NRCeditor | Center For Research

Jennifer Focht, M.A.

May 2013

Exercise has so many health benefits: it can help prevent osteoporosis, lower cholesterol, reduce the pain of fibromyalgia, ease the symptoms of menopause, and reduce your risk of developing breast cancer, colon cancer, and prostate cancer. But did you know that physical activity is also a fountain of youth for our brains? Some research suggests that, just by being active, seniors can improve their ability to think, focus, plan, and recall words, as well as perform many other brain activities.

These brain activities (also called cognitive function)¹ include:

Language
Thought
Memory
Executive function (the ability to plan and carry out tasks)
Judgment
Attention
Perception
Remembered skills
Ability to have a purposeful life

Most of the research recommends aerobic exercise. Aerobic exercise refers to any activity that increases your breathing and heart rate. This could be walking quickly, running, biking, dancing, or any number of other fun activities.

What kind of exercise? How much?

The Centers for Disease Control and Prevention (CDC) recommends that adults ages 65 and older who are “generally fit, and have no limiting health conditions” participate in at least 2.5 hours of “moderate-intensity aerobic activity” every week and total body muscle-strengthening activities 2 or more days every week.²

If 2.5 hours per week won’t fit into your schedule, an alternative is doing 1 hour and 15 minutes of “vigorous-intensity aerobic activity” every week while still including muscle-strengthening activities on a couple of days.

The exercise doesn’t have to be done all at one time. You can exercise just 10 minutes at a time as long as it adds up. These recommendations are the minimum you need to do to get health benefits. If you can do more, go for it!

Can’t I just do crossword puzzles, Sudoku and other cognitive exercises to improve my cognitive health?

Researchers have been surprised to find that doing mental exercises doesn’t benefit your brain as much as physical exercises. Both are good for you,³ but you can’t substitute one for the other.

Bottom line

When cognitive skills deteriorate, it becomes harder for an older person to maintain overall health and manage day to day activities like preparing meals, bathing, and eating. When an older person is no longer “with it,” it makes communication difficult and care more burdensome for their loved ones. To get the most out of your “golden years,” talk to your doctor about creating an exercise plan that is safe and will work for you. Remember to avoid dehydration, skin cancer (from exposure to the sun), and over-training as you exercise.

Jennifer Focht, M.A.

May 2013

Domestic violence is a fact of life in the U.S. for approximately 35% of women and 28% of men in their lifetimes.⁴ When we learn someone is in an abusive relationship, the first question many people ask is “Well, why doesn’t she just leave?” Unfortunately, the most dangerous time in an abusive relationship is when the victim tries to leave; that is when he or she is most likely to be killed by the abuser. Homicide is one of the top 10 causes of death for women aged 20-44,⁵ and more women are killed by their partners than by anyone else.⁶

The threat to personal safety is not the only reason many people find it difficult to end an abusive relationship. No one wants to be abused, but people may blame themselves or grow up thinking that abuse is a normal part of a close relationship. If getting out of the situation were as easy as people like to think, every single person would leave at the first warning sign.

Barriers to Leaving an Abusive Partner

Shame/Social Acceptance

Even in 2013, many people still believe domestic abuse is okay. Facing questions from friends and family like, “What did you do to make him hit you?” or comments like, “You must not have minded him treating you like that, since you stayed so long” can be enough to keep some people from leaving. The longer the person stays, the more shame she or he may feel—first for ending up in an abusive relationship, and then for not immediately ending it. This shame can make it all the more difficult to get out of the relationship.

Money

Ending a relationship, especially a marriage, can be extremely expensive. Just finding a safe place to live can cost hundreds or thousands of dollars. Many people don’t make enough money to support themselves without a partner’s income, so they may have to choose between suffering the abuse and not being able to afford groceries, utilities, or transportation to work.

Kids

Lots of parents think that raising children in a two-parent home is better for the kids than raising them alone, regardless of whether or not the parents have a healthy relationship. Some don’t want their children to lose the love and security associated with a 2-parent family. The victim may see the abuser as a good parent or fear losing their children’s love if they end the relationship. For many parents, staying in the abusive relationship seems like what is best for their children, which can make it extremely hard to leave.

Religion

For many people who are married to their abusers, leaving the relationship is inconsistent with their religious beliefs. Even for people of faith whose religion does not specifically forbid divorce, it may feel like their significant other’s behavior is part of a greater plan or part of a spiritual test. In some circumstances, ending the relationship requires not only a break up with the abuser, but possibly rejection by their religious community as well.

Immigration status

For immigrant victims, day-to-day living may be subject to the abuser’s control regardless of whether the abuser is also an immigrant or a U.S. citizen. An abuser may hide or destroy their partner’s immigration documents, and without them, it will be very difficult for the victim to prove they are in the country legally. In situations where there are no immigration documents, an abuser may threaten to have the victim deported if he or she tries to leave the relationship. Although leaving the country, even by government force, could potentially be an effective way to break off the relationship, abusers may maintain control of their partners, maybe even from a distance, by making and carrying out threats of violence against the victim’s loved ones.

Fear of Being Outed

Despite changing attitudes, in many communities, people live in fear of others finding out they are gay, lesbian, bisexual, or transexual. An abuser—whether in a same-sex or opposite-sex relationship—may threaten to disclose the victim’s sexuality to their family, friends, or coworkers which could put the victim at further risk of violence. If the person thinks they will lose their job or their friends and family by being outed, then staying in the abusive relationship may seem like a better option.

He/She Promises to Change

When the abuser promises to change, many victims decide that it’s riskier to leave than it is to stay. Staying in a relationship when the other person promises to stop being abusive can mean avoiding the failure associated with the end of a marriage or long-term relationship.

Love

It’s easy to assume that someone cannot possibly love an abuser, but abusive relationships are just as complex as any other. Sometimes the person doesn’t necessarily want to break off the relationship; sometimes they just want the violence to stop. Even after years of abuse, the victim may still feel love for the abuser and want to give them “one more chance” to change.

Bottom Line

If you know someone who you believe is in an abusive relationship, be supportive. Abusers often isolate victims from their friends and family to make them feel like they have nowhere to go for help. Come up with a way you can safely keep in touch with the person being abused. (For example, if the abuser is monitoring their cell phone, try e-mail instead.) Find resources to help the victim, like the telephone number for the local domestic violence advocacy program, or safety information.

Remember to be patient with the person. It may seem obvious to you that the victim should just leave the abuser, but situations are rarely that simple. Sometimes leaving just isn’t a realistic option, and victims in those circumstances need support too. In a lot of cases, leaving the abuser doesn’t actually end the abuse. It is extremely common for people who have left abusive relationships to eventually go back, and it often takes several attempts before a person can successfully and permanently end the relationship.

If you are in an abusive relationship, you can call the National Domestic Violence Hotline at any time of day or night to speak to someone trained to help you. The Hotline operates 24 hours a day, seven days a week. All calls are confidential and anonymous, and interpreter services are available for more than 170 languages.

1-800-799-SAFE (7233)

1-800-787-3224 TTY

Rebecca Silverman

May 2013

How often do you get a good night’s sleep and wake up feeling totally rested? It’s increasingly hard to disconnect from work and technology, and it just seems like there aren’t enough hours in the day to get everything done. As a result, sleep rarely makes our “to-do” list.

While many of us think 5-6 hours of sleep a night are enough, it is recommended that adults (for teens and sleep, read here) sleep 7-9 hours a night in order to be fully rested and functioning the next day. ⁷

Did you know that not getting enough sleep can cause health problems beyond just feeling tired and worn out? Recent studies have found that lack of adequate sleep is related to weight gain, sexual problems, reduced concentration, mental health problems, and even Alzheimer’s disease.

The Link between Sleep Deprivation and Weight Gain
How Sleep Deprivation Can Affect Your Sex Life
Lack of Sleep and its Effect on Attention, Reaction time, and Motor Function
Sleep Deprivation is Connected to Changes in Mood and Mental Health
Poor Sleep and Alzheimer’s disease
What You Can Do to Improve Your Sleep and Your Health
Bottom Line

The Link between Sleep Deprivation and Weight Gain

A study published in 2012 found that sleep deprivation affects metabolism. After four nights of 4.5 hours of sleep a night, the fat cells of the study’s seven participants “aged.”⁸ Aged fat cells are less sensitive to insulin, making a person more likely to gain weight gain and develop diabetes. Does not getting enough sleep for several nights in a row age your fat cells permanently, or does it take weeks and years of poor sleep to create insulin resistance? The study didn’t answer that question but it’s one that researchers are interested in.

A 2013 study of 16 healthy men and women by Rachel Markwald and colleagues from the University of Colorado found that those who slept only 5 hours a night ate more carbohydrates and snacked more after dinner than those who slept 9 hours. ⁹ While the group who slept 5 hours a night burned more calories per day than the group who slept 9 hours, those who slept less ended up consuming more food and gained an average of 2 pounds during the two-week study.

If a week or two without sufficient sleep can throw off your metabolism and add pounds, what happens if you don’t get enough sleep for much longer? Researchers who followed the sleep patterns and weight gain of 68,183 women for over 16 years found that those sleeping 5 hours or less a night weighed on average 5.4 pounds more than those sleeping 7 hours a night.[endPatel S, Atul M, White P, Gottlieb D, Hu F. Association between reduced sleep and weight gain in women. American Journal of Epidemiology.2006:164(10):947-954.] The women who slept the least per night were the ones who put on weight the fastest.

While too little sleep seems to cause people to put on pounds, too much weight causes people to sleep poorly. Research shows that excess weight can lead to sleep apnea, the leading cause of daytime sleepiness.¹⁰ People with sleep apnea stop breathing during sleep for at least 10 seconds at a time.¹¹ Other symptoms include loud and chronic snoring, pauses in snoring, and chokes and gasps after the pauses. There are two kinds of sleep apnea: obstructive sleep apnea, caused by a blockage of soft tissue in a person’s airways, and central sleep apnea, which occurs when the brain fails to regulate a person’s breathing.

Researchers at the University of Wisconsin School of Medicine studied 690 randomly selected Wisconsin residents for breathing problems during sleep using electrodes that measure breathing patterns and changes in the body. The participants were weighed and their sleep was measured at the beginning of the study and then again four years later. The study found that participants whose weight increased by 10% were six times more likely to have been recently diagnosed with moderate to severe breathing problems during sleep, such as obstructive sleep apnea.¹²

How Sleep Deprivation Can Affect Your Sex Life

Sleep apnea may also contribute to sexual problems, including erectile dysfunction in men and women’s loss of interest in sex.

A 2011 study in The Journal of Sexual Medicine by Marian Peterson and colleagues in Scandinavia compared 80 women with obstructive sleep apnea against 240 women without sleep apnea between the ages of 28 and 64. The study found that women with sleep apnea had significantly higher rates of sexual dysfunction.¹³ A previous study published in the same journal looked at 401 men suspected of having sleep apnea and found that 69% of those confirmed as having sleep apnea also had erectile dysfunction. Only 34% of men without sleep apnea were unable to achieve or maintain an erection.¹⁴

Lack of Sleep and its Effect on Attention, Reaction time, and Motor Function

Studies show that partial sleep deprivation increases a person’s reaction time and decreases alertness. Gregory Belenky and colleagues recruited 66 healthy participants to spend two weeks living in a laboratory. After 3 days of adapting to their new sleep environment, participants were randomly assigned to one of four sleep groups: 3 hours of time in bed, 5 hours of time in bed, 7 hours of time in bed, or 9 hours of time in bed each night.¹⁵

Participants took a test that measured their reaction time, requiring them to click a button every time a light appeared on a screen in front of them. The reaction time of those who were only allowed 3 hours to sleep grew a little bit worse every day during the seven days of restricted sleep. For those who were only given 5 or 7 hours to sleep, speed and lapse time worsened at the beginning of the week and then stayed at the same lower rate for the remainder of the week. For those who had 9 hours in bed each night, speed and lapse time remained the same over the course of the study.

During the last 3 nights of the study, participants were given the opportunity to recover—all were allowed 8 hours of time in bed a night. Once again, their reactions were measured. Participants from the 5 and 7 hour groups didn’t show any real recovery; their performance stayed the same as it was at the end of the 7 nights of restricted sleep! The 3 hour group showed some improvement, but their performance on the tests ended up being about the same as that of the 5 and 7 hour groups. None of the groups were able to perform as well on the tests as they had before the sleep restriction began—even after 3 nights of 8 hours in bed! These findings suggest that the effects of sleep deprivation last longer than people would expect.

A 2006 study sponsored by the National Center on Sleep Disorders Research and the National Highway Traffic Safety Administration reported that too little sleep impairs a driver’s ability to focus on the road, leading to crashes and car accidents.¹⁶ Not getting enough sleep slows reaction time, decreasing a person’s ability to avoid collisions. Sleepiness also decreases attention, causes delayed response, and decreases the accuracy of short term memory.

According to a report by the National Highway Traffic Safety Administration, 832 deaths and 30,000 driving-related injuries in 2009 were caused by crashes involving a drowsy driver.¹⁷ These statistics vastly underestimate the problem—many more people are killed or injured by tired drivers than are reported. More than a quarter of drivers surveyed admitted to feeling in the past month “so sleepy that they had a hard time keeping their eyes open.”¹⁸

Sleep Deprivation is Connected to Changes in Mood and Mental Health

A University of Pennsylvania study found that getting only 4.5 hours of sleep a night had a significant effect on participants’ mood.¹⁹ When participants were allowed only 4.5 hours of sleep a night for one week, they reported feeling more stressed, angry, sad, and mentally exhausted. After returning to a regular sleep schedule, participants reported a dramatic improvement in mood.

A 2010 study conducted at University of Sydney in Australia found a relationship between sleep deprivation and psychological distress in young adults ages 17 to 24.²⁰ Young adults who sleep less than recommended are more likely to feel distressed and have “low mood,” which includes symptoms of depression, hopelessness, and anxiety and can lead to more serious mental disorders. As with weight gain, it is hard to know if lack of sleep causes mood problems or if it is the mood problems themselves that prevent people from sleeping well.

Poor Sleep and Alzheimer’s disease

A study published in 2013 concluded that there is a link between poor sleep and the presence of a molecule that leads to the formation of plaque in the brain, which is associated with Alzheimer disease.²¹ Previous studies have shown that sleep problems, including unintentional napping and insomnia, are common in patients who already have Alzheimer disease.²²

Researchers were curious if poor sleep patterns were present in the earliest stages of Alzheimer’s prior to any obvious symptoms of the disease. They hypothesized that the presence of the molecule ß-amyloid (Aß) negatively affects sleep patterns and that poor sleep may make people more likely to develop ß-amyloid. The study included 142 cognitively normal participants ages 45 to 75. Researchers observed the participant’s sleep and wake cycles while also measuring Aß42 levels in their cerebrospinal fluid, an indicator of ß-amyloid. The results showed that the 32 men and women with ß -amyloid had worse sleep quality than those without ß-amyloid. The researchers were not able to conclude whether poor sleep leads to ß-amyloid formation. More research is needed to fully understand the relationship between poor sleep or lack of sleep and Alzheimer’s disease.

What You Can Do to Improve Your Sleep and Your Health

Regardless of your work and family obligations, these are some ways that you can improve your sleep:

Establish a routine: Going to sleep and waking up around the same time each day helps regulate your body and promote a consistent sleep cycle.²³ Avoid sleeping late on the weekends because doing this throws a wrench into your sleep cycle, making you more tired during the week.
Exercise: Daily exercise has been proven to help people sleep. However, exercise right before bed is not a good idea because it can keep a person awake for longer. Studies suggest that you should exercise no later than 5 to 6 hours before your normal bedtime.
Finish eating 2-3 hours before bedtime: Eating a large meal before bed can make it difficult to fall asleep. Avoid drinking liquids close to bedtime to prevent trips to the bathroom during the night.²⁴
Avoid Caffeine, Nicotine, and Alcohol: Caffeine, which is found in coffee, chocolate, tea, and some soft drinks, keeps people awake. Smokers often experience light sleep due to nicotine, and alcohol makes it difficult to fall and stay asleep until morning.
Avoid naps: While you may be tired during the day, naps can interfere with getting a full night’s sleep.
Wear a sleep mask: Research shows that sleeping in total darkness allows your body to produce as much of the hormone melatonin as possible, which is responsible for regulating your body’s internal clock, thus allowing you to sleep longer and deeper.
Do not take sleeping pills: A study on the danger of sleeping pills found that people who take prescription sleep medication are significantly more likely to be diagnosed with cancer or die earlier than people who don’t take them. According to a 2012 article in Consumer Reports, people using popular sleeping pills like Ambien take 33 to 46 minutes to fall asleep and only get about half an hour more sleep than if they had not taken a pill in the first place.²⁵

If you have sleep apnea there are things you can do to improve your condition:

Lose Weight: Even losing a little weight can reduce symptoms.²⁶
Use a mouthpiece: A dentist or orthodontist can make a custom-fit plastic device to wear in your mouth while sleeping that helps keep your airways open. Mouthpieces may need to be adjusted or replaced over time.²⁷
Continuous positive airway pressure machine (CPAP): The CPAP machine blows air into your throat to keep your airways open while you sleep. The machine uses a mask that fits over your mouth and nose, or just over your nose. While studies show that CPAP masks can result in significant improvement in symptoms of sleep apnea, some people find the masks bothersome or uncomfortable.²⁸ CPAP treatment may cause side effects in some people, including a dry or stuffy nose, irritated skin around the face, dry mouth, and headaches.
Surgery: Surgery to remove tissue from the back of the throat has been used to treat severe sleep apnea. The University of Maryland Medical Center reports that success rates for this surgery are rarely higher than 65% and often deteriorate with time, averaging about 50% or less over the long term.²⁹ More research is needed to compare surgery to the other treatments for sleep apnea.

Bottom Line

Although most adults deny it, adults require 7 to 9 hours of sleep a night to function at their best, so put “sleep” on your to-do list!
Getting a full night’s sleep most nights is essential to your health. It helps you control your weight and keep your mind focused.
Sleep deprivation can have devastating short-term effects, like making you more prone injury and death from accidents, and is linked to a range of other health problems that can shorten your life, such as obesity and depression.
There are simple, proven ways to help you get to sleep faster, sleep longer, and wake up feeling more refreshed. Sleeping pills are not included in that list.

Division of Dockets Management
Food and Drug Administration
5630 Fishers Lane, Room 1061 (HFA-305)
Rockville, Maryland 20852

May 8, 2013

Comments of the National Research Center for Women & Families and the TMJ Association
on
“Dental Devices; Reclassification of Temporary Mandibular Condyle Prosthesis”
[Docket No. FDA-2012-N-1239]

The National Research Center for Women & Families and the TMJ Association oppose the reclassification of Temporary Mandibular Condyle prosthesis, a preamendments class III device, into class II. The proposed special controls are not rigorous enough to provide a reasonable assurance of the device’s safety and effectiveness.

The permanent mandibular condyle prosthesis is a class III device that requires the more stringent Premarket Approval application (PMA). If the FDA allows the temporary device to be cleared through the 510(k) process for a supposedly temporary indication to treat patients who had oral cancers removed, that creates a loophole for manufacturers to avoid the more thorough PMA process.

Temporary mandibular condyle prostheses should remain class III devices because they glide across the fossa of the skull, which, if penetrated, opens to the brain. Renaming this device a “temporary mandibular condyle reconstruction plate” (TMCRP), for short-term use not to exceed 2 years, is disingenuous and misleading. Since surgeons are very unlikely to recommend a surgical procedure of this magnitude for a patient without an urgent need, it is unlikely that these devices will be removed within 2 years except in cases where the temporary devices fail in that time. In fact, a search of PubMed and other major sources has not found any research indicating the length of time the devices are implanted. There are case reports indicating that the devices are often implanted for more than two years. In some cases, the patients were seriously harmed by long-term implantation.³⁰ One study of 110 patients indicated that devices could fail even within the first 6 months.³¹ With so little scientific data, it is impossible to know how often these serious adverse events are occurring. When the devices are being used beyond the two years, patients are inappropriately exposed to the health risks identified by FDA.

Nearly a dozen serious health risks are listed for the TMCRP, including the “user error” when a TMCRP is “used as a permanent prosthesis rather than a temporary reconstruction plate.”³² No clinical data are available to determine the risks if these devices remain implanted for more than two years. Other documented health risks of the device include facial nerve paralysis, chronic pain, infection, malocclusion, mechanical failure and migration of the screws or plates. Research is needed to identify if migration of the device wears away the skull or causes further damage to mandibular bones.³

A down classification from Class III to Class II, and the resulting 510(k) clearance process, would allow a manufacturer to use less rigorous reviews to clear its device such as bench and biocompatibility tests. The special controls FDA has proposed in its draft guidelines do not include clinical trials, which would provide high-quality data demonstrating safety and effectiveness.

Even if these devices are actually used temporarily, the same products could then be used off-label for indications that FDA has designated are high risk and should require a PMA. Down-classification for any indication creates a loophole which would allow manufacturers to avoid the more rigorous PMA review process.

Although the Dental Products Panel “only recommended that class II was appropriate for plates indicated in tumor resection cases,” the FDA has proposed using the device in “patients who have undergone any resective surgical procedures requiring removal of the mandibular condyle and mandibular bone.”³ Tumor patients are less likely to live for more than 2 years, so by expanding the usage to any patient undergoing resective procedures, this would dramatically increase the number of patients being treated with a device that lacks the more rigorous PMA review for safety and effectiveness, and the number of patients whose device would be implanted for more than 2 years.

One of the reasons FDA stated for reclassifying the device from class III into class II is “the relative absence of adverse events reports despite the longstanding use of these devices,” but it is well known that adverse events are under-reported on the MAUDE data base. Under-reporting is especially likely for patients who are seriously ill, such as those with mandibular tumors. Family members who are facing the likely death of a loved one will also be unlikely to use the MAUDE system to report adverse events and relate the device failure to the disease progression. The lack of MAUDE reports is negated by the publication of case reports indicating serious adverse events, especially since case reports are rarely published.

While we support the Dental Products Panel’s 1997 recommendation that special controls include a registry to track the temporary mandibular condyle prosthesis devices, we are concerned that the panel did not state who would run the registry (the government or a private entity), and we note that the registry was not included in the FDA’s draft guideline special controls for TMCRP devices. The special controls also do not specify who will have access to the registry.

We strongly disagree with FDA’s assertion that their proposed special controls “are appropriate to provide reasonable assurance of safety and effectiveness” for TMCRP devices. These devices should remain in class III and require PMA review with clinical trials to ensure that the devices truly are safe and effective.

National Research Center for Women & Families
The TMJ Association

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

Carla Bozzolo

May 2013

Suddenly, everyone is talking about adding flaxseed to your diet. What is flaxseed and how can eating it make you healthier?

What is Flaxseed?

Flaxseed is the seed of the flax plant and can be eaten as whole seeds, ground into a powder (flaxseed meal), or the oil can be taken in liquid or pill form.[1] There is evidence that it is a great way to incorporate dietary fiber, antioxidants, and omega-3 fatty acids into your diet.

Flaxseed has been shown to lower cholesterol in some people and it may even reduce the risk of breast cancer. People take flaxseed to help with many digestive conditions, including chronic constipation, diarrhea, diverticulitis (inflammation of the lining of the large intestine), irritable bowel syndrome (IBS), ulcerative colitis (sores in the lining of the large intestine), gastritis (inflammation of the lining of the stomach), and enteritis (inflammation of the small intestine). According to the National Institutes of Health (NIH), more study is needed to prove that flaxseed benefits people who have these conditions.[2]

What’s in this miracle seed?

Omega-3 Essential Fatty Acids

Flaxseed is the richest source of omega-3 fatty acids,[3] which is good for our hearts, brains, and normal growth and development. [4] Omega-3 fatty acid can also be found in fish, plants, nuts, and oils made from nuts. No matter how you consume flaxseed—whole, ground or the oil—you will increase your intake of omega-3 fatty acids.

Lignans

Lignans are a type of plant estrogen that may help slow down certain cancers—cancers that depend on hormones to grow. Lignans also work as an antioxidant, which means they protect cells from the damage that comes with aging. Antioxidants—found in berries and many other foods—may help fight certain cancers. [5] Lignans are concentrated in the coat of the seed so when flaxseed is expressed into oil, the anti-cancer and antioxidant benefits of the lignans are lost.

Dietary Fiber

Dietary fiber helps regulate the digestive system and can lower bad cholesterol.[6] Dietary fiber in flaxseed is only found in whole and ground flaxseeds, not in flax oil.

Flaxseed and Breast Cancer

For women who have gone through menopause, a small daily serving of flaxseed (just over half a teaspoon) was enough to lower breast cancer risk. [7] While more research is needed, some studies suggest that for younger women who have not yet gone through menopause flaxseed reduces the risk of breast cancer and slows down the progress of certain breast cancers and other cancers that need estrogen to grow.[8],[9] A study published in 2013 found that eating flaxseed decreased a woman’s chance of getting breast cancer by 82%.[10]

Flaxseed and Cholesterol

Flaxseed (but not flax oil) seems to decrease bad cholesterol among people who have relatively high cholesterol.[11],[5] Once again, women who already went through menopause seemed to benefit most: their “bad” cholesterol dropped more than the bad cholesterol of men or younger women. This is important for older women, because bad cholesterol tends to increase after menopause, as estrogen levels decline.[12]

Who Benefits the Most?

Flaxseed has the potential to benefit everyone as a great source of dietary fiber with almost no side effects. People with high levels of bad cholesterol and women who are post-menopausal benefit the most.

Different Ways to Eat It

Flaxseed is sold as whole seeds, ground seeds (flaxseed meal), liquid oil, and oil in a pill form. It can easily be added to cereal, baked goods, salad, yogurt, and many other types of food. Since whole seeds tend to go through the body undigested, ground seeds are considered to be more beneficial. Flaxseed oil delivers essential fatty acids but it doesn’t have fiber or lignans. If you want to get all the benefits of flaxseed—omega-3 fatty acids, fiber, anti-oxidant and cancer-fighting properties—choose ground flaxseed.

Cautions

Few side effects have been reported from flaxseed. When taken to reduce constipation, it should be taken with plenty of water.[1]

The fiber in the flaxseed may also lower the body’s ability to absorb medications that are taken by mouth, so it should not be taken at the same time of day that you take pills or dietary supplements.[1]

The Bottom Line

Flaxseeds are a great source of dietary fiber and omega-3 essential fatty acids for men and women of all ages. They don’t have any known serious side effects, and ground flaxseeds are easy to include in the foods you eat every day.

References

[1] National Institutes of Health. National Center for Complimentary Medicine. Herbs At A Glance: Flaxseed and Flaxseed Oil. April 2012: http://nccam.nih.gov/health/flaxseed/ataglance.htm

[2] National Institutes of Health. National Library of Medicine. Flaxseed: MedlinePlus Supplements. August 2011. http://www.nlm.nih.gov/medlineplus/druginfo/natural/991.html

[3] Gebauer S, Psota T, Harris W, and Kris-Etherton P. n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. American Journal of Clinical Nutrition. 2006; 83(6): 1526S-1535S.

[4] National Institutes of Health. National Cancer Institute. Antioxidants and Cancer Prevention: Fact Sheet. July 2004. http://www.cancer.gov/cancertopics/factsheet/prevention/antioxidants

[5] National Institutes of Health. National Cancer Institute. Antioxidants and Cancer Prevention: Fact Sheet. July 2004. http://www.cancer.gov/cancertopics/factsheet/prevention/antioxidants

[6] Brown L, Rosner B, Willett W, and Sacks F. Cholesterol-lowering effects of dietary fiber: a meta-analysis. American Journal of Clinical Nutrition. 1999; 69:30-42.

[7] Cotterchio M, Boucher BA, Kreiger N, Mills CA, & Thompson LU. Dietary phytoestrogen intake–lignans and isoflavones–and breast cancer risk (Canada). Cancer Causes Control.2008; 19:259–272

[8] Buck K, Zaineddin AK, Vrieling A, Linseisen J, & Chang-Claude J. Meta-analyses of lignans and enterolignans in relation to breast cancer risk. American Journal of Clinical Nutrition. 2010; 92:141–153

[9] Velentzis LS, Cantwell MM, Cardwell C, Keshtgar MR, Leathem AJ, & Woodside JV.Lignans and breast cancer risk in pre and post-menopausal women: meta-analyses of observational studies. British Journal of Cancer. 2009; 100:1492–1498

[10] Lowcock E, Cotterchio M, & Boucher B. Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk. Cancer Causes Control. 2013. E-publicaton ahead of print. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23354422.

[11] Pan A, Yu D, Demark-Wahnefried W, Franco O, and Lin X. Meta-analysis of the effects of flaxseed interventions on blood lipids. American Journal of Clinical Nutrition. 2009; 90:288-297.

[12] Fukami K, Koike K, Hirota K, Yoshikawa H, and Miyake A. Perimenopausal changes in serum lipids and lipoproteins: a 7-year longitudinal study. Maturitas. 1995; 22:193-197.

Carla Bozzolo

May 2013

Monthly changes in hormones affect nearly all women. Some of the symptoms are more bothersome or noticeable than others, and sometimes they signal health problems. Studies show that 4% to 18% of women of reproductive age have a condition called polycystic ovary syndrome (PCOS). It can be difficult to diagnose because it is similar to so many other conditions. What is PCOS, and what are the signs?

Also known as “Stein-Levanthal Syndrome,” PCOS is caused by hormone problems.[1] It is hard to identify in some women, particularly adolescents, because the symptoms vary widely and are not unique to PCOS. A woman can experience any combination of the following:[1],[2],[3]:

Obesity
Weight gain/Difficulty losing weight
Male pattern hair growth (e.g., stomach, nipples, and face) called Hirsutism
Irregular periods
No period after puberty
Acne
Chronic high blood sugar
High bad cholesterol (LDL)
High testosterone levels (male hormone)
Ovarian “cysts”
Infrequent ovulation/difficulty getting pregnant

PCOS is not a disease, and there is no cure; there are just different ways to lessen the impact of the various symptoms.

What are women with PCOS at high risk for?

It is important to know if you have PCOS, because it increases the chances of you developing the following health problems:

Type 2 diabetes[1],[2],[3],[4]
Gestational diabetes [3]
Endometrial cancer [3]
Infertility [1],[2],[3]
High cholesterol [1],[3],[4]
Hypertension [1],[4]
Heart disease [1],[3]

Research suggests that PCOS may also slightly increase the risk of breast cancer, but more research is needed before any conclusions are possible.[5],[6]

Women with PCOS who are pregnant, women who needed hormone treatments to help them get pregnant, and pregnant women with PCOS who are obese (Body Mass Index over 30) are at higher risk for gestational diabetes, a kind of diabetes that occurs only during pregnancy but can have lasting effects on the mother and the baby. [1]

What tests are needed to diagnose PCOS?

Unfortunately, there is no one reliable test to tell you if you have PCOS or not. [3]

Instead, there are a variety of tests you will need to take. Some of the tests are to rule out conditions that cause the same symptoms.

Fasting Glucose

The fasting glucose (blood sugar) test can help determine if you have the warning signs for developing type 2 diabetes. Not all women with high fasting blood sugar have PCOS, but many women with PCOS have high fasting blood sugar.

Testosterone Levels

A high level of testosterone in the blood is the major sign of PCOS. Testosterone is a hormone that all men and women have, but levels are higher in men, and it is responsible for PCOS symptoms such as acne, excess body hair, and irregular periods. Your doctor will also test the levels of other hormones at the same time.

Cholesterol Test

A high level of bad cholesterol (LDL) in the blood is a common sign of PCOS, especially in younger women.

Thyroid Function Test

Many symptoms related to thyroid disorders are similar to PCOS symptoms, so a thyroid function test is helpful to eliminate that condition as a reason for the symptoms.

Vaginal Ultrasound

The name “polycystic ovary syndrome” is misleading because it implies that all women with the condition have cystic ovaries. Not all women do, and even those who seem to have cysts actually have immature follicles in the ovary. A vaginal ultrasound can identify if there are any immature ovary follicles, which look like cysts and can cause irregular menstruation and irregular ovulation.

What are the treatments for PCOS symptoms?

While there is no cure, there are different ways to reduce the impact of PCOS on your everyday life. Studies have found that being overweight or obese worsens all of the symptoms, except the presence of ovarian “cysts”. The most successful way to treat PCOS is a healthy lifestyle. Eating a healthy diet, regularly exercising, and achieving and maintaining a healthy weight are the most effective ways of eliminating or at least reducing symptoms. [1],[3]

Other ways of coping with and minimizing symptoms include:

Excess body hair: Electrolysis (permanent and semi-permanent laser hair removal); or the prescription drug, Spironolactone. Spironolactone can cause serious side effects, although they are relatively rare. More common side effects include frequent urination, dehydration, and fatigue, among others.

High cholesterol: Change in diet or cholesterol-reducing drugs.

Ovarian “cysts”: Laparoscopy is an operation involving small cuts in the abdomen or pelvis and a camera to guide the surgeon.

Birth Control Pills: Birth control pills contain female hormones that may reduce abnormal hair growth and improve acne. However, birth control pills increase the risk of blood clots, so they should be taken only if contraception is needed. Different types of birth control pills have different risks and benefits for women with PCOS. Some women find that birth control pills help them control symptoms; while others say that the pills make their symptoms worse!

What is still unknown about PCOS?

PCOS seems to run in families, but the exact gene has not been found. Also, the way a woman experiences PCOS varies even within a family—your mother’s PCOS may have had very different symptoms from yours.

PCOS is also difficult to diagnose in adolescents because many of the symptoms, like irregular periods, are ones that can occur in any adolescent girl.

Bottom Line

If it is not diagnosed and no efforts are made to treat it, PCOS can be emotionally challenging and lead to health problems. The more overweight a woman with PCOS is, the worse those health problems are likely to be. Women with PCOS may feel uncomfortable with their looks if they have a lot of body or facial hair, and being unable to get pregnant can result in depression. Getting a diagnosis and getting help for symptoms reassures women that these are not “personal failings,” but rather symptoms of a health condition that can be controlled. As with so many health problems, eating nutritious food, exercising, and maintaining a healthy weight go a long way to combat the most serious health risks and noticeable symptoms.

References

[1] Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2011, Issue 7.

[2] Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obesity Reviews 2013; 14 (2), 95-109.

[3] Hakim EAE, and Wardle E. Polycystic ovary syndrome—what the GP can do. General Practice Update 2009; 2(2).

[4] Rajkhowa M, Glass MR, Rutherford AJ et al. Polycystic ovary syndrome: a risk factor for cardiovascular disease? British Journal of Obstetrics and Gynaecology 2000;107, 11-18.

[5] Anderson KE, Sellers TA, Chen PL et al. Association of Stein-Leventhal syndrome with the incidence of postmenopausal breast carcinoma in a large prospective study of women in Iowa. Cancer 1997; 79, 494-9.

[6] Vollenhoven B, Clark S, Kovacs G et al. Prevalence of gestational diabetes mellitus in polycystic ovarian syndrome (PCOS) patients pregnant after ovulation induction with gonadotrophins. Australian and New Zealand Journal of Obstetrics and Gynaecology 2000; 40, 54-8.

Chairman Tom Harkin
731 Hart Senate Office Building
Washington, DC 20510

Comments from Members of the Patient, Consumer, and Public Health Coalition
Re: HELP Committee’s Draft Proposal on Pharmaceutical Compounding

Dear Chairman Harkin:

As members of the Patient, Consumer, and Public Health Coalition, we welcome the opportunity to provide our views on the HELP Committee’s draft proposal on pharmaceutical compounding.

We are very concerned that the draft does not adequately address the public health threats posed by compounding pharmacies and will not do enough to prevent future health care crises. Although it might reduce the likelihood of the deaths from products made by companies such as NECC, it will do little to protect the health and safety of thousands of patients who are unwitting customers of large compounding pharmacies that sell defective oral drugs to treat cancer or other life-threatening diseases, or that sell large quantities of sterile products within a state.

An example of the types of patients that would not be protected by the draft legislation are the cancer patients who received diluted cancer drugs from a Kansas City compounding pharmacy in 2000. We are also concerned about compounders that will avoid FDA oversight by limiting their high-volume sales of sterile products to a single state. The risk posed by sterile compounded products, or any other high-risk medical products, does not change based on whether or not the product crosses a state line.

We are concerned that the draft proposal too narrowly defines compounding manufacturers and does not give the FDA adequate authority to regulate compounding manufacturers.

In addition, the draft proposal does not give the FDA access to records of companies that define themselves as traditional compounders, making it next to impossible for the FDA to identify compounding manufacturers that have misrepresented themselves as traditional compounders. This is particularly worrisome because the FDA now attempts to obtain the records and inspect any pharmacy which has been the subject of complaints. Pharmacies have challenged the FDA in court, but the agency has been able to prevail in some cases. This legislation could potentially reduce the agency’s current authority.

We strongly urge you to ensure that the final legislation clarifies and enhances the FDA’s authority to regulate compounding pharmacies that have the potential to harm thousands of patients, even if they do not meet all three criteria for non-traditional compounding manufacturers set forth in the current draft version of the bill.

Below are our comments on specific sections of the draft proposal:

Compounding Manufacturer (page 2)

We agree that compounding manufacturers should be regulated by the FDA. However, the definition of compounding manufacturer is too narrow. It requires that entities meet all three of the following criteria: 1. Compounds at least one sterile drug. 2. Compounds before receiving a prescription. 3. Ships (sells) those drugs interstate.

In order to protect the public, the definition of compounding manufacturers should be broader, such as any entity that meets either the 2^nd or 3^rd criteria. Sterile drugs are not the only high-risk drugs made by compounders. Incorrect dosage for non-sterile cancer or other life-safe-giving drugs can be just as deadly, and are almost impossible to detect since drugs for seriously ill patients are not always effective. Therefore, when a cancer patient or heart patient dies after taking a compounded medication, it is unlikely that anyone will question the medication, and would instead assume that the drug just didn’t work on that patient.

In addition, a compounded antimicrobial drug that is not as potent as it should be will be ineffective and also add to our growing antibiotics resistance problem. By making the definition of manufacturing compounders too narrow, we are setting the stage for future public health disasters.

To protect patients across the country, we strongly believe that compounders who sell across state lines or sell “in anticipation” of prescriptions should be regulated as compounding manufacturers. This protection is especially essential when compounders sell drugs with the potential to save lives, where defective drugs could result in death or serious injury.

Traditional Compounder (page 3)

The phrase “compounds a drug in limited quantities” needs to be defined. What does “limited quantities” mean? A dozen, one hundred, or more?

Drugs That May Not Be Compounded (page 6)

The Secretary needs more flexibility to amend the list as needed. The bill should specify that the Secretary has administrative authority to update the Do Not Compound List (drugs added or taken off the list) and should not have to seek regulatory authority from Congress whenever a change is needed.

Licensed Pharmacist Oversight (page 18)

What does the term “direct supervision over the operations of the compounding manufacturer” mean? If a compounding manufacturer produces products 24 hours a day, does that mean a licensed pharmacist will be there at all times, directly supervising? Or could a licensed pharmacist just set up the operations and rarely be present? We urge you to clarify this definition to ensure robust oversight.

Listing of Drugs (page 18)

We support the six-month look-back on drugs that are made by compounding manufacturers. This allows the FDA to scrutinize them for products that should not be compounded such as commercially available products.

Adverse Event Reporting and Maintenance of Records (page 19)

We support Adverse Event Reporting and Maintenance of Records for compounding manufacturers. However, to truly protect public health, traditional compounders should also be required to report adverse events in a timely manner and maintain records of all serious adverse drug events for 10 years.

Labeling of Drugs (page 20)

The goal of the labeling is to make sure health care professionals and patients know that the drug is a compounded product. We support the label stating: “This is a compounded drug.” However, the draft proposal adds “or a reasonable comparable alternative statement that identifies the drugs as a compounded drug.” That sentence opens the door for vaguely worded compounded drug labels, which may be misunderstood by patients and healthcare providers. The alternative statement should either be deleted from the final draft or changed to “a statement that uses language suitable for an 8^th grade reading level that clearly identifies the drug as a compounded drug that has not been evaluated by the FDA for safety and effectiveness or compliance with manufacturing and sterility standards.” In addition, we support the proposed labeling “not for resale” on compounded drugs sold to health care entities (page 17).

Amount of Establishment Fee (page 22)

The establishment fee for compounding manufacturers is designed to cover inspection costs. How was the $15,000 fee ($5,000 for small firms) per drug establishment determined? Did the FDA suggest this amount? What is the average cost for the FDA to inspect manufacturing compounders? Will the FDA have sufficient resources to do their job?

Applications of Inspection Requirements to Compounding Manufacturers (page 32)

The FDA should have access to the records of compounding manufacturers and traditional compounders. If the FDA cannot review traditional compounders’ records, then it does not have the means to independently verify that the companies are actually traditional compounders. This lack of access creates a Catch-22. Unless the FDA can prove the pharmacy meets its compounding definition, it cannot exert oversight. But it cannot prove the definition without access to records.

This lack of access also will make it difficult for the FDA to respond to complaints it receives about pharmacies, particularly in states where oversight may be lax.

What if the company meets all criteria of a compounding manufacturer but has not registered with the FDA? At the very least, the FDA should have, upon the receipt of a complaint or evidence that the pharmacy is violating federal law, access to all records and the right to inspect.

Language Missing in the Proposed Draft

There is no mention of penalties for compounding manufacturers who fail to follow the new regulations. FDA should have the authority to issue substantial civil penalties to serve as a disincentive for any compounding manufacturers that fail to register and pay an establishment fee to the FDA, or that fail to report adverse events within 15 days, and fail to retain records for ten years. Those penalties must be stringent enough to discourage compounders from considering penalties part of the cost of doing business.

Other suggested revisions to the draft

The draft should make clear that states that wish to ban the sale of certain compounded pharmaceutical products will not be pre-empted from doing so.

The draft should also require a GAO study of the impact of the bill on the FDA’s ability to effectively oversee compounding pharmacies, and address problems swiftly to prevent patient harm.

The draft should require the FDA to warn the public and the compounding pharmacy’s customers of any violations that threaten public health within 24 hours of discovering such violations.

Thank you for the opportunity to comment on this important draft legislation. It is our goal to work with you to make the improvements necessary so that this bill will provide the protections from unsafe medical products that the American public expects and deserves.

American Medical Student Association

Annie Appleseed Project

Consumers Union

Community Catalyst

Jacobs Institute of Women’s Health

National Consumers League

National Research Center for Women & Families

National Women’s Health Network

Center for Science and Democracy, Union of Concerned Scientists

U.S. PIRG

WoodyMatters

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

May 2, 2013

My name is Caitlin Kennedy and I am a senior fellow at the National Research Center for Women & Families. I am reading the statement of our President, Dr. Diana Zuckerman, who could not be here today.

Our nonprofit research center does not accept funding from pharmaceutical or device companies, so I have no conflicts of interest. We scrutinize research to determine which medical treatments are safe and effective for adults and children.

The benefits of a dermal filler are cosmetic and can also affect quality of life, so any cosmetic or health risks must be weighed carefully before the FDA makes a decision about approval.

The effectiveness scale, the Midface Volume Deficit Scale, hasn’t been used before to support FDA approval, and it isn’t scientifically reliable. Inter-rater and between-site reliability was very low. FDA scientists point out that there was exact agreement for the two live evaluating reviewers only 41% of the time. The two evaluators often differed by two points or more on a 6-point scale – sometimes differing by 4 points!

The objectivity of these reviewers is questionable since the patients were less likely to report an improvement of 1-point or more than the reviewers were.

The MFVDS scores at post-6 month time points showed even lower levels of agreement.

Patient satisfaction scores are high, but those are not considered scientifically valid because of cognitive dissonance and because many patients don’t want to take the chance of offending the doctors that they depend on when things go wrong.

Given these questionable benefits, what are the risks?

This Juvederm Voluma product has many short-term complications such as pain and swelling, as do similar products. Of greater concern is that 78% were moderate or severe, as FDA scientists pointed out. Most had moderate complications, which are “of sufficient severity to make the subject uncomfortable” and influence daily activities. 19% had severe complications that caused “severe discomfort” and compromised performance of daily activities.

After 30 days, these complications are called adverse events. 52% had adverse events, although the doctors did not always report that they were related to Voluma. But even 20% is too high to ignore.

That does not include complications or adverse reactions after the second treatment, or the patients who dropped out of the study for reasons that were not reported but could have included adverse events.

Bottom line: if a person is choosing this product to look and be their best, especially for a special occasion, it defeats the purpose if there is a substantial risk that they might look worse rather than better.

We are also concerned that there were so many exclusion criteria for the study, and the average age was only 54. This doesn’t give enough information about safety or effectiveness in the real world, especially for older patients.

In the ideal world, patients would be told exactly what the likely risks and benefits are as part of informed consent and could decide whether to take the chance. However, in the real world, we know that many consumers will not be given accurate, understandable information to make an informed choice. Even if provided in writing, most consumers will rely on the physician’s recommendations, not written warnings.

Please urge the FDA to use a higher standard of safety and effectiveness BEFORE approving this product, including research on older patients and larger volume. This product is not urgently needed so a post-market study is not good enough. If a cosmetic dermal filler leaves many patients looking and feeling worse instead of better, it is not effective.

May 2, 2013

I am Dr. Jennifer Yttri and I am speaking on behalf of the Cancer Prevention and Treatment Fund of the National Research Center for Women & Families. Our non-profit research center scrutinizes medical data, evaluating scientific evidence of benefits and risks for patients. We analyze and review research and provide objective and understandable health information to patients, health care providers, and policy makers. Our organization does not accept funding from pharmaceutical companies and therefore I have no conflict of interest.

Today’s fundamental question is whether the one completed Phase 3 clinical trial is enough to approve the new drug tivozanib as a treatment for patients with renal cell carcinoma.

FDA guidelines recommend two trials that support efficacy of a drug. In some cases, FDA will approve a new drug based on only one trial if that trial shows a significant improvement over existing therapy. In the FDA’s own words: “A conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study. Reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity… and [when] confirmation of the result in a second trial would be practically or ethically impossible.”

The new drug application submitted for tivozanib relies on one Phase 3 study comparing tivozanib to sorafenib. While tivozanib was shown to increase progression free survival by 3 months in patients with renal cell carcinoma, it did not improve overall survival. In fact, there was a non-significant lower overall survival for tivozanib, suggesting the drug may actually harm patients more than it helps them. This one study alone is not enough to meet the FDA’s guidelines for drug approval.

In addition, the study results have inconsistencies that raise red flags about the research and about the drug itself.

1. Patients receiving tivozanib had increased progression free survival, so why were they more likely to die in the first 30 days due to disease progression, compared to sorafenib. This does not make sense. The deaths in the first 30 days could be due to chance, but the disease free survival could also be due to chance. More research is needed to clarify the risks as well as the long-term benefits.

2. FDA noted that 70% of sorafenib patients stopped taking the drug at least temporarily and 44% ended up with a reduced dose. This is much higher than other studies – for example one study highlighted by the FDA had only 14% interruption and 10% reduction. There is no logical explanation for this, but these unusual problems could make sorafenib seem inferior to tivozanib, when in fact it might be superior.

These inconsistencies may be due to chance or to irregularities in how the studies were conducted in other countries. Standard of care and assessment of disease varies in the US and other countries, and fewer than 10% of patients enrolled in the trial were in the US. We agree with the FDA reviewer that it is preferable to enroll US patients, so that the study reflects the disease burden and treatment in the US and can provide better insight into treatment outcomes for US patients.

Regardless of the reason for the inconsistencies in the study, a second, independent, Phase 3 study would help determine the safety and efficacy of this drug for treatment of renal cancer.

We urge you to recommend that the FDA require the sponsor to complete a second trial to confirm the positive effect of tivozanib on PFS; address the concern over lower OS; and provide better information on how generalizable the results are in the US population. Based on the data provided, there are no ethical concerns with requiring another trial. With the additional information, the FDA can make an informed decision as to whether tivozanib meets their standards of safety and efficacy. That is not possible based on this one study with such inconsistent results.

Division of Dockets Management

Food and Drug Administration

5630 Fishers Lane, Room 1061 (HFA-305)

Rockville, MD 20852

January 30, 2013

Comments of the Patient, Consumer, and Public Health Coalition

“Creating an Alternative Approval Pathway for Certain Drugs Intended to Address Unmet Medical Need” Public Hearing

[Docket No. FDA-2012-N-1248]

As members of the Patient, Consumer, and Public Health Coalition, we recognize the need for new drugs to reach patients with serious or life-threatening diseases. However, based on our knowledge of existing accelerated approval strategies and the widespread off label use of prescription drugs, we have grave concerns about the creation of a new, vaguely defined pathway intended to approve drugs for limited populations.

There are currently six mechanisms designed to facilitate the expedited development and review of drugs to “address unmet medical need,” some of which are based on extremely small studies. How effective are the existing pathways, and in what way is this new pathway needed or likely to be superior? Moreover, in the PCAST recommendations, from which this proposal was derived, the council understood that such a pathway would be ineffective without overhauling FDA’s approval and regulatory processes to protect patients.[1] No such overhaul is underway.

Until the FDA has persuasively shown that a new pathway is needed and will not foster the development of drugs with unproven benefits that leave vulnerable populations at risk for death and other serious adverse effects, we cannot support this proposal.

We highlight our major concerns below.

A new pathway for drug approval for small, limited populations is not needed because it will not promote faster access to safe and effective treatments.

Based on the way the FDA applies the six existing pathways, we estimate that 40% of drugs approved every year already meet the qualifications for expedited review or approval. Additionally, the FDA has the flexibility to adjust indications for broad or narrow populations and already does so in some cases to approve new drugs based on exceptionally small clinical trials or high risks for the majority of patients.

Since the new pathway would rely on studies with fewer patients and reduced follow-up times, the FDA needs to make a stronger case to explain why this new pathway is needed. The FDA proposal has not indicated how such a pathway could accurately identify benefits, and for whom.

Limited population studies will not provide the patient-centered data needed to ensure that patients benefit from the new drugs. Without conclusive benefit, no increased risk should be acceptable.

To improve access to new and better treatments, the FDA needs to refine the standards for clinical testing of new drugs. The FDA has been making some approval decisions based on clinical trials that are poorly designed and use inappropriate surrogate endpoints rather than only accepting ones relevant to patients, which reflect mortality and quality of life. Additionally, the drugs will not be adequately tested in the target populations. It is difficult to identify specific target populations of patients with “serious unmet needs” because diagnostic tools are out of date and co-morbidities cloud identification of treatable patients. Instead, the approval of a drug through this new pathway will be based on ad hoc analysis from larger studies without scientific proof of safety and efficacy. With such limited clinical trials, there will be insufficient evidence to prove these drugs actually meet patients’ serious needs.

The proposed new approval pathway does not address either how small clinical studies will adequately show a benefit to patients nor how an appropriate population will be identified. Instead, as physicians attempt to determine who will benefit based on limited clinical trial data, millions of patients will be put at risk as drugs with unproven benefits and unknown risks remain on the market for years before even the most serious adverse reactions are identified through larger, post-market studies. As currently outlined, the proposal leaves room for approval of drugs without conclusive benefit, exacerbating the problems of antibiotic resistance and disease progression.

Without effective policies to prevent misbranding and illegal promotion, millions of other consumers will also be put at risk.

Even if a drug is approved for a small, targeted population, the FDA has neither the resources nor the authority to restrict promotion and misbranding of drugs. There is clear evidence that companies will advertise these products widely, thus attracting consumers well beyond the targeted, defined population who would be most likely to benefit. Without appropriate regulation and monitoring measures, millions of patients are at risk for unforeseen complications, potentially costing our already overburdened healthcare system billions of dollars.

With off-label drug use accounting for 21% of prescriptions,[2] and even higher rates in pediatrics (62%),[3] relying on shortened and smaller clinical trials increases the risk to all patients and consumers, whether the drugs are later approved for broader indications or not. Most off-label prescriptions are based on poor or no scientific support. A 2011 report from the Agency for Healthcare Research and Quality determined that atypical antipsychotics are frequently prescribed for off-label uses and that many of the most common off-label uses, such as substance abuse and ADHD, have no clinical data to support their use.[4] Moreover, despite a black box warning about high death rates when used by elderly patients, research indicates that 9% of nursing home patients continue to receive these drugs.[5] Despite billions of dollars in fines to America’s largest pharmaceutical companies for kickbacks and illegal promotion of atypical antipsychotic drugs, and despite enormous media attention to inappropriate and over prescribing of antipsychotics to foster children, nursing home patients, and other vulnerable populations, the FDA has been unsuccessful in protecting these or other patients and these drugs continue to be the most widely prescribed in the U.S.[4]

Since 2004, there have been 28 settlements with drug companies over promotion of drugs for unapproved use, with many cases targeting patient populations in whom these drugs have never been tested. In addition to billions of dollars in fines, these cases have resulted in billions of dollars in fraudulent Medicaid and Medicare claims. Major fines in 2012 against GlaxoSmithKlein, Johnson & Johnson, and Amgen prove that misbranding and illegal promotion continues to be a problem. In many of these cases, an initial FDA approval for use in a limited population was successfully used to market a drug to a broader population. The FDA has not developed effective strategies to stop this.

The situation is even more difficult now that the U.S. Court of Appeals for the Second Circuit determined that pharmaceutical representatives can promote off-label use under the First Amendment.[6] The FDA has not challenged that ruling, which could weaken the FDA’s already limited ability to protect patients from drugs being promoted for off-label use.

Reliance on insurance and post-market studies will not protect patients from risks of using misbranded drugs. Patients need to be warned about the limited population approval before choosing to use one of these drugs.

Lack of insurance reimbursements for off-label use will not be an adequate deterrent. Many Americans currently do not have prescription drug coverage, and many physicians and patients will be willing to prescribe and pay for drugs that they assume are safe and effective since they are FDA approved. Patients are often unaware that they are taking a drug for an unapproved use, and many physicians do not fully understand the risks inherent in off-label use.[7] A label change does not provide sufficient information for a patient to understand if a drug approved for a limited population will benefit them. Approval of drugs for limited populations will only shift the burden of proving safety and benefit to patients, who will be unwitting guinea pigs.

In conclusion, the proposed new pathway represents a vaguely worded and dangerous plan. There is no clear evidence that the new pathway would be any better than—or even as good as—any existing pathway. In contrast, the risks are clear that patients can be harmed if the FDA approves new drugs based on smaller, shorter-term studies using surrogate endpoints that are not patient-centered. For those reasons, we urge the FDA not to implement this drug approval pathway.

American Medical Student’s Association

American Medical Women’s Association

Annie Appleseed Project

Breast Cancer Action

Connecticut Center For Patient Safety

Consumers Union

Jacobs Institute of Women’s Health

National Physicians Alliance

National Research Center for Women & Families

National Women’s Health Network

Our Bodies Ourselves

TMJ Association

Union of Concerned Scientists

U.S. PIRG

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

[1] PCAST report to the President on Propelling Innovation in Drug Discovery, Development and Evaluation, 2012 http://www.whitehouse.gov/sites/default/files/microsites/ostp/pcast-fda-final.pdf

[2] LePendu, P. et al. Analyzing patterns of drug use in clinical notes for patient safety. AMIA Summits Transl Sci Proc. 2012

[3] Bazzzano, A. et al. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009.

[4] Maher, A. and Theodore, G. Summary of the comparative effectiveness review on off-label use of atypical antipsychotics. J Manag Care Phar. 2012.

[5] Dorsey E.R, et al. Impact of FDA black box advisory on antipsychotic medication use. Arch Inter Med. 2010.

[6] United States v. Caronia. Docket No. 09-5006-cr (2nd Cir. 2012).

[7] Chen, D.T. et al. U.S. physician knowledge of the FDA-approved indications and evidence base for commonly prescribed drugs: results of a national survey. Pharmacoepidemiol Drug Saf. 2009.