Matthew Perrone, AP Health Writer

April 15th, 2014

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

To view as a PDF, click here.

April 8, 2014

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

Re: Flibanserin

Dear Dr. Woodcock,

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

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

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

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

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

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

Sincerely,

 

American Medical Student Association

American Medical Women’s Association

Annie Appleseed Project

Breast Cancer Action

National Research Center for Women & Families

Our Bodies Ourselves

The TMJ Association

WoodyMatters

 

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

 

 

 

 

 

 


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

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

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

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

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

By Celeste Chen

April 2014

Over the next 40 years, the number of people in the world with Alzheimer’s Disease, the most common form of dementia, is expected to triple.1  Because Alzheimer’s strikes as people get older, the U.S. is expecting a big increase in this brain-wasting disease as baby boomers become seniors.

Pesticides, which kill insects by attacking their nervous systems, and herbicides, which wipe out some plants but not others, are increasingly being linked to diseases that attack our nervous systems and brains. Several studies have shown that individuals regularly exposed to pesticides and herbicides are more likely to develop Parkinson’s Disease (PD), which makes it difficult for people to control their movements and can cause emotional changes.2 Now, there is reason to believe that pesticide exposure can also increase a person’s chances of developing Alzheimer’s Disease. 3

A study published in 2014 in the prestigious medical journal JAMA showed a link between Alzheimer’s and DDT, an ingredient in many pesticides in the 1970s.4  Farmers and other agricultural workers who were exposed to high levels of DDT decades ago are much more likely to suffer from dementia, including Alzheimer’s, than are other people. DDT was banned in the U.S. in 1972, but people continue to come into contact with this dangerous pesticide by:

  • Buying imported foods from countries such as India, Spain, Mozambique, and Ethiopia where DDT or DDT-like pesticides are still in use.5 6
  • Living in agricultural areas where DDT was once sprayed as a pesticide. Even though it has not been used for over 40 years in the US, DDT is still present in our soil because it takes decades for DDT to be broken down naturally.7 8
  • Living near former industrial sites. In the 1970s, manufacturing plants dumped waste products containing DDT, which contaminated riverbeds and local waters. The Palo Alto Superfund site is one example of an area contaminated with DDT and other chemicals. Fish at these sites still contain DDT because DDT remains in the water for over 300 years. 9  10  
  • Chance.  When DDT breaks down, it produces DDE, another harmful chemical. Both DDT and DDE enter the air as they evaporate from contaminated water and soil. As a result, DDE and DDT are sometimes found far away from the source of DDT dump sites. DDE and DDT have even been found in such remote areas as the Arctic and Antarctica. As DDT and DDE evaporate, they are made safer by sunlight. Unfortunately, the process of evaporation also helps spread and deposit the chemicals to new places.11

 

DDT/DDE and Alzheimer’s

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

This tells us that DDT is only one possible cause of Alzheimer’s and dementia, and also suggests that some people are genetically more vulnerable to the harmful impact of DDT. For instance, individuals with the e4 version of the APOE gene (apolipoprotein) are more likely to have late-onset Alzheimer’s than people with e2 or e3 versions.12

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

 

What the Study doesn’t tell us

This 2014 study looked at organochlorides, which is only one type of chemicals found in pesticides. After DDT was banned, replacement pesticides were introduced but none of these were tested for safety.  Other types of chemicals used in pesticides, such as organophosphates, may also increase a person’s risk of developing Alzheimer’s. We simply don’t know yet.  There is some evidence that a popular alternative to DDT, malthion, may cause cancer.13  Malthion is an organophosphate. Children exposed to organophosphates have been found to have a higher risk of developing childhood cancer and having behavioral problems and decreased mental functioning.

 

BOTTOM LINE

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

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

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

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

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

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

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

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

 

By Melanie Brown

April 2014

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

Blood Thinners

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

Aspirin is also a blood thinner, but it works differently from prescription blood thinners like Coumadin. Aspirin keeps blood cells from clumping together (antiplatelet) while Coumadin lengthens the time (anticoagulant) it takes for a blood clot to form. Those who have atrial fibrillation and are at low risk for stroke may be prescribed aspirin. Aspirin poses less bleeding risks than Coumadin, but is usually not as effective for patients with atrial fibrillation. 14

How is Pradaxa different from Coumadin?

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

Pradaxa is only approved for use in patients with non-valvular atrial fibrillation, the most common type of atrial fibrillation. 15  Coumadin, on the other hand, is approved for the prevention and treatment of several health issues in addition to atrial fibrillation. These include pulmonary embolism (blockage of an artery in the lung) and venous thrombosis (blood clot in a vein). Additionally, Coumadin is sometimes prescribed to patients who have had a heart attack in order to prevent another heart attack. 16

Dose: Coumadin comes in several different doses.  While this can cause some confusion, it also allows doctors to prescribe the dose that is best for a particular patient, based on age, weight, and other health factors. In the U.S., Pradaxa is available in only two doses, taken twice a day: 75 mg and 150 mg.  The 75 mg dose is prescribed for those with kidney problems and is less effective in preventing stroke than the higher doses. In other countries, a 110 mg dose (also taken twice a day) is also available. This “in-between” dose appears to offer a lower bleeding risk while still being effective.  Experts question why the FDA did not approve the 110 mg dose for sale in the United States, since it has the potential to be safer for some people than the 150 mg dose.17

Overdose and Bleeding: Coumadin interferes with your body’s ability to use vitamin K (found in many foods, including leafy greens), which your body needs to form clots and prevent excessive bleeding. This is why patients experiencing excessive bleeding due to a Coumadin overdose are given Vitamin K.18  Pradaxa works slightly differently from Coumadin. Those considering taking Pradaxa should know that there is no Vitamin K equivalent for this drug. If a person taking Pradaxa experiences excess bleeding (blood in stool, urine, coughing up blood or what looks like coffee grounds, small red spots under the skin), there is nothing that can undo or reverse its effects!19 That can be deadly.

Anticoagulants rank among the riskiest drugs on the market.  However, certain anticoagulant drugs carry a higher bleeding and death risk than others.  In a report monitoring adverse events for anticoagulants, it was found that bleeds associated with Pradaxa use were 5 times more likely to end in death than bleeds from Coumadin. 20 This may be influenced by the fact that there is no reversal agent for Pradaxa so once someone starts to bleed excessively it is very difficult to save them.

Blood Monitoring: People taking Coumadin have to have their blood monitored regularly to make sure it is not becoming dangerously thin, since that could result in bleeding. Patients see Pradaxa as more convenient because they don’t need to get their blood monitored; this convenience can increase sales. This supposed benefit, however, presents risks: people who get their blood monitored regularly can find out if their blood has become too thin before it becomes a medical emergency. Without blood monitoring, a bleeding complication may be detected when it is too late to do anything to save the patient.  Earlier this year, documents from the drug manufacturer, Boehringer Ingelheim, were released by a federal judge in response to thousands of lawsuits filed by users of Pradaxa and their families. According to experts who have seen these documents, Boehringer Ingelheim employees have expressed concern that the company’s own research shows that people may benefit from blood monitoring while on Pradaxa. 21 This raises serious questions about the safety of Pradaxa and whether the lack of blood monitoring is beneficial and safe for all patients.

A study published in 2014 looking at patients with atrial fibrillation taking Pradaxa found that the ones who suffered a stroke or major bleeding had much higher concentrations of Pradaxa in their blood.22 The study used both the 110 mg. dose available outside of the U.S. and the 150 mg. dose used in the U.S.  How patients metabolized the drug ended up being much more important than the difference between the two doses. The huge range in blood concentration levels was just as large for each dose. The women in the study had Pradaxa blood concentrations 30% higher than the men, and people 75 and older had concentrations 68% higher than in people under 65.23 The researchers suspect that the high blood concentrations of Pradaxa in older people are the result of their kidneys not working as well, making it harder for them to clear the drug from their bodies. These findings suggest that, until tests are available to predict how people will metabolize Pradaxa, older patients and others may need to take doses even lower than 110 mg. or take their doses less frequently.

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

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

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

 

The Bottom Line:

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

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

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

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

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

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



 


April 1st, 2014

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

March 31, 2014

My name is Dr. Anna Mazzucco.  Thank you for the opportunity to speak today on behalf of the National Research Center for Women and Families.   After completing my Ph.D. at Harvard Medical School, I conducted research at the National Institutes of Health.  Since last year, I have been using those skills and perspectives to analyze the safety and efficacy of prescription drugs that the FDA is considering for approval

Our research center conducts research, analyzes data in the research literature, and then explains the evidence of risks and benefits to providers, 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 scientific resources that the FDA needs to do its job.  Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.

Like you, I have been scrutinizing the risks and benefits of Dalvance for the treatment of adult patients with acute bacterial skin and skin structure infections.

The main goal in antibiotic drug development is finding new drugs to target strains that are resistant to currently available drugs.  Unfortunately, most vancomycin resistant organisms are resistant to dalbavancin as well through van A mechanism.

A careful analysis of the data calls into question the efficacy of Dalvance.  In the DUR001-301 trial, 19% of patients who initially responded at the first time point later failed to achieve complete resolution of all local symptoms of infection, versus 11% in the comparator arm.  Of patients with bacteremia due to Gram-positive aerobes at baseline, 25% of patients receiving Dalvance were initially non-responders at the first time point, compared to 12% in the comparator arm.  Both those statistics indicate Dalbavandin patients are approximately twice as likely to have worse clinical outcomes compared to  patients taking the comparison drug, vancomycin.  The FDA also concluded that while there was inconsistency between the two phase III trials, sensitivity analyses showed that Dalbavandin performed less favorably at end-of-treatment in both trials when stricter criteria were used for judging success based on erythema. Why should the FDA approve a drug with such poor results when more effective options are already available?

Of course, the outcome patients most care about is getting well of surviving.  But another clinical endpoint that is important to patients is pain, because that is a common symptom of these infections.  And yet, there was no clinical endpoint to assess pain, which is a key symptom.

In addition to concerns that this drug isn’t very effective, it has serious risks.  There was a significant hepatotoxicity signal in this trial which could not be attributed to anything other than the drug.  Specifically, 6 patients who took Dalvance had alanine aminotransferase (ALT) elevation of more than 5 times the upper limit of normal.  This could cause serious liver damage, especially in patients with compromised liver function.  None of the comparison group patients had such a severe reaction .

There is no logical explanation for this liver toxicity, other than the drug.  The patients assigned to Dalvance were comparable to the comparator patients in terms of relevant co-morbidities and elevated ALT at baseline.

We agree with the sponsor, which concluded that based on these findings, “it is likely that Dalvance may cause elevations of liver enzymes especially in patients with pre-existing liver dysfunction”.

This is a major risk for patients, because patients with chronic liver disease are more susceptible to MRSA due to impaired neutrophil function.  Bottomline: thousands of patients could be at risk of serious liver damage if given this drug, and yet the drug is not even as effective as other alternatives already on the market.

And while studies have shown that Hispanic and African-American patients are more likely to contract MRSA, 9 out of 10 patients in both phase III trials were white.  We know that naturally occurring genetic variations can affect the way certain drugs are metabolized and work in certain racial and ethnic groups.

And yet, only 28 patients were African American, and we cannot even determine the number of Hispanics from the data as it is presented.  Although the sponsor states that they observed similar safety and efficacy results in all patient ethnic groups, there are too few patients to be confident that would be true of the general population.

Based on the weaker efficacy compared to other drugs, the lack of any safety or efficacy data for African Americans or Hispanics, and the extremely  serious risk of liver damage, Dalvance seems inferior compared to other antibiotics.  If the sponsor does additional research that includes subgroup analysis of African Americans and Hispanics, measures pain as an outcome, and determines which patients are most likely to benefit, then FDA should consider this drug at that time.  But today, speaking not on behalf of any company but instead on behalf of our nation’s public health and the patients who rely on safe and effective antibiotics, we strongly urge the panel to REJECT approval of Dalvance at this time.

I want to emphasize: more research is needed BEFORE approval.  Sometimes Advisory Committees recommend approval based on their hopes for a drug and ask the FDA to require post-market studies for more conclusive data.  The companies are more focused on selling the new drug than studying it, so research shows that it takes about 10 years for the company to complete and analyze a post-market study.  The risks of Dalvance are too great to allow sales now and then wait that long for better data.  The company should be required to add a more diverse population and one that consists of patients who are immunocompromised BEFORE this drug can be approved.

In 2009, FDA withdrew the antibiotic Tequin from the market due to fatal blood-sugar events that were particularly dangerous for diabetic patients.  As diabetic patients are at higher risk for MRSA, this drug must be adequately tested for safety and efficacy in this group.  The FDA has also recently put out warnings for doripenem and tigecycline ,citing increased mortality risks. In fact, more than 40% of antibiotics approved since 1980 have subsequently been withdrawn, highlighting the risks of approving drugs based on insufficient data.

 

 

March 31, 2014

My name is Dr. Anna Mazzucco.  Thank you for the opportunity to speak today on behalf of the National Research Center for Women and Families.   After completing my Ph.D. at Harvard Medical School, I conducted research at the National Institutes of Health.  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 providers, 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 pharmaceutical companies, and therefore I have no conflicts of interest.

We have concerns about Sivextro for the treatment of adult patients with acute bacterial skin and skin structure infections.  The main goal in antibiotic drug development is finding new drugs to target strains that are resistant to currently available drugs.  However, Sivextro is already known to share cross-resistance with linezolid-resistant strains with chromosomal mutations, which is the majority.  This is a major shortcoming of this drug.  In non-inferiority trials, it is particularly critical to adequately establish safety and efficacy in critical patient populations.  Otherwise, patients could be treated with a drug that is actually worse than what is already available.  Several placebo-controlled trials have shown that antibiotics are ineffective for abscesses, and 30% of the patients in this trial had abscess, making the non-inferiority design even more problematic.  These infections often among the elderly and those with compromised immune systems — but these patients were NOT represented in the pivotal trials.  In the two phase III trials, only 9% and 13% of the patients treated with Sivextro were 65 or older – that is only 69 patients.  Only 18 patients in both trials together were 75 and older, which is a critical group to test the drug for the proposed indication. 

Similarly, while studies have shown that Hispanic and African-American patients are more likely to contract MRSA, 85% of patients in all the phase III trials were white.   With such a low percentage, any safety or efficacy problems specific to minority patients would be invisible because the small number of African Americans and Hispanics were combined in the analysis with the much larger sample of whites. We know that naturally occurring genetic variations can affect the way certain drugs are metabolized and work in certain racial and ethnic groups.

The percentage of Minority patients would not be important if there were a large enough number of these patients to analyze separately in subgroup analyses.  But, only 77 were African American and only 16 patients were in any other racial or ethnic groups – obviously too small to evaluate safety. And while subgroup analysis was not conducted for secondary endpoints, for the primary clinical endpoint, patients over 65, and the ethnic group labeled “other” had poorer outcomes.

Another problem with the studies is that diabetic patients are particularly susceptible to these infections, but only 4% and 10% of the trial participants had diabetes, which totals only 58 patients  treated with Sivextro in both phase III trials combined.  Again, 58 patients is too few to draw conclusions about, BUT the sponsor should have at least analyzed this group of patients separately to see if the drug is equally effective for them.  They didn’t.

The proposed clinical dose is specified for patients 12 and older, yet the minimum patient age among all the phase III trials was 17.  Kids do a lot of growing during those teenage years, and teens of different ages can metabolize drugs differently than adults.  The drug should not be approved for patients who were not studied. The sponsor did not provide a further breakdown of patient age between 18 and 65 years, so we do not know if there is enough data to justify approval for younger adults either.  Drug metabolism starts to change quite dramatically in middle age.

While there were comparable numbers of men and women in the trial, the sponsor did not separately analyze the safety and efficacy for each group separately.  They should have, to make sure it is safe and effective for men and for women.  The company is asking that this drug, which is primarily for elderly patients and those with compromised immune systems, be approved for millions of patients it wasn’t tested on: teenagers, perhaps young adults, African Americans, Hispanics, diabetics, and the frail elderly.    It is impossible to know if the drug is safe or effective for those patients.  Wishful thinking isn’t good enough.

We appreciate that Sivextro is more convenient than other drugs – it would be taken just once a day and for4 to 8 fewer days than other antibiotics.  But that doesn’t justify approval for a drug that hasn’t been adequately tested for the target indication.

I know that many of you are VERY concerned about options for MRSA, and that can pressure you to consider approving new drugs that haven’t been studied as well as you’d like.  But we all know that sometimes new antibiotics do more harm than good.  For example, years after approving the antibiotic Trovan, the FDA had to warn physicians that it could cause life-threatening hepatotoxicity in certain types of patients.  Before that warning, patients were harmed by Trovan, and many of those patients could have safely taken other drugs instead.  That’s just one example of how patients can be harmed – even killed – by a new drug that wasn’t adequately tested for the patients who were likely to take it. Azithromycin and Levofloxacin are just two other examples, which have both been the subject of recent FDA action because of serious safety problems.

Some of you may think post-market studies will solve the problem of poorly designed research.  But, if Sivextro is approved before additional research is conducted, the company has little incentive to quickly conduct required post-market studies on a more generalizable patient population.  For that reason, we believe that Sivextro should NOT be approved until additional research is conducted.

However, if you disagree, we’d like to suggest a compromise, that could get the drug approved more quickly and still address some of these serious concerns:

Prior to approval, FDA should:

Require a subgroup analysis of the 77 African American patients to check efficacy in the secondary endpoints, including sustained clinical response and pain.  It’s not many patients, but better than nothing.  If there is a signal of possible problems, require more African American patients BEFORE the drug is approved or require the label to explain that Sivextro is not approved for non-whites.

Do a separate analysis for the 58 patients in the studies who have diabetes.  If the results look worrisome, the label should clearly state that the drug is not approved for diabetes patients until more are studied.

The label should clearly warn that Sivextro is not approved for patients under 18 or over 75, since they were not studied.  Depending how many patients were under 25 or 35 (we cannot know from how the data is presented here), it may be necessary to exclude that group as well.  Or, if the sponsor prefers, they should add patients in those age groups to existing clinical trials before the drug is approved.

IN summary, whether Sivextro is approved or not, more research is needed to establish safety and efficacy in the most relevant patient populations, such as among the elderly, diabetic patients, and other ethnic groups.

IN conclusion: we urge you to reject Dalvance until better research is conducted, because of questions about efficacy.

But, if the FDA wants to move forward more quickly, we strongly urge FDA to require subgroup analyses on diabetics, African Americans, and older patients in the Sivextro studies BEFORE an approval decision is made.  Based on the results, the FDA should either require additional patients be studied BEFORE approval, or limit the indication to white patients between 18-65 who are not diabetic until post-market studies provide safety and efficacy data for those groups.

 

March 27, 2014

 

Good afternoon. My name is Laurén Doamekpor, and I am a senior fellow at the NationalResearchCenter for Women & Families. Our non-profit research center assesses scientific and medical data and provides objective health information to patients, providers and policy makers. Our organization does not accept funding from drug companies, and therefore I have no conflicts of interest.

We have carefully reviewed the data provided to your committee by the sponsor and the FDA and are here to share our perspective and concerns.

As you can see, Serelaxin had NO benefit in terms of one of the primary endpoints: shortness of breath during 3 time points in the first 24 hours.  It had no benefit in terms of the two secondary endpoints – which really are the crucial outcome measures: days alive and out of the hospital through Day 60 OR in terms of cardiovascular death or rehospitalization from heart failure or renal failure through Day 60.

The so-called success of the RELAX-AHF clinical trial is based on just one primary end point:  patients on Serelaxin reported more improvement in shortness of breath from baseline through Day 5 compared to the placebo. This was only statistically significant because of an imputation protocol that was inappropriate and methodologically unsound.

In addition, this measure is a subjective measurement that has been found in the research literature to not be very accurate for measuring changes due to treatment. (We will provide those citations to the FDA, which show, for example, a test-retest reliability score that is only half as reliable as what is considered “satisfactory.”) Those of you who have taken courses on research methods know that a 7-point Likert scale is more accurate because the gradations are greater than for the 100-point VAS. (That’s because most people can’t really distinguish between discomfort rated as 33 compared to 43 on a 100-point scale, but they can distinguish between 4 and 6 on a 7-point scale.)

The VAS can provide useful information but also can have lots of “false positives” in terms of improvement.  Scores can change as patients get used to being short of breath, for example, not because they are getting better.  We agree with FDA scientists that the results of this test – whether statistically significant or not – is unlikely to be clinically meaningful.

Given these methodological problems, NONE of us can have any confidence that this drug will actually benefit patients.

That may seem harsh, but as many of you know, clinical trials must be designed correctly, patient outcomes must be measured using very accurate instruments (which VAS is not), and results must be analyzed correctly to be meaningful. It is always possible to get what seems like statistically significant results if the data are manipulated in particular ways.

It doesn’t matter if the manipulation of data is intentional or not – in this study, the only significant finding used the weakest scale and was contaminated by the imputation protocol.  The other 3 endpoints showed no improvement.  And 2 of those endpoints were the ones that really matter: survival and staying out of the hospital for 60 days.

As noted in the FDA’s review, the imputation protocol allowed subjects with worsening heart failure to be given the VAS score of 0 for the remainder of the observation period. As a result, this end point did not take into account the severity or the length of each episode of worsening heart failure. When this was corrected, the sensitivity analyses showed that there was no difference in the degree of patients’ reported dyspnea. That means, there was no reported benefit to the patients regarding shortness of breath or anything else.

The sponsor submitted an addendum last week that includes a series of analyses addressing this methodological problem. That is not how the FDA process is supposed to work.  All data presented at this meeting should be fully vetted by FDA scientists and statisticians and provided to the Advisory Committee in advance.  The new analyses need to be carefully and cautiously analyzed by unbiased FDA scientists to determine whether or not this drug is effective at all.

Let me emphasize that 3 out of 4 endpoints found no improvement compared to the placebo.  The sponsor is claiming a very modest benefit in shortness of breath through day 5 – a difference that is very subjective and that the FDA believes is not clinically meaningful.  And, if the data were not analyzed correctly, there is no benefit at all.  We can’t assume that this last-minute analysis by the sponsor proves that the drug is beneficial. This needs to be carefully vetted by the agency and since the Advisory Committee did not have access to that vetting, you should not take this last-minute analysis into consideration when you vote today.

Another important concern about this trial is the lack of diversity. An overwhelming majority of patients in this trial were White and less than 5% were African American. This should not be acceptable in a study for a drug for heart failure, the #1 killer in every racial and ethnic minority group in the U.S. In particular, African Americans are more likely to have heart failure, more likely to suffer more severely, and more likely to get worse faster.

Even though they used a definition of Latino that is not the one that FDA requires, at most, less than 10% of the patients were Latinos.   Latinos are at very high risk of heart disease, and as the largest minority group in the country, the sponsor should have included more in the study. .

Research tells us that some naturally occurring genetic variations may influence the way certain drugs are metabolized and work in women compared to men, older patients compared to younger, and certain racial and ethnic groups. For this reason, subgroup analyses are essential to make sure a drug is safe and effective at particular doses for these major groups.

There were not enough African American patients in the study to conduct subgroup analyses to find out if this drug is safe or effective for African Americans.  There were perhaps enough Latinos to do a subgroup analysis, but the company didn’t do one.  FDA should have required the company to have enough African American and Hispanic patients to separately analyze safety and efficacy for those two large minority groups.

But they didn’t.  So, in addition to not knowing if this drug has any meaningful benefits for any patients, we know nothing at all about the benefits or risks for people of color.

The FDA has very clear guidelines that urge sponsors to include women and minorities in their clinical trials. When sponsors ignore those guidelines, using one excuse or another, Advisory Committees like this one should speak up about it.  I hope some of you will.  It isn’t enough to require more diversity in post-market studies, for the simple reason that companies too often ignore that requirement – they no longer have any incentive to follow FDA guidelines once the drug is on the market.  The FDA’s own data confirms this in a report they released last year (the 907 report).

I don’t think that our country’s largest minority groups — African Americans and Latinos — should be paying for drug treatments that have not been adequately studied on them.

But in the case of this drug, I don’t think ANY patients should pay for treatment that is not conclusively proven to work either.

The company pointed out that the Serelaxin patients had lower all-cause mortality.  But, as you know, with all the statistical analysis, this could easily occur by chance.  There is no evidence it was a result of the drug, given that 60-day mortality and hospitalization did not differ from placebo.

Given the lack of credible evidence that this injected drug is more effective than placebo, we urge you to advise the FDA to NOT approve it at this time, and to require better research as well as subgroup analyses on African Americans and Latinos.

This is not a life-saving drug. Post-market studies usually take 10 years to be completed. Proof that it works should be required before it is on the market. It would be terribly unfair to patients and providers to approve it without clear evidence and then wait 10 years for post-market studies to be completed.

The FDA Advisory panel voted unanimously against approval at the end of the meeting.

 

To view as PDF,click here.

Diana M. Zuckerman, Daniel M. Fox March, 6 2014

In this issue of The Milbank Quarterly, the article “Improving Medical Device Regulation: The United States and Europe in Perspective,” by Corinna Sorenson and Michael Drummond, examines recent changes intended to improve the effectiveness of regulations for pre- and postmarket surveillance of medical devices in the United States and Europe. The authors deftly analyze the numerous weaknesses of current policies in both countries, urge that changes be implemented “in a timely manner,” and recommend further actions to enhance their effectiveness. They conclude that these relatively small changes in regulatory policy will make a substantial difference in the safety and quality of medical devices.[1]Our analysis of the recent history of device regulation in the United States, however, leads to a less optimistic conclusion: that these changes in regulatory policy fail to adequately address the central shortcoming in the regulation of medical devices in the United States and Europe. This shortcoming is the ongoing reluctance of government regulators to exert their existing authority to ensure that lifesaving and life-sustaining medical devices are safe and effective.The historical record reveals that for years neither the US Food and Drug Administration (FDA) nor the European “Competent Authorities” have fully used their existing authority to ensure safety. For example, since 1976, US law has directed the FDA to require clinical trials and premarket inspections as part of the premarket approval (PMA) process for high-risk devices defined as “implanted and life-supporting or life-sustaining devices.”[2] Devices that posed moderate risks and were “substantially equivalent” to devices already on the market in 1976 could be cleared through a less stringent review, called the 510(k) process, which did not require evidence of safety or effectiveness based on clinical trials or premarket inspections and could not require companies to promise to conduct postmarket studies.

Since 1976, medical implants have become much more prevalent and considerably more complicated, which should have resulted in implants being more likely to require PMA today than they were in 1976. Instead, the trend has been in the opposite direction. Rather than defining them as the high-risk devices that they are, the FDA cleared for example, numerous heart valves and intra-aortic balloon pumps, virtually all artificial hips and knees, and many spinal fusion implants through the 510(k) process. Although the FDA has the authority to require clinical trials as part of the 510(k) process, regulations do not mandate such studies, and the FDA rarely requires them. Persuasive evidence of the FDA’s reluctance to use its own authority is that it has so narrowed the definition of Class III devices that only 1% of all medical devices approved in the United States are currently regulated through the PMA process.[3]

Sorenson and Drummond point out that a 2012 law allows the FDA to more easily reclassify grandfathered devices. Unfortunately, the FDA has used the new law to lower rather than raise its standards. Agency officials have proposed to down-classify most of the grandfathered Class III (high-risk) devices to Class II, so that they can legally be reviewed through the 510(k) process rather than PMA. These include 11 types of lifesaving devices, such as implanted catheters used for dialysis, external pacemakers, external counter-pulsating cardiac devices, and mechanical cardiopulmonary resuscitation (CPR) devices. The FDA justified these down-classifications by claiming that they are based on “valid scientific evidence . . . from clinical and preclinical tests or studies that demonstrate the safety or effectiveness of the device.”[4]

The medical profession has rarely criticized the lack of scientific rigor for device approval. Indeed, many orthopedic surgeons and invasive cardiologists, for instance, have strongly supported reliance on the 510(k) process.[5] It is possible that some of these individuals have been influenced by consulting and speaking fees from device manufacturers, some of which, when defined legally as “kickbacks,” led to multimillion-dollar fines.[6] Congressional concerns about these financial ties resulted in the Physician Payment Sunshine Act, a provision of the Affordable Care Act (ACA) that requires companies that make medical products to publicly list all physicians who have received an individual payment or gift valued at more than $10 or total gifts or payments exceeding $100 in 2013 (adjusted for inflation in subsequent years). “Physician preference items,” the label for implantable devices in hospital-purchasing jargon, has acquired a double meaning.

The quality of scientific evidence for the FDA’s down-classifications has, however, been repeatedly questioned by independent experts from nonprofit patient, consumer, and public health organizations that assess the quality of medical care.[7] They emphasize that the “special controls” that the FDA sometimes requires for devices cleared through the 510(k) process are weak substitutes for clinical trials proving that a device is safe and effective for patients.

The absence of clinical trials for so many implants and lifesaving devices is especially alarming because of the increasing subjectivity of the FDA’s criteria for defining “substantial equivalence” to another device. This definition is so broad that a dental implant has served as a “predicate” for (that is, as the equivalent of) a spinal implant, for example. As Sorenson and Drummond observe, the result of these determinations is that the majority of high-risk recalls of medical devices have been of those that were cleared by the 510(k) process.[8] In fact, approximately 18% of medical devices cleared through the 510(k) process in recent years have been subsequently subject to either a high-risk or a moderate-risk recall.[9] Even moderate-risk recalls can require potentially debilitating surgical removal of an implant, with metal-on-metal hip replacements being a recent example.

Additional evidence of the FDA’s weak use of its current authority is that it often does not require clinical trials for modified PMA applications[10] and even when it requires clinical trials for PMA applications, its scientific standards are much lower than for evaluating pharmaceutical drugs. Whereas pharmaceutical companies usually are required to submit two well-designed, randomized, controlled clinical trials, the FDA has routinely approved even the highest-risk medical devices on the basis of one relatively small, uncontrolled clinical trial. For example, the FDA is currently considering approving a cochlear implant, with well-established serious risks, for adults ages 18 and older based on one study of 50 patients, only one of whom was under 37 years of age.[11] Unfortunately, few clinical trials of new devices compare their effectiveness and safety to other treatment options, and none has approached the methodological sophistication of the systematic reviews of the comparative effectiveness of pharmaceutical drugs in particular classes on which collective purchasers and physicians have increasingly relied for more than a decade.[12]

The FDA, like the European Union (EU), has been shifting the burden of obtaining evidence of safety for both devices and prescription drugs from premarket to postmarket studies. Unlike the EU, however, regulators in the United States have access to relatively limited data from registries or other postmarket methodologies. Moreover, the ease with which manufacturers can change devices already on the market means that long-term evidence is increasingly irrelevant to the safety and effectiveness of devices currently on the market, thus diminishing the value of registries that collected data on earlier versions of medical devices.

As Sorensen and Drummond describe, in 2013 the FDA issued final regulations requiring manufacturers to use “unique device identifiers” (UDIs) to assist in tracking adverse events associated with devices that are in use. This will eventually provide better data on devices, but the FDA’s final rule gives manufacturers 3 additional years after most official deadlines to fully comply with the UDI regulations, even though the law requiring UDIs was first enacted in 2007.[13] This is an example of the FDA’s underwhelming response to a recommendation in 2011 by a committee of the Institute of Medicine that the agency accord priority to “developing an integrated pre-market and post-market regulatory framework.”[14]

Patients in many other industrial democracies have an important safeguard that US patients lack: their universal national health plans do not pay for devices unless they have been proven in clinical trials to benefit patients, which is a much higher standard than is required for either EU or FDA approval. In the United States, as soon as the FDA approves a device, it is likely to be covered by most public and private purchasers. This policy has contributed to the United States having the most expensive health care in the world and may put some American patients at greater risk of injury than are their counterparts in countries that apply more rigorous criteria for coverage and, hence, payment. Moreover, many devices are less expensive in Europe than in the United States because most EU member countries determine allowable wholesale prices, and hospitals and surgeons are reimbursed at lower rates than they are in the United States.[15]

Sorenson and Drummond explain that the European Union began to utilize its full authority to regulate medical devices only with the reforms of 2012; prior to that, even when clinical trials were required for high-risk devices, they rarely were randomized or had a control arm; sample sizes were small; and outcomes focused on safety and “performance,” not whether the device benefits patients. The lack of transparency in the process reduced the opportunity for oversight or public outrage. In the United States, congressional hearings and media attention in the 1990s resulted in the FDA’s requiring clinical trials for breast implants and jaw implants, although it has not done so for many implants that are equally risky or pose even higher risks for patients.[16] Only when similar congressional and media attention focused on metal-on-metal hip implants 20 years later did the FDA announce a plan to require clinical trials for them as well. Other implants, including numerous lifesaving cardiac devices, have been shown to be even more harmful when they fail but have received less attention from Congress and the media. The FDA has still not required clinical trials for many of those implants.

What accounts for the FDA’s reticence regarding more stringent regulation of medical devices? This is the same agency that Harvard political scientist Daniel Carpenter, in a history of its regulation of pharmaceuticals published in 2010, called the “most powerful regulatory agency in the world.”[17] Sorenson and Drummond justifiably accuse the FDA and the EU of issuing regulations that “not only introduce risks to patients but also the wrong incentives to . . . evaluate the benefits and risk of new devices.” They offer some history of this failure in the EU, but hardly any for the FDA. This omission may be partly a result of the absence of scholarship on the recent history of device regulation comparable to Carpenter’s work on pharmaceuticals. Such timely scholarship would build on the article by Sorenson and Drummond and a review of recent literature by Christa Altenstetter.[18]

Evidence has nevertheless accumulated about the impact of politics on device regulation in the United States. The presence of the device industry in every state and many congressional districts enhances its effectiveness in lobbying influential members of the House and Senate across the political spectrum. In addition, a lobbyist for AdvaMed, the device industry’s trade association, left this job to become deputy chief of staff for Speaker of the House John Boehner,[19] and the current senior executive vice president of AdvaMed was previously a key health adviser to the late Senator Edward M. Kennedy.[20] In the Senate, liberal Democrats Al Franken (MN), Patty Murray (WA), Barbara Mikulski (MD), and Elizabeth Warren (MA), for example, have joined with conservative Republicans such as Kelly Ayotte (NH), Tom Coburn (OK), Rand Paul (KY) and Marco Rubio (FL) to support initiatives promoted by device industry lobbyists, including a proposed delay or repeal of a 2.3% tax on medical devices in the ACA that helps pay for health insurance subsidies. AdvaMed and individual device companies make substantial contributions to Congressional candidates and spend tens of millions of dollars on lobbying every year.[21] This makes it impossible to distinguish between the impact of Congressional concerns about the legitimate needs of device company constituents and the impact of campaign contributions. Regardless of causation, however, the result has been Congressional hearings that criticized FDA efforts to improve scientific standards for devices, and legislation that fails to ensure that most devices are either safe or effective.

The device industry and AdvaMed have, moreover, thwarted legislation to require price transparency for devices, arguing that prices are a trade secret under the US Commercial Code.[22] They also have resisted attempts by investigative reporters to obtain information about adverse events associated with implants and conflicts of interest among physicians who select those devices. Exceptions include notable stories by Barry Meier of the New York Times and Peter Whoriskey of the Washington Post.[23]

Sorenson and Drummond write that the FDA’s decisions have frequently benefited device manufacturers rather than the public. We augment their conclusions by emphasizing the influence of interest-group politics on the agency’s regulatory reticence. The device industry wields enormous influence at the FDA as well as in Congress. For example, the last four directors of the FDA’s Center for Devices and Radiological Health subsequently worked for the device industry as consultants or full-time employees, starting with James Benson, who left the FDA in 1992 to head the trade association that preceded AdvaMed.[24-27] But the revolving doors between industry and government, which have been widely criticized at the Pentagon and other agencies, have rarely captured public attention when they benefit the medical device industry. Regardless of FDA conflict-of-interest and regulatory policies, revolving doors undermine the quality and integrity—and add to the costs—of the US healthcare system because the relationships involved could contribute to the agency’s failure to require solid scientific evidence of the safety and effectiveness of most moderate-risk and high-risk medical devices upon which patients rely.

To view as PDF, click here.

March 21, 2014

 

The Honorable Louise Slaughter
U.S. House of Representatives
2469 Rayburn House Office Building
Washington, DC 20515

 

Dear Congresswoman Slaughter,

As members of the Patient, Consumer, and Public Health Coalition, we strongly support H.R. 1150, the Preservation of Antibiotics for Medical Treatment Act.  The Act would help to preserve the effectiveness of antimicrobials used to treat diseases in both animals and humans.

The many antibiotics routinely fed to farm animals are most often used to spur growth rather than to fight infections. The Centers for Disease Control and Prevention’s (CDC) recent report explains that the overuse of antibiotics for animals helps to spread antibiotic resistance, because “drug-resistant bacteria can remain on meat from animals” and “the bacteria can spread to humans.”[1] In 2011, “80% of antibiotics sold by weight in the U.S. were used for meat and poultry production.”[2]   Although the FDA recently issued a voluntary guidance on the use of antibiotics for animals, it has been sharply criticized as being weak and ineffective.

The CDC has noted that more than 2 million Americans fall ill and more than 23,000 die each year due to pathogens that are antibiotic resistant.  Your legislation directly addresses this serious problem in a reasonable manner by requiring an applicant seeking approval of a new antimicrobial animal drug to demonstrate that the new drug’s  nontherapeutic use (use in feed or water or for healthy farm animals) will not harm humans by promoting antimicrobial resistance.  H.R. 1150 would also phase out the routine use of eight classes of medically important antibiotics in farm animals while still allowing the treatment of sick animals.

The CDC has stated that “Perhaps the single most important action needed to greatly slow down the development and spread of antibiotic resistant infections is to change the way antibiotics are used.”1  Your bill directly addresses this issue by promoting good stewardship, protecting new and old drugs from being used when they are not needed, thus saving them for when other drugs are ineffective. For instance, your bill prohibits giving antimicrobial drugs to a healthy food-producing animal for disease control unless there is a significant risk that a disease will be transmitted to the animal.

We strongly agree with the National Academy of Sciences (NAS) that “substantial efforts must be made to decrease inappropriate overuse [of antimicrobials] in animals and agriculture.”[3] That is why we strongly support H.R. 1150, which will reduce antimicrobial resistance by reducing or eliminating the use of these drugs in healthy farm animals.  We look forward to working with you on this critical public health legislation.

 

American Medical Student Association

American Medical Women’s Association

Annie Appleseed Project

Breast Cancer Action

Connecticut Center for Patient Safety

Jacobs Institute of Women’s Health

National Consumers League

National Physicians Alliance

National Research Center for Women & Families

National Women’s Health Network

WoodyMatters

 

 

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

 


[1] U.S. Department of Health and Human Services Centers for Disease Control and Prevention.  Antibiotic Resistance Threats in the United States, 2013.  Accessed February 5, 2014.  http://www.cdc.gov/drugresistance/threat-report-2013/.

[2] Plumer B, (December 14, 2013). The FDA is cracking down on antibiotics on farms. Here’s what you should know. The Washington Post. Accessed February 5, 2014. http://www.washingtonpost.com/blogs/wonkblog/wp/2013/12/14/the-fda-is-cracking-down-on-antibiotics-at-farms-heres-what-you-should-know/

[3] National Research Council. Microbial Threats to Health: Emergence, Detection, and Response. Washington, DC: The National Academies Press, 2003. Accessed March 13, 2014. http://www.nap.edu/catalog.php?record_id=10636