeded a g-max score of 165: Zuckerman D. Risks of head injuries on artificial turf fields in Washington, D.C. National Center for Health Research. 2017. http://www.center4research.org/risks-head-injuries-artificial-turf-fields-washington-d-c/ 
  10. Sadon R. Hardness test results reveal wider scope of artificial turf failures. DCist. October 12, 2017. http://dcist.com/2017/10/even_more_artificial_turf_fields_fa.php 
  11. Synthetic Turf Council. Guidelines for synthetic turf performance. 2011. https://cdn.ymaws.com/www.syntheticturfcouncil.org/resource/resmgr/guidelines/STC_Guidelines_for_Synthetic.pdf
  12. D.C. Department of General Services. Artificial athletic turf fields: Frequently asked questions. September 21, 2017. https://dgs.dc.gov/sites/default/files/dc/sites/dgs/service_content/attachments/UPDATED%20-%20FAQ%20Artificial%20Athletic%20Turf%20Fields%20-%209-21-17.pdf 
  13. McCray Q. Safety checks at D.C. playgrounds under question after boy injured on crumb rubber floor. WJLA. October 27, 2017. http://wjla.com/news/local/safety-checks-at-dc-playgrounds-under-question-after-boy-injured-on-crumb-rubber-floor
  14. Infections are the result of increased incidence of abrasions on artificial turf, see Williams S, Trewartha G, Kemp SP, Michell R, Stokes KA. The influence of an artificial playing surface on injury risk and perceptions of muscle soreness in elite rugby union. Scand J Med Sci Sports. 2016. 26(1): 101-108. https://www.ncbi.nlm.nih.gov/pubmed/25644277.  Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant staphylococcus aureus among professional football players. N Engl J Med. 2005. 352(5): 468-475. https://www.nejm.org/doi/full/10.1056/NEJMoa042859.  Van den Eijnde W, Masen M, Lamers E, van de Kerkhof P, Peppelman M, Van Erp P. The load tolerance of skin during impact on artificial turf using ex-vivo skin as the readout system. Science and Medicine in Football. 2018. 2(1): 39-46. https://www.tandfonline.com/doi/full/10.1080/24733938.2017.1390593
  15. Graphic one-minute video of student with serious infection from synthetic turf in DC
  16. The Children’s Environmental Health Center of the Icahn School of Medicine at Mount Sinai. Letter to DC City Council concerning state of fields and playgrounds maintained by the District Public Oversight Roundtable. October 12, 2017.
  17. The Children’s Environmental Health Center of the Icahn School of Medicine at Mount Sinai.  Artificial turf: A health-based consumer guide. May 2017. http://icahn.mssm.edu/files/ISMMS/Assets/Departments/Environmental Medicine and Public Health/CEHC Position Statement on Recycled Rubber Turf Surfaces May 10 2017.pdf
  18. Booker N, Fox-Rawlings S. Children and athletes at play on toxic turf and playgrounds. National Center for Health Research. 2018. http://www.center4research.org/children-athletes-play-toxic-turf-playgrounds/
  19. Canepari S, Castellano P, Astolfi ML, Materazzi S, Ferrante R, Fiorini D, Curini R. (2018) Release of particles, organic compounds, and metals from crumb rubber used in synthetic turf under chemical and physical stress. Environ Sci Pollut Res Int. 25(2): 1448-1459. https://link.springer.com/article/10.1007%2Fs11356-017-0377-4
  20. EPA. Federal research on recycled tire crumb used on playing fields. 2018 https://www.epa.gov/chemical-research/federal-research-recycled-tire-crumb-used-playing-fields
  21. York T. Greener grass awaits: Environmental & fiscal responsibility team up in synthetic turf. Recreation Management. February 2012. http://recmanagement.com/feature_print.php?fid=201202fe02.
  22. Magnusson K, Eliasson K, Fråne A, et al. Swedish sources and pathways for microplastics to the marine environment, a review of existing data. Stockholm: IVL- Swedish Environmental Research Institute. 2016. https://www.naturvardsverket.se/upload/miljoarbete-i-samhallet/miljoarbete-i-sverige/regeringsuppdrag/utslapp-mikroplaster-havet/RU-mikroplaster-english-5-april-2017.pdf
  23. Kole PJ, Löhr AJ, Van Belleghem FGAJ, Ragas AMJ. Wear and tear of tyres: A stealthy source of microplastics in the environment. Int J Environ Res Public Health. 2017 14(10). pii: E1265. https://www.ncbi.nlm.nih.gov/pubmed/29053641/
  24. Kosuth M, Mason SA, Wattenberg EV. Anthropogenic contamination of tap water, beer, and sea salt. PLoS One. 2018. 13(4): e0194970. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895013/
  25. Oehlmann J, Schulte-Oehlmann U, Kloas W et al.  A critical analysis of the biological impacts of plasticizers on wildlife. Phil Trans R Soc B. 2009. 364: 2047–2062. http://rstb.royalsocietypublishing.org/content/364/1526/2047
  26. Thompson RC, Moore CJ, vom Saal FS, Swan SH. Plastics, the environment and human health: Current consensus and future trends. Philos Trans R Soc Lond B. 2009. 364: 2153–2166. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873021/
  27. Thoms AW, Brosnana JT, Zidekb JM, Sorochana JC. Models for predicting surface temperatures on synthetic turf playing surfaces. Procedia Engineering. 2014. 72: 895-900. http://www.sciencedirect.com/science/article/pii/S1877705814006699
  28. Penn State’s Center for Sports Surface Research. Synthetic turf heat evaluation- progress report. 2012. http://plantscience.psu.edu/research/centers/ssrc/documents/heat-progress-report.pdf
  29. Stier JC, Steinke K, Ervin EH, Higginson FR, McMaugh PE. Turfgrass benefits and issues. Turfgrass: Biology, Use, and Management, Agronomy Monograph 56. American Society of Agronomy, Crop Science Society of America, Soil Science Society of America. 2013. 105-145. https://dl.sciencesocieties.org/publications/books/tocs/agronomymonogra/turfgrassbiolog

FDA Repays Industry by Rushing Risky Drugs to Market

Caroline Chen, ProPublica. June 26, 2018.


Nuplazid, a drug for hallucinations and delusions associated with Parkinson’s disease, failed two clinical trials. In a third trial, under a revised standard for measuring its effect, it showed minimal benefit. Overall, more patients died or had serious side effects on Nuplazid than after receiving no treatment.

Patients on Uloric, a gout drug, suffered more heart attacks, strokes and heart failure in two out of three trials than did their counterparts on standard or no medication.

Nevertheless, the U.S. Food and Drug Administration approved both of these drugs — with a deadly aftermath. Uloric’s manufacturer reported last November that patients on the drug were 34 percent more likely to die from heart disease than people taking an alternative gout medication. And since the FDA fast-tracked approval of Nuplazid and it went on the market in 2016 at a price of $24,000 a year, there have been 6,800 reports of adverse events for patients on the drug, including 887 deaths as of this past March 31.

The FDA is increasingly green-lighting expensive drugs despite dangerous or little-known side effects and inconclusive evidence that they curb or cure disease. Once widely assailed for moving slowly, today the FDA reviews and approves drugs faster than any other regulatory agency in the world. Between 2011 and 2015, the FDA reviewed new drug applications more than 60 days faster on average than did the European Medicines Agency.

Europe has also rejected drugs for which the FDA accelerated approval, such as Folotyn, which treats a rare form of blood cancer. European authorities cited “insufficient” evidence of health gains from Folotyn, which shrinks some tumors but hasn’t been shown to extend lives. It costs more than $92,000 for a seven-week course of treatment, according to research firm SSR Health.

As patients (or their insurers) shell out tens or hundreds of thousands of dollars for unproven drugs, manufacturers reap a windfall. For them, expedited approval can mean not only sped-up sales but also — if the drug is intended to treat a rare disease or serve a neglected population — FDA incentives worth hundreds of millions of dollars.

“Instead of a regulator and a regulated industry, we now have a partnership,” said Dr. Michael Carome, director of the health research group for the nonprofit advocacy organization Public Citizen, and a former U.S. Department of Health and Human Services official. “That relationship has tilted the agency away from a public health perspective to an industry friendly perspective.”

While the FDA over the past three decades has implemented at least four major routes to faster approvals — the current commissioner, Dr. Scott Gottlieb, is easing even more drugs’ path to market. The FDA okayed 46 “novel” drugs — whose chemical structure hadn’t been previously approved — in 2017, the most in at least 15 years. At the same time, it’s rejecting fewer medications. In 2017, the FDA’s Center for Drug Evaluation and Research denied 19.7 percent of all applications for new drugs, biologics, and efficacy supplements, down from a 2010 peak of 59.2 percent, according to agency data.

President Trump has encouraged Gottlieb to give patients faster access to drugs. “You’re bringing that down, right?” Trump asked the commissioner at a May 30 event, referring to the time it takes to bring drugs to market. “You have a lot of good things in the wings that, frankly, if you moved them up, a lot of people would have a great shot.”

Faster reviews mean that the FDA often approves drugs despite limited information. It channels more and more experimental treatments, including Nuplazid, into expedited reviews that require only one clinical trial to show a benefit to patients, instead of the traditional two.

The FDA also increasingly allows drugmakers to claim success in trials based on proxy measurements — such as shrunken tumors — instead of clinical outcomes like survival rates or cures, which take more time to evaluate. In return for accelerated approval, drug companies commit to researching how well their drugs work after going on the market. But these post-marketing studies can take 10 years or longer to complete, leaving patients and doctors with lingering questions about safety and benefit.

“Clearly, accelerated approval has greater uncertainty,” Dr. Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, said in an interview. When only a single trial is used for approval, “in some cases, there may be more uncertainty about safety findings or with the magnitude of effectiveness.”

She attributed the increased use of expedited pathways to more drugmakers developing treatments for rare diseases, “where there’s unmet need, and where the patient population and providers are eager to accept more uncertainty.”

The FDA’s growing emphasis on speed has come at the urging of both patient advocacy groups and industry, which began in 1992 to contribute to the salaries of the agency’s drug reviewers in exchange for time limits on reviews. In 2017, pharma paid 75 percent — or $905 million — of the agency’s scientific review budgets for branded and generic drugs, compared to 27 percent in 1993.

“The virginity was lost in ’92,” said Dr. Jerry Avorn, a professor at Harvard Medical School. “Once you have that paying relationship, it creates a dynamic that’s not a healthy one.”

Industry also sways the FDA through a less direct financial route. Many of the physicians, caregivers, and other witnesses before FDA advisory panels that evaluate drugs receive consulting fees, expense payments, or other remuneration from pharma companies.

“You know who never shows up at the [advisory committee]? The people who died in the trial,” lamented one former FDA staffer, who asked not to be named because he still works in the field. “Nobody is talking for them.”

The drug industry’s lobbying group, Pharmaceutical Research and Manufacturers of America, continues to push for ever-faster approvals. In a policy memo on its website, PhRMA warns of “needless delays in drug review and approval that lead to longer development times, missed opportunities, higher drug development costs and delays in treatments reaching patients.”

The agency has internalized decades of criticism that painted it as an obstacle to innovation, said Daniel Carpenter, a professor of government at Harvard and author of a 2010 book on pharmaceutical regulation at the FDA. “They now have a built-in fear of over-regulation that’s set in over the last 20 years.”

To be sure, nobody wants the FDA to drag out drug reviews unnecessarily, and even critics acknowledge that there’s no easy way for the agency to strike the perfect balance between sufficient speed and ample information, particularly when patients have no other treatments available, or are terminally ill.

“I think it’s reasonable to move drugs faster particularly in the case where you’re dealing with an extremely promising new product which treats a serious or life-threatening disease,” said Dr. Aaron Kesselheim, an associate professor at Harvard Medical School. “The key, though, when you do that is that you’ve got to make sure you closely follow the drug in a thoughtful way and unfortunately, too often we don’t do that in the U.S.”

Gregg Gonsalves used to be a member of ACT UP, the HIV advocacy group that tried to take over the FDA’s headquarters in Rockville, Maryland, in 1988, accusing the agency of holding back cures. While he didn’t storm the FDA building, Gonsalves participated in other protests that led the FDA to accelerate approvals. Now an assistant professor of epidemiology at Yale School of Public Health, he said he fears HIV activists “opened a Pandora’s box” that the industry and anti-regulation think tanks pounced on.

“We were desperate. We naively had the idea that there were hundreds of drugs behind a velvet curtain at the FDA being held back from us,” he said. “Thirty years of our rash thinking has led us to a place where we know less and less about the drugs that we pay more and more for.”

After thalidomide, taken by pregnant women to prevent nausea, caused thousands of babies in the early 1960s to be born with stunted limbs, Congress entrusted the FDA with ensuring that drugs going on the market were both safe and effective, based on “substantial evidence” from multiple trials.

Assembling this evidence has traditionally required three stages of clinical trials; the first in a small cohort of healthy volunteers to determine a safe dosage; the second to assess the drug’s efficacy and side effects; and then, if results are positive, two larger trials to confirm the benefit and monitor for safety issues. An FDA team of in-house reviewers is then assigned to analyze the results and decide whether the agency should approve the drug. If reviewers want more input, the agency can convene an advisory committee of outside experts.

As the FDA’s responsibilities expanded in the 1970s, review times began to lag, reaching more than 35 months on average in 1979. The AIDS crisis followed soon thereafter, prompting complaints from Gonsalves and other activists. Their protests spurred the Prescription Drug User Fee Act in 1992, which established industry fees to fund FDA staff salaries. In return, the FDA promised to review drugs within 12 months for normal applications, and 6 months for priority cases.

The more that the FDA relied on industry fees to pay for drug reviews, the more it showed an inclination towards approval, former employees say.

“You don’t survive as a senior official at the FDA unless you’re pro-industry,” said Dr. Thomas Marciniak. A former FDA medical team leader, and a longtime outspoken critic of how drug companies handle clinical trials, Marciniak retired in 2014. “The FDA has to pay attention to what Congress tells them to do, and the industry will lobby to get somebody else in there if they don’t like you.”

Staffers know “you don’t get promoted unless you’re pro-industry,” he added.

This tilt is reflected in what senior officials choose to highlight. The agency’s Center for Drug Evaluation and Research gives internal awards to review teams each year, according to Marciniak and the former FDA employee who requested anonymity. Both said they had never seen an award granted to a team that rejected a drug application. The FDA did not respond to ProPublica’s request for a list of award winners.

Higher-ups would also send congratulatory emails to medical review teams when a drug was approved. “Nobody gets congratulated for turning a drug down, but you get seriously questioned,” said the former staffer, adding that the agency’s attitude is, “Keep Congress off your back and make your life easier.”

Dr. Peter Lurie, a former associate commissioner who left the FDA in 2017, recalled that John Jenkins, director of the agency’s Office of New Drugs from 2002 to 2017, gave an annual speech to employees, summing up the year’s accomplishments. Jenkins would talk “about how many approvals were done and how fast they were, but there was nothing in there saying, we kept five bad drugs off the market,” said Lurie, now president of the nonprofit Center for Science in the Public Interest in Washington, D.C. Jenkins declined to comment.

“I personally have no interest in pressuring people to approve things that shouldn’t be approved — the actual person who would be accountable would be me,” Woodcock said. She added that the FDA’s “accountability to the public far outweighs pressure we might feel otherwise.”

Congress has authorized one initiative after another to expedite drug approvals. In 1988, it created “fast track” regulations. In 1992, the user fee law formalized “accelerated approval” and “priority review.” When the law was reauthorized in 1997, the goal for review times was lowered from a year to 10 months. In 2012, Congress added the designation, “breakthrough therapy,” enabling the FDA to waive normal procedures for drugs that showed substantial improvement over available treatments.

“Those multiple pathways were initially designed to be the exception to the rule, and now the exceptions are swallowing the rule,” Kesselheim said.

Sixty-eight percent of novel drugs approved by the FDA between 2014 and 2016 qualified for one or more of these accelerated pathways, Kesselheim and his colleagues have found. Once described by Rachel Sherman, now FDA principal deputy commissioner, as a program for “knock your socks off, home run” treatments, the “breakthrough therapy” label was doled out to 28 percent of drugs approved from 2014 to 2016.

Nuplazid was one of them. It was created in 2001 by a chemist at Acadia Pharmaceuticals, a small biotech firm in San Diego. Eight years later, in the first of two Phase 3 trials, it failed to prove its benefit over a placebo.

The company, which had no approved drugs and hence no revenue stream, halted the second trial, but wasn’t ready to give up. Acadia executives told investors that the trials failed because the placebo patients had a larger-than-expected improvement. They asked the FDA for permission to revise the scale used to measure benefit, arguing that the original scale, which was traditionally used for schizophrenia assessments, wasn’t appropriate for patients with Parkinson’s-related psychosis. The agency agreed to this new scale, which had never been used in a study for drug approval.

Since there were no treatments approved for Parkinson’s-related psychosis, the FDA also granted Acadia’s request for the breakthrough therapy designation, and agreed that Nuplazid needed only one positive Phase 3 trial, instead of two, for approval.

In 2012, Acadia finally got the positive trial results it had hoped for. In a study of 199 patients, Nuplazid showed a small but statistically significant advantage over a placebo.

FDA medical reviewer Dr. Paul Andreason was skeptical. Analyzing all of Nuplazid’s trial results, he found that you would need to treat 91 patients for seven to receive the full benefit. Five of the 91 would suffer “serious adverse events,” including one death. He recommended against approval, citing “an unacceptably increased, drug-related, safety risk of mortality and serious morbidity.”

The FDA convened an advisory committee to help it decide. Fifteen members of the public testified at its hearing. Three were physicians who were paid consultants for Acadia. Four worked with Parkinson’s advocacy organizations funded by Acadia. The company paid for the travel of three other witnesses who were relatives of Parkinson’s patients, and made videos shown to the committee of two other caregivers. Two speakers, the daughter and grand-daughter of a woman who suffered from Parkinson’s, said they had no financial relationship with Acadia. However, the granddaughter is now a paid “brand ambassador” for Nuplazid. All begged the FDA to approve Nuplazid.

“Acadia or its consultants interacted with some of the potential speakers to facilitate logistics and reimburse for travel, as is common practice,” Acadia spokeswoman Elena Ridloff said in an email. “…All speakers presented their own experience in their own words.”

The only speaker who urged the FDA to reject the drug was a scientist at the National Center for Health Research who has never had any financial relationship with Acadia.

The witnesses’ pleas affected the panel members, who voted 12-2 to recommend accelerated approval. “If there were a safe and effective alternative on the market, I would not have voted yes,” said Almut Winterstein, a professor of pharmaceutical outcomes and policy at the University of Florida. “But I think that, in particular, the public hearing today was very compelling. There clearly is a need.”

Dr. Mitchell Mathis, director of the FDA’s division of psychiatry products, sided with the advisory panel, overruling Andreason. “Even this small mean improvement in a disabling condition without an approved treatment is meaningful,” Mathis wrote, adding that its safety profile was no worse than other antipsychotics on the market. Like other antipsychotics, Nuplazid carries a warning on the label of increased deaths in elderly patients with dementia-related psychosis. Since Nuplazid’s approval in 2016, Acadia has raised its price twice, and it now costs more than $33,000 a year.

As Nuplazid began to reach patients, reports of adverse events poured in. While it’s impossible to ascertain whether the treatment was responsible for them, the sheer numbers, including the 887 deaths, are “mind boggling,” said Diana Zuckerman, president of the National Center for Health Research.

In more than 400 instances, Nuplazid was associated with worsening hallucinations — one of the very symptoms it was supposed to treat.

That’s what happened to Terrence Miller, a former Hewlett Packard and Sun Microsystems employee who was diagnosed with Parkinson’s in the early 1990s. About five years ago, Miller began to experience mild hallucinations, such as seeing cats and dogs in his home in Menlo Park, California. At the time, he realized that the animals weren’t real, and the visions didn’t bother him, so he didn’t take any medication for them. But two years later, after surgery for a hip injury, the hallucinations worsened.

“He was convinced that he hadn’t had the surgery yet and people were going to harvest his organs,” recalled his wife, Denise Sullivan. “He’d see spaceships outside the window and they had to call security to help restrain him.”

In 2016, Dr. Salima Brillman prescribed Nuplazid. Miller tried Nuplazid twice, for a few months each time. His hallucinations became darker. “I’d say, ‘Who are you talking to?’ and he said, ‘They’re telling me to do bad stuff,’” Sullivan said. Afraid “he might hurt me because of what his evil ‘friends’ were telling him,” Sullivan, who was paying more than $1,000 a month for the drug out of her own pocket, then stopped the treatment.

What Sullivan and Miller didn’t know is that Brillman earned $14,497 in consulting fees from Acadia in 2016, ranking as the company’s seventh highest paid doctor, government records show. The top five prescribers of Nuplazid in Medicare, the government’s health program for the elderly, all received payments from Acadia. Dr. David Kreitzman of Commack, New York, prescribed the most: $123,294 worth of Nuplazid for 18 patients in 2016, according to data company CareSet. He was paid $14,203 in consulting fees.

Brillman and Kreitzman didn’t respond to multiple requests for comment.

Miller’s new doctor switched him onto Seroquel, an old drug long used off-label for Parkinson’s-related psychosis. With it, he’s sleeping better and the hallucinations, while remaining, have become more benign again, Sullivan said. Patients like Miller, whose hallucinations worsen, may not have been on Nuplazid for long enough, said Ridloff, the Acadia spokeswoman.

The 887 reported deaths of Nuplazid patients may be an undercount. A nurse in Kansas, who specializes in dementia care, said a resident in one of the facilities she worked at had no history of cardiac issues, yet died from congestive heart failure within a month of starting on Nuplazid. The nurse requested anonymity because she continues to work in nursing care facilities.

“We questioned the ordering physician whether this should be reported to the FDA in relation to Nuplazid and he said, ‘Oh no, the drug rep said this couldn’t have happened because of Nuplazid,’ and it was never reported,” she said.

Acadia’s Ridloff said such behavior by a sales representative would be “absolutely not consistent with our protocols, policies and procedures.”

She said that deaths are to be expected among patients who are elderly and in an advanced stage of Parkinson’s, and that Nuplazid does not increase the risk of mortality.

“Acadia’s top priority has been, and continues to be, patient safety,” she said. “We carefully monitor and analyze safety reports from clinical studies and post-marketing reporting to ensure the ongoing safety of Nuplazid. Based on the totality of available information, Acadia is confident in Nuplazid’s efficacy and safety profile.”

After a CNN report in April about adverse events related to Nuplazid prompted lawmakers to question the FDA, Gottlieb said he would “take another look at the drug.” Agency spokeswoman Sandy Walsh confirmed that that an evaluation is ongoing, and the FDA “may issue additional communications as appropriate.”

Nuplazid isn’t the only drug approved by an FDA senior official against the advice of lower-level staffers. In 2016, internal reviewers and an advisory committee called for rejecting a drug for a rare muscular disease called Duchenne muscular dystrophy. Only 12 patients participated in the single trial that compared the drug, Exondys 51, with a placebo. Trial results showed that Exondys 51 produced a small amount of dystrophin, a protein Duchenne patients lack. But the company didn’t show that the protein increase translated into clinical benefits, like helping patients walk.

Woodcock approved the drug. Internal FDA documents later revealed that she was concerned about the solvency of the drugmaker, Sarepta Therapeutics in Cambridge, Massachusetts. A memo by the FDA’s acting chief scientist recounted Woodcock saying that Sarepta “needed to be capitalized” and might go under if Exondys 51 were rejected. Exondys 51 went on the market with a price tag of $300,000 a year.

“We don’t look at a company and say they’ll have a lower standard because they’re poor, but we’re trying to recognize that, small or large, companies will never work on developing a drug if they won’t make a profit,” said Woodcock. “Our job is to work with the field, and with the firms to try and find a path forward,” especially on rare diseases where a large trial is impractical, she said.

Last month, the European Medicines Agency’s advisory committee recommended rejection of Exondys 51’s application, saying “further data were needed to show … lasting benefits relevant to the patient.”

Sarepta is asking the committee to reconsider, the company said in a June press release.

The debate over Exondys 51 centered on the value of a so-called surrogate endpoint, a biological or chemical measure that serves as a proxy for whether the drug actually treats or cures the disease. Surrogate measures speed drug development because they’re easier and quicker to measure than patient outcomes.

Some surrogate measures are well-established. Lowering cholesterol has been proven repeatedly to help reduce heart attacks and strokes. But others aren’t, like how much dystrophin needs to be produced to help Duchenne patients, raising concerns that drugs may be approved despite uncertain benefits.

The jury is still out on two other drugs, Folotyn and Sirturo, which received expedited approval based on surrogate measurements. There’s no proof that Folotyn helps patients with a rare cancer — peripheral T-cell lymphoma — live longer, while Sirturo, an antibiotic for multi-drug-resistant tuberculosis, has potentially fatal side-effects. Yet since both drugs were aimed at small or under-served populations, the FDA rewarded their manufacturers with valuable perquisites.

In a clinical trial, Folotyn reduced tumors in 29 of 107 patients, but the shrinkage lasted longer than 14 weeks in only 13 people. Since everyone in the study got Folotyn, it wasn’t apparent whether the drug would help patients do better than a placebo or another drug. Meanwhile, 44 percent of participants in the trial suffered serious side effects, including sores in mucous membranes, including in the mouth, lips and digestive tract, and low levels of blood cells that help with clotting. One patient died after being hospitalized with sores and low white blood-cell counts.

While tumor shrinkage is a commonly used surrogate measurement in cancer trials, it often has a low correlation with longer life expectancy, according to a 2015 study. “I would say to a patient, this drug may be more likely to shrink a tumor either partially or even completely, but that may in fact be a pyrrhic victory if it doesn’t help you live better or longer,” said Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic Cancer Center, who voted against approving Folotyn at the FDA’s advisory panel discussion in 2009. He was out-voted 10 to four. Three years later, the European Medicines Agency rejected the drug.

Because peripheral T-cell lymphoma only affects about 9,000 Americans each year, the FDA designated Folotyn as an “orphan” drug, giving its manufacturer, Allos Therapeutics, tax incentives and at least two extra years of patent exclusivity. Nevada-based Spectrum Pharmaceuticals acquired Allos in 2012. At more than $92,000 per course of treatment, Folotyn is Spectrum’s top-selling product, earning $43 million in 2017.

Dr. Eric Jacobsen, clinical director of the adult lymphoma program at Dana-Farber Cancer Institute in Boston, has become disillusioned with Folotyn since he helped Allos run the original trial. “Enthusiasm for the drug has waned,” he said. “It’s been on the market for a long time, and there’s no additional data suggesting benefit.” He now prescribes other options first, particularly because of the mouth sores Folotyn can cause, which make it painful to eat or drink.

The FDA approved Sirturo in 2012 without requiring Johnson & Johnson, the manufacturer, to demonstrate that patients on the drug were cured of tuberculosis. Instead, Johnson & Johnson only had to show that the treatment, when added to a traditional drug regimen, killed bacteria in the sputum faster than did the regimen alone. Sirturo was successful by that measure, but 10 patients who took it died, five times as many as the two in the group on placebo.

Dean Follmann, a biostatistics expert at the National Institutes of Health, voted as an FDA advisory committee member to approve Sirturo but wrestled with how to read the sputum data in light of the higher death rate: “The drug could be so toxic that it kills bacteria faster, but it also kills people faster.”

The imbalance in deaths during the trial “was a safety signal” that led the FDA to require “its most serious warning in product labeling,” known as a boxed warning, said agency spokeswoman Walsh. The packaging, she added, specified that Sirturo “should only be used for patients for whom an effective TB regimen cannot otherwise be provided. Thus, current labeling provides for a safe and effective use.”

Under a 2007 provision in the user-fee law, aimed at spurring treatments for developing nations, Sirturo’s approval qualified Johnson & Johnson for a voucher given to manufacturers who successfully get a tropical disease drug to market. The voucher can be used in the future, for any drug, to claim priority review – within six months instead of the usual 10. Time is money in the drug industry, and beating your competitor to market can be worth hundreds of millions of dollars. Vouchers may also be sold to other drugmakers, and have garnered up to $350 million. Sarepta received a voucher under a similar program for pediatric rare diseases when the FDA approved Exondys 51.

In South Africa, where Sirturo is mainly used, the drug is seen as a helpful option for highly drug-resistant patients. A study at one South African hospital by Dr. Keertan Dheda found that 45 out of 68 patients who took Sirturo were cured, as against 27 out of 204 before the drug was available. That doesn’t rule out the possibility that Sirturo may be killing a small subset of patients, said Dheda, but the risk is “very minor compared to the disease itself.”

Adrian Thomas, Johnson & Johnson’s vice president of global public health, said in an interview that observational results since the drug went on the market make him “much more confident that there is no more unexplained imbalance in mortality” and that the “benefit/risk in drug-resistant tuberculosis is incredibly reasonable when you don’t have other treatment choices.”

Still, the World Health Organization said in a 2016 report that the “quality of evidence remains very low” regarding Sirturo. “There is still some residual uncertainty for mortality,” the group said, and “specific harms” to the respiratory system “continue to be observed.”

While the FDA expedites drug approvals, it’s content to wait a decade or more for the post-marketing studies that manufacturers agree to do. Definitive answers about Sirturo are likely to be lacking until 2022, when Johnson & Johnson is expected to finish its study, a full decade after the drug was approved. Studies of Nuplazid and Folotyn aren’t expected until 2021. Spectrum has missed two FDA deadlines for post-marketing studies on Folotyn. Spectrum spokeswoman Ashley Winters declined comment.

Post-marketing studies often take far longer to complete than pre-approval trials, in part because it’s harder to recruit patients to risk being given a placebo when the drug is readily available on the market. Plus, since the drug is already on the market, the manufacturer no longer has a financial incentive to study its impact— and stands to lose money if the results are negative. Of post-marketing studies agreed to by manufacturers in 2009 and 2010, 20 percent had not started five years later, and another 25 percent were still ongoing.

And, despite taking so long, most post-marketing studies of drugs approved on the basis of surrogate measures rely on proxy criteria again rather than examining clinical effects on patients’ health or lifespans. In fact, Folotyn’s post-marketing trials will measure what’s known as “progression-free survival,” or the time it takes before tumors start growing again, but not whether patients live longer.

Proving that a drug extends survival is especially hard in cancer trials because patients don’t want to stay in a trial if their disease gets worse, or may want to add another experimental treatment. “In cancer, we’re probably not going to get a clean answer,” Woodcock said. Instead, the best evidence that cancer drugs are effective would be an increase in national survival rates over time, she said.

By law, the FDA has the authority to issue fines or even pull a drug off the market if a drugmaker doesn’t meet its post-marketing requirements. Yet the agency has never fined a company for missing a deadline, according to Woodcock.

“We would consider fines if we thought companies were simply dragging their feet, but we would have the burden to show they really weren’t trying, and it’d be an administrative thing that companies could contest,” said Woodcock.

Even when post-marketing studies belatedly confirm that drugs are dangerous, the agency doesn’t always pull them off the market. Consider Uloric, the gout treatment. Even though it consistently lowered uric acid blood levels, the FDA rejected it in 2005 and again in 2006, because trials linked it to cardiovascular problems. But a third study by the manufacturer, Takeda Pharmaceutical of Osaka, Japan, didn’t raise the same alarms. So the agency decided in 2009 to let the drug on the market, while asking Takeda for a post-marketing study of 6,000 patients to clarify the drug’s cardiovascular effects.

Takeda took more than eight years to complete the study. It found that patients on Uloric had a 22 percent higher risk of death from any cause and a 34 percent higher risk of heart-related deaths than patients taking allopurinol, a generic alternative. The FDA issued a public alert in November 2017, sharing the results of the trial, but left Uloric on the market.

Public Citizen has warned patients to stop taking Uloric. “There is no justification for using it,” said Carome. “If the results of the most recent study had been available prior to FDA approval, the FDA likely would have rejected the drug.”

FDA spokeswoman Walsh said it is “conducting a comprehensive evaluation of this safety issue and will update the public when we have new information.”

Takeda is working with the FDA to “conduct a comprehensive review,” spokeswoman Kara Hoeger said in an email. The company wants to ensure that “physicians have comprehensive and accurate information to make educated treatment decisions.” Thomas Moore, senior scientist of drug safety and policy at the Institute for Safe Medication Practices, warned that future post-marketing findings on Nuplazid could be similarly bleak. Uloric “is the story of [Nuplazid] but a few years down the pike,” he said.

Nevertheless, FDA Commissioner Gottlieb is forging ahead with more shortcuts. In May, he announced plans to approve gene therapies for hemophilia based on whether they increased the level of clotting proteins, without waiting for evidence of reduced bleeding.

Two years ago, a prescient Dr. Ellis Unger, FDA’s Director of the Office of Drug Evaluation, had warned against precisely this initiative. After Woodcock approved Exondys 51 in 2016, Unger wrote, “A gene therapy designed to produce a missing clotting factor could receive accelerated approval on the basis of a tiny yet inconsequential change in levels of the factor…The precedent set here could lead to the approval of drugs for rare diseases without substantial evidence of effectiveness.”

Gottlieb seems less worried than Unger.

“For some of these products, there’s going to be some uncertainty, even at the time of approval,” Gottlieb said when announcing the plan. “These products are initially being aimed at devastating diseases, many of which are fatal and lack available therapy. In these settings, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies.”

His decision pleased investors. That day, while biotechnology stocks overall fell, shares of hemophilia gene therapy manufacturers rose.

Read the original story here.

What are Artificial Turf and Playgrounds Made Of? Can They Cause Cancer? Obesity? Asthma?

Diana Zuckerman, PhD, National Center for Health Research


Is your child playing on rubber and plastic instead of grass?  Grass has been replaced with artificial materials at schools and parks all over the country.

Regardless of what they look like, there is growing evidence that all artificial fields and playgrounds are made with materials that can be dangerous for children and adults.

Many athletes don’t like artificial turf, and only 2 professional ballparks now use it, and many football stadiums have also switched back to grass. In addition to plastic “grass,” rubber and other synthetic materials are used to keep the “grass” in place and provide more cushioning. Unfortunately, artificial turf increases “turf burn” abrasions from sliding, puts additional stress on joints, and can become dangerously hot in the sun.

Recycling Tires from Playgrounds

More than 20 million recycled rubber tires are processed every year for playground surface cover and sports surfaces.

Using tire scraps seemed like a great idea at first – keeping them out of landfills and providing a potentially softer landing on the playground. It was known that burning old tires released harmful, smelly chemicals into the air, but parents didn’t realize that recycled tires and new rubber used on fields and playgrounds can also be dangerous.

You may think of rubber as a natural product – but rubber is a mix of latex from rubber trees mixed with petroleum products. That means it can include phthalates, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and other chemicals known or suspected to harm human health.1 For example, phthalates are chemicals that affect hormones and many have been banned from children’s toys because they can increase the risks of obesity, early puberty, attention problems, and cancer. The EPA warns that breathing air contaminated with PAHs may increase the chance of developing cancer, and the U.S. Agency for Toxic Substances and Disease Registry warns that PAHs may increase the risk of cancer and birth defects.2,3

Why Aren’t They Proven Safe?

There is no government agency that requires synthetic playground surfaces to be tested before they can be sold. In fact, the materials used in these products are often not made public — the lack of disclosure is justified as “trade secrets.” However, some researchers independently have examined the safety of these playground surfaces.

It would not be ethical to conduct a study exposing children to tire shreds, knowing they could be unsafe, so the California Office of Environmental Health Hazard Assessment conducted three studies that mimicked children’s exposures instead.4 Results showed that a single incident of eating or touching tire shreds would probably not harm a child’s health, but repeated or long-term exposure might. Five chemicals, including four PAHs, would get on children’s skin if they played on these surfaces. One of the PAHs, chrysene, was higher than the level considered safe, and could increase the chances of a child developing cancer.

In addition, only 10 of the 32 California playgrounds studied met the state’s safety standard for falls, which meant that falling could cause a brain injury of other serious harm. In contrast, all five surfaces made of wood chips met the safety standard. In Washington, D.C., 37 of their 51 artificial turf fields failed 2017 safety tests, due to hardness scores above 165. That’s what the turf industry considers the maximum score for safety.

A 2015 report by Yale scientists analyzed 14 different samples used for school athletic fields and playgrounds.5 They detected 96 chemicals, most of which have never been carefully studied, so their health risks are unknown. However, 20% of the chemicals that had been tested are considered to probably cause cancer. In addition, 40% are irritants that can cause breathing problems such as asthma and/or irritate skin or eyes.

What About your Schools or Parks?

Here are a few of the many materials to be concerned about:

  • Loose tire shred (“crumb rubber”) or other synthetic materials on a surface that can be raked, such as playgrounds or artificial “grass” fields. In some cases, triclosan, an antibacterial that is banned in soap, is used on this “infill.”
  • Tiles made from tire shreds and binder that have been factory-molded, then glued to a playground surface.
  • Tire crumb or “virgin” colorful rubber that is “poured in place” (PIP) can contain many of the same dangerous materials as recycled tire shreds.

How to Protect your Children

Children are much more likely to be harmed by exposure to chemicals in their environment than adults because they are smaller (so the exposure is greater) and because their bodies are still developing. Pregnant women should be even more careful to avoid these exposures.

Parents in many communities are persuading local officials to conduct safety tests on artificial turf fields and playgrounds every year, and to  install grass or wood chips because they are safer in terms of chemical exposure, heat, and if their children fall. But as you can see from the photo below from a school in Silver Spring, Maryland, there are more likely to be signs aimed at protecting the fields, rather than protecting the children using those fields.

What can I do?

  1. Children should avoid mouth contact with playground surfacing materials. Some of these materials are small and look like seeds, mulch, or small candies. They may pose a choking hazard as well as a dangerous chemical exposure.
  2. Avoid eating food or drinking beverages while directly on playground surfaces and wash hands before handling food.
  3. Limit the time at a playground on hot days. Children tell us they can often see the heat waves rising off the fields on warm, sunny days. The temperature of artificial turf can be 70 degrees hotter than the air or natural grass.
  4. Clean hands and other exposed skin after visiting the playground, and consider changing clothes if residue from the rubber is visible on fabrics.
  5. Clean any toys that were used on a playground after the visit.

These safeguards will help reduce your child’s exposure. However, if your child is playing on these fields for hours every week, there is still reason for you to be concerned.

That’s why our Center has testified before the Washington, D.C. City Council and why we are working with parents across the country who seek our help in convincing their communities to choose grass and avoid artificial turf whenever possible.

If you would like to download and print a PDF version, click here.

References:

  1. Llompart M, Sanchez-Prado L, Lamas JP, Garcia-Jares C, et al. Hazardous organic chemicals in rubber recycled tire playgrounds and pavers. Chemosphere. 2013;90(2):423-431. http://www.sciencedirect.com/science/article/pii/S0045653512009848
  2. US Environmental Protection Agency (EPA). Polycyclic Aromatic Hydrocarbons (PAHs)-Fact Sheet. November 2009. https://www.epa.gov/north-birmingham-project/polycyclic-aromatic-hydrocarbons-pahs-fact-sheet Accessed May 2016.
  3. Agency for Toxic Substances and Disease Registry (ATSDR). Polycyclic Aromatic Hydrocarbons. September 1996. http://www.atsdr.cdc.gov/toxfaqs/tfacts69.pdf Accessed May 2016.
  4. State of California-Office of Environmental Health Hazard Assessment (OEHHA), Contractor’s Report to the Board. Evaluation of Health Effects of Recycled Waste Tires in Playground and Track Products. January 2007. http://www.calrecycle.ca.gov/publications/Documents/Tires%5C62206013.pdf Accessed May 2016.
  5. Yale Study Reveals Carcinogens and Skin Irritants in Synthetic Turf. http://wtnh.com/2015/09/03/new-yale-study-reveals-carcinogens-and-skin-irritants-in-synthetic-turf/

Hormonal Therapy for Post-menopausal Women with Early Stage Breast Cancer

Anna Mazzucco, PhD, Brandel France de Bravo, MPH, Caroline Halsted, Danielle Shapiro, MD, MPH, and Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund

Breast cancer is the most common type of cancer in women around the world, and the second leading cause of cancer deaths among U.S. women. The survival rate for early-stage breast cancer is very high.  For women whose cancer is diagnosed when it is only in the breast, the 5-year survival rate is 99%.  For women whose breast cancer has spread to the lymph nodes, the 5-year survival rate is 85%.

Women who are diagnosed with early-stage breast cancer almost always undergo surgery to remove the cancer (either lumpectomy/partial mastectomy or mastectomy). Most will also choose at least one other treatment in addition to surgery:

1) If they have a lumpectomy, they often undergo radiation to either shrink the tumor before surgery or to kill any cancer cells in the breast that were missed during surgery.

2) If their cancer is estrogen receptor positive (about 84% of breast cancers), many women will try to take hormonal therapy for at least five years after surgery to lower the chance of cancer coming back in either breast the future. For pre-menopausal women, the standard treatment is tamoxifen. For women who have completed menopause (post-menopausal breast cancer), tamoxifen and/or an aromatase inhibitor can be used.[1]

Types of Hormonal Therapies for Early-Stage Breast Cancers

Hormonal therapy (also called endocrine therapy or anti-estrogen therapy) is the opposite of the type of hormones women sometimes take to reduce the symptoms of menopause. It lowers your estrogen levels instead of increasing them.[1]

Hormonal therapy is recommended for most women with breast cancer, and sometimes it is taken by women who have not been diagnosed with breast cancer but are at high risk for it based on their genes or family history. When hormonal therapy is used before breast cancer develops, it is called “primary prevention” or “chemoprevention.” Chemoprevention is completely different from the drugs used in chemotherapy to treat breast cancer.[1]  See our article on breast cancer prevention.

Four types of hormonal therapy are FDA-approved for early-stage breast cancer treatment for post-menopausal women: tamoxifen, exemestane, letrozole, and anastrozole.[3]

For post-menopausal women, there are many recommended ways to take hormone therapy, including: [4]

  • Taking tamoxifen for 5 to 10 years
  • Taking an aromatase inhibitor for 5 to 10 years
  • Taking tamoxifen for 5 years, then switching to an aromatase inhibitor for the next 5 years
  • Taking tamoxifen for 2-3 years, then switching to an aromatase inhibitor for the next 5 years

How Does Hormonal Therapy Work?

Tamoxifen:

Tamoxifen is a selective estrogen receptor modulator (SERM), which means it blocks estrogen activity in breast tissue, but promotes estrogen activity in other tissues (such as in bone and the inner lining of the uterus). Tamoxifen is only effective in breast cancers that are estrogen receptor positive.[3,4]

Aromatase inhibitors:

In post-menopausal women, the ovaries slow down the production of estrogen, but the body uses an enzyme called aromatase to make estrogen from other hormones. Aromatase inhibitors block aromatase, which lowers the amount of estrogen in the body. By taking away the supply of estrogen, aromatase inhibitors help to stop the growth of cancer cells.[3,4]

How Effective are the Treatments?

The effectiveness of treatments is often reported in terms of risk or risk reduction. Risk is another word for chance–what is the chance that something will happen, such as cancer returning or the patient dying? Risk can be reported in terms of relative risk or absolute risk. Let’s use simple numbers to show what we mean: In a study 100 women are given a new drug and 100 other women are given an older drug.  What if the study showed that 4 patients (4%) taking the older drug became nauseous compared to only 2 patients (2%) taking the new drug.  The relative risk of patients getting nauseous is 50% lower for patients taking the new drug, and that sounds impressive.  But the absolute difference is only 2% – when you subtract 2% taking the new drug compared to 4% taking the old drug.

Based on the statistics, the odds may favor taking the new drug. But if the new drug costs much more or has other side effects, a patient might decide she is willing to take the 2% greater risk of becoming nauseous. We prefer to use the absolute difference in risk as it is more informative for patients than the relative risk.

Tamoxifen

Over decades of clinical trials in hundreds of thousands of women, tamoxifen has been shown to reduce the chances of breast cancer recurrence and breast cancer death. But it is important to consider exactly what the benefits are likely to be for you.

Breast cancer recurrence:

A landmark report showed that about 23% of women aged 55 and older who took tamoxifen for 5 years after their cancer was removed had a breast cancer recurrence within 10 years compared to about 42% of women 55-69 and 44% of women 70 and older who did not take tamoxifen.  In that study, women with early-stage breast cancer included women with Stage 1, Stage 2, and Stage 3A; in other words, it ranges from a very tiny breast cancer to a large cancer that has spread to several lymph nodes. The researchers defined breast cancer recurrence as the first appearance of any breast cancer including, cancer in the same breast, cancer in the opposite breast, or distant spread of cancer.[6]

Breast cancer deaths

Among women who were 55-69 years old at the time of diagnosis, about 90% who did not have a breast cancer recurrence were alive for at least 10 years, regardless of whether they took tamoxifen or not. For women in that age group, about 16% of women who took tamoxifen and had a recurrence died from breast cancer within 10 years of the initial diagnosis, compared to 26% of women who did not take tamoxifen and had a recurrence.[6]

Among women who were 70 years old or more at the time of their diagnosis and did not have a breast cancer recurrence, 80% who took tamoxifen were alive 10 years later, compared to 70% of women who did not take tamoxifen. Importantly, this difference was not statistically significant, meaning it could have happened by chance and is unlikely to be related to tamoxifen therapy.  Among women in this age group who had a breast cancer recurrence, about 20% who took tamoxifen and had a recurrence died from breast cancer within 10 years of the initial diagnosis compared to 37% of women who did not take tamoxifen and had a recurrence. [6]

Living Longer

Most women who are diagnosed with breast cancer do not die from breast cancer.  Of course, eventually they die of something else.  For women who were 55-69 years old at the time of their diagnosis, 5 years of tamoxifen helped women live longer.  More than 90% of women who did not have a breast cancer recurrence were alive 10 years later, regardless of whether they took tamoxifen or not. In contrast, about 76% of women who took tamoxifen and had a breast cancer recurrence were alive 10 years after the initial diagnosis, compared to 67% of women who did not take tamoxifen.[6]

By the time women are over 70, they are likely to have health issues whether or not they are diagnosed with breast cancer. Among those who did not have a breast cancer recurrence, about 80% of women taking tamoxifen and 70% of women not taking tamoxifen were alive 10 years later.  However, this apparent 10% difference was not statistically significant and therefore is probably not related to tamoxifen. In contrast, among women who had a recurrence, about 67% of women who took tamoxifen were alive 10 years later compared to 47% of women who did not take tamoxifen.[6]

As you can see, the benefits of tamoxifen depend on how old and healthy a woman is when she is diagnosed In addition, certain characteristics of early-stage breast cancers, including size of the tumor, types of cancer cells, and how many lymph nodes the cancer had spread to prior to surgery, can help doctors predict the chances of breast cancer recurrence. Therefore, it is important for you to talk with your doctor about these specific issues and which treatment options may be right for you.  Remember that some benefits (such as survival) might be more important to you than others (such as recurrence) – or not!

Aromatase Inhibitors:

Aromatase inhibitors have also been shown to benefit post-menopausal breast cancer patients.  An international breast cancer study showed that about 84% of women taking letrozole were alive and cancer free at 5 years compared to about 81% of women taking tamoxifen. Despite the difference in dying from breast cancer, however, there was no difference in terms of the percentage of women who were alive 5 years after diagnosis.

The benefits of aromatase inhibitors continued 10 years after diagnosis, with about 19% of women who took letrozole having any cancer recurrence compared to about 23% of women who took tamoxifen. Breast cancer recurrence included any breast cancer in the same breast, the opposite breast, or distant spread of cancer.[3]

When considering your treatment options, talk with your doctor about your overall health and your heart health, because all women (including women with breast cancer) are more likely to die from heart disease than breast cancer. And some treatments for breast cancer can harm your heart. Read more about heart health and breast cancer in our article.

Treatment Considerations

There are many ways to take hormone therapy, including switching between the types of therapy, and taking the hormone therapy for additional years. The choices can be confusing. Here are some questions to think about: 

What are the benefits of extending therapy? Studies show that extending therapy after an initial 5-year period can lower a woman’s chances of cancer recurrence (including any breast cancer in the same breast, the opposite breast, or distant spread) by a small, but statistically significant 2% to 4%. The study looked at different hormone regimens including “primary” AI (AI for 5 years), “sequential” AI (tamoxifen for 2 years followed by 3 years of AI), and extended AI (5 years of AI after 5 years of tamoxifen). For example, about 7% to 12% of women who took any hormone therapy for 5 years had a recurrence compared to 5% to 8% of women who extended their therapy.[10]

For how long should women extend therapy? A 2018 study found that women adding on 2.5 extra years of letrozole had the same chances of surviving without their breast cancer returning as women adding letrozole for 5 years. However, about 1% of women who took letrozole for an extra 5 years had a new breast cancer develop in the opposite breast compared to 3% in the 2.5 year group. That difference is small but it is a way to lower your already small risk of developing a new cancer in your other breast and making it even smaller.[11,12]

As you consider your treatment options,  it is important to consider the risks as well, as described later in the next section of this article.

Side Effects and Risks of Treatment

Tamoxifen increases the chances of a woman developing endometrial cancer and blood clots in legs and lungs, especially for women over 50 years of age.[3,16] Women taking tamoxifen are also more likely to develop endometrial cancer, although the overall risk is still low; about 2 women out of 1,000 taking tamoxifen will get endometrial cancer each year.[16] In a Danish study, the 5-year risk of developing blood clots was about 1.2% in women with breast cancer taking tamoxifen compared to 0.5% in women with breast cancer who were not taking tamoxifen. Moreover, tamoxifen therapy often causes side effects similar to those experienced in menopause, including hot flashes and irregular periods.[16] In one study, 41% of women taking tamoxifen experienced hot flashes, and 10% experienced abnormal vaginal bleeding.[19]

Aromatase inhibitors increase the risk for osteoporosis compared with tamoxifen or taking no hormonal therapy at all.  Exemestane, a commonly used aromatase inhibitor (brand name Aromasin), also increases the risk for visual disturbances, allergic reaction, or diarrhea.  In one study, about 36% of women experienced joint problems while taking anastrozole, (brand name Arimidex) compared to about 30% of women taking tamoxifen.

The most common complications from hormonal therapy are listed above.  In addition, in very rare cases, other side effects of hormonal therapy can be fatal or can harm a patient’s quality of life.  Close monitoring of women for symptoms, such as abnormal uterine bleeding, is needed, and women taking tamoxifen should receive annual pelvic exams.[3]

Different women respond differently to the various forms of hormonal therapy, which is why it is not uncommon for women to switch to different hormonal treatments after starting.

The Bottom Line

There are many ways to treat early-stage breast cancer in post-menopausal women, in addition to surgery. A woman’s age, tumor characteristics, overall health, and personal wishes/goals may impact her decision. Talk with your doctor about which treatment options may be right for you by asking about the exact benefits of specific treatments on recurrence and overall survival, and considering these specific issues and not just what is best for cancer patients on average.

Footnotes:

  1. American Cancer Society. Cancer Treatment and Survivorship: Facts and Figures 2016-2017. Available online: https://www.cancer.org
  2. Burstein HJ. et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. Journal of Clinical Oncology. 2017;34(14): 1689-1701. Doi: 1200/JCO.2015.65.9573
  3. National Cancer Institute. Breast Cancer Treatment (PDQ). (Nov. 2017). Available online: https://www.cancer.gov/types/breast/patient/breast-treatment-pdq#section/_125
  4. Adjuvant Therapy for Breast Cancer. (Aug. 2017). Available online: https://emedicine.medscape.com/article/1946040-overview#showall
  5. Colleoni M. et al. Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V. J Clin Oncol. 2016;34(9): 927-935. doi: 1200/JCO.2015.62.3504
  6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793): 771-784. doi:1016/S0140-6736(11)60993-8
  7. Gierach GL, Curtis RE, Pfeiffer RM, et al. Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting. JAMA Oncol. 2017;3(2): 186–193. doi:1001/jamaoncol.2016.3340
  8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001): 1341 – 1352. doi: http://dx.doi.org/10.1016/S0140-6736(15)61074-1
  9. Pohlmann PR and Isaacs C. Extended Adjuvant Endocrine Therapy for Postmenopausal Women: Treating Many to Benefit a Few, JNCI: Journal of the National Cancer Institute. 2018;110(1): djx142, doi: https://doi.org/10.1093/jnci/djx142
  10. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer. Journal of Clinical Oncology. 2010;28(23):3784-3796. doi:10.1200/JCO.2009.26.3756.
  11. Blok EJ, et al. Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05). JNCI: Journal of the National Cancer Institute. 2018; 110(1): djx134, https://doi.org/10.1093/jnci/djx134
  12. Van de Velde, C.J.H. et al. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006–05). European Journal of Cancer. 2017;72(Supp1):S9. doi: http://dx.doi.org/10.1016/S0959-8049(17)30108-9
  13. Gianni L. et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncology. 2011;12(3): 236-44. doi: https://doi.org/10.1016/S1470-2045(11)70033-X
  14. Cameron D. et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075): 1195-1205. doi: https://doi.org/10.1016/S0140-6736(16)32616-2
  15. Stenger M. ASCO Post: 11-Year Follow-up of Adjuvant Trastuzumab in the HERA Trial. (March 2017). Available online: http://www.ascopost.com/News/48405
  16. Gogas H, Markopoulos C, Blamey R. Should women be advised to take prophylactic endocrine treatment outside of a clinical trial setting? Ann Oncol. 2005;16:1861-1866. Available online: https://watermark.silverchair.com
  17. Fisher B, et al. J Natl Cancer Inst. 1994; 86:527-537.
  18. Bonneterre, et al. J Clin Oncol. 2000; 18:3748-3757.
  19. Howell A, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453): 60-2. doi: 1016/S0140-6736(04)17666-6
  20. Bliss JM. et al. Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study. Journal of Clinical Oncology. 2012;30(7): 709-717. doi: 1200/JCO.2010.33.7899
  21. Drugs and Diseases: Gosarelin. Available online: https://reference.medscape.com/drug/zoladex-la-goserelin-342129
  22. Drugs and Diseases: Trastuzumab. Available online: https://reference.medscape.com/drug/herceptin-ogivri-trastuzumab-342231#5

Statement of National Center for Health Research Supporting A CDC Review to Save Women’s Lives


The National Center for Health Research strongly supports the announcement that the Centers for Disease Control and Prevention may conduct a review of the potential benefits of biopsies for women scheduled for hysterectomy or fibroid removal.  The review is essential because a recent article, published in the medical journal Obstetrics & Gynecology reports that the rate of unsuspected cancer is dangerously high in women undergoing hysterectomy.  When those women undergo surgery, particularly procedures involving a medical device called a power morcellator, the cancer can spread inside the woman’s abdomen, resulting in an early-stage cancer being upstaged to a much more dangerous metastatic (stage 4) cancer.  The risks are especially high for women ages 55 and older, reaching almost 10% for undiagnosed uterine cancer.

The study authors, from Yale Medical School and the Columbia University College of Physicians and Surgeons, studied more than 26,000 women who underwent hysterectomy or fibroid removal, and found that undetected cancers were much higher than previously estimated.  The implications are that the FDA’s warnings regarding the risk of power morcellation, which estimated one hidden cancer in every 352 women, are inadequate to provide informed consent for patients considering these surgical procedures.

We thank Dr. Redfield for his attention to this matter and urge the CDC leadership to move forward as soon as possible to develop guidelines pertaining to tissue biopsy methods that will identify women with gynecological cancer before the women undergo a surgical procedure to remove the uterus or fibroid.  Such testing could save thousands of women’s lives.

Diana Zuckerman, PhD
President
See our related letter to CDC Dirtector Dr. Robert Redfield here.