To view as a PDF, click here.

 

April 21, 2014

Comments of members of the Patient, Consumer, and Public Health Coalition

on research entitled

“Disclosure Regarding Additional Risks in Direct-To-Consumer (DTC) Prescription Drug Television Advertisements”

Docket No. FDA-2014-N-0168

 

Members of the Patient, Consumer, and Public Health Coalition applaud FDA’s efforts to clearly and effectively communicate risks and benefits to consumers in direct-to-consumer (DTC) advertisements.  However, we are concerned about this study’s definition of “serious and actionable” risks, the diversity of the population being studied, the administration of the study in an online setting only, and the timing of the major statement in the ad (at the end of the ad instead of the beginning or middle).

Background

The FDA document describes research plans to analyze the effect of limiting risk information in the major statement in DTC advertisements.  This proposal would compare giving limited risk information in the major statement (combined with a disclaimer statement alerting consumers of additional undisclosed risks) versus using a complete major statement (as is currently used).

The aim of the research is to identify differences in participant understanding of the disclosure and perception of the risks and benefits of a particular medication, product quality, sponsor trustworthiness, and interest in the product.  There is concern that overly long major disclaimer statements lead to reduced consumer attention, thereby compromising understanding of the presented risks.

We also have specific concerns regarding this proposal as follows:

  • The definition of “serious and actionable” risks must be clarified.  This research proposal describes limiting risks mentioned in the major statement in DTC advertisements to those which are “serious and actionable.”  However, no definition is given for what medical risks would fall into this category.   Detailed and explicit criteria must be set for what risks will be considered “serious and actionable.”   As an informative example of this definition, FDA should also state what specific information will be included in the four versions of the major statement used for each patient group during this investigation.  It should also be noted that some patients and consumers may have different preferences towards acceptable risk levels.  For example, patients with a disease that lacks effective treatment are likely to be willing to take greater risks than patients for whom treatments are currently available, even if imperfect.  FDA should describe how  its definition of “serious and actionable” will take such diversity into account.
  • A diverse participant population must be ensured.  This research proposal does not include any specific information about how exactly the participants will be recruited for the investigation, other than stating that recruitment will take place online.  We are concerned that recruitment which occurs solely through the internet may bias the participant population to younger and more affluent and Internet-adept populations who have easy access to the Internet.  In fact, the consumers most likely to be reached online may be those who are least likely to watch commercials on TV.  FDA needs to describe in detail how  it will ensure a diverse participant population in terms of age, race, gender, ethnicity, and educational background.  These factors could heavily influence perception of the presented information, and thus skew the results of this investigation.  As FDA plans to recruit participants who self-identify as having one of three possible medical conditions, the nature of these medical conditions could also introduce bias into the participant population.  Care must be taken to ensure adequate diversity to reflect the general U.S. consumer audience.
  • The study conditions must be as similar to real life situations as possible.  This proposal describes the study as being administered in an online setting only.  This situation, under a conscious test scenario, sitting close to a personal computer, is very different from the situation in which direct-to-consumer advertising usually takes place, which is often during leisure time in the presence of other distractions, where the consumer often sits further from the screen.  FDA should consider ways to make  its test protocol more realistic in order to account for these differences.
  • Other changes to the major statement, such as timing, should also be considered in the test.  Given that the major statement usually occurs at the end of an advertisement, having a shorter major statement alone may not guarantee increased consumer comprehension under real world situations.  One consideration would be to introduce another version of the advertisement to the test protocol, in which the major statement is given earlier in the advertisement, when a greater proportion of consumers may be paying attention.

Lastly, we must note that the length and types of risk information provided in direct-to-consumer advertising are not the only variables that influence whether patients pay attention and understand that information.  For example, TV commercials continue to provide risk information while visual and auditory stimuli are distracting the viewer from the risks being listed.  In other words, the FDA has continued to allow companies to design and use ads that are clearly intended to persuade consumers to request their products and to encourage them to ignore risk information, rather than to educate them about the true risks and benefits.  In the absence of comparative effectiveness research, the FDA also continues to approve new medical products with little benefit compared to other treatment alternatives, and then regularly gives companies numerous opportunities to mislead consumers in their advertisements, using a much lower threshold for accuracy than the FTC’s criteria of “misleading the average consumer”  for food and supplement advertising.

 

American Medical Student Association
American Medical Women’s Association
Annie Appleseed Project
Breast Cancer Action
Community Access National Network
Connecticut Center for Patient Safety
Jacobs Institute of Women’s Health
National Consumers League
National Research Center for Women & Families
National Women’s Health Network
The TMJ Association
Center for Science and Democracy at the Union of Concerned Scientists
U.S. PIRG
WoodyMatters

 

For more information, contact Anna Mazzucco, PhD at (202)223-4000 or am@center4research.org

Matthew Perrone, AP Health Writer

April 15th, 2014

WASHINGTON (AP) – A high-tech screening tool for cervical cancer is facing pushback from more than a dozen patient groups, who warn that the genetic test could displace a simpler, cheaper and more established mainstay of women’s health: the Pap smear.

The new test from Roche uses DNA to detect the human papillomavirus, or HPV, which causes nearly all cases of cervical cancer. While such technology has been available for years, Roche now wants the FDA to approve its test as a first-choice option for cervical cancer screening, bypassing the decades-old Pap test.

But a number of women’s groups – including the American Medical Women’s Association and Our Bodies Ourselves – warn that moving to a DNA-based testing model would be a “radical shift” in medical practice that could lead to confusion, higher costs and overtreatment.

“It replaces a safe and effective well-established screening tool and regimen that has prevented cervical cancer successfully in the U.S. with a new tool and regimen not proven to work in a large U.S. population,” state the groups in a letter to FDA Commissioner Dr. Margaret Hamburg. The letter, dated Monday, is signed by 17 patient advocacy groups, including Consumers Union, the Cancer Prevention and Treatment Fund and the National Alliance for Hispanic Health.

Chief among the advocates’ concerns is that HPV-only testing could lead to overtreatment of younger women who carry the virus but have little risk of developing actual cancer. Most sexually active young people will contract HPV, though their bodies usually eliminate the virus within a few months. Only years-long infections develop into cancer.

“Unfortunately the HPV test by itself isn’t very useful because so many young women have HPV that will disappear without any treatment,” said Diana Zuckerman of the Cancer Prevention and Treatment Fund. “Having an HPV test without also getting a Pap smear to check for problems is going to scare a lot of women who are not developing cervical cancer.”

An FDA spokeswoman said the agency could not comment on the letter since it deals with a product under review.

For decades the Pap test was the only screening option for cervical cancer – and it’s had a remarkably successful track record. The number of cervical cancer cases reported in the U.S. has decreased more than 50 percent in the past 30 years, primarily due to increased Pap screening. Still, an estimated 12,000 cases of cervical cancer are expected to be diagnosed this year, a fact that has spurred development of genetic tests like the one from Roche and other test makers.

Medical guidelines have been evolving rapidly to try and incorporate both techniques. Under the latest guidelines from the American Cancer Society, a Pap test is recommended every three years for women 21 to 29 years old. Women 30 and older should have both a Pap test and an HPV test every five years, or a Pap test alone every three years. Women who have had an HPV vaccine should still follow screening guidelines.

HPV screening is not recommended for women in their 20s because it increases the odds of more invasive testing that can leave the cervix less able to handle pregnancy later in life.

But Roche is seeking FDA approval to market its test to women age 25 and up.

That approach was endorsed unanimously last month by a panel of FDA advisers who voted 13-0 that Roche’s cobas HPV test appears safe and effective as a first-choice screening tool. The FDA is weighing that recommendation as it considers approval the company’s application.

Despite the overwhelming endorsement, patient advocates say FDA approval would fly in the face of current medical guidelines, none of which recommend testing with HPV alone for younger women. They point out that the U.S. Preventive Services Task Force, which sets federal medical guidelines, gave HPV testing a “D” rating in women under age 30, warning that testing could lead to “unnecessary treatment and the potential for adverse pregnancy outcomes.”

Even physicians who support HPV testing as an important option warn that introducing a DNA-only testing regimen may lead to confusion that disrupts care. The American College of Obstetricians and Gynecologists says many physicians are already confused by the two existing testing options: Pap alone or Pap with HPV testing.

“Introducing a third screening alternative will likely further increase confusion, and the risk to women of getting either over or under screened,” the group said in comments at the FDA meeting last month. The group, which represents 57,000 U.S. obstetricians and gynecologists, did not sign the letter sent to FDA this week.

Finally there is the cost. An HPV test costs between $80 and $100, at least twice as much as a $40 Pap. And under Roche’s proposal, women who test positive for HPV would be referred for colposcopy, a more invasive testing procedure that can cost up to $500.

All these factors have consumer advocates urging the FDA to break from its advisers and deny first-choice status to the Roche test.

“Sometimes the FDA overrules the advisory committee and it’s OK,” said Dr. Susan Wood, a former FDA official who now directors the Jacobs Institute of Women’s Health.

 Article also appears in The Washington PostABC NewsNBC News, Star Tribune, Business Week, The Washington Times

Brady Dennis, The Washington Post

April 17, 2014

The Food and Drug Administration on Thursday took the rare step of urging doctors to stop performing a surgical procedure used on tens of thousands of women each year to remove uterine growths, saying the practice risks spreading hidden cancers within a woman’s body.

The procedure, known as power morcellation, has long been used in laparoscopic operations to remove fibroid tumors from the uterus, or to remove the uterus itself. It involves inserting an electric device into the abdomen and slicing tissue in order to remove it through a small incision. The surgery is far less invasive than traditional abdominal operations.

But the FDA on Thursday agreed with a growing chorus of researchers and clinicians who oppose the procedure, saying that it can recklessly spread undetected cancers throughout the body and make the disease more lethal in the process. The agency is not seeking to ban the practice or the roughly two dozen FDA-approved devices used to perform it, but hospitals and gynecologists are likely to abandon the procedure because of potential liabilities.

The FDA said its analysis determined that an estimated 1 in 350 women who undergo morcellation have an unsuspected form of uterine cancer called uterine sarcoma.

“The existence of the risk is not new,” said William Maisel, chief scientist at the FDA’s Center for Devices and Radiological Health. “What is new is that the magnitude of the risk appears to be higher than was appreciated by the clinical community.”

Maisel acknowledged that the agency was spurred to action — or at least moved more quickly — because of a high-profile campaign waged in recent months by a Massachusetts couple, both doctors, for a moratorium on the practice.

Anesthesiologist Amy Reed, a mother of six who last spring treated Boston Marathon bombing victims as well as one of the suspected bombers, underwent what was supposed to be a routine procedure last fall to end bleeding from fibroids. The procedure spread undetected, cancerous tumor fragments throughout her abdomen. Now she is battling stage-four leiomyosarcoma, a rare and aggressive form of uterine cancer.

Her husband, Hooman Noorchashm, a Harvard-affiliated cardiothoracic surgeon, responded by launching a campaign to ban the widely used procedure. He has e-mailed numerous regulators, doctors and lawmakers, written to medical journals and lobbied hospitals. The couple started a Change.org petition to end the practice.

Noorchashm said Thursday that he appreciated the FDA’s relative speed in addressing the problem. “You don’t even have to be a doctor to recognize that if tissue or a tumor has malignant potential, you should not mince it up inside someone’s body,” he said. “That’s just bad medicine.”

Many women develop uterine fibroids — benign growths that originate in the muscle tissue in the wall of the uterus. Although many fibroids do not cause problems, others can result in frequent urination, prolonged menstrual bleeding and pelvic pain.

Of the more than 500,000 hysterectomies performed in the United States each year, about 11 percent, or more than 50,000, involve morcellation, according to the American Congress of Obstetricians and Gynecologists. Some doctors advocate performing a morcellation only when using an “isolation bag” in an effort to minimize the spread of tissues, but that method is not foolproof, as the bags can break.

“When you consider what the benefit is, which is a shorter hospital stay and less pain, then consider what the risk is — this could kill you — most women would not choose that risk if they really understood what is at stake,” said Diana Zuckerman, president of the Cancer Prevention and Treatment Fund.

Even before Thursday’s announcement by the FDA, the push to limit uterine morcellations had gained traction.

In February, Temple University Hospital issued guidelines instructing surgeons not to perform the procedure on fibroids over a certain size. Doctors may use the procedure for smaller fibroids only after informing patients about the risks and, in most cases, using isolation bags. Even before that, prompted by Noorchashm’s campaign, Massachusetts General Hospital and Brigham and Women’s Hospital in Boston took similar measures.

On Thursday, the heads of obstetrics and gynecology at both Boston hospitals promptly notified their staffs to suspend use of power morcellation until further notice.
Margaret Jacobson, the medical director of Whatcom Hospice in Bellingham, Wash., cried upon hearing of FDA’s action on Thursday.

In March 2012, her sister, Elizabeth Jacobson, had a hysterectomy by morcellation. Elizabeth Jacobson did not want to miss much work, and the promise of a minimally invasive procedure appealed to her.

But inside the large fibroid that a doctor shredded lurked malignant cells that spread throughout her abdomen, her sister said. Soon, Elizabeth Jacobson was diagnosed with aggressive uterine cancer. She then had a second surgery, rounds of chemotherapy and long stretches of misery. She died Jan. 8, 2013.

“She suffered terribly,” Margaret Jacobson said. “It devastated our family.”
Thursday’s news brought a measure of relief, she said, that other women might avoid the same fate, especially given that safer surgical alternatives already exist.
“It’s a victory ,” Jacobson said. “It’s not okay to tolerate these deaths. . . . My sister’s life was extraordinary; she was beautiful and loving. She does not deserve to be an easily dismissed statistic.”

JON KAMP and JENNIFER LEVITZ, Wall Street Journal

April 17, 2014

The U.S. Food and Drug Administration on Thursday advised doctors to stop using power morcellators in women’s abdomens to remove uterine growths called fibroids, citing the risk of spreading cancer.The popular devices—which typically use a tube-shaped blade to grind up and remove fibroids or the entire uterus to avoid the long surgical scars associated with traditional, open surgery—can also spread an often undetectable cancer known as a uterine sarcoma. In a rare safety alert for medical devices, the FDA cited estimates that this cancer affects one in 350 women undergoing such procedures and can significantly worsen the odds of long-term survival.

“For this reason, and because there is no reliable method for predicting whether a woman with fibroids may have a uterine sarcoma, the FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids,” the agency said in a safety communication posted on its website Thursday. Myomectomy is the removal of just fibroids.

“In general, the procedure should not be performed,” Dr. William Maisel, deputy director for science and chief scientist at the FDA’s Center for Devices and Radiological Health, said Thursday at a media briefing.

If doctors do perform such procedures, the FDA said, they should advise patients of the cancer-spreading risk.

The safety alert was addressed to doctors, medical associations, hospitals, women, device manufacturers and advocacy groups. The FDA’s alert follows a series of Wall Street Journal articles, starting in December, which documented the risk of spreading cancer and a campaign by two Boston-area physicians to halt the procedures.

Amy Reed, a 41-year-old mother of six and anesthesiologist at Boston’s Beth Israel Deaconess Medical Center, developed advanced uterine cancer shortly after a routine hysterectomy in October. The hospital where she was treated, Brigham and Women’s Hospital, acknowledge that use of morcellation worsened her cancer.

The FDA began its review in December, “when some high-profile cases covered in the media came to our attention,” Dr. Maisel said.

The FDA’s alert triggered immediate action on Thursday. Dr. Isaac Schiff, the chief of the Department of Obstetrics & Gynecology at Massachusetts General Hospital, said, “I have asked our doctors to stop the procedure immediately until we have more information.”

The FDA’s move could change the way many women are treated for symptomatic fibroids, which are common but often painful growths that spur about 40% of the roughly half-million hysterectomies performed in the U.S. each year, by some estimates.

Morcellators, first introduced in the 1990s, have helped gynecologists perform about 50,000 of these procedures each year through tiny holes, rather than longer incisions that can lead to bigger scars and a longer recovery.

Diana Zuckerman, president of the nonprofit National Research Center for Women & Families, and an advocate for stiffer medical device regulations, said the FDA’s statement should have a major impact. Going against the FDA’s recommendation could increase doctor’s liability if there are mishaps, she said.

“What surgeon is going to take the chance of using this device if they FDA has made such a strong warning?” she said. The FDA’s action “is going to save a lot of lives.”

Dr. Maisel said the clinical community has been aware of the risk of cancer since the advent of the procedure, although he said the rate of that risk is only now coming into focus. He also said it’s conceivable that some patients may believe the risks of alternative procedures outweigh the risks of laparoscopic surgery with morcellation. They should be explicitly told of the risks, he said.

With the issue gaining steam since December, gynecological societies had already been doing their own reviews of power morcellation. Commenting on the FDA move on Thursday, the American College of Obstetricians and Gynecologists said its own review, which includes an assessment of risks for various groups of patients, is ongoing. “We greatly appreciate the urgency behind the issue,” the group said.

Dr. Maisel said older women have a higher risk of having a hidden sarcoma than younger women.

Many gynecologists have argued there are other ways to perform these procedures without cutting up tissue in the open abdomen, including performing vaginal procedures or cutting tissue manually and inside protective bags.

Gynecologists have acknowledged they seldom used these bags during hysterectomies and fibroid procedures previously. But a number of top hospitals, including Brigham and Women’s and Massachusetts General, have recently told their doctors to only morcellate inside such bags for added protection.

The FDA noted these changes, although Dr. Maisel also said bags have some downside, including obscuring surgeons’ view during procedures, and are “not a panacea.”

The FDA on Thursday said it will convene a public advisory committee meeting this summer to discuss whether such bags can enhance the effective use of morcellators, amid other issues. The agency instructed manufacturers “to review their current product labeling for accurate risk information for patients and providers.”

The FDA recommended “routine follow-up” with physicians for women who have already had hysterectomies or myomectomies, don’t have symptoms and were told post-surgery tests were normal. Tissue is commonly checked for cancer afterward. But women with “persistent or recurrent symptoms or questions should consult their health-care provider,” the agency said.

By Anna E. Mazzucco, Ph.D.

 

April 17, 2014

 

Does a friend or family member have a child with autism?  Autism rates seem to be skyrocketing.  Among children who are 8 years old, autism has nearly doubled  from 1 in 150 (for children born in 1992) to 1 in 68 for children born in 2002.1

 

Autism is part of a larger group of related conditions, called autism spectrum disorders (ASDs), all of which usually involve delayed verbal communication and difficulties in social interactions.  Studies suggest that children with autism tend to have other problems with how their brain functions, with as many as 20-30% developing seizures or epilepsy.

 

What Causes Autism?

The exact cause or causes of autism are still unclear, and some theories have sparked controversy, such as the role of vaccinations (see our article on vaccination safety here) or the importance of dietary factors such as gluten (see our article on gluten here.)  There is clear evidence for a possible genetic link.   Autism and related conditions seem to run in families; if one identical twin is diagnosed with autism, the other twin has a much higher chance of also having autism.  We also know that children who are born prematurely have a greater chance of being autistic, and children with older fathers are at slightly higher risk of autism.2,3

 

While genetic causes of autism are still being investigated, other studies suggest that certain environmental exposures in the womb may increase the chances of a child developing autism. In addition, certain geographical areas of the country have much higher rates of autism, such as California, Texas, North Carolina and Utah.4 Are doctors or parents in these states quicker to suspect and diagnose autism, or is something else going on that is causing more kids to develop autism?

 

States that require a physician or psychologist to diagnose autism for families to qualify for special education benefits tend to have lower overall rates of autism.    It’s also true that children who live in urban areas and whose parents are better off are more likely to be diagnosed with autism,  but again that finding doesn’t explain the higher rates of autism in California, Texas, North Carolina and Utah. Some scientists have suggested that higher amounts of environmental toxins in these areas may explain the relatively high rates of autism.4

 

New Research on Autism and Our Environment

 

Sex hormones, medications, certain metals such as lead, pesticides, and chemicals used to make plastic hard or pliable have long been suspected of having a role in autism.4  They have not been proven to cause autism, but these are known to trigger or worsen other health problems, including some that affect the brain.  Many studies have shown that chemical exposures during development in the womb can have much more serious health effects than the same exposures would in adults.

 

A large 2014 study investigated the connection between autism and genital malformations using health insurance claims from almost a third of the U.S. population.4 Like autism, genital malformations are increasing: cases of undescended testicle(s) increased 200% between 1970 and 1993, and the percentage of boys born with a deformity of the penis known as hypospadia doubled.5,6  Many studies have shown that these malformations are more common among children whose mothers have high levels of chemicals that affect the hormones in their bodies, such as phthalates which are found in cleaning products, medicines, and personal care products like shampoos and creams (see our article on phthalates here.) The link between these chemicals and genital malformations has surfaced in other studies, particularly those involving women in professions (chemists, health care workers, housekeepers) that require working daily with these chemicals.7,8,9

 

The 2014 study based on insurance claims found that boys born with genital defects were much more likely to be diagnosed with autism.  Boys with autism spectrum disorders (ASD) were 5.5 times more likely to be born with genital malformations than males without ASD.  However, there was no connection between genital malformation and intellectual disability. A similar pattern was observed for girls, but the connection wasn’t as strong.  No one knows why but, ASD is 5 times more common in boys than girls.

 

As found in previous studies, the children with autism in this study were more likely to live in cities and be from families with higher income. For every additional $1,000 in income above the country average, the rate of autism went up by about 3%. A similar trend was seen with measurements indicating how urban a household’s location was. However, city-living and wealth had a much weaker connection to autism than genital malformations.

 

While this study doesn’t prove that exposures to chemicals in our environment cause autism, it suggests that whatever is behind the increase in genital malformations could be behind the increase in autism. Researchers need to continue to investigate the possibility that environmental exposures are contributing to autism.

 

Diagnosis of Autism: What We Do Know

Autistic children benefit from early diagnosis, preferably in the first two years of life.  Early diagnosis allows behavioral therapy or other treatments to begin early when it seems to be most effective.  If you are concerned about your child, talk to your doctor about a referral to see a specialist who can help determine if follow-up is needed.  Signs of autism may include symptoms such as:

 

  • no babbling or pointing by age 1
  • no single words by 16 months or two-word phrases by age 2
  • no response to name
  • loss of language or social skills
  • poor eye contact
  • excessive lining up of toys or objects
  • no smiling or social responsiveness10

 

A final diagnosis should be made by a team of qualified professionals including a neurologist, psychologist, psychiatrist, and speech pathologist.  The outlook for children with autism is improving as we learn more, and many children can improve significantly within a few years of treatment.

 

 

APRIL 17, 2014

The FDA has saved lives today by announcing that they discourage surgeons using an FDA-approved device called a power morcellation device to remove the uterus or uterine fibroids.

This announcement is the result of excellent media coverage explaining that when uterine fibroids contain undiagnosed cancer, the use of power morcellation during laproscopic surgery  can spread the cancer.  The result is that a small contained cancer can spread and become a stage 4, fatal cancer.

This example indicates several major flaws in the system intended to protect patients from unsafe medical products and procedures:

1.      FDA standards for approving medical devices is much too low, resulting in unsafe devices such as the power morcellation.

2.      While many patients have been irreparably harmed by power morcellation devices that spread their undiagnosed cancer, surgeons and other health professionals rarely reported when that happened.  The voluntary system of reporting serious medical harm from devices, including deaths, is not working because most physicians are not reporting most incidents, regardless of how serious they are.

3.      The FDA apparently hardly noticed the problems with power morcellation until two Boston physicians, Amy J. Reed and her husband, Dr. Hooman Noorchashm, became outspoken advocates against it in the media.  Dr. Reed was diagnosed with a rare uterine cancer as a result of morcellation of what was thought to be a benign fibroid, and she and her husband have used their medical connections and the media to try to prevent that from happening to any other women.  We thank them for their courage in speaking out and our prayers are with them.

The FDA needs to do more to prevent these and similar tragedies due to inadequately tested medical products that too often are used by physicians who are inadequately trained to use them safely.  And patients need to be better informed of the risks of medical procedures, not just of the possible benefits.

To read a recent medical journal article on power morcellation, see http://jama.jamanetwork.com/article.aspx?articleid=1828692

To view as a PDF, click here.

April 8, 2014

Janet Woodcock, MD
Director
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002

Re: Flibanserin

Dear Dr. Woodcock,

As members of the Patient, Consumer, and Public Health Coalition, we are writing to support the agency’s evidence-based evaluation and decision regarding flibanserin.  We agree with the FDA that there is no evidence that the very modest benefit would outweigh the risks.

Concerns that have been raised about gender equity and the variety of prescription drugs approved for male sexual dysfunction compared to zero for women’s sexual satisfaction are not relevant to the overriding issue: benefits should outweigh the risks.  For example, the drugs approved for men are all taken on an as-needed basis, whereas flibanserin, a central nervous system serotonergic agent with effects on adrenaline and dopamine in the brain, requires daily, long-term use, which is much more dangerous.

However, the concerns that have been expressed about the FDA’s rejection of flibanserin, to some extent reflect the public’s concern and confusion about recent FDA approval decisions that seem to hold other prescription drugs, for women and men, to a lower standard.  For example:

  • Brisdelle (a low dose version of the antidepressant Paxil) was approved for hot flashes even though the women taking it in randomized clinical trials had similar numbers and severity of hot flashes to women taking placebo.  But, Brisdelle increased the risk of suicide dramatically compared to placebo among women who were not depressed prior to taking the drug.[1][2]
  • Farxiga was approved for diabetes, although the patients taking it in randomized clinical trials were 5 times as likely to be diagnosed with bladder cancer, twice as likely to be diagnosed with breast cancer, and had increased risk of renal failure.[3] It lowered blood sugar, comparable to other diabetes drugs, but actual health benefits were questionable.  In clinical trials for Farxiga, less than 4% of patients were African-Americans, a group with the highest diabetes rate in the country.3
  • Sirturo (bedaquiline) was approved for multidrug-resistant tuberculosis even though patients taking it with the standard drug regimen were 5 times more likely to die than patients who only took the standard drug regimen.[4]

Too often, the FDA has decided in favor of approving a new drug even when there are many existing alternatives that are safer and equally or more effective.  This inconsistency is opening the FDA to criticism when the FDA makes appropriate decisions to deny approval for unsafe or ineffective drugs.

As patient, consumer and public health organizations long engaged with the FDA, we support the agency’s concern for drug safety shown in its handling of the flibanserin applications.  We ask that the very reasonable standards that you used in this decision be applied to other drugs that have similarly modest or unproven benefits with potentially serious risks.

Sincerely,

 

American Medical Student Association

American Medical Women’s Association

Annie Appleseed Project

Breast Cancer Action

National Research Center for Women & Families

Our Bodies Ourselves

The TMJ Association

WoodyMatters

 

For more information, contact Paul Brown at (202) 223-4000 or pb@center4research.org

 

 

 

 

 

 


[1] Food and Drug Administration (June 28, 2013). FDA approves the first non-hormonal treatment for hot flashes associated with menopause. FDA News Release.  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm359030.htm

[2] Food and Drug Administration (March 4, 2013). Advisory Committee for Reproductive Health Drugs. Background Document.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM341587.pdf

[3] Food and Drug Administration (December 12, 2013). Advisory Committee Materials for Endocrinologic and Metabolic Drugs. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm331504.htm

[4] Food and Drug Administration (November 28, 2103). Advisory Committee for Anti-Infective Drugs.  http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm337696.pdf

By Celeste Chen

April 2014

Over the next 40 years, the number of people in the world with Alzheimer’s Disease, the most common form of dementia, is expected to triple.11  Because Alzheimer’s strikes as people get older, the U.S. is expecting a big increase in this brain-wasting disease as baby boomers become seniors.

Pesticides, which kill insects by attacking their nervous systems, and herbicides, which wipe out some plants but not others, are increasingly being linked to diseases that attack our nervous systems and brains. Several studies have shown that individuals regularly exposed to pesticides and herbicides are more likely to develop Parkinson’s Disease (PD), which makes it difficult for people to control their movements and can cause emotional changes.12 Now, there is reason to believe that pesticide exposure can also increase a person’s chances of developing Alzheimer’s Disease. 13

A study published in 2014 in the prestigious medical journal JAMA showed a link between Alzheimer’s and DDT, an ingredient in many pesticides in the 1970s.14  Farmers and other agricultural workers who were exposed to high levels of DDT decades ago are much more likely to suffer from dementia, including Alzheimer’s, than are other people. DDT was banned in the U.S. in 1972, but people continue to come into contact with this dangerous pesticide by:

  • Buying imported foods from countries such as India, Spain, Mozambique, and Ethiopia where DDT or DDT-like pesticides are still in use.15 16
  • Living in agricultural areas where DDT was once sprayed as a pesticide. Even though it has not been used for over 40 years in the US, DDT is still present in our soil because it takes decades for DDT to be broken down naturally.17 18
  • Living near former industrial sites. In the 1970s, manufacturing plants dumped waste products containing DDT, which contaminated riverbeds and local waters. The Palo Alto Superfund site is one example of an area contaminated with DDT and other chemicals. Fish at these sites still contain DDT because DDT remains in the water for over 300 years. 19  20  
  • Chance.  When DDT breaks down, it produces DDE, another harmful chemical. Both DDT and DDE enter the air as they evaporate from contaminated water and soil. As a result, DDE and DDT are sometimes found far away from the source of DDT dump sites. DDE and DDT have even been found in such remote areas as the Arctic and Antarctica. As DDT and DDE evaporate, they are made safer by sunlight. Unfortunately, the process of evaporation also helps spread and deposit the chemicals to new places.21

 

DDT/DDE and Alzheimer’s

In the 2014 study on Alzheimer’s Disease and DDT, not all the individuals who had the disease had high levels of DDE (the chemical produced when the body breaks down DDT) in their blood. Moreover, some of the participants in the study who didn’t have Alzheimer’s also had detectable levels of DDE.

This tells us that DDT is only one possible cause of Alzheimer’s and dementia, and also suggests that some people are genetically more vulnerable to the harmful impact of DDT. For instance, individuals with the e4 version of the APOE gene (apolipoprotein) are more likely to have late-onset Alzheimer’s than people with e2 or e3 versions.22

The Alzheimer’s patients who scored worst on the reasoning and memory tests in the 2014 study were men and women who had both the APOE e4 gene and the highest levels of DDE in their blood. From these results, the scientists speculated that DDT/DDE may somehow interact with the APOE e4 gene to significantly increase a person’s risk of Alzheimer’s.

 

What the Study doesn’t tell us

This 2014 study looked at organochlorides, which is only one type of chemicals found in pesticides. After DDT was banned, replacement pesticides were introduced but none of these were tested for safety.  Other types of chemicals used in pesticides, such as organophosphates, may also increase a person’s risk of developing Alzheimer’s. We simply don’t know yet.  There is some evidence that a popular alternative to DDT, malthion, may cause cancer.23  Malthion is an organophosphate. Children exposed to organophosphates have been found to have a higher risk of developing childhood cancer and having behavioral problems and decreased mental functioning.

 

BOTTOM LINE

Though this study was limited to studying the effects of organochlorides (DDT), it is possible that other types of chemicals in pesticides will someday be linked to diseases like Parkinson’s and Alzheimer’s. What kills an insect or plant quickly, could—with enough exposure over time—harm your neurons, which are your brain’s building blocks.

Although DDT was banned more than 40 years ago, many of us are still exposed today though imported foods, through our own contaminated soil and water, or by eating fish that live in those waters.

In the U.S., prescription drugs have to be proven safe before they can be sold, but chemicals do not have to be proven safe before they can be sold.  It often takes many years of use before it becomes obvious how dangerous a chemical can be. When DDT was found to be dangerous, it was just replaced by other chemicals whose safety was unknown.  Some of those chemicals may be just as dangerous as DDT, and there is increasing evidence that they can harm human health.

Changing the laws of our country to require better safety studies could save lives and potentially decrease the risk of Alzheimer’s disease.  In the meantime, we can help make our home environments safer:

  1. Always cover exposed skin with long sleeves, socks, gloves and eyewear when applying pesticides and wash yourself thoroughly afterwards.
  2. Always rinse fruits and vegetables with water before eating them, and peel them if at all possible.
  3. When applying insecticides/pesticides indoors or outdoors, always follow the instructions on the label exactly, and keep children, toys, and pets away from the area until the insecticide or pesticide dries or for as long as instructed.

For more information on how to limit your exposure to pesticides, check out these safety guides:

  1. http://www.epa.gov/oppfead1/Publications/Cit_Guide/citguide.pdf
  2. https://www.osha.gov/SLTC/youth/agriculture/chemicals.html

Atrial fibrillation: is the new blood thinner Pradaxa better or worse than Coumadin (warfarin)?

 

By Melanie Brown

April 2014

When it comes to blood thinners to prevent blood clots and reduce the risk of stroke, there is a new kid on the block. The brand name is Pradaxa but the drug is dabigatran etexilate mesylate.  The most important question is: is Pradaxa a safe alternative to Coumadin (also called warfarin)?

Blood Thinners

Blood thinners are prescribed to people with heart or blood vessel diseases, or whose blood doesn’t flow well to the brain. Some people take a blood thinner for a very short time (usually heparin), and some people must take blood thinners regularly for years. For instance, people with an abnormal heart beat caused by atrial fibrillation are at a much higher risk of stroke than other people, and often take blood thinners their whole life. Atrial fibrillation, the most common cause of an irregular heartbeat, is a condition where the two upper chambers of the heart don’t contract normally.

Aspirin is also a blood thinner, but it works differently from prescription blood thinners like Coumadin. Aspirin keeps blood cells from clumping together (antiplatelet) while Coumadin lengthens the time (anticoagulant) it takes for a blood clot to form. Those who have atrial fibrillation and are at low risk for stroke may be prescribed aspirin. Aspirin poses less bleeding risks than Coumadin, but is usually not as effective for patients with atrial fibrillation. 24

How is Pradaxa different from Coumadin?

Like Coumadin, Pradaxa is an anticoagulant but it is also what is called a “thrombin inhibitor.” Both Coumadin and Pradaxa are supposed to reduce clotting, but not stop it completely. Stopping clotting completely can lead to excessive bleeding.

Pradaxa is only approved for use in patients with non-valvular atrial fibrillation, the most common type of atrial fibrillation. 25  Coumadin, on the other hand, is approved for the prevention and treatment of several health issues in addition to atrial fibrillation. These include pulmonary embolism (blockage of an artery in the lung) and venous thrombosis (blood clot in a vein). Additionally, Coumadin is sometimes prescribed to patients who have had a heart attack in order to prevent another heart attack. 26

Dose: Coumadin comes in several different doses.  While this can cause some confusion, it also allows doctors to prescribe the dose that is best for a particular patient, based on age, weight, and other health factors. In the U.S., Pradaxa is available in only two doses, taken twice a day: 75 mg and 150 mg.  The 75 mg dose is prescribed for those with kidney problems and is less effective in preventing stroke than the higher doses. In other countries, a 110 mg dose (also taken twice a day) is also available. This “in-between” dose appears to offer a lower bleeding risk while still being effective.  Experts question why the FDA did not approve the 110 mg dose for sale in the United States, since it has the potential to be safer for some people than the 150 mg dose.27

Overdose and Bleeding: Coumadin interferes with your body’s ability to use vitamin K (found in many foods, including leafy greens), which your body needs to form clots and prevent excessive bleeding. This is why patients experiencing excessive bleeding due to a Coumadin overdose are given Vitamin K.28  Pradaxa works slightly differently from Coumadin. Those considering taking Pradaxa should know that there is no Vitamin K equivalent for this drug. If a person taking Pradaxa experiences excess bleeding (blood in stool, urine, coughing up blood or what looks like coffee grounds, small red spots under the skin), there is nothing that can undo or reverse its effects!29 That can be deadly.

Anticoagulants rank among the riskiest drugs on the market.  However, certain anticoagulant drugs carry a higher bleeding and death risk than others.  In a report monitoring adverse events for anticoagulants, it was found that bleeds associated with Pradaxa use were 5 times more likely to end in death than bleeds from Coumadin. 30 This may be influenced by the fact that there is no reversal agent for Pradaxa so once someone starts to bleed excessively it is very difficult to save them.

Blood Monitoring: People taking Coumadin have to have their blood monitored regularly to make sure it is not becoming dangerously thin, since that could result in bleeding. Patients see Pradaxa as more convenient because they don’t need to get their blood monitored; this convenience can increase sales. This supposed benefit, however, presents risks: people who get their blood monitored regularly can find out if their blood has become too thin before it becomes a medical emergency. Without blood monitoring, a bleeding complication may be detected when it is too late to do anything to save the patient.  Earlier this year, documents from the drug manufacturer, Boehringer Ingelheim, were released by a federal judge in response to thousands of lawsuits filed by users of Pradaxa and their families. According to experts who have seen these documents, Boehringer Ingelheim employees have expressed concern that the company’s own research shows that people may benefit from blood monitoring while on Pradaxa. 31 This raises serious questions about the safety of Pradaxa and whether the lack of blood monitoring is beneficial and safe for all patients.

A study published in 2014 looking at patients with atrial fibrillation taking Pradaxa found that the ones who suffered a stroke or major bleeding had much higher concentrations of Pradaxa in their blood.32 The study used both the 110 mg. dose available outside of the U.S. and the 150 mg. dose used in the U.S.  How patients metabolized the drug ended up being much more important than the difference between the two doses. The huge range in blood concentration levels was just as large for each dose. The women in the study had Pradaxa blood concentrations 30% higher than the men, and people 75 and older had concentrations 68% higher than in people under 65.33 The researchers suspect that the high blood concentrations of Pradaxa in older people are the result of their kidneys not working as well, making it harder for them to clear the drug from their bodies. These findings suggest that, until tests are available to predict how people will metabolize Pradaxa, older patients and others may need to take doses even lower than 110 mg. or take their doses less frequently.

Dietary Restrictions: People taking Coumadin are advised not to eat excessive amounts of foods high in Vitamin K. Vitamin K can decrease the effectiveness of Coumadin.  Additionally, those taking Coumadin should avoid or limit alcohol as it can increase the effectiveness of the drug which may result in excessive bleeding. If you are taking Pradaxa for your atrial fibrillation, you don’t need to worry about whether your foods have Vitamin K or not. While Pradaxa does not require dietary restrictions, you should talk to your doctor about using alcohol if you are taking this drug.

Cost: Pradaxa costs around $3,000 per year while Coumadin usually runs about $200 per year.  Coumadin requires blood test monitoring which does involve some additional cost, but it still will not cost as much as treatment with Pradaxa.

Pradaxa Coumadin
Prevents clotting for those with atrial fibrillation Yes Yes
Reliable reversal agent available No Yes
Dietary restrictions No Yes
Requires routine blood monitoring/testing No Yes
Approved for other indications (post heart attack) No Yes
Dosage availability 2 doses available in the United States. Dosage determined by blood test.  Several doses exist.

 

The Bottom Line:

Pradaxa is an option for those with non-valvular atrial fibrillation, but it comes with several serious risks. Anyone thinking about taking this drug should consider the following:

•Pradaxa is not more effective at preventing strokes than its competitor, Coumadin.

•Pradaxa does not require blood test monitoring by a physician. It is possible that not getting regular monitoring could increase your risk for complications.

•As with Coumadin, bleeding can occur with Pradaxa. The most serious bleeding would include gastrointestinal and bleeding of the brain, and is life-threatening.

•There is no known medicine or substance to reverse excess bleeding due to using Pradaxa.

•The 110 mg dose of Pradaxa, which is not available in the U.S. but is available in other countries, is less likely to cause excess bleeding than Coumadin and the 150 mg dose of Pradaxa.



 


April 1st, 2014

My name is Laurén Doamekpor, a senior fellow speaking on behalf of the National Research Center for Women & Families and our Cancer Prevention and Treatment Fund. Thank you for the chance to speak today.

Our research center evaluates data and provides objective health information to patients, providers and policy makers. We strongly support the inclusion of women, racial and ethnic minorities, and the elderly in clinical trials for drugs and devices.

The Section 907 report reveals that there is more work to be done to achieve greater diversity in clinical trials.  We believe that the key question today should be: what can the FDA do to ensure:

  1. greater diversity in clinical trials submitted to FDA,
  2. subgroup analyses submitted to the FDA
  3. Information from subgroup analyses are used as a basis of approval and labeling decisions, and made widely available in a user-friendly format to providers, patients, and other stakeholders.

The responsibility of collecting sufficiently representative demographic subgroup data sits solely on the shoulders of device and drug companies. The companies know how to persuade – they do it everyday in commercials.  Similarly, if they identify persuasive incentives for patients to participate in studies, and minimize disincentives, patients will participate and be available for follow-up.

The FDA’s crucial role is to hold companies accountable. The FDA guidance regarding diversity and subgroup analyses is regularly ignored by companies, and unfortunately the FDA then approves their drugs and devices anyway.  If the FDA’s actions clearly showed that sponsor applications will be rejected — or perhaps approved for White men under 60 only — if companies do not include the relevant demographic data and conduct the necessary subgroup analyses – we are confident that companies will find a way to comply.

To successfully persuade companies to conduct subgroup analyses for the major subpopulations that will use their products, the FDA must consistently demonstrate that they believe those data are essential for proving safety and efficacy.

This is essential because research tells us that naturally occurring genetic variations may influence the way certain drugs are metabolized and work in women compared to men, older patients compared to younger, and certain racial and ethnic groups. Currently, the main challenges in conducting subgroup analyses is that the sample sizes are too small, and get miniscule when age and race and sex are all considered.  We understand that not every ethnic group or age group can be separately analyzed. However, we disagree with the assumption that it is not feasible to power studies to detect subgroup differences. It can be done, and should be done for major subgroups. If the FDA required this practice and held companies accountable, companies will find a way to achieve this.

Our Center participates in many FDA Advisory Committee meetings, and rarely is the lack of diversity in clinical trial data mentioned for more than one second by anyone other than us.  When the FDA’s clinical summaries provided to Advisory Committee members and the public, do not criticize the lack of diversity or lack of subgroup analyses, the FDA sends the message that safety and efficacy for all subgroups are not important.

In the last week, for example, we spoke at one FDA Advisory Committee meetings for a drug for heart failure and 2 for drugs forMRSA. Heart failure is the #1 killer of men and women of all races in the U.S. and MRSA disproportionately harms minority patients.  However, African American patients comprised less than 5% of the cardiac drug trial and less than 6% for one of the MRSA drugs.  NONE of the companies did subgroup analyses for all the primary and secondary endpoints. The lack of data was similar for Hispanic patients.

And, although many of these drugs are used primarily on elderly patients, few patients over 65 were included.  For one of the MRSA drugs, only one analysis of efficacy for patients over 65 was conducted and it clearly showed that the new drug was less effective than the comparison drug.  But, the FDA didn’t even mention that in their summary and the Advisory Committee recommended approval of the drug for all adults over 18 anyway.

On the rare occasion when our concerns about diversity inspires Advisory Committee members to speak up, the result is usually a recommendation to achieve better diversity in the post-market study.  Unfortunately, companies rarely do better in post-market studies, because the incentives to please FDA weaken greatly once their drug or device has already been approved for the general population.

In addition to showing companies that they must achieve diversity and conduct subgroup analyses, there is another action that the FDA should take.  FDA should gather information comparing recruitment and retention strategies from companies that are achieving greater and lesser diversity in their trials to determine which strategies are successful, and share that information with companies that need to improve.

Ultimately, patients and providers need to know whether subgroup data were collected, what the findings are, and how scientifically solid those results are. This information is essential for providers and patients to make well-informed medical decisions. The FDA should require that subgroup data be provided on labels and promotional efforts, using wording that is easy to understand by patients and providers.

Again, thank you for the opportunity to speak at this meeting. We hope that you will incorporate our comments and recommendations into the Action Plan.