By Christina Silcox, PhD

October 20, 2014

 

With the Ebola situation changing daily, here’s what you need to know to stay safe.

 

WHAT IS EBOLA?

Ebola (scientific name: Zaire Ebolavirus) is a deadly virus that is spread through direct contact with the bodily fluids of a person who already has symptoms of the disease. Death is generally caused by massive organ failure. There is a 30%-50% chance of survival.

 

WHAT ARE THE SYMPTOMS?

Ebola starts as severe flu-like symptoms: a high fever, weakness, vomiting and diarrhea. Sneezing and coughing are not common symptoms of Ebola.

As the person becomes sicker, he or she may start bleeding from the eyes, ears and nose, as well as internally. This bleeding causes the person’s blood pressure to drop and the person’s organs start to fail. Death usually occurs within 2 weeks after the high fever begins.

 

HOW DOES EBOLA SPREAD?

Ebola is spread through direct human contact with body fluids, not by merely touching a person who is sick. A sick person’s blood or other bodily fluids need to pass into another person’s body through the eyes, nose, mouth or cuts or abrasions in the skin.  Ebola cannot be caught by breathing the same air as an infected person, sitting near them, or by shaking hands.

 

IF I AM AROUND AN INFECTED PERSON, AM I GOING TO GET SICK?

People who have Ebola but aren’t yet showing symptoms do not spread the virus. Even after a person has a fever, bleeding, or other symptoms, they won’t spread the Ebola virus unless their blood, mucus, vomit, feces, sweat, tears, breast milk, urine, or semen get inside a cut or other opening in another person’s body (such as getting it on one’s hands and then touching their mouth).

It’s reassuring that none of the friends or family that lived with the Liberian Ebola patient in Texas became ill, nor has anyone who visited him before he went to the hospital.  Since friends and family were not wearing the protective gear worn by hospital workers, this shows that the early stages of Ebola are not very contagious, even after the patient has already shown some symptoms.

An Ebola patient is much more likely to infect others as the disease progresses and he or she becomes very sick, and the amount of Ebola virus in the patient’s body greatly increases.  At that point, many patients are bleeding or vomiting, which also makes it easier to spread.  That is why healthcare workers treating patients with or suspected of having Ebola need to take extensive precautions, using gloves and covering their entire bodies with what look like space suits so they can’t accidentally touch a patient’s bodily fluids and then touch their mouth or eye.  Only two of the dozens of nurses and doctors who came in contact with the Liberian patient with Ebola in Texas became ill.

 

MY FAMILY MEMBER IS A HEALTHCARE WORKER. SHOULD I BE WORRIED?

Unless your family member is caring for Ebola patients, you don’t need to worry.  If your family member is treating Ebola patients, or patients that might have Ebola, they need to be trained how to use and remove protective gear and to follow directions exactly in order to protect themselves. The CDC and the Department of Defense has also committed to sending a “rapid-response” team of experts to any hospital that admits a patient with Ebola to help with logistics and training.1

 

HOW LONG AFTER A PERSON IS INFECTED WILL THEY GET SICK?

A person will start to get sick between 2 and 21 days after he or she is infected by an Ebola patient who is already showing symptoms of the disease.  The 21 days has already ended for the friends and family members of the Liberian Ebola patient in Texas, and none of them became ill.

 

CAN ANIMALS GET OR SPREAD EBOLA?

Experts believe that fruit bats spread the disease to humans in Africa.  When pigs, horses, and goats have been infected in experimental studies, they did not get seriously ill and did not spread the disease.

There have been no reports of dogs or cats getting sick with or spreading the Ebola virus, in Africa or any other country.  In previous Ebola outbreaks, dogs have been exposed to Ebola and have developed antibodies to it, but have not gotten sick.

There is no evidence that mosquitoes or other insects can transmit Ebola virus.2

 

HOW LONG DOES THE VIRUS LIVE OUTSIDE THE BODY?

The Ebola virus can live for several days outside the body in blood or other body fluids. However, once the fluid dries, the virus will only survive a couple of hours and then will no longer be dangerous. Bleach and other hospital-grade disinfectants will kill Ebola, as will careful incineration at high temperatures.

 

WHAT IS THE TREATMENT?

Currently, there is no known cure for Ebola. People who are infected with this strain of Ebola have a 30%-50% chance of survival (BMC).  The healthier the patient is when they get infected, the more likely they are to survive.

When a patient is admitted to the hospital and diagnosed with Ebola, blood pressure and blood oxygen levels are carefully monitored and maintained. It is especially important not to make sure the patient doesn’t get dehydrated. Other symptoms are treated as soon as they appear.  These treatments increase the chances of recovery. (CDC)

 

WHAT ABOUT EXPERIMENTAL TREATMENTS?

Experimental treatments and vaccines are being used for a small number of patients, but we do not know how effective they are.  Some patients have survived after getting experimental treatments, but others have died.

An experimental drug called ZMapp made headlines when three American health workers who got Ebola while treating patients in Liberia were treated with it. Although it had only been tested on a small number of monkeys and never in humans, the FDA allowed it to be used on these patients through a special humanitarian policy for people in urgent need of treatment.  Of the 7 patients who are reported to have gotten ZMapp, 5 survived and 2 died. It is impossible to know if the drug worked or if those patients would have lived even without the experimental treatment. As of August, the company that makes ZMapp has said they do not have any more of the drug and it takes a long time to manufacture. The US government has announced it will pay millions of dollars to several advanced laboratories to start producing it.

Another experimental drug named TKM-Ebola, which is still being studied to determine if it is safe or effective, has also been used to treat some patients. Two vaccines are also in development.

Another treatment is made from antibodies in the blood of people who have survived Ebola. Nicknamed “gold in the blood”, there is no conclusive proof that it works. However, several small experiments have shown the treatment has promise and the World Health Organization (WHO) has endorsed its use during this epidemic.  It has been used by at least one of the Texas nurses who got sick.

 

By Ed Silverman, The Wall Street Journal

October 17, 2014

Cigarette_smokingIn a setback for Pfizer PFE -0.07%, an FDA advisory panel yesterday voted overwhelmingly to maintain the most serious warnings on its Chantix smoking cessation pill.

The drug maker had sought to remove a so-called Black Box warning noting the risk of psychiatric side effects, such as suicidal thoughts and behavior, in hopes reviving the fortunes of a medicine that was once seen as a blockbuster, but has since sputtered among sensational news accounts and litigation.

Shortly after Chantix was approved in 2006, the pill became associated with stories of suicide and violence, which dampened use. Sales fell to $648 million last year from $846 million in 2008. And Pfizer spent hundreds of millions of dollars to settle hundreds of lawsuits.

Last month, however, the FDA altered another portion of the Chantix label portion of the Chantix label to indicate the pill may not carry the risks of suicidal thoughts and behavior. That change was part of an effort by Pfizer to lessen concerns about prescribing and usage, which have fallen since the Black Box was issued in 2009.

To persuade the FDA panel, Pfizer pointed to a meta-analysis of five studies the drug maker says did not show an increase in suicidal activity compared to those on a placebo. Pfizer also cited four observational studies involving thousands of patients the drug maker claimed did not show an increased risk  (see hereherehere and here).

But 11 members of an FDA advisory panel voted to recommend the agency maintain the Black Box warning, while six members voted to strengthen the labeling, suggesting that references to sleep disturbances, for instance, should be added. Only one panel voted in favor of removing the Black Box.

The panel also recommended that any further thought to changing the warnings should not be considered until after Pfizer completes a promised post-marketing study, which the drug maker expects to finish in the third quarter of 2015.

The panel, essentially, took the same position as FDA staffers, who questioned the designs of the observational studies. Several consumer groups recently cited both the study designs and thousands of side effect reports to petition the FDA to increase the Chantix warnings.

“I think Pfizer took quite a chance trying to get the box deleted. They obviously wouldn’t have done it if they thought they could convince people, but they failed completely,” says Diana Zuckerman, the president of the National Center for Health Research, a non-profit think tank.

“They had the best presentation money could buy – very good analyses and complicated statistics to prove their point. And the company trotted out these studies and tried to make a very strong case for why the Black Box should be deleted, but only one person voted their way.

“Pfizer took a big chance, but I think they did so because they were afraid the next study wouldn’t be so favorable and maybe they could get rid of the Black Box warning now. Remember, if it were removed, it would be hard to get it reinstated later, even if a post-marketing study showed risk.”

Pfizer is not flinching. “The completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication,” says Steven Romano, a Pfizer senior vp who heads the medicines development group.

Read original article here.

October 16th, 2014, Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

My name is Dr. Laurén Doamekpor, and today I am speaking on behalf of many members of the Patient, Consumer, and Public Health Coalition. The Coalition includes large and small nonprofit organizations across the country that are united to ensure that medical treatments are safe and effective, and to enhance the scientific and public health focus of the FDA.  The coalition does not have paid staff and does not accept funding from any outside sources, such as pharmaceutical companies or law firms, so I have no conflicts of interest.

Smoking kills thousands of Americans, and we agree that Chantix should be an available option for smokers who want to quit.

Last week, these 5 major national organizations filed a Citizens Petition for a stronger Black Box Warning for Chantix:

  •   Consumer Reports
  •   Institute for Safe Medication Practices
  •   National Center for Health Research
  •   National Physicians Alliance
  •   Public Citizen

We agree with those organizations that the black box warning is essential and should be improved, not weakened.

The sponsor identified 5 observational studies and 2 meta-analysis studies showing no statistically significant differences in various psychiatric adverse effects between Chantix and other smoking cessation drugs. The sponsor suggests that this evidence supports the removal of the boxed warning for serious psychiatric adverse events.

You need to consider whether the meta-analysis and observational data that the sponsor has identified prove that the black box warning is not needed.

  •  The studies in the meta analysis share the same methodological flaws. They do not assess all 4 serious psychiatric side effects that have been reported for Chantix: suicidal behavior, aggression/violence, psychosis, and depression
  •  And the value of a meta analysis depends on what studies are included.  But no justification was given for the inclusion and exclusion criteria used in the 2 meta-analysis studies.
  •  One of the meta-analysis studies included only 5 studies
  • The studies did not assess hostility/aggression, depression or psychosis.

It included 2 studies of smokers who were previously diagnosed with schizophrenia or depression  in other words, patients who already were suffering from delusions, uncontrollable thoughts, or depression BEFORE taking Chantix were studied to see if Chantix caused those psychiatric symptoms.  Those 2 studies should have been excluded from the meta-analysis, since a meta-analysis is intended to combine studies that are similar in terms of study design and outcome measures.

That left only 3 other studies of smokers who were not previously diagnosed with mental illness, and yet there are at least 14 other studies that should have been considered for the meta analysis.

The observational studies also had fatal flaws in study design.

  •  They didn’t analyze all psychiatric side effects. They only analyzed psychiatric hospitalizations, even though 82% of the 4 serious psychiatric side effects seen in adverse event data did not result in hospitalization
  •  The British Medical Records Study only examined suicidal behaviors and depression – but nearly 47% of the study population had present or previous use of antidepressant medication. It was obviously not a representative sample.
  •  The Danish Medical Records study only captured hospitalization and ER visits for the first 30 days after Chantix use was initiated

In conclusion, because of the very serious flaws of these studies, they can not prove that Chantix does or does not increase psychiatric side effects.

From a scientific and public health standpoint, these studies do not provide an assurance of safety that patients need and deserve.

We strongly urge you to recommend that the FDA keep a strongly worded black box warning and delete the misleading conclusions regarding the meta-analyses from the Chantix label

 

 

By Harold Bishop, Wolters Kluwer Law & Health Blog

October 15, 2014

 

Even though the FDA has recently proposed a new program to provide earlier market access to high-risk medical devices, FDA Commissioner Margaret Hamburg nevertheless came under fire for the agency being to slow to approve medical devices at the annual conference of the Advanced Medical Technology Association (AdvaMed) in Chicago. The implication of her inquisitors was that FDA delays are driving the medical device business to Europe, where device approval standards are more lax. Other health industry research groups disagree, believing that the FDA is acting responsibly, while Europe may be reexamining its lower approval standards.

New Expedited Program

The new FDA program was announced on April 22, 2014, through the issuance of a draft guidance entitled “Expedited Access for Premarket Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions.” The Expedited Access PMA or EAP program is designed to provide earlier access to high-risk medical devices that are intended to treat or diagnose patients with serious conditions whose medical needs are unmet by current technology and are subject to premarket approval (PMA) applications. The program features earlier and more interactive engagement with FDA staff during device development and more interactive review of investigational device exemption (IDE) applications. The FDA also intends to work interactively with the sponsor to create a data development plan specific to the device.

In addition to the EAP program, the FDA published a separate draft guidance outlining the agency’s policy on when data can be collected after product approval and what actions are available to the FDA if approval condidtions, such as postmarekt data collection, are not met. Entitled “Balancing Premarket and Postmarket Data collection for Devices Subject to Premarket Approval,” the draft guidance also includes advice on the use of surrogate or independent markers to support approval, cimilar to the data points used for accelterated prescription drug approval.

AdvaMed Discussion

In response to reports that slow FDA approvals have sent medical device startups and clinical trials to Europe, Commissioner Hamburg responded (as reported in MedCityNews) that “It’s not a race to who’s first – it’s a race to get the best possible product to people.” Hamburg continued that “approval in Europe doesn’t mean it’s broadly available in the healthcare systems of those countries,” adding that Europe is “in a moment of examination of their regulatory system for devices” due to the emergence of some safety issues.

One example of this “moment of examination” may involve the European Union recall of tens of thousands of defective breast implants. According to an article in Reproductive Health Matters (RHM), “In the U.S., breast implants are regulated as high-risk medical devices that must be proven reasonably safe and effective in clinical trials and subject to government inspection before they can be sold. In contrast, clinical trials and inspections have not been required for breast implants or other implanted devices in the EU; approval is based on other information. As a result of these differing standards, the PIP [Poly Implant Prothese] breast implants that were recalled across Europe had been removed from the market years earlier in the U.S., a decision U.S. government health agencies can point to with pride.”

In an interview with Wolters Kluwer, Diana Zuckerman, PhD, President of the National Center for Health Research, and co-author of the RHM article, indicated she supported Commissioner Hamburg’s position on this issue. According to Zuckerman, recent studies show that devices get on the market in the U.S. about as fast as they do in other countries. In addition, “It is much easier to get insurance coverage for devices in the U.S.  In most other countries, the national health plans won’t pay for devices unless they are proven safe and effective and sometimes need to be proven cost-effective.  In the U.S., such requirements have been  rare.  It is very easy to get devices on the market in Europe and other countries, but difficult to get coverage until studies prove the device’s value.  For that reason, and because devices cost so much more in the U.S. than other countries, device companies are always going to want to sell their products in the U.S.  Whether their headquarters are in the U.S. or not, they need FDA approval to sell in the U.S.  So, that is not going to influence whether a U.S. company moves to another country.”

From a follow-up discussion at the AdvaMed conference, The Boston Globe quotes Mark Deem, managing partner of the medical device startup The Foundry LLC, as stating that “the horse has already left the barn. It’s gotten to the point where entrepreneurs are just moving all their early stage medical device activities lock, stock, and barrel overseas.” With regard to the FDA’s EAP program, MedCityNews further opines that “Deem worries that it has taken so long for the FDA to realize it’s been shellacked by Europeans that it could be too little, too late.” Zuckerman, however, disagrees.  According to Zuckerman, “the decision of some device companies to leave the U.S. is clearly related to the tax advantages of doing so, not related to the FDA approval process or standards for clinical trials in the U.S.”

Opposition to the EAP Program

Lest anyone think that the FDA’s new EAP program has full support, on July 22, 2014, members of the Patient, Consumer, and Public Health Coalition sent comments to the FDA indicating their lack of support for the program. While the coalition members sympathize with patients who suffer from life threatening or irreversibly debilitating disease, they believe that “the standards for PMA are already substantially lower than for prescription drugs…and yet, the [EAP program] lowers the bar for certain PMA medical devices even further.” The coalition believes “there is no guarantee that the [program] benefits would outweigh the risks for patients.” While the members indicate their support the program’s emphasis on earlier interactive communication between sponsors and the FDA, they also believe the program “gives undue emphasis on postmarket studies that are poorly monitored, have high loss to follow-up, and are rarely conducted in a timely manner that provides useful results.”

Read original article here.

By Diana Zuckerman, PhD

American Association for the Advancement of Science

October 14, 2014

One of the most pressing scientific issues facing Congress today is the risk that antibiotic resistance presents to human health. Unlike other political-scientific hot potatoes, such as global warming, the House and Senate crossed the aisle to pass a bipartisan bill to speed new antibiotics to market, and are working on a new bill to make FDA approval even easier.

Unfortunately, there is an enormous gap between what the science tells us is needed and the Congressional approach.

In addition to the obvious biological cause of antibiotic resistance, two major problems contribute to antibiotic resistance—lack of new antibiotics to fight resistant bacteria and misuse and overuse of existing antibiotics.

Congress has focused on the first by creating financial incentives for companies to develop new antibiotics, and changing the scientific criteria for FDA approval to make it easier to get new antibiotics approved. The GAIN (Generating Antibiotic Incentives Now) ACT, passed in 2012 as part of a larger law, provides an additional five years of patent protection for certain antibiotics and makes them eligible for fast-track review by the FDA.

Congress is currently considering the Antibiotic Development to Advance Patient Treatment (ADAPT) Act, which offers companies an even easier pathway to FDA approval for antibiotics used by “a limited population of patients” who urgently need new drugs. But ADAPT contradicts that purpose by specifying that doctors have the authority to prescribe these drugs for any patient under any circumstances. The bill also encourages FDA to approve these drugs based on smaller studies, Phase 2 rather than controlled Phase 3 trials, and surrogate endpoints rather than meaningful health outcomes.

In contrast, the Center for Disease Control and Prevention 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.” Unfortunately, neither GAIN nor ADAPT does anything to discourage the overuse of new or old antibiotics.

Human misuse includes prescribing antibiotics for colds, flu and other viral infections for which antibiotics are ineffective. It also includes widely prescribing new antibiotics when older antibiotics would be just as effective, instead of saving new antibiotics for when they are most needed. Changing doctors’ prescribing habits is difficult, however, despite recent efforts such as the “Choosing Wisely Campaign.”

The most important issue missing from these legislative efforts isn’t human-centered at all—it is the routine use of antibiotics in animals. The FDA reports that 80 percent of antibiotics in the U.S. are used for food-producing animals, not for humans, and that many are used to promote animal growth in cows, sheep, chickens and hogs, rather than to keep them healthy. The resulting resistant bacteria can spread from animals to humans.  And yet, a bill to address that problem, introduced by Rep. Louise Slaughter and other House members in every Congress since 1999, has never had a hearing or vote in the House. Nor has Sen. Dianne Feinstein’s recent companion bill in the Senate. In fact, a much weaker bill introduced by Rep Henry Waxman last year, which would merely require data collection on use in farm animals, attracted only 10 co-sponsors and never had a hearing, vote or Senate companion bill.

Provisions to reduce human misuse of antibiotics were in the GAIN Act, but deleted before it was passed. Earlier this year, the FDA proposed strategies to reduce the use of antibiotics in livestock—unfortunately, they are voluntary and unenforceable.

Last month, however, the President’s Council on Advisors on Science and Technology issued a report on antibiotic resistance that takes a very different approach than Congress or the FDA. Rather than focusing on financial incentives and reducing the research burden on pharmaceutical companies, this report includes a range of scientific insights and strategies about what kind of research is needed to develop antibiotics that will save lives. The challenge now is to translate those complex and evidence-based ideas into a bill that can pass Congress.

Read original article here.

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

October 14, 2014

Comments of Members of the Patient, Consumer, and Public Health Coalition
on Draft Guidance
“De Novo Classification Process (Evaluation of Automatic Class III Designation)”
[Docket No. FDA-2011-D-0689]
October 14, 2014

As members of the Patient, Consumer, and Public Health Coalition, we have serious reservations about the use of the de novo classification process for implants, life-sustaining, and life-saving devices. We believe that all such high-risk devices should be Class III devices reviewed through the more rigorous PMA process.  That is why we urge CDRH to revise the draft guidance to explicitly state when the de novo process may be used and when it cannot be used.

We strongly support language in the draft guidance that states the de novo process should be used for devices that are “low to moderate risk” (Class I or Class II devices).  We also support language that states, “The de novo should include all (emphasis added) information and evidence regarding the safety and effectiveness of the device,” and “provide data demonstrating that general controls or general and special controls support a classification of Class I or Class II.” However, we urge the FDA to revise the second sentence to read: “provide publicly available scientific data and test results demonstrating that general controls…support a classification of Class I or Class II.”

We support the draft guidance section on “Supporting Protocols and/or Data.” It recommends that an applicant “Provide a summary of all performance and clinical testing” and that “the summary should include the objective of the testing, a description of study design, and a description of results.” If companies fail to provide this information, FDA should deny their de novo application. In the National Center for Health Research’s recent study of cleared 510(k) implants, researchers found companies provided no scientific data in 4 out of 5 recent 510(k) applications, because they either did not provide summaries or their summaries provided vague information such as “all required testing was completed and the results were satisfactory.”3  This is very disturbing since current law states that the summary must include “sufficient detail to provide an understanding of the basis for a determination of substantial equivalence.” 4

 

Devices ineligible for de novo

We strongly support the following language that clearly states that a device is ineligible for the de novo process, if the “device falls under a class III classification regulation, or if it is a direct de novo and the device is not low-moderate risk, we [FDA] intend to decline your de novo.”   However, we disagree with the restriction that a de novo review would not be considered “if a likely predicate device exists.”  In many cases, implanted devices are listed as predicates even when they differ in size, shape, materials, or mechanism of action from new devices, and a de novo review would be a better choice than a 510(k) review.

The draft guidance states that if general and special controls are “insufficient to provide reasonable assurance of safety and effectiveness or…the data provided in the de novo are insufficient to determine…a reasonable assurance of safety and effectiveness, we [FDA] will decline the de novo and you may not legally market the device.”  We are concerned about this wording, however, because the FDA’s definition of sufficient evidence is often very subjective and this has resulted in terrible harm to patients when based on assumptions that have proven to be incorrect, such as for Vena Cava filters (product code DTK).

Regarding the final sentence of the draft guidance, it states “All information posted to the FDA website will be redacted to protect any confidential commercial, trade secret, or personal privacy information.” FDA should delete the first word, “all” because the intent of the language is not to redact all information, which is how it currently reads.  Moreover, we strongly urge the FDA to err on the side of transparency when redactions take place.  In the past, information that is publicly available elsewhere has been redacted from documents by the FDA.

 

Conclusions

The de novo process should be used to strengthen the approval standards for low-to-moderate risk devices by replacing the 510(k) process.  It should not be used to lower the approval standards for high risk (Class III) devices, which should always be reviewed through the more stringent PMA process. We strongly urge the FDA to revisit their classifications of many implants, 95% of which now go through the 510(k) process, according to recent research.1  We also urge the FDA to reconsider the Class II classifications of many other life-sustaining and life-saving devices that have also been cleared through the 510(k) process based on predicates that differ substantially from the new devices in ways that have clear implications for safety and effectiveness, such as surgical robotic systems that were cleared as substantially equivalent to surgical tools.  To protect public health and ensure that medical devices provide a reasonable assurance of safety and effectiveness, the draft guidance must unambiguously describe when the de novo process may and may not be used to clear a medical device.

 

Annie Appleseed Project
Breast Cancer Action
Center for Medical Consumers
Connecticut Center for Patient Safety
National Center for Health Research
Our Bodies Ourselves
Center for Science and Democracy at the Union of Concerned Scientists
WoodyMatters

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

 

Division of Dockets Management (HFA-305)
Food and Drug Administration
5600 Fishers Lane, Room 1061
Rockville, MD 20852

October 14, 2014

Comments of Members of the Patient, Consumer, Public Health Coalition
on the Draft Guidance
“Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics”
[Docket No. FDA-2014-D-0900]

As members of the Patient, Consumer, and Public Health Coalition, we strongly oppose the draft guidance Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics.  The three major shortcomings of the guidance are as follows:

  1. It focuses on benefits and risks that cannot be accurately measured in the absence of large, long-term, well-designed clinical trials.  Such studies are never available for new devices being considered for 510(k) clearance.  In fact, even small, short-term, well-designed clinical trials are almost never available.
  1. The wording of the guidance is vague and rather than clarifying the criteria for substantial equivalence, the guidance illustrates the very subjective decisions that the Food and Drug Administration (FDA) relies on.  The lack of consistent, clear standards is unfair to device companies and physicians and harmful to patients and the public health.
  1. The specifics regarding surrogate endpoints, emphasis on postmarket data, and patients’ perspectives on risk assessment would further reduce the already extremely limited safeguards available to ensure the safety and effectiveness of new medical devices cleared through the 510(k) process.

 

Principal Benefits and Risk Factors for Performance Data

This section states that the FDA will assess “on a case-by-case basis” what it may find acceptable in a substantial equivalence decisions. We oppose these subjective judgments made on case-by-case assessments because they do not foster a standardized approach.  The Center for Devices and Radiological Health (CDRH) should be able to make clear guidelines about what substantial equivalence means and how it needs to be proven scientifically.

 

Assessment of the Benefits of Devices

The FDA takes into account the following four factors in assessing information provided in a 510(k) submission: Type of benefits, magnitude of the benefits, probability of the patient experiencing one or more benefits, and the duration of effects.

Type of benefits

The draft guidance list of benefits includes patient health, patient satisfaction, quality of life, and probability of survival among other benefits.  It then adds that “these endpoints denoting clinical benefit…may be demonstrated by use of validated surrogate endpoints.”  The word “validated” is not defined.  The FDA should avoid using surrogate endpoints because the FDA’s judgment of what is validated has been very subjective.  Patients want improved health, relief from symptoms, longer life, and improved quality of life.  Even if surrogate endpoints correlate with any of those outcomes, the surrogate endpoints would need to be scientifically validated for specific demographic subgroups, such as women, men, Whites, Blacks, Hispanics, and people over 60.  The CDRH does not have a good track record on surrogate endpoints or subgroup analysis, unfortunately.

Magnitude of the benefits

The draft guidance states, “The change in clinical study subjects’ condition or clinical management” allows the FDA to assess the benefits patients receive from the treatment. However, a recent study showed that only about 6% of 510(k) implant applications—including implants with different technological characteristics than the predicate device—mention the existence of clinical data in their summaries, whereas many more mention the use of non-clinical data.5  If the FDA is using clinical data as the basis of substantial equivalence decisions, the law requires that information to be publicly available “in sufficient detail.”6

Probability of the patient experiencing benefits

The guidance does not explain the evidence that will be used to determine patient benefits.  Since 510(k) applications so rarely include any clinical data, and those that are included tend to be a small study, it is misleading to claim that the FDA can determine the “[d]emonstration of a large benefit experienced by a small proportion of subjects [which] may raise considerations that differ from those in instance where a small benefit is experienced by large proportion of subjects.”  The key question is, given the small or non-existent clinical studies of new devices included in virtually all 510(k) applications, how can the proportion of subjects who experience a large benefit be identified or targeted? This would require that accurate diagnostics be available to identify populations that would benefit the most from the device, which is often not the case.

Regarding the assessment of probable risks and harms by reviewing factors individually and in the aggregate, we agree that “When multiple harmful events occur at once, they have a greater aggregate effect.”  However, we are concerned that the draft guidance use of “number and rates” of harmful events associated with a device is not practical, since it is commonly known that Manufacturer and User Facility Device Experience (MAUDE) undercounts adverse events.  The same can be said for device-related non-serious adverse events and procedure-related complications.  In the absence of clinical trials or registry data for the vast majority of 510(k) devices, CDRH does not have accurate reporting mechanisms currently functioning to accurately reflect these numbers. The FDA is still years away from using unique device identifiers (UDIs) and device registries on enough devices to accurately measure adverse events.

Regarding the probability of a harmful event, the draft guidance states, “FDA would factor whether an event occurs once or repeatedly into the measurement of probability.” In the absence of long-term clinical trials, accurate measurement of repeated harmful events is not possible.  Even if it were possible, it would not weigh the seriousness of an event. For example, death happens only once.  The draft guidance also states that the FDA may be able to predict which patients “may experience a harmful event.” Again, this seems unlikely given that very few 510(k) devices have clinical trial data and those that do usually have relatively few patients, little diversity, and no subgroup analyses.

Duration of effects

The draft guidance states that some devices can cause temporary or minor harms, others can cause repeated but reversible harm, and others can cause permanent, debilitating injury.  The FDA plans to consider the severity and duration of the harm. Again, in the absence of clinical trials or more accurate adverse reporting systems, the FDA is not able to accurately evaluate the likelihood or severity of harms. Moreover, the FDA and patients may have different definitions for “reversible harm.” For example, when metal-on-metal hips were recalled, the FDA classified the recall as Class II, “moderate risk” recalls.  And yet, removal of those implants required multi-hour surgery that could cause permanent harm or death, and revision hip surgery almost always leaves patients with disabilities or limited abilities compared to the first hip surgery.  A failed revision surgery can result in patients losing mobility and thus having to move from independent living to a nursing home.

 

Patient tolerance for risk

The draft guidance states that the FDA may consider the patient’s perspective and notes that some patients are “willing to accept a higher level of risk to achieve a higher probable benefit.” There are two major fallacies with that statement:

  1. Patients may say they are willing to accept a higher risk, but when they have a negative outcome they inevitably wonder why the FDA allowed such an unsafe product on the market, and why this terrible harm happened to them.
  1. A 510(k) device is cleared for everyone, not just those willing to accept a higher risk. Also, the device can then be used as a predicate for a new device, which will also be used by patients who did not choose to accept the high level of risks.  By catering to those patients who say they are willing to accept higher risks, the FDA by default makes all patients who may use the device accept higher risks.

 

Risk mitigation

The draft guidance states that if a new device has an increased risk, the FDA may approve it, “if the risk is appropriately mitigated.” The draft guidance recommends “appropriate information within labeling (e.g., warnings, precautions, contraindications)” to mitigate risks. What evidence does the FDA have to conclude that health care professionals read the labels, are influenced by warnings on them, or share that information with their patients?  On the contrary, in our work with thousands of patients, most tell us that their physicians did not ask even simple questions about allergies or illnesses that were listed on the label as contraindications.  Our work with physicians has clearly shown that many do not read device labels and that surgeons often do not ever see the labels on the devices they use in the operating room.

 

Degree of uncertainty and innovative technology

We oppose the statement, “FDA may accept a greater degree of premarket uncertainty regarding a device’s benefit-risk profile through a greater reliance on postmarket controls…if FDA’s overall assessment is sufficiently balanced by other factors…”  This is too vague to provide meaningful guidance. Moreover, it is the FDA’s mission to provide reasonable assurance of safety and effectiveness before a device is put on the market, not to wait years after millions of patients may have used it.  A recent review of postapproval studies for medical devices found that “small sample sizes, delays in reaching protocol agreement, and lack of availability of findings may hinder their ability to be clinically useful.”7

Regarding innovative technology, the draft guidance states that the FDA “may accept greater uncertainty” in assessing benefits and risks compared to the predicate device when the technological improvements are “important for public health.”  We oppose this statement because the phrase “important for public health” is too vague and subjective, especially when combined with the other statement in this section that the FDA will evaluate innovative changes on a “case-by-case basis.”

 

Conclusions

We oppose the draft guidance as written and strongly urge the FDA to rewrite it.  The current draft guidance relies on vague wording and subjective judgments, not science or technological assessments.  When it is more specific, it promotes the use of surrogate endpoints and the risk tolerance of a small number of patients whose views come to the FDA’s attention.

American Medical Student Association
American Medical Women’s Association
Annie Appleseed Project
Breast Cancer Action
Center for Medical Consumers
Connecticut Center for Patient Safety
MISSD
National Center for Health Research
National Consumers League
The TMJ Association
WARS
WoodyMatters

The Patient, Consumer, and Public Health Coalition can be reached through Paul Brown at 202-223-4000 or pb@center4rersearch.org

By Matthew Perrone

AP article that appeared on ABC News and many other websites

October 8, 2014

Public safety advocates are asking the federal government to strengthen warnings on Pfizer’s anti-smoking drug Chantix, even as the drugmaker prepares to argue that a bold-letter warning about psychiatric problems should be removed from the medicine’s label.

Five advocacy groups petitioned the Food and Drug Administration on Wednesday to expand Chantix’s boxed warning, calling for more detailed language about potential side effects like suicidal behavior, hostility and depression. The groups also say that the prominent warnings should include information about blackouts, convulsions and other problems reported in some patients.

“It would be illogical to discount the reports of thousands of consumers who told of frightening or destructive experiences with Chantix,” states the petition, filed by Consumer Reports, Public Citizen, the National Center for Health Research, National Physicians Alliance and the Institute for Safe Medication Practices.

The groups urge the FDA to revisit the boxed warning, first added in 2009, arguing that it “substantially underestimated the psychiatric adverse effects and accident risks of Chantix.” They also argue that Chantix should be contraindicated for people working in critical or hazardous occupations, like pilots, air traffic controllers, police and military personnel. The petition notes that the Federal Aviation Administration and the Department of Defense already restrict the use of Chantix among certain employees.

A spokesman for Pfizer Inc. noted that the petition is based on patient reports of injury “which have several limitations, including missing data, reporting biases, and no ability to determine that the adverse event was caused by the drug.” The company reiterated that its own studies “do not show evidence of an increased risk of serious neuropsychiatric events” in patients taking Chantix, versus other smoking-cessation products.

The move by safety advocates comes just over a week before the FDA meets publicly to review Chantix’s risks. Pfizer has conducted several studies showing no link between its drug and suicidal behavior and the FDA added information from those studies to the drug’s label last month. Company executives say they plan to use next Thursday’s FDA advisory panel meeting to argue that the boxed warning is no longer warranted. The FDA will hear input from the company, a panel of outside experts and members of the public.

New York-based Pfizer has paid roughly $300 million to settle more than 2,500 lawsuits alleging that Chantix caused various psychiatric problems, injuries and suicides. Two experts who studied Chantix for the Institute for Safe Medication Practices — one of the petitioning groups — also served as paid expert in the litigation against Pfizer.

The FDA first began investigating potential side effects with Chantix in 2007, the year after it hit the market.

The drug’s labeling tells patients to stop taking Chantix immediately if they experience agitation, depressed mood, suicidal thinking and other behavioral changes. Doctors are advised to weigh the drug’s risks against its potential benefit of helping patients quit smoking.

Pfizer’s drug works by binding to the same spots in the brain that are activated by nicotine when people smoke. The drug, known chemically as varenicline, blocks nicotine from binding to those spots and prevents the release of “feel-good” brain chemicals that make smoking so addictive.

Chantix had global sales of $648 million last year. That was down about 26 percent from the drug’s peak sales of $883 million in 2007.

Pfizer shares rose 59 cents to $29.38. Its shares are down more than 4 percent in the year to date.

Read original article here.

Read our citizen’s petition here.

 

By Sabriya Rice, Modern Healthcare
October 8, 2014

 

“Prove it.” That was the resounding message to medical-device manufacturers during the annual Advanced Medical Technology Association conference in Chicago this week. Innovation is needed to advance medicine and better patients’ quality of life, but gone are the days of sticking higher price tags on products that only provide incremental improvements, the leaders of health insurance companies, health systems, quality improvement and consumer organizations told the industry.

“We don’t want to squelch innovation,” said Dr. Scott Josephs, national medical officer for the health insurance provider Cigna Corp. “But tell me what I’m getting for my healthcare costs. Show me that these new technologies are superior,” he told the audience during a session Wednesday morning.

 

Payment reform puts medical-device industry on the defensive

Josephs was joined on the panel by Susan DeVore, president and CEO of the health improvement organization and group purchasing organization Premier; and Mark Neaman, CEO of the Chicago area’s NorthShore University HealthSystem. An essential element in the aim for higher efficiency will be the need to more critically assess the value of new innovations, the panelists said.

“If it’s clinically appropriate but equally efficacious to existing technology, then frankly it’s just adding costs to the system,” Josephs said. “That’s not something we would prefer.”

Fee for service is dead and the current landscape “is a bit chaotic,” noted DeVore, who said health providers are in the process of integrating what has been a fragmented industry. In light of that, the old ways of doing things are not going to suffice, Neaman said. “The stakes are very high for us as providers,” he told the audience.

New payment models aimed at improving efficiency and getting a handle on costs have proliferated quickly in recent years, nurtured by provisions of the Patient Protection and Affordable Care Act. Many providers are joining accountable care organizations, which are risk-sharing mechanisms available through government payers like Medicare as well as private payers, in which members agree to strive for cost and quality targets and share savings or losses.

Monday, AdvaMed promoted an industry-funded white paper based on the responses of officials from nine unnamed health insurance companies who were interviewed about their movement toward pay-for-performance and risk-based contracts. Officials from five insurers said they had become more selective about approving coverage for new technologies in the past three years. Four said they plan to demand more evidence before covering products. All said costs were driving their organizations to explore new reimbursement models.

The trade group representing medical-device manufacturers worried these rapidly burgeoning pay-for-performance and risk-based reimbursement models will result in what AdvaMed CEO Stephen Ubl called “unintended consequences.”

Too many of the arrangements emphasize cost targets over quality benchmarks, said Joe Almeida, the trade group’s chairman as well as CEO of the medical-device manufacturer Covidien. “They run the risk of really tipping too far, so physicians have incentive not to adopt things that really benefit patients,” said David Nexon, an AdvaMed senior vice president.

Health economists countered that the white paper may have overstated those concerns and that it’s hard to make the extrapolation. Insurers agreed, saying truly superior innovations would not be overlooked, even if they come at higher costs. And most health officials interviewed by Modern Healthcare said the key factor is the proof.

“The thing that’s been missing from the model until now is the evidence,” said Diana Zuckerman, a researcher who has been critical of the Food and Drug Administration’s procedures for approving and monitoring medical devices.

The federal agency’s recent plans for an accelerated approval pathway for some medical devices has been met with criticism by consumer advocates who say such efforts put patients in danger.

During a conference session on Tuesday afternoon, FDA Commissioner Dr. Margaret Hamburg said that as science and technology advance at extraordinary rates, the agency wants to stay up to speed as a partner with the medical technology community. A more efficient system overall will allow for the delivery of new science and technology for patients in more reliable and cost-effective ways, but the emphasis on speed doesn’t mean a step away from scientific rigor, she said.

As new products make their way to the forefront, no matter how rapidly, the onus is increasing for manufacturers to ensure that providers are convinced the innovations are worth the financial investment.

It’s not about the lowest price point, that’s just one part of the overall value equation, Cigna’s Josephs said. It’s about having more data and conceiving of partnership arrangements to help get there, according to Premier’s DeVore. “Bring your evidence and data, and bring a willingness to collaborate and take risks,” she said.

Follow Sabriya Rice on Twitter: @MHsrice

Read original article here.

Oct. 9, 2014

Thank you for the opportunity to speak today. I am Dr. Christina Silcox, I have a PhD in Medical Engineering and Medical Physics from MIT and Harvard Medical School, 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. These are the perspectives I bring here today. We do not accept funding from pharmaceutical or device companies and so I have no conflicts of interest.

We support the FDA’s recommendation that More-than-Minimally Manipulated (MMM) Allograft Heart Valves be classified as Class 3 devices and therefore subject to the premarket approval process. All other types of heart valves under the oversight of the Center for Devices and Radiological Health at the FDA are classified as class 3. There is no reason that these heart valves should be an exception.

MMM allograft heart valves are indisputably used to support and sustain human life and are of substantial importance in preventing impairment of human health, which is the definition of a Class 3 device.

Only Class 3 devices are subject to pre-market manufacturing process review. Manufacturing processes are critical to the safety of this device. In addition, the effectiveness of MMM heart valves are also highly dependent on the manufacturing process, affecting the performance and longevity of the valve and the likelihood of immune rejection.

There is currently insufficient information to determine all the general and special controls that would be necessary to provide reasonable assurance of the safety and effectiveness of this device in order to classify the device as Class 2.

Certainly, clinical trials would be one type of control needed. Currently, most of the information about these devices consists of small studies (under 50 subjects per valve type), often funded by a single device company. None of the studies were randomized. Half did not include a control group.

Few studies looked at the immunologic responses of the MMM valves, and only two of those did a comparison of MMM valves vs standard allograft valves. Follow-up of all four immunological studies was 1 year or less – which is not enough to tell us how safe or effective these valves are.

Most studies of MMM heart valves have focused only on the resulting heart valve function. As a result, we have almost no information about other potential side effects.

Post-market study data from the single currently-approved MMM allograft heart valve is not currently available, and when completed it will focus on pulmonary valve replacement, which studies suggest is much less immunogenic than aortic valve replacement.

To summarize – heart valves are high risk devices and that’s why all other heart valves regulated by the Center for Devices are Class 3. Given these MMM allograft heart valves are relatively new, with limited information available about exactly how the processing changes the tissue, we do not know enough to control potential risks with special controls. For example, mechanical valves have been used in humans for over 50 years but are still Class 3 because a 510(k) with special controls is not sufficient to protect patients’ lives.

We recommend the Advisory Panel vote to classify these devices as Class 3, which will save lives by ensuring the safety and effectiveness of these devices be proven in well-designed clinical trials and pre-market inspections.