December 15, 2014

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

Comments of members of the Patient, Consumer, and Public Health Coalition on
the proposed order to reclassify External Pacemaker Pulse Generator devices and Pacing System Analyzers
Docket No. FDA-2011-N-0650

As members of the Patient, Consumer, and Public Health Coalition, we strongly oppose the down-classification of External Pacemaker Pulse Generator (EPPG) devices and Pacing System Analyzers (PSAs) from Class III to Class II. EPPGs are clearly life-sustaining devices and they should remain in Class III and be reviewed by the more rigorous Premarket Approval (PMA) process, which will better ensure that the devices are safe and effective.

The Cardiovascular Devices Panel stated on March 9, 1979 that these devices should be classified into Class III because the device “provided temporary life-support and that certain kinds of failures could cause this device to emit inappropriate electrical signals, which could cause cardiac irregularities and death.”1] This statement is as accurate today as it was then, as one of the uses for these devices listed in the 2014 FDA Federal Register notice is as “a temporary substitute for the heart’s intrinsic pacing system until a permanent pacemaker can be implanted.”2.]

One of the predictable tragedies if this life-saving device malfunctions would be death.  A review of the Manufacturer and User Facility Device Experience (MAUDE) database for the last five years (1/01/2010 through 11/30/2014) shows reports of 25 deaths associated with EPPG devices (product code DTE), 264 reports of injuries, and more than 3,500 malfunctions.3 The FDA proposed order states that “The low frequency of serious adverse events” reported in the MAUDE database supports “the reclassification of these devices to class II.”2  We don’t consider 25 deaths, 264 injuries, and more than 3,500 malfunctions a “low frequency” and point out that other devices have been restricted or recalled for much lower rates of reported serious adverse reactions.  The FDA’s Total Product Life Cycle (TPLC) database is consistent with the high MAUDE numbers we found. TPLC data shows 3,235 problems reported for EPPG devices in the last five years.4 Unfortunately, as the FDA knows well, adverse events are almost always greatly under-reported, especially when problems have not been widely reported in the media.

While the FDA states in the 2014 Federal Register notice that they believe new information since the 1979 designation warrants reclassification of these devices into Class II with special controls, the recent data from the MAUDE and TPLC databases irrefutably contradicts that proposal.

The 2011 Federal Register notice stated that these devices pose “risks to health,” including a failure of the electronic circuitry, which can cause failure to pace the patient’s heart; improper pacing leading to high rate-electric failure, which can lead to arrhythmias or unwanted stimulation; and micro/macro shocks resulting in an arrhythmia or cardiac tissue damage.1  The 2014 Federal Register notice adds an additional risk of “misdiagnosis,” which can result in the physician prescribing “a course of treatment that places the patient at risk unnecessarily.”2 The above-mentioned adverse events reported and these newly identified risks to health suggest that EPPG devices should stay in Class III.

Several risks associated with these devices cannot be adequately mitigated by Class II with special controls.  For example, “Failure to pace” is listed as one of the risks associated with these devices, which can be caused by “failure of mechanical/electrical components of the device.”2 Non-clinical performance testing cannot prevent malfunctions of individual devices.  Instead, manufacturing inspections, a key feature of the PMA process, are absolutely essential to ensure that these devices are properly manufactured.  For these reasons, Class II with special controls for EPPG devices do not provide reasonable assurance of their safety and effectiveness.

Regarding Pacing System Analyzers (PSA), we oppose the down-classification of the device from Class III device to Class II because for the six identified risks of the device (including “Micro/Macro Shock”2), the FDA relies on labeling to mitigate the risks.  We strongly doubt that labeling will adequately reduce risks since the preponderance of evidence indicates that health care providers often do not read or follow labeling instructions.

 

Conclusion

In January 2012, members of the Patient, Consumer, and Public Health Coalition submitted comments opposing the down-classification of EPPG devices. The FDA stated that in 2012 it received the following comments on the proposed reclassification: EPPG devices should stay in Class III, that the reclassification was “not adequately supported by new publicly valid scientific evidence” and that the performance standards (special controls) “are insufficient.”2 Those comments are still valid today.  The FDA has not provided any scientific evidence to contradict them.

At a September 11, 2013 Advisory Committee meeting, one of our coalition partners, the National Research Center for Women & Families (which has since changed its name to the National Center for Health Research) spoke against the down-classification.

In conclusion, after reviewing the regulatory history, adverse event reporting, and risks associated with these devices, we strongly oppose down-classifying EPPG device to Class II with special controls. The devices should remain in Class III.  This designation is needed to assure physicians and their patients that patients will not be harmed by these devices when their lives may depend on them.    We also strongly oppose the down-classification of PSAs, in that case because the special controls rely heavily on labeling to mitigate risks, and there is no evidence that would be sufficient to protect the health of patients.

 

Annie Appleseed Project
Center for Medical Consumers
Connecticut Center for Patient Safety
Jacobs Institute of Women’s Health
MAME
MISSD
National Center for Health Research
National Consumers League
National Organization for Women
National Physicians Alliance
Our Bodies Ourselves
Center for Science and Democracy at the Union of Concerned Scientists
Women Advocating Reproductive Safety
WomenHeart: The National Coalition for Women with Heart Disease.

 

The Patient, Consumer, and Public Health Coalition can be reached through Paul Brown at (202) 223-4000 or at pb@center4research.org

By Margaret Dayhoff-Brannigan, PhD

December 2014

Dementia is a term that is used to describe a wide range of brain diseases that cause long-term problems with memory and the ability to think and reason clearly. Alzheimer’s disease is a common form of dementia, and is usually diagnosed in people over 65 years old. Although memory loss and confusion are often called Alzheimer’s by doctors, patients, and family members, the only way to confirm diagnosis is by an autopsy after the patient has died. Most of the time when a doctor says a patient has Alzheimer’s, what they really mean is that the patient has dementia that might be caused by Alzheimer’s.

There are a few types of dementia that can be cured because they are caused by specific diseases such as hypothyroidism or Lyme disease.  There are no cures for the other forms of dementia, including Alzheimer’s disease. There are drugs to slow the progression of dementia and Alzheimer’s, but these have very limited efficacy.

 

Signs of Alzheimer’s/dementia

Many of the common signs of early Alzheimer’s and dementia are similar. Many of these symptoms can also be typical age-related changes. For example, having difficulty finding something like a recipe can be typical age-related change, however difficulty following a recipe could be a symptom of dementia.   More dramatically, forgetting where you put your car keys can be a sign of aging, whereas forgetting what the key is for is a sign of dementia.  If you or a loved one has one or more of the following symptoms you may want to talk about them with a doctor.

  1. Memory loss that disrupts daily life
  2. Challenges in planning or solving problems
  3. Difficulty completing familiar tasks at home, at work or at leisure
  4. Confusion with time or place
  5. Trouble understanding visual images and spatial relationships
  6. New problems with words or in speaking or writing
  7. Misplacing things and losing the ability to retrace steps
  8. Decreased or poor judgment
  9. Withdrawal from work or social activities
  10. Changes in mood and personality

 

Ways to prevent or delay dementia or Alzheimer’s

A family history of Alzheimer’s or other types of dementia increases the chances of developing the condition, but there are strategies that help prevent these conditions.  Exercise and a healthy lifestyle can be effective ways to reduce your risk of Alzheimer’s disease and other forms of dementia. These include:

  1. Regular physical exercise
  2. Eating healthy
  3. Maintaining a healthy weight
  4. Not smoking and moderating alcohol intake (to one drink a day)
  5. Mental stimulation and maintaining an active social life
  6. Stress management and quality sleep

Exercise has been shown to have the largest impact on preserving memory and thinking skills. Exercise was shown to protect against the brain shrinking even if people with a family history of Alzheimer’s disease. Mutations in a specific gene (the APOE-e4 gene), found in 30% of the population, can make it 10 times more likely that you will develop Alzheimer’s. Brisk walking, jogging, swimming or cycling at least three times a week makes brain shrinkage less likely in people with and without the gene mutation. Although the amount or type of exercise that is best is not known, in general, physical exercise that is physically healthy will also be mentally healthy 5,6

Long-term exposure to pesticides and other toxins that affect the neurological system, such as DEET and organophosphates, may increase the risk of Alzheimer’s and other types of dementia.7  Common exposures include mothballs (and other “bug killers”), insect repellants used inside the home (such as RAID), on the lawn or farms (Round Up and DTT) and on the body (OFF and other bug repellants).

 

Possible Causes

There are several theories about why Alzheimer’s disease develops, but none are proven. The leading theory is that the disease is caused by a buildup of proteins in the brain called “plaques.” One type of plaque is caused by misshapen proteins that accumulate as the person ages. When shaped normally, these proteins are important for developing and maintaining a healthy brain. These plaques are often found during autopsies of Alzheimer’s patients. One theory is that the plaques cause brain cells to weaken and die, which can cause the brain to shrink.

More research is needed to fully understand Alzheimer’s and other types of dementia. If it develops early, which happens rarely, it is probably influenced by one’s genes. The disease can take many years to start showing symptoms, and once symptoms appear, it can take many more years for the symptoms to obviously worsen.

 

Recent study linking Dementia to Anti-Anxiety Medications

A recent article published online in the prestigious British Medical Journal found a link between dementia and the use of anti-anxiety medications such as Valium, Xanax and other benzodiazepines (often referred to as “benzos”). The researchers examined almost 9,000 older adults for 6 years after the use of the medication for insomnia or anxiety.  People in their study were 51% more likely to develop dementia if they had ever taken benzodiazepines, and the longer they took the drugs the more likely they were to develop it.8  However, anxiety and sleep disorders could be early symptoms of dementia, rather than caused by dementia. This study didn’t examine whether using the drugs occurred before or after dementia started.  Since dementia usually takes years to develop, and this study only followed patients for 6 years, it is very likely that many of these patients were already developing the disease before taking benzodiazepines. The study was also missing information about other risk factors that the patients may have had for Alzheimer’s, such as smoking and alcohol use.

There are many reasons to be cautious about taking benzodiazepines, particularly if other treatments are available. However further research is needed before concluding that benzodiazepines cause dementia.

 

More information about pesticide use and Alzheimer’s can be found here.

More information about these signs and symptoms can be found here.

December 9, 2014

My name is Dr. Anna Mazzucco.  Thank you for the opportunity to speak today on behalf of the National Center for Health Research.   After completing my Ph.D. at Harvard Medical School, I conducted research at the National Cancer Institute.  Those are the perspectives I bring today.

Our research center conducts research, analyzes data in the research literature, and then explains the evidence of risks and benefits to policymakers and consumers.  Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the resources that the FDA needs to do its job.  Our organization does not accept funding from chemical or consumer product companies, and therefore I have no conflicts of interest.

We applaud the agency for holding this meeting, and for its interest in expanding the Redbook to enhance the safety of the food and products we eat and use every day.  We enthusiastically welcome further action from the FDA on all substances over which the Center for Food Safety and Applied Nutrition has authority.  While the FDA has taken steps to address safety concerns regarding some substances, we strongly urge the agency to use its full authority to ensure the safety of all food-related and consumer products.  Specifically,

  • The FDA has banned bisphenol A from baby bottles and children’s cups.  Yet it is still present in the canned and bottled food consumed by everyone else, including pregnant women, nursing mothers, and young children.  The greatest risk of BPA is probably prenatal exposure, and yet pregnant women are constantly exposed to BPA in food containers.  In addition, BPA exposure can reduce the effectiveness of chemotherapy for breast cancer patients.9   The very limited ban on BPA must be expanded to include all food containers.  As the FDA has now acknowledged the harms of BPA, everyone should be afforded the same protections from it.
  • Current evaluation of food additives for carcinogenic activity is narrowly focused on genotoxic mechanisms of action.  The FDA should add tests for endocrine disruption to its toxicological evaluation of food contact substances and additives to ensure that all food contact substances, both old and new, are safe.  As studies show that BPA substitutes may have similar harmful endocrine-disrupting properties, such a step is critical to achieve meaningful change.10
  • Studies have raised health concerns about numerous ingredients in cosmetics, such as phthalates, linking them to cancer, infertility, brain development and other health problems.  The Consumer Product Safety Commission bans the most dangerous phthalates from toys and other products for children under 3, but there is enormous exposure for pregnant and nursing women as well as children over 3 and all adults. The FDA should implement stronger chemical safety requirements for these products which Americans use regularly and long-term.11  One study found that teenage girls use up to 17 personal care products a day.12
  • A 2010 Government Accountability Office report asserted that the FDA needs to strengthen its regulation of food safety and, in particular, its application of the GRAS designation.  We enthusiastically support the recommendations of this report, which included requiring companies to file GRAS studies with the FDA and to make them public.13  When will that be implemented?

Lastly, we ask that sufficient resources be dedicating to these safety programs in order for the FDA to be able to do its important work which we all rely on.

Thank you for the opportunity to address the panel today.

 

 

 

December 5, 2014

My name is Dr. Anna Mazzucco.  Thank you for the opportunity to speak today on behalf of the National Center for Health Research.   After completing my Ph.D. at Harvard Medical School, I conducted research at the National Institutes of Health before joining the Center’s staff.  Those are the perspectives I bring today.

Our research center conducts research, analyzes data in the research literature, and then explains the evidence of risks and benefits to health professionals, patients, and policymakers.  Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the FDA’s budget, so that it can do its job well. Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.

We are all concerned about the growing problem of antibiotic resistance.  We want to ensure effective treatment options for those with serious infections.  However, ineffective antibiotics actually worsen our situation by increasing antibiotic resistance.  They also expose patients to unnecessary risks, with no chance for benefit, and delay effective treatment.  For these reasons, we must be sure that antibiotics are adequately studied and demonstrate clear safety and efficacy before being used.

With these considerations in mind, we are gravely concerned about the minimal evidence being presented here today.  You are asked to consider a new drug based on preliminary data from a recently unblinded phase III trial for only one of the three indications being sought.  The remaining phase III trials are either ongoing or still being analyzed. We urge the committee to clearly recommend that the FDA wait until these trials have been completed and further analysis has been done before making any recommendations regarding approval.

Although preliminary, the phase III trial data on complex intra-abdominal infections (cIAI) showed that patients who had moderate renal impairment at baseline (MRIB) had a lower clinical cure rate when treated with CAZ-AVI + MTZ compared to  meropenem.  Of even greater concern, 8 deaths were observed in the CAZ-AVI + MTZ group versus only 3 deaths in the comparator.  Not surprisingly, the sponsor believes that this safety signal and the lack of efficacy are unlikely to be related to the study drug.  However, that claim is not based on conclusive evidence.  The size of this subgroup is too small to make a conclusion, which the sponsor has acknowledged.  Furthermore, the agency has not yet reviewed this data, making any conclusions inappropriate.

But even after the FDA reviews the data, the samples are too small to draw the conclusion that this new drug is safe or effective.

The FDA has stated that the sponsor’s pooled meta-analysis from the literature has several uncertainties and should only be used as additional supportive evidence.  We strongly agree.  The only other evidence we have is from two small phase II trials, which the FDA has stated were not analyzed in a formal statistical manner and had no pre-specified hypotheses.  Instead, the results of these trials were summarized descriptively.

The totality of this evidence is not sufficient for informed decision-making.  While I personally would not seek an antibiotic with a higher death rate, it would make sense for the panel to strongly urge the FDA to wait until all the phase III trials have been completed and the agency has fully reviewed the data before making a decision.

We have carefully reviewed the agency’s regulatory approach regarding this drug combination and the section 505(b)(2) pathway as described in the background material.  The FDA background document states that “the contribution of avibactam will be demonstrated by in vitro studies, animal models of infection and with limited clinical data. Safety of avibactam will be determined from Phase 1 studies of avibactam alone and phase 1 and 2 studies of CAZ-AVI.” We are alarmed that the agency would consider this new combination entity on such limited data.  In fact, in the 1970 Upjohn versus Finch court case it was determined that for “…combination drugs purported to have advantages exceeding those of the components, there must be adequate, well-controlled data documenting the claimed advantages.”14  That type of evidence is NOT presented here.

Although I am a scientist, I also want to speak on behalf of patients today.  Patients care about antibiotics that make them feel better sooner and save their lives.  Animal and in vitro studies cannot ensure either.  Furthermore, as stated before, antibiotics are unique among drugs in that ineffective antibiotics can worsen a patient’s condition and also create new problems.  There are numerous unfortunate examples of antibiotics that were approved and subsequently withdrawn from the market due to safety concerns.  In fact, the withdrawal rate of antibiotics over the last three decades was triple that of other drug classes, with 26 out of 61 antibiotics approved during that time being subsequently withdrawn.15

We strongly urge the committee to ask for completion of the remaining phase III trials and the agency’s review before making any recommendations about approval.

Thank you for the opportunity to address the panel today.

By Jessica Rothman

December 2014

 

What is it?

Cushing’s syndrome is a condition you probably have never heard of, but for those who have it, the symptoms can be quite scary.  Worse still, getting it diagnosed can take a while.  Cushing’s syndrome occurs when the tissues of the body are exposed to high levels of cortisol for an extended amount of time. Cortisol is the hormone the body produces to help you in times of stress. It is good to have cortisol at normal levels, but when those levels get too high it causes health problems.  Although cortisol is related to stress, there is no evidence that Cushing’s syndrome is directly or indirectly caused by stress.

Cushing’s syndrome is considered rare, but that may be because it is under-reported. As a result, we don’t have good estimates for how many people have it, which is why the estimates for the actual number of cases vary so much–from 5 to 28 million people.16 The most common age group that Cushing’s affects are those 20 to 50 years old.  It is thought that obesity, type 2 diabetes, and high blood pressure may increase your risk of developing this syndrome.17

What causes Cushing’s syndrome?

Cushing’s syndrome is caused by high cortisol levels. Cushing’s disease is a specific form of Cushing’s syndrome. People with Cushing’s disease have high levels of cortisol because they have a non-cancerous (benign) tumor in the pituitary gland.  The tumor releases adrenocorticotropin hormone (ACTH), which causes the adrenal glands to produce excessive cortisol.

Cushing’s syndrome that is not Cushing’s disease can be also caused by high cortisol levels that result from tumors in other parts of the body.  One of the causes is “ectopic ACTH syndrome.” This means that the hormone-releasing tumor is growing in an abnormal place, such as the lungs or elsewhere.  The tumors can be benign, but most frequently they are cancerous. Other causes of Cushing’s syndrome are benign tumors on the adrenal gland (adrenal adenomas) and less commonly, cancerous adrenal tumors (adrenocortical carcinomas). Both secrete cortisol, causing cortisol levels to get too high.

In some cases, a person can develop Cushing’s syndrome from taking steroid medications, such as prednisone. These drugs, known as corticosteroids, mimic the cortisol produced by the body. People who have Cushing’s syndrome from steroid medications do not develop a tumor.18

What are the signs and symptoms of Cushing’s syndrome?

The appearance of people with Cushing’s syndrome starts to change as cortisol levels build up. Regardless of what kind of tumor they have or where the tumor is located, people tend to put on weight in the upper body and abdomen, with their arms and legs remaining thin; their face grows rounder (“moon face”); they develop fat around the neck; and purple or pink stretch marks appear on the abdomen, thighs, buttocks or arms. Individuals with the syndrome usually experience one or more of the following symptoms: fatigue, muscle weakness, high glucose levels, anxiety, depression, and high blood pressure. Women are more likely than men to develop Cushing’s syndrome, and when they do they may have excess hair growth, irregular or absent periods, and decreased fertility.19

Why is Cushing’s syndrome so frequently misdiagnosed?  

These symptoms seem distinctive, yet it is often difficult for those with Cushing’s syndrome to get an accurate diagnosis.  Why?  While Cushing’s is relatively rare, the signs and symptoms are common to many other diseases. For instance, females with excess hair growth, irregular or absent periods, decreased fertility, and high glucose levels could have polycystic ovarian syndrome, a disease that affects many more women than Cushing’s.   Also, people with metabolism problems (metabolic syndrome), who are at higher than average risk for diabetes and heart disease, also tend to have abdominal fat, high glucose levels and high blood pressure.20

Problems in testing for Cushing’s

When Cushing’s syndrome is suspected, a test is given to measure cortisol in the urine. This test measures the amount of free or unbound cortisol filtered by the kidneys and then released over a 24 hour period through the urine. Since the amount of urinary free cortisol (UFC) can vary a lot from one test to another—even in people who don’t have Cushing’s—experts recommend that the test be repeated 3 times. A diagnosis of Cushing’s is given when a person’s UFC level is 4 times the upper limit of normal.  One study found this test to be highly accurate, with a sensitivity of 95% (meaning that 95% of people who have the disease will be correctly diagnosed by this test) and a specificity of 98% (meaning that 98% of  people who do not have the disease will have a test score confirming that).21 However, a more recent study estimated the sensitivity as only between 45%-71%, but with 100% specificity.22  This means that the test is very accurate at telling people who don’t have Cushing’s that they don’t have it, but not so good at identifying the people who really do have Cushing’s.  The authors that have analyzed these studies advise that patients use the UFC test together with other tests to confirm the diagnosis, but not as the initial screening test.23  

Other common tests that may be used to diagnose Cushing’s syndrome are: 1) the midnight plasma cortisol and late-night salivary cortisol measurements, and 2) the low-dose dexamethasone suppression test (LDDST).  The first test measures the amount of cortisol levels in the blood and saliva at night.  For most people, their cortisol levels drop at night, but people with Cushing’s syndrome have cortisol levels that remain high all night. In the LDDST, dexamethasone is given to stop the production of ACTH.  Since ACTH produces cortisol, people who don’t have Cushing’s syndrome will get lower cortisol levels in the blood and urine. If after giving dexamethasone, the person’s cortisol levels remain high, then they are diagnosed with Cushing’s.24

Even when these tests, alone or in combination, are used to diagnose Cushing’s, they don’t explain the cause. They also don’t distinguish between Cushing’s syndrome, and something called pseudo-Cushing state.

Pseudo-Cushing state

Some people have an abnormal amount of cortisol that is caused by something unrelated to Cushing’s syndrome such as polycystic ovarian syndrome, depression, pregnancy, and obesity. This is called pseudo-Cushing state.  Their high levels of cortisol and resulting Cushing-like symptoms can be reversed by treating whatever disease is causing the abnormal cortisol levels. In their study, Dr. Giacomo Tirabassi and colleagues recommend using the desmopressin (DDAVP) test to differentiate between pseudo-Cushing state and Cushing’s.  The DDAVP test is especially helpful in people who, after being given dexamethasone to stop cortisol production, continue to have moderate levels of urinary free cortisol (UFC) and midnight serum cortisol.25

An additional test that is often used to determine if one has pseudo-Cushing state or Cushing’s syndrome is the dexamethasone-corticotropin-releasing hormone (CRH) test. Patients are injected with a hormone that causes cortisol to be produced while also being given another hormone to stop cortisol from being produced. This combination of hormones should make the patient have low cortisol levels, and this is what happens in people with pseudo-Cushing state.  People with Cushing’s syndrome, however, will still have high levels of cortisol after being given this combination of hormones.26

How can Cushing’s be treated?

Perhaps because Cushing’s is rare or under-diagnosed, few treatments are available. There are several medications that are typically the first line of treatment.  None of the medications can cure  Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails.

The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and remove the tumor.  Radiation may also be used instead of surgery to shrink the tumor.  In patients whose Cushing’s is caused by ectopic ACTH syndrome, all cancerous cells need to be wiped out through surgery, chemotherapy, radiation or a variety of other methods, depending on the location of the tumor. Surgery is also recommended for adrenal tumors.  If Cushing’s syndrome is being caused by corticosteroid (steroid medications) usage, the treatment is to stop or lower your dosage.27

Medications to control Cushing’s (before treatment or if treatment fails)

According to a 2014 study in the Journal of Clinical Endocrinology and Metabolism, almost no new treatment options have been introduced in the last decade. Researchers and doctors have focused most of their efforts on improving existing treatments aimed at curing Cushing’s.  Unfortunately, medications used to control Cushing’s prior to treatment and when treatment fails are not very effective.

Many of the medications approved by the FDA for Cushing’s syndrome and Cushing’s disease, such as pasireotide, metyrapone, and mitotane, have not been extensively studied.  The research presented to the FDA by the makers of these three drugs did not even make clear what an optimal dose was.28 Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society.  In another 2014 study, published in Clinical Epidemiology, researchers examined these three same drugs, along with ten others, and found that only pasireotide had moderate evidence to support its approval.  The other drugs, many of which are not FDA approved for Cushing’s patients, had little or no available evidence to show that they work.29 They can be sold, however, because the FDA has approved them for other diseases.  Unfortunately, that means that neither the FDA nor anyone else has proven the drugs are safe or effective for Cushing patients.

Pasireotide, the one medication with moderate evidence supporting its approval, caused hyperglycemia (high blood sugar) in 75% of patients who participated in the main study for the medication’s approval for Cushing’s.  As a result of developing hyperglycemia, almost half (46%) of the participants had to go on blood-sugar lowering medications. The drug was approved by the FDA for Cushing’s anyway because of the lack of other effective treatments.

Other treatments used for Cushing’s have other risks.  Ketoconazole, believed to be the most commonly prescribed medications for Cushing’s syndrome, has a black box warning due to its effect on the liver that can lead to a liver transplant or death.  Other side effects include: headache, nausea, irregular periods, impotence, and decreased libido. Metyrapone can cause acne, hirsutism, and hypertension. Mitotane can cause neurological and gastrointestinal symptoms such as dizziness, nausea, and diarrhea and can cause an abortion in pregnant women.30

So, what should you do if you suspect you have Cushing’s syndrome?

Cushing’s syndrome is a serious disease that needs to be treated, but there are treatment options available for you if you are diagnosed with the disease. If the symptoms in this article sound familiar, it’s time for you to go see your doctor. Make an appointment with your general practitioner, and explain your symptoms to him or her.  You will most likely be referred to an endocrinologist, who will be able to better understand your symptoms and recommend an appropriate course of action.

Below are some additional resources you might find helpful if you suspect you may have Cushing’s syndrome or have been recently diagnosed:

List of doctors that are the experts in treating Cushing’s syndrome:

 http://csrf.net/resources/cushings-doctors/

Information on getting disability and assistance if needed: 

http://csrf.net/resources/disability-assistance/

December 4, 2014

My name is Dr. Margaret Dayhoff-Brannigan and I am a senior fellow at the National Center for Health Research. Our research center scrutinizes scientific and medical data and provides objective health information to patients, providers and policy makers. We do not accept funding from drug companies, and therefore I have no conflicts of interest.

Thank you for the opportunity to speak here today.

I completed my Ph.D. in Biochemistry and Molecular Biology at the Johns Hopkins School of Public Health. A few years ago I lost my grandfather to a hospital acquired antibiotic resistant infection.  I bring a perspective as both a researcher and someone personally affected by the need for safe and effective antibiotics today.

Antibiotic resistance and the inability to treat common infections is an increasingly urgent public health crisis which affects everyone, especially some of the most vulnerable in our society.  Finding treatment options for unmet populations is urgently important but ineffective antibiotics lead to an increase in antibiotic resistance.  Noninferiority trials provide limited information – not enough to provide the best treatment for patients and certainly not enough to reduce resistance.  Unfortunately, the benefits of new antibiotics over existing antibiotics are not well established by clinical trials.

Many drugs approved based on data from noninferiority trails are subsequently withdrawn from the market.  Examples include fluoroquinolones and cephalosporins many of which were withdrawn for safety concerns. In fact, among 61 new antibiotics approved between 1980-2009, 43% were later withdrawn for safety or efficacy reasons. This rate is about 3 times as often as the 13% of non-antibiotics drugs approved over the same time period.

Withdrawn antibiotics pose risks for patients receiving them, and increase the risk of developing resistant pathogens that could spread. We must ensure that proper clinical trials are preformed to reduce the number of antibiotics that are unsafe and ineffective.

Ten new antibiotics by 2020 will not help us if they are withdrawn later for safety of efficacy.

Superiority trials are the best way to test new antibiotics for use in patients with unmet needs. New antibiotics need to be tested in patient populations like those that will be getting the drug, not in healthy populations.  This is important because often bacterial infections can be self-resolving in healthy populations, therefore biasing the results. Also, patients with resistant infections do not react to treatments in the same way as patients with susceptible infections.  The health of the patient and whether they have other diseases play a large role in the effectiveness of the treatment.   So, studying the right type of patients is crucially important.

The proposed “streamlined” approach, which would increase the noninferiority margin in order to do smaller trials, means that patients would take on more risk and will not benefit from the drug.  That is not ethical since other options already exist.

To avoid delays in treating populations with resistant infections, we need to develop better methods for accurate diagnosis of particular pathogens. Better diagnostic tools will improve the ability of industry to design clinical trials in appropriate populations.

In conclusion, we want to provide the best treatment for patients and reduce the number of patients put at risk by taking antibiotics that are later withdrawn from the market due to their lack of safety or efficacy.  The best way to accomplish both of those goals is to improve the standards for clinical testing. Superiority trails are critical because they will require that these drugs show effectiveness in the population most likely to benefit from the drug.

December 3, 2014.

The FDA’s regulation of blood establishment computer software (BECS) and BECS accessories has enhanced the safety of blood transfusion.  In the 90’s the FDA found numerous problems with BECS software, including the potential release of infectious blood. Part of the problem was that as the programs added complexity, the software testing utilized by the software companies became inadequate. In response, CBER started regulating BECS with 510(k) premarket reviews in August 1996. We believe that the FDA’s regulation of BECS has been an important improvement.

However, it should be noted that the only national statistics we have to measure safety are based on a passive reporting system. Analysis of the CDC’s National Blood Collection and Utilization Survey in 2009 suggested that it underestimates the number of adverse events. One study showed a 30-fold increase in bedside transfusion errors using active tracking instead of the current passive tracking[i]. In addition, studies have shown that the number of near-misses is nearly 18 times higher than the number of adverse events. Human error is the cause of many of these near-misses and adverse events. Blood establishment computer software (BECS) and BECS accessories, meanwhile, have greatly reduced adverse events and near-misses.

With that in mind, we strongly support the FDA’s suggested special controls for BECS and BECS accessories. We would like to emphasize the importance of the verification, validation, and hazard analysis. We urge you to ensure that this should include substantial system security testing.

We are concerned that the special controls do not specify the need for validation at the user facility. Numerous studies have emphasized the importance of training and usability for the success of BECS. Unsurprisingly, it turns out that human error can overcome even the best automation. One example illustrates this well: a user hands over unlabeled specimen bottles to colleagues because he doesn’t understand how to print the labels. Another common example is when users override the system because the users doesn’t think it is correct.

The FDA itself has a Guidance to Industry entitled “Blood Establishment Computer System Validation in the User’s Facility” which suggests the agency realizes the importance of this sort of testing.  We agree and urge you to recommend that the agency explicitly specify this type of validation testing in the special controls.

In summary, we recommend that the Advisory Panel vote to classify BECS and BECS accessories as Class 2 with well-designed and carefully monitored special controls. Validation in the user’s facility should be required as one of the special controls listed.

Thank you.

By Laurén A. Doamekpor

December, 2014

 

In case you hadn’t noticed, open enrollment season is upon us!

Open enrollment is the time every fall when you have the chance to either stick with your old health insurance plan or pick a new one. Whether you get health insurance through your job, Medicare, Obamacare, or as in individual, open enrollment season is important to you.  That’s true whether you plan to stay with your current insurance plan or want to shop around for another one or even another insurance provider. Open enrollment is when you need to make sure that you’re not paying more than you should be for the benefits and services you and your family need.

Every year, health insurance companies can make changes to the benefits and services they provide as well as to premiums, deductibles, and co-payments. During this open enrollment season it’s important to review your plan’s 2015 coverage to make sure it still meets your needs.

Why is the open enrollment period so important?

Think of the open enrollment period as a time when you get to rethink or redo decisions about your health insurance that you made last year. Or to get health insurance for the first time!  If you don’t check your options now, you could miss an opportunity to get better quality coverage for the same amount of money or pay less for the coverage you now have.

Millions of Americans are receiving health insurance through the Affordable Care Act (“Obamacare”) on healthcare.gov (sometimes called the marketplace or the exchange).  Millions more will get their health insurance through their employer. Most employers will send out reminders about open enrollment and set aside a two-week period for people to look over the available health plans.

Whether you already had a health plan this year or not, here are some basic tips you should think about:

  • Do your homework. Review your options because with a few clicks could save you hundreds or even thousands of dollars. Make sure you’ve selected the right plan. For example, it may be cheaper for your children to be on your spouse’s insurance plan instead of yours.
  • Double-check that the medications you are taking and the doctors you see are covered by the plan you choose. Choosing a cheap plan may end up costing you more in the long run if your doctor is not in the plan network or if your medications are not covered. Most insurance companies will have a website where you can check which doctors and medications are covered under which plan.
  • Are you going to need specific services that some insurance plans exclude, such as bariatric surgery, certain types of counseling or smoking cessation programs, or surgery to fix complications from cosmetic surgery?  These exclusions are often hard to find – until you try to get services that the policy always excludes.  You may want to call an insurance company to check before signing up.
  • Don’t forget about specialty benefits like vision and dental plans. These plans cover preventive services like eye exams and teeth cleaning and are sometimes available at low cost. Making sure to regularly get your teeth and eyes checked could help prevent more serious medical problems down the road, but these plans often cost more than you will get in benefits, so consider your own needs before making a decision.

If you are buying an insurance plan through Obamacare on healthcare.gov or state exchange websites:

Remember that if you had a plan on the exchange in 2014 you will be automatically enrolled into the same plan or a similar plan. But, that renewed plan might be a bad one for you in 2015.  So:

  • Make sure you update your household and income information to ensure that you have the right plan choices and savings for 2015. If you are making less money than you did the year before, you may be eligible for smaller premiums or other plans with lower deductibles and co-payments. If you are making more money, that could also change your costs.
  • If you’ve been automatically enrolled in a different plan than you were in 2014, check that the plan covers what you need.
  • Start early!

If you are buying health insurance through healthcare.gov, here are the most important dates for 2015 coverage:

December 15, 2014: The last date to enroll for coverage that starts January 1, 2015.

December 31, 2014: Date when all 2014 coverage ends, no matter when you enrolled.

January 1, 2015: The date 2015 coverage can start if you apply by December 15, 2014, or if you accept automatic enrollment in your 2014 plan or a similar plan.

February 15, 2015: The last day to enroll in 2015 coverage. If you miss this deadline, you can’t sign up for a health plan inside or outside the exchange for the rest of 2015. The only exception is if you qualify for a Special Enrollment Period. Click here to learn more about the Special Enrollment Period.

To learn more about how healthcare.gov works, check out  https://www.healthcare.gov/quick-guide/

 

December 3, 2014

Anna E. Mazzucco, Ph.D.

Thank you for the opportunity to participate in this meeting.  My name is Dr. Anna Mazzucco, and I am speaking on behalf of the Cancer Prevention and Treatment Fund.  I received my Ph.D. in cell biology from Harvard Medical School, and I conducted post-doctoral research at the National Cancer Institute.  Those are the perspectives I speak from today.

Our organization conducts research and shares information with health professionals, patients, and consumers.

We applaud the efforts of the EPA to protect the public from harmful chemicals in their food, water, air and products they use every day.  We strongly support the agency’s efforts to test chemicals more efficiently, and with the best possible scientific methods.  Research has implicated endocrine-disrupting chemicals in cancer, infertility, and other health problems.  We must be able to quickly identify such agents in order to prevent them from entering our food and environment, and from affecting our health for generations to come.

Use of high-throughput technologies is critical to expediting chemical screening, and we support the agency in these efforts.  However, we have several concerns regarding the high-throughput screening approach as described in the EPA White Paper.  Specifically,

  • The EPA needs to spell out more clearly how prioritizing will be decided using this screening approach. The program should explicitly prioritize compounds based on risk contexts, such as those with widespread and persistent exposure profiles, and those with the most serious potential health effects.
  • We know that chemical exposures during sensitive periods such as prenatal and adolescent development can greatly impact health in adulthood.  These critical windows should be prioritized in bio-monitoring and population-based studies.  This approach would protect the most vulnerable among us, and also ensure the greatest public health benefits for everyone.
  • Other stakeholders have expressed concern over lack of clarity regarding the relationship between the area-under-the-curve model and potency as indicated by traditional assays.  We are also concerned that the model has not been tested on a sufficiently diverse set of chemical structures.  The agency needs to address these issues and provide additional evidence to support use of the current methodology, as opposed to other possible models.
  • These screening assays must be relevant to real world exposures in order to be meaningful.  Broad bio-monitoring and exposure studies are vital to informing extrapolation modeling in order to reap the benefits offered by high-throughput screening.
  • As these high-throughput assays are further developed, the most orthogonal assays with the most downstream read-outs possible should be used, in order to capture the broadest possible range of mechanisms-of-actions.
  • We agree with the EPA that metabolites could be missed using in vitro studies alone, and therefore some in vivo studies will be needed.
  • We strongly urge the EPA to make the computational model fully accessible for independent assessment.  That would increase transparency and stakeholder participation in this project.

 

Lastly, we share the concerns expressed in the Inspector General’s 2011 report that this process has not progressed as quickly as it should have.  We strongly urge that adequate resources be dedicated to these efforts, in order that the agency may meet its goals in a timely fashion.

Thank you for the opportunity to address the panel today.

By Amelia Murphy

December 2014

 

119498489859501915trebuchement_yves_guillo_01.svg.medThe leading cause of injuries in older adults is falling.31 Falls can lead to loss of independence, early admission into long-term care facilities, disability, and even death. In fact, falls are the leading cause of fatal injuries in older adults.

We often hear about ways to prevent heart disease, cancer, osteoporosis, or viral infections, but what about preventing something as simple as falling? One out of every three people 65 years and older fall each year, and once they’ve fallen, they’re two to three times more likely to fall again.32

It is ironic that millions of women take medication or dietary supplements to prevent bone fractures when the safest, most effective  way to prevent broken bones is to prevent falling. Falls can cause fractures of the spine, hip, forearm, leg, ankle, pelvis, upper arm, and hand.  Even when bones aren’t broken, falls can result in a trip to the emergency room. In 2012, 2.4 million older adults went to the ER due to a fall, and over 722,000 of those patients were hospitalized. Overall, these falls cost $30 billion in 2012—and that’s just in medical costs. About 22,900 older adults died in 2011 from injuries due to falling.33

Unfortunately, as our population ages, this problem isn’t going away.

Many older adults are not aware they are at risk of falling until it happens. Little by little, it gets harder to pick up their feet or balance on one leg. These gradual changes are hard to notice until the person falls. It doesn’t help that threats—objects that can trip us up or make us lose our footing—are all around us in everyday life, such as stairs, throw rugs, slippery bathtubs, concrete curbs in parking lots, tree roots, and even pets.34

Besides conditions in their homes and communities, older adults’ medications can increase the risk of falling. For example, drugs for high blood pressure, depression, and anxiety can cause dizziness, confusion, and poor concentration, which can result in falls. Atypical antipsychotic medications are too often given in nursing homes, and can be especially harmful. Medication given to help people sleep better often still cause drowsiness the next morning, and that increases the risk of falling.

 

How can we fix this problem?

We can start by lowering the chances of a fall happening just as we would with any other risk to our health and wellbeing, such as washing our hands to prevent a cold or wearing a helmet to prevent injury while biking.

 

Things you can change around the house:

  • This is the easiest one: Get rid of throw rugs and make sure your carpet is even
  • Make sure your furniture would not topple if grabbed for support (if it does, bolt it to the wall)
  • Improve lighting (Aging eyes might need better light and also need nightlights )
  • Install grab bars where they might be needed (near toilets and showers)
  • Wear an electronic pendent with a button to push to call for help

If you check out long-term care facilities, you will see some of the safeguards that can help. To better understand how an older person might see, architects and designers walk around with tinted, blurry glasses. Some of their ideas include installing floor lighting, like the kind used in the aisles of airplanes, to highlight the pathway to the bathroom. They have also tried painting the shower edge or the edge of the stairs a contrasting color to make these areas more visible.

 

Steps an individual can take to decrease their risk of falling:

 

Improve balance and strength

  • Take regular exercise classes that include moves or postures that require balance, such as yoga or Tai chi. These forms of exercise involve slow deliberate movements along with breathing and muscle activity, which improves balance.
  • Integrate balance and strength practice into everyday life. For example: stand on one foot while brushing your teeth, or stand with one foot in front of the other.

Maintain health

  • Drink water! Dehydration can cause dizziness.
  • Eat foods with VitaminD to increase muscle strength.35
  • Get screened for osteoporosis (a condition where bones get weak or brittle) but only get treated if necessary – these medications have risks and only modest benefits.
  • Have your eyes checked yearly.

Wear the right glasses

  • Bifocal and progressive lenses make falling more likely, so wear single vision glasses when needed for safe walking.36

Reduce your drug dosage, or eliminate unnecessary ones

  • Hypertension drugs can lead to a higher risk of falls with uncertain benefits for the heart for older people.37
  • Avoid sleeping pills and anti-anxiety medication that can reduce concentration and instead try warm milk, hot chamomile tea, or listen to soft music to relax.

Focus on your mindset

  • Many people develop a fear of falling after they’ve fallen. Although caution is helpful, fear can cause older people to limit their activities, which leads to less movement, loss of physical fitness, and can eventually increase their risk of falling.38
  • People may resist the transition to a cane or walker, but using these aids can prevent problems down the road.

 

The Bottom Line

Preventing falls can save lives and improve the quality of life for millions of people. The good news is that while falls are dangerous, there are ways to prevent them. Better yet, researchers have started a five-year, $30 million study to figure out the most effective ways of preventing falls in older people living on their own. This is the largest study of its kind, and it is funded by the Patient-Centered Outcomes Research Institute (a nonprofit organization) and the National Institute on Aging.39 Once the results of this study are released, we may have even better tips for preventing falls in the home. Meanwhile, focus on maintaining your balance and health, and work to make your home as safe as possible.