Tag Archives: FDA

More Than Half Of Surgical Stapler Malfunctions Went To Hidden FDA Database

Sydney Lupkin and Christina Jewett, KHN; May 30, 2019

UNITED STATES – NOVEMBER 9 – The outside of the Food and Drug Administration headquarters is seen in White Oak, Md., on Monday, November 9, 2015. The FDA is a federal agency of the United States Department of Health and Human Services and has been in commission since 1906. (Photo By Al Drago/CQ Roll Call)

The Food and Drug Administration has acknowledged that more than 56,000 never-before-disclosed surgical stapler malfunctions were quietly reported to the agency from 2011 through 2018.

The newly acknowledged reports were detailed in an executive summary for FDA advisers. The agency convened a meeting of experts this week to help it determine whether surgical staplers should be moved out of its lowest-risk category — reserved for simple devices like tongue depressors and bandages — to a higher grade that may require testing and additional oversight. Surgical staplers are used to cut and seal vessels and tissues inside the body.

When the FDA initially announced the meeting in March, it acknowledged in a letter to doctorsthat “many more device malfunction reports” were reported to the agency than it had publicly disclosed. The FDA executive summary published this week shows that the total reports more than doubled when the agency took nonpublic reports into account, totaling nearly 110,000 malfunctions or injuries from 2011 through 2018.

“It shocks the conscience,” said Chad Tuschman, a lawyer representing Mark Levering, 62, of Toledo, Ohio, who suffered a serious brain injury after a stapler malfunction caused massive bleeding in 2018. The surgeon, hospital and device maker Covidien, a division of Medtronic, have all denied allegations of wrongdoing in an ongoing legal case.

Surgical staplers have a unique ability to harm patients if they malfunction. Often used in minimally invasive surgeries, they are meant to both cut tissue and vessels and then quickly seal them. Patients have been gravely harmed when staplers have failed to fire or seal tissue, suffering from massive bleeding or infections if stomachs or intestines aren’t sealed properly.

The nonpublic reports were sent to the FDA as “alternative summary” reports, the topic of a recent Kaiser Health News investigation that focused on the agency accepting millions of hidden reports related to medical devices — including for surgical staplers.

The agency had previously acknowledged that in 2016, even as it posted fewer than 100 stapler-related injuries in a public database called MAUDE, it accepted nearly 10,000 reports into its little-known internal alternative summary reporting database. (The data in the FDA’s executive summary contains reports for staplers and staples, which experts have said were just different names for the same problem.)

Tuschman said he was stunned that there were more hidden reports than public ones in the executive summary. “The first question should be ‘Why?’ Why would they have the right to submit to a hidden database?”

Leading surgical stapler makers include divisions of Medtronic and Johnson & Johnson. Medtronic has said the FDA granted it exemptions for stapler-related malfunctions; Johnson & Johnson said it has not. (Ethicon is the name of its subsidiary medical devices company.)

On Thursday, the advisory panel recommended switching surgical staplers to a higher-risk classification with additional safety requirements, according to meeting attendee Jack Mitchell, director of health policy for the nonprofit National Center for Health Research. FDA spokeswoman Stephanie Caccomo declined to confirm this, citing a media office policy against telling reporters what happens at advisory committee meetings, which are open to the public.

“Every surgeon that I have ever worked with has had stapler failures,” said Dr. Doug Kwazneski, a Michigan surgeon who authored a survey in 2013 about “unacknowledged” stapler problems after searching the FDA’s public database of device incidents and coming up empty-handed.

“Going into something without data is dangerous,” Kwazneski said. “If the information exists, we should have access to it.”

More than 400 deaths have been reported since 2011 in the FDA’s public MAUDE database; fatalities can’t be reported to the alternative summary reporting database. Deaths were associated with Ethicon and Covidien products.

In recent communications about stapler safety to doctors, the FDA has advised against using the staplers on large blood vessels.

Kwazneski said surgical staplers are a time-saving tool, which lessens the risk of anesthesia complications during surgery, for example. But it’s important for physicians to remember they can fail.

Diana Zuckerman, president of the National Center for Health Research, said that alternative summary reports are “a well-kept secret” and that any reports related to their existence were “done in a way that was not understood as a repository for hundreds of thousands of serious adverse event reports.” […]

See the original story here.

Does the FDA Have a High Enough Standard for Drug Approvals?

Shayla Love, STAT News: September 28, 2015

Is the FDA ’s approval process broken? […] Here are some excerpts of the conversation, edited for clarity.

Let me start off by asking: What do you think needs to be improved in the FDA approval process?

Zuckerman: I am increasingly concerned when the standards and criteria for what’s safe and what’s effective is moving more from the pre-market stage, before approval decisions are made, to the post-market stage. More drugs and devices are being approved on a basis of preliminary data, smaller samples, shorter time frames, and sometimes lacking control groups, as what recently happened with Duchenne muscular dystrophy. When that happens, it has a chilling effect on those who are trying to develop treatments and cures. Why would a company spend all of its energy working to do the best possible research if they can get an approval based on a shorter-term study, less definitive data, as long as they encourage patient groups to advocate and lobby for them?

What about the notion that patients and parents living with the disease are really the only ones who can understand what that’s like, and they should be in a position to assess the benefit and risk?

Zuckerman: I think patient perspectives absolutely should be factored in. And they should be factored in at every level. It’s not just important for patients who are wanting a treatment, it’s also equally important for the patients who get harmed. There are some folks in this room who have been harmed by unsafe medical products. They feel like FDA doesn’t listen to them. It’s really important to listen to patients, both the patients who can talk about the benefits of the drugs, or devices, but also the patients who can talk about the risks and the complications.


Going forward, why wouldn’t we be concerned that other companies won’t be emboldened to try and put an application in, and then force the issue? What we saw with this Duchenne episode is that when you have an effective pressure campaign, that can have an effect. And I’m not saying that’s necessarily a bad thing, that introduces a very human element into the discussion, and it can provide additional information.


Zuckerman: I want to get into the specifics of why this particular decision concerned us so much. The scientists all said this drug isn’t proven to work, we don’t know if it works, and therefore it doesn’t meet the legal standards that FDA is supposed to use to make a drug approval decision.

The company said they didn’t have a control group because it would be unethical to have a control group. That is a very frightening statement. If you think that it is not ethical to have a control group to study a drug that you don’t know whether it works or not, then you will never be able to find out if the drug works. You have to have a control group, particularly if you have a small sample like that.

Another big issue is the company announced the same day of the approval that this drug is going to cost $300,000 a year. This is a drug that has to be taken every year for the rest of these boy’s lives. It’s not a cure, it’s management. Now, these patients who have been getting this drug, presumably, for free as part of a clinical trial will somehow have to come up with $300,000 a year to continue to get the drug. I don’t know if insurance companies are going to pay for it, considering that the data show there’s not evidence that it works.


To see the original article, click here

Obama Extends Controversial Program for Rare Pediatric Drugs

Ed Silverman, STAT: September 30, 2016

Despite objections from his own regulators, President Barack Obama Friday signed into law a bill that will briefly extend a voucher program that rewards drug makers for rare pediatric medicines.

As a result, the program will run through Dec. 31 while Congress attempts to further extend the effort for another few years. […]

“This is important because if he hadn’t signed this extension, there would have been a gap in the program,” said Nancy Goodman, who is executive director of Kids v Cancer, a patient advocacy group. “And we need to maintain incentives for companies to develop these types of drugs.”

At issue is the pediatric review program, which was created in 2012 and awards a voucher to a drug maker that wins approval of a treatment for a rare pediatric disease, an area of drug development that was seen as neglected at the time.

The vouchers have gained notice in the pharmaceutical industry because they are valuable – companies can later redeem them when seeking approval from the US Food and Drug Administration for another medicine to treat any illness. […]

Moreover, the newly signed law appears to expand the potential for awarding vouchers. How so? The language may widen the patient population for which a drug may be used by broadening the definition of a rare pediatric disease to include symptoms that emerge any time before 18 years of age.

The language reflected an effort to modify the approach taken by the FDA for viewing certain diseases, according to Paul Melmeyer, associate director of public policy with the National Organization for Rare Disorders. This could also become a boon to drug makers. As the FDA Law Blog noted, “diseases that are extremely severe in childhood but tend to be less severe in adulthood may qualify” for vouchers.

Nonetheless, the voucher program is not universally embraced.

[…] the FDA strongly objects to the program.

FDA officials told the GAO they have not seen any evidence the program has encouraged increased development of drugs for rare pediatric diseases. They also maintained the program hinders their ability to set priorities because agency staff must provide priority reviews of new drugs that would not otherwise qualify.

Nonetheless, the push for an extension is also a timing issue. “It’s just before the election, so it’s not surprising for Congress or the White House” to support the extension, said Diana Zuckerman, who heads the National Center for Health Research, a nonprofit think tank.

Read the original article here.

Senate Approves FDA’s ‘Breakthrough Pathway’ for Medical Devices

Gail Kalinoski , Contributing Reporter, Health Care Business:  March 23, 2016

A bipartisan Senate committee has approved three bills that could help get medical devices to patients sooner by creating a “breakthrough pathway” through the U.S. Food and Drug Administration, but not everyone is happy about the actions.


Diana Zuckerman, president of the National Center for Health Research, wrote on behalf of the watchdog group that it was “concerned that the focus of these bills is on getting medical products to market more quickly, instead of making sure they are safe and effective.” The group’s letter added: “Whether creating a new breakthrough pathway for devices (which already are approved based on much lower standards than drugs) or deregulating health IT software, for example, patients will be at risk.”

The group said it strongly opposed one of the bills passed, the Medical Electronic Data Technology Enhancement for Consumers’ Health Act, (S. 1101) known as MEDTECH, stating it would remove “potentially lifesaving and life-threatening health IT software entirely from the FDA’s regulatory oversight, and could possibly eliminate recalls for IT devices with life-threatening flaws.”

But the Advanced Medical Technology Association (AdvaMed) applauded the bills approved earlier this month by the Senate’s Health, Education, Labor & Pensions (HELP) Committee.


AdvaMed also supported the HELP committee’s work on the Advancing Breakthrough Devices for Patients Act (S. 1077) and the Combination Product Regulatory Fairness Act (S. 1767).

“Taken together, these three bills will help improve patient access to some of the latest medical advancements and foster a more efficient, predictable and transparent review process within the FDA, all the while maintaining the agency’s strong standards for safety and effectiveness,” Scott stated.

Zuckerman’s group disagreed, once again opposing the bills for lowering standards and undermining or micromanaging the FDA. Her letter stated that the vague language on what classified a device as “breakthrough” may “encourage many device companies to apply for ‘breakthrough’ status, overwhelming the resources of the FDA.”

The National Center for Health Research also claimed that smaller clinical trials could compromise the majority of patients because they may have “fewer women, people of color and patients over 65 – often too few to ensure that the device is safe and effective for those groups.”


Read full article here.

F.D.A. faulted for problems with drug tracking

By Sabrina Tavernise, New York Times
January 14, 2016

WASHINGTON — Federal investigators said Thursday that there were flaws in the way the Food and Drug Administration tracked drugs after they came to market, raising questions about the agency’s effectiveness as the country’s main drug overseer.

Once the agency approves a drug, it is required to monitor the drug’s safety as well as efforts by the company that makes it to study how the drug is doing in the marketplace, for example whether many patients are reporting problems while taking it. The investigators, from the Government Accountability Office, a nonpartisan investigative arm of Congress, looked at how the F.D.A. was doing with those tasks.

The answer was not very well.

F.D.A.’s data on post-market safety issues and studies were found to be incomplete, outdated, to contain inaccuracies, and to be stored in a manner that made routine, systematic analysis difficult,” the accountability office concluded in its report.


“We are shortcutting an important part of the approval process in the hope that we get the information later, but now we’re finding out that’s not happening,” said Diana Zuckerman, president of the National Center for Health Research, a nonprofit consumer research group.


To read the full article, click here.

No more Pap smears?

By Diana Zuckerman, PhD

If you’re a woman over 21, that headline probably got your attention. After all, who likes Pap smears? Wouldn’t it be great to never need one again?

Well, don’t get too excited because the alternative could be worse, if a Food and Drug Administration (FDA) advisory committee gets its way. The committee proposes replacing Pap smears with an equally invasive but less conclusive test, the HPV test, when women reach the age of 25. And then, if the HPV test indicates the presence of HPV (or human papillomavirus, which is very common in sexually active young women and usually goes away by itself), the committee proposes following up the test with an even more invasive procedure called a colposcopy. Patients describe a colposcopy as being like a Pap smear that takes 20 minutes instead of a few seconds.

The purpose of a Pap smear is to test for abnormal cells in your cervix that could eventually turn into cervical cancer. Two strains of HPV virus are responsible for 70 percent of cervical cancers. It’s very common for sexually active women to be infected with HPV, but usually the body gets rid of the virus within a year or two all on its own. HPV can only cause cancer when it lingers in the body for several years and starts to damage the cervix.

Even if a woman has had an HPV vaccine, she could still potentially develop cervical cancer, so experts advise women to get a Pap smear every three years, starting at age 21 and ending at age 65.  Starting at age 30, women are given the option of asking their doctor to use the same sample for a Pap smear and the test for HPV. If nothing suspicious is found, they can get screened using both tests every five years instead of every three for the Pap smear alone.

Current guidelines recommend that if a woman has an abnormal Pap smear and an HPV test indicating that she has the types of HPV that can cause cervical cancer, she should undergo a colposcopy to see if she needs surgery. Most women get Pap smears to screen for problems, and typically only get an HPV test if their Pap results indicate abnormal cells.

That’s why not many women currently get the HPV test. The company that makes HPV tests would like to sell more of them. So it’s asked the FDA to change the agency’s instructions for using the HPV test to screen healthy women. Instead of an optional use with Pap smears, it wants FDA approval to use the HPV test on its own to screen all healthy women starting at age 25.

Unfortunately, the HPV test by itself isn’t very useful because so many young women have HPV that will disappear without any treatment. 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.  Instead of waiting a few months to see if the HPV goes away by itself (which it typically does), the company wants those women to get a colposcopy, which is as painful as a Pap smear but the pain lasts longer and the procedure costs more. And like a Pap smear, the test isn’t always accurate.

Otherwise, it’s a great idea.

We’re not the only ones who believe that the current guidelines should not be changed. The unbiased experts at the U.S. Preventive Services Task Force recommend that the HPV test only be used on women 30 and over, and only in combination with a Pap smear. They point out that if the HPV test is used on younger women, the results can’t distinguish between HPV that would go away on its own and HPV that could cause cancer. This would lead to unnecessary worry for young women and many unnecessary colposcopies.

At an FDA Advisory Committee meeting this month, Anna Mazzucco, PhD, from our staff expressed her concerns about replacing Pap smears with HPV tests. She pointed out that Pap smears provide inexpensive and and effective screening. In fact, the women who get cervical cancer are usually women who did not regularly get Pap smears or follow-up.

Research indicates that the way to save lives is to help women get screened with Pap smears, not to put them through unnecessary follow-up procedures. The American College of Gynecologists—the doctors who do Pap smears, HPV tests, and colposcopies—also expressed concerns about changing current policies, since there is no evidence that the proposed changes would save as many lives.

In addition, we believe that the more expensive and painful procedures would discourage women from getting screened or following up after receiving suspicious results.

What is going on at the FDA? Why are they choosing advisors who ignore the research evidence in favor of a new, unproven screening strategy? The FDA needs advisors who focus on scientific evidence and who make recommendations based on facts, rather than embracing every new “innovation” in health care, regardless of whether it will work.

When the “old ways” are effective, let’s not throw them out unless there is proof that the new, more expensive way is better.


A version of this post appeared in Huffington Post and Maria’s Country Kitchen.

Statement of Laurén Doamekpor on the importance of including women, minorities, and the elderly in studies of the safety and effectiveness of new drugs and devices (FDASIA section 907 hearing)

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.


The worst new drug of 2014

DIANA ZUCKERMAN, PHD, PRESIDENT OF The Cancer Prevention & Treatment Fund 

It’s only February, so it may seem early to be talking about one of the Food and Drug Administration’s (FDA’s) worst decisions of 2014. Yes, the year just started, but the FDA has already made a decision that could potentially harm thousands of patients.

The agency just approved a new diabetes medication that doesn’t noticeably improve health but may in fact cause cancer.

It’s called Farxiga (Dapagliflozin) and it will be available—and probably widely advertised—very soon. The good news is that the drug lowers blood sugar, which is a major symptom of type 2 diabetes. However, lowering blood sugar is not necessarily a way to improve health. The new drug is meant to reduce medical problems such as heart disease or kidney damage. Unfortunately, there is no evidence that it actually improves health—in fact, quite the opposite.

The FDA reports that the most common side effects of Farxiga are genital fungal infections and urinary tract infections. Not fun, but those aren’t its most serious side effects. If a patient has moderate or severe kidney damage (as many diabetics do), the drug is not beneficial and could cause further damage, possibly even renal failure.

But the more frightening news is that patients taking Farxiga in studies done for the FDA were more than five times more likely to contract bladder cancer than the patients who took an older diabetes drug. Based on the findings of the companies making and selling Farxiga, FDA scientists concluded that the drug might stimulate bladder cancer in patients already at risk. The fear is that patients take diabetes drugs for years, and the longer someone takes this drug, the greater their risk of cancer.

Bladder cancer can be fatal, and is especially dangerous in people who have diabetes.

The companies’ studies also found that patients taking the drug were more than twice as likely to get breast cancer as diabetics not taking the drug, but they say this could have happened by chance.

It’s important to mention that only a small number of African Americans were studied. Because African Americans are more likely to have diabetes than Caucasians, these studies should have included greater numbers of them to find out if the drug is safe or effective for them.

With so many other diabetes drugs already on the market, why would anyone want to take this drug, and why would FDA approve it?  Here’s the scorecard, based on information provided by FDA scientists and available on the FDA website:

  1. Is the drug new? Yes.
  2. Does it reduce the medical problems caused by type 2 diabetes, such as blindness, heart disease, kidney damage, or amputations? No.
  3. Can it cause kidney damage or make it worse? Yes.
  4. Does research show that patients taking it are more likely to get bladder cancer. Probably.
  5. Does research show that patients taking it are more likely to develop breast cancer? Maybe.
  6. Does research show it is more effective than most diabetes drugs on the market? No.
  7. Will it cost more than most other diabetes drugs on the market? No information on cost yet, but new drugs usually do cost more.

The FDA is requiring that the label for the drug warn patients with bladder cancer that they shouldn’t take Farxiga because it might make their cancer worse. Ya think? And, the agency is requiring the companies to study 17,000 diabetes patients for at least four years to determine whether and how often patients taking Farxiga are diagnosed with cancer, liver problems, or heart disease when the drug is taken for a longer period of time.

The FDA rejected this drug two years ago because of these cancer concerns and questions about how well the drug prevents the major risks of diabetes. But the FDA has been beaten up by many complaining congressmen since then, and by some patient groups, pushing it to approve more new drugs quickly rather than waiting for safety studies to be completed. Also, the pharmaceutical companies don’t like to take no for an answer, they spend lots of money on lobbying, and they are very effective at pushing FDA to reconsider rejections. Because of that, the FDA selected an advisory committee to review the data in December, and those doctors and scientists also expressed concerns about risks and benefits. I was at the meeting and pointed out that there were too many serious unanswered questions.

Despite my concerns, the concerns of FDA scientists and other experts, and the concerns of the advisory committee members themselves, the committee recommended that if the companies continued to study the drug after it was approved, in order to figure out what the actual risks are, the company could sell it now.

It’s too early to say whether this will be the worst decision the FDA makes in 2014. Maybe the diabetes patients who take it will be lucky and not be harmed by the drug. Or maybe only a few patients will develop cancer or kidney failure as a result of taking it. Or the FDA scientists who expressed their concerns could be wrong, and I could have made a mistake when I agreed with them. But regardless of what happens with this drug, it still would be a bad decision to allow the sale of a drug with such serious (potentially fatal) unanswered questions.

Given the epidemic of diabetes in this country, the risks are huge. For that reason, this drug worries me even more than some of FDA’s similarly mind-boggling decisions of 2013, such as:

  • drug for hot flashes that has no meaningful benefits but can increase the risk of suicide among women who weren’t depressed
  • An antibiotic for pneumonia that seems to kill more patients than other antibiotics

I’ve always respected the scientists at the FDA for working so hard to try to keep all of us safe. I still do. But decisions are being made at the agency that seem to ignore scientists and science, and that is dangerous for all of us. Whether we have diabetes, hot flashes, pneumonia, cancer, or any other disease, we deserve better.


A version of this post appeared in The Huffington Post, Maria’s Farm Country Kitchen

 In 2018, the U.S. Food and Drug Administration (FDA) announced a new warning on Farxiga and other SGLT2 inhibitors because they can cause a rare but life-threatening infection of the genitals and area around the genitals. The infection is called necrotizing fasciitis of the perineum or Fournier’s gangrene.  

Clinical evidence in FDA drug approvals varies widely, study finds

by Sabriya Rice, Modern Healthcare
January 21, 2014

Not every new drug approved by the U.S. Food and Drug Administration has undergone the rigorous clinical testing that physicians and their patients might expect, according to new research.

A study published Tuesday in the Journal of the American Medical Association finds that the FDA has “flexible standards” for approving of new therapies. Using publicly available information from the FDA drug database, investigators identified 188 novel therapies for treating 206 conditions approved between 2005 and 2012. Of these, 37% were approved on the basis of a single clinical trial, 38% on the basis of two trials and 25% had been tested in three or more trials.

Although most therapies were supported by at least one randomized, double-blind trial—the gold standard for clinical research—there was wide variation in the duration, size and completion rates. Comparative-effectiveness data was available for less than half of the indications.The purpose of the study, according to its authors, was not to suggest that the FDA is not rigorous in its approach to drug reviews. The regulatory flexibility allows for a customized approach, and the agency can rapidly approve potentially effective therapies for life-threatening diseases and those for which there is no existing, effective treatment, such as orphan diseases, said Dr. Joseph Ross, assistant professor of general internal medicine at Yale University School of Medicine and one of the study authors.

According to Ross, the drug approval variability is problematic in the sense that both patients and physicians feel the research is the same across all drugs approved.

The FDA, in a statement responding to the findings, explained that drugs may be tested in clinical trials that enroll hundreds of participants, while others, particularly those seeking to treat rare diseases, may be tested in trials that enroll only a handful of participants. “In all cases, however, the statutory standards of safety and efficacy must be met in order for the drugs to be marketed in the United States,” the agency said.

Whether or not the process has become too lenient has become a topic of debate among advocates.

The Progressive Policy Institute, a center-left think tank, acknowledged in a policy brief (PDF) that the FDA must strike a difficult balance. “If it is too lenient, (the FDA) will allow the sale of drugs and medical technology that could harm vulnerable Americans. Too tight, and the U.S. is being deprived of key innovations that could cut costs, increase health, and create jobs.”

Some argue, however, that physicians don’t have time to sift through statistical data on every new drug approved, and when they do, there is little information to choose from as they make decisions about the safety of new therapies.

“With new drugs, there is often an exaggeration of the benefits and underreporting of the risks,” said Diana Zuckerman, president of the National Research Center for Women & Families, who has testified at several hearings on drug safety. “There’s so much emphasis on drugs being the latest, the most innovative and novel—but unfortunately this usually means it’s just new, not necessarily better,” she said.

Zuckerman conceded that it’s a given that the FDA should have the flexibility to provide access to new treatments when there are no available options. “But the FDA shouldn’t be rushing studies for diseases that have good alternatives. It’s better to have an old treatment that is proven to be safe and effective than a new treatment that we don’t know is safe and may not improve health.”

“I think we can all agree that if you have a disease for which there are no available treatment options, that is the time to be flexible, although you’d still want the best possible research,” she said.

Ross, the Yale researcher who worked on the study, encourages physicians to be more nuanced with how new treatments are presented to patients. When prescribing newly approved drugs that have limited trial data, he said physicians should be clearer with patients about what the research shows. The physician should say, “There are not a lot of options, this drug was just approved, but we don’t know if it extends your life,” rather than giving the patient the impression the drug does things for which it has not been tested.

To view the original article in Modern Healthcare, click here.

Comments of the Cancer Prevention and Treatment Fund on FDA draft guidance to industry on Acrylamide in foods

January 14, 2014

The Cancer Prevention and Treatment Fund strongly supports the Food and Drug Administration in its efforts to advise industry on reduction of acrylamide in food products.  The Grocery Manufacturers Association estimates that acrylamide is present in approximately 40% of the total caloric intake in a typical American diet.1 Given this near-ubiquity, and the fact that the chemical reaction which produces acrylamide also produces commercially desirable color, taste and texture characteristics, reduction of acrylamide represents a challenge.  However, the evidence of possible human harm necessitates its treatment as a significant public health issue. While this report represents an important step in FDA regulation of acrylamide and suggests many possible acrylamide reduction methods, we are concerned that this guidance is not specific enough in providing clear and concrete recommendations that can be implemented.  Although FDA guidance does not have the force of law or regulation, the addition of terms such as “when feasible” implies that the FDA is not serious in its efforts to persuade companies to substantially reduce acrylamide.  FDA monitoring of acrylamide in 2002 indicated wide variation even among products from the same food category –as much as 5 or 10 fold differences in several categories.  This is clear evidence that significant acrylamide reduction can be accomplished without losing desirable product qualities. Thus, although there is clearly much room for improvement, this report contains few immediately implementable guidelines for industry. Since 2002, it has been known that acrylamide is created in food products as the result of a reaction between carbohydrates and the amino acid asparagine at high temperatures during browning (i.e., the Maillard reaction).2  In addition to its known neurotoxic properties, both animal toxicology and human epidemiological studies suggest that acrylamide may be cancer-promoting, which has led to its carcinogen classifications by EPA, NTP and IARC.3,4,5,6 Higher dietary acrylamide consumption has been associated with increased risk of endometrial, ovarian, pancreatic, renal and possibly breast cancer.7,8,9,10.  Acrylamide is already regulated in drinking water and was classified by EPA as “likely to be a carcinogen to humans” and was classified by the National Toxicology Program as “reasonably anticipated to be a human carcinogen,” both more than a decade ago.  The European Food Safety Authority has been overseeing acrylamide monitoring within the European Union since 2007, and the European Commission has set recommended indicative values for acrylamide in food products, providing a quantitative framework for both assessment of reduction efforts and investigative action.  This is a very important health issue and we strongly urge the FDA to intensify its efforts and assert leadership of both the national and international efforts to regulate acrylamide and ensure public safety. Our areas of specific concern are the following:

  • While encouraging manufacturers to conduct their own testing, FDA should update and expand its own monitoring efforts.  Monitoring of acrylamide in food products over time is needed for any reduction efforts to be assessed and successfully implemented.  The current FDA monitoring strategy tested only several hundred foods in four geographic regions annually between 2002 and 2006, and the last publicly available information is from 2006.11  Given the wide range of acrylamide levels even within a single food category, more extensive and up-to-date monitoring is needed to adequately evaluate acrylamide levels and the success of reduction methods.
  • While this report encourages manufacturers to monitor acrylamide levels, it does not give any specific values which should prompt corrective efforts.  Without such guideposts, monitoring alone is unlikely to result in significant reductions.  Recommended target values or action levels, together with active monitoring, will allow FDA and manufacturers to directly access efficacy of reduction efforts and trigger investigation when needed.  The European Commission has set indicative values for acrylamide in food products, including separate values for products intended for infants and young children, and these values are intended to be gradually reduced.12  Indeed, these indicative values have been broadened to include more specific categories and some have already been lowered since their release in 2011, and the European Food Safety Authority is currently conducting a risk assessment at the request of the European Commission to determine if current recommendations are sufficiently protective.  Such a system provides a quantitative framework for reduction efforts and allows increased surveillance of items of special health importance.  Values at least as low as the 2013 European Commission indicative values should be adopted, with the shared intent of gradual lowering of these values as reduction efforts improve.
  • Without accurate and affordable detection techniques, manufacturers are unlikely to measure acrylamide in their products, especially when participation is voluntary.  This guidance encourages manufacturers to be aware of acrylamide levels in their food products.  This is a crucial step towards evaluating reduction efforts.  However, this vital imperative is followed by a discussion of both the technical limitations and expense associated with current methods of acrylamide detection.  While FDA has committed to improving these techniques, they remain costly and fraught with technical limitations, making widespread voluntary use, especially by small manufacturers, unlikely.  FDA should continue to investigate means to improve acrylamide detection and make specific recommendations to industry regarding best possible techniques in order to facilitate participation in monitoring.  As an example, the European Commission has recently set measurement uncertainty (MU) values and tasked the European Committee for Standardisation (CEN) with analytical standardization of LC-MS and GC-MS for acrylamide detection.  Such efforts, in addition to adoption of standard references, will increase consistency and improve confidence in acrylamide detection efforts.
  • In this guidance, the FDA specifically states that it does not intend to recommend one method over another.  This is unfortunate because it leaves both guesswork and legwork to industry.  FDA states that “this guidance is intended to suggest a range of possible approaches to acrylamide reduction and not to identify specific recommended approaches.”  The role of federal agencies should include evaluating reduction approaches to determine which are more efficacious and feasible than others, and providing that potentially useful information to industry, even if only to help identify and encourage prioritization of those approaches first, in addition to continuing research in this area.  Clear communication of superior and cost-effective approaches to acrylamide reduction may result in higher industry participation and more successful reduction efforts.
  • FDA monitoring since 2002 has shown that many foods contain higher levels of acrylamide than the level considered safe by the EPA for drinking water.  Some of the highest acrylamide levels are found in potato and cereal products which are common in the American diet.  These surveys also show that a healthy diet which includes whole grains can have significant acrylamide levels, potentially even higher than a diet which includes less healthful choices such as potato chips and French fries.  The FDA has maintained its message to consumers that a balanced, healthy diet is a way to manage concern over acrylamide consumption, when the evidence shows that this advice is not accurate. 
  • The effects of acrylamide reduction on overall product nutrition should be considered in the context of all health risks and benefits.  For example, lower temperature frying reduces acrylamide, but also requires longer cooking time, resulting in higher fat content in fried foods.  While we commend thorough consideration of all possible health implications of acrylamide reduction methods, FDA should also consider which outcomes can be more easily mitigated by other dietary or lifestyle interventions in order to fully assess risks and benefits.

Lastly, as acrylamide accumulates in food as a result of the handling and cooking process, rather than in the raw food itself, and is a serious human health concern, it could be viewed as source of food adulteration and regulated as such under Section 402(a) of the Federal Food, Drug and Cosmetic Act with action levels.  We ask that FDA consider these improvements to this draft guidance, and use its full authority to ensure that the public is sufficiently protected.

The Cancer Prevention and Treatment Fund

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