Tag Archives: FDA

MedPage Today: FDA Panels Like Long-Acting Buprenorphine

A joint FDA advisory committee has voted in favor of approval of two long-acting buprenorphine formulations, though they expressed concerns about higher doses of both products. Suzanne Robotti, founder of the MedShadow Foundation and a consumer representative who voted against approving the drug at any dosage, said many questions remained unanswered. Read Su Robotti’s comments and the article in its entirety here.

FDA Wants Doctors to Rethink Opioid Cough Suppressants for Children

Concern expressed by the American Academy of Pediatrics and the American Academy of Family Physicians about the use of cough suppressants, and in particular opioid cough suppressants, in children has lead FDA chief Scott Gottlieb to make that the subject of an upcoming meeting of the Pediatric Advisory Committee.

Gottlieb announced today that the panel will focus on creating processes for determining risk-benefit judgments in the use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients.

The AAP and AAFP participated in a roundtable in the spring with other interested groups. Some of the key points focused on determining the right treatment based on the length and severity of the symptoms, as well as treating what’s causing the symptoms, rather than just quieting the cough. And depending on the situation, representatives suggested that other medications or non-drug therapies may be more appropriate.

In a statement, Gottlieb said, “It is vital we understand the potential complications that can occur when using opioid-containing medications in children, even according to labeled instructions. This is an area that the agency is continuing to evaluate.“

Why an FDA Drug Safety Monitoring System Is Failing

The late 1990s and early 2000s saw a number of prescription drugs come to market that ended up causing grave harm. Most famous among these was the arthritis and pain drug Vioxx (rofecoxib).

Approved by the FDA in May 1999, Vioxx soon became a multibillion-dollar drug, with peak sales of $2.5 billion a year, and was prescribed to millions of people. By 2001, initial studies indicated that the drug might be putting people at higher risk for heart attacks and strokes.

Alarm bells went off and a high-profile, wide-scale probe followed. The problem was confirmed and in September 2004, Merck pulled the drug from the market. But not before it resulted in an estimated 88,000 to 140,000 people having heart attacks or strokes, and as many as 56,000 deaths, according to a 2005 report conducted by the FDA.

How could that have happened? The short answer is that the way drugs get approved — often based on just a handful of studies in a few thousand people — can’t pick up every possible adverse effect or safety problem of a new drug. Only wide use, in tens of thousands or even millions of people, over many years will reveal some problems.

the pharmaceutical industry, researchers and the FDA have long known this. But it’s cost prohibitive to test drugs on tens of thousands of people. So “the system” relies on monitoring drugs after they’re approved to see if problems crop up with “real world” use.

In the wake of Vioxx and several other high-profile cases of post-approval harm — sometimes years after approval — lawmakers in Congress asked a simple question: If we have to live with imperfect pre-approval detection of possible problems, why can’t we radically improve the way we monitor drugs after they enter the market?

Birth of the Sentinel System

Very good question. In 2007, Congress mandated that the FDA develop a computer-based system to track and analyze the safety of drugs after they hit the market — and do it pronto.

Following a year of debate and discussion, in May 2008, HHS (Department of Health and Human Services) and FDA launched something called the Sentinel Initiative. It was the brainchild of then-HHS secretary Mike Leavitt and Mark McClellan, then the FDA commissioner.

Leavitt, somewhat of a hi-tech geek, pledged “a national, integrated, electronic system for monitoring medical product safety.” Ultimately, he said, Sentinel would “help monitor medical products throughout their entire life cycle and thus better ensure the protection and promotion of public health.”

Leavitt also linked Sentinel to another George W. Bush administration initiative, the Nationwide Health Information Network (NHIN), built in part on electronic health records. The NIHN was going to “connect clinicians across the healthcare system and enable the sharing of data as necessary with public health agencies,” Leavitt said.

You have probably guessed where this is going. The NHIN never materialized — at all. It was thwarted by what became a chaotic, controversial and expensive ($20 billion) program to push doctors and hospitals to adopt electronic health records.

Little Impact from Sentinel?

As for Sentinel, it still exists. But it, too, has dashed hopes and suffered from a combination of bureaucratic inertia, technical obstacles and a lack of urgency.

I took part in launching Sentinel from 2007 to 2010 as a consumer representative to the project. At the time, I worked at Consumers Union/Consumer Reports and co-directed a project — which also still exists — called Consumer Reports Best Buy Drugs.

We continue to lack a robust, comprehensive and modernized computer-based system in the US to detect problems with drugs once they come on the market.

To make a long story short, initial enthusiasm for Sentinel waned over time. The history and a probing critique of Sentinel are well told in a recent piece from the health and medical site STAT.

The article alleges that Sentinel has had “little measurable impact” after 10 years and a cost of $207 million. The current budget is $20 million per year. Most experts STAT spoke to questioned “whether Sentinel can adequately identify risks involving drugs.”

To date, the article says, Sentinel has led to changes in the labels of only 2 medications out of several hundred that have been assessed. None were removed from the market. Drug labels guide doctors in prescribing drugs, warn of potential serious problems to watch for, and help both doctors and consumers discern possible side effects.

In a written response to my email query about the STAT article and their perspective on Sentinel, the FDA emphasized that looking at just label changes or drugs pulled from the market was not an accurate or comprehensive way to assess Sentinel.

They said Sentinel had “informed the issuance of 5 safety communications, including 2 safety label changes” but also provided “reassuring” evidence for dozens of other drugs.

In their words: “This leads FDA to not take any visible action because FDA has concluded that the prescribing information adequately describes the risks and benefits.”

Most notably, the agency said, a full-scale FDA analysis that included a Sentinel analysis assessed whether long-term use of stimulant drugs to treat ADHD (attention deficit/hyperactivity disorder) was associated with cardiomyopathy and heart failure. The analysis “provided important new safety information and a deeper understanding of these medical products” the agency stated in its response, but led to no regulatory action. In other words, the drugs were cleared.

Fair enough. It is important to be reassured that medicines taken by millions, and especially children, are safe.

Is Drug Safety Monitoring System Underutilized?

But then FDA’s response turned somewhat more disingenuous. For example, FDA claims that Sentinel has been “fully operational” for only 18 months. That’s technically true because the agency called the program a “pilot” and “mini-Sentinel” for 8 years.

FDA basically claims Sentinel was not ready for prime time, and that during those 8 years it was “developing infrastructure and methods.”

Since I was involved and followed the program I know that by year 5 or 6, FDA had significant capabilities under Sentinel and did not use the tools and network at their disposal to fully test things out.

The network is, in fact, impressive, and another reason to wonder why the yield of meaningful information is not yet more useful. Sentinel is one of the largest “distributed data” networks in the US today and possibly the world. According to Harvard Pilgrim Health Care, the nonprofit health insurer based in Wellesley, MA, that now manages the program under contract to FDA, Sentinel now encompasses:

  • 18 organizations, including many of the nation’s largest health insurers (Aetna, Anthem, Humana, Kaiser Permanente) and various disease registries
  • 88 hospitals and other inpatient facilities
  • Prescription drug data on some 200 million people, with the routine accrual of data on 48 million
  • 4 billion prescriptions
  • 4 billion doctor or lab visits and hospital stays
  • 42 million acute inpatient stays
  • 7.2 billion unique medical encounters

The thing is, it’s well known that several of the insurers in this network already had their own drug and medical product safety monitoring systems in the early to mid 2000s. Indeed, Kaiser Permanente’s system picked up a signal on Vioxx in 2001-2002 that helped trigger the wider probes.

Why has it taken so long then to get things together and generate information about hundreds of drugs — safety, side effects, effects on different populations, special considerations — for both doctors and consumers? That was the promise, and it was a worthy one.

FDA’s explanation to me: Capturing the right and accurate data — for example, on both inpatient hospitalizations and outpatient clinic visits, and on deaths inside and outside the healthcare system — is just plain hard.

Yes, it is. I concur. That was the challenge — to overcome the obstacles and make it happen in the interests of public health.

FDA Slow to Develop Sentinel and Get It Rolling

The FDA officials who corresponded with me wrote: “FDA is [now] exploring novel linkages to vital records data systems to inform these outcomes, which could improve Sentinel’s ability to connect the dots between monitored products and fatalities occurring outside of the healthcare system.”

That should have happened years ago.

The problems and slow development of Sentinel would perhaps create less rancor if it were not the second time the agency had failed to build an adequate drug safety alert system.

Sentinel was designed to complement and supplement a legacy drug safety monitoring system called FAERS (FDA Adverse Event Reporting System), a database that contains information on adverse event and medication error reports submitted to the FDA by doctors, nurses, pharmacists, hospitals, lawyers, manufacturers and consumers.

Reporting into the system is voluntary except for drug manufacturers; they must report problems. FAERS has some big weaknesses, which the agency acknowledges. For one, because reporting is voluntary, only an estimated 10% of adverse events are reported. Reports are also not validated and many don’t contain enough data to permit a full evaluation of a potential safety problem, such as whether there is a causal relationship between a drug and an event.

And while FAERS data is available to doctors and the public, it’s not easy to use and so is rarely consulted by either. But in fairness, FAERS has resulted in some important drug label changes over the years, and helped push a few bad drugs off the market.

The upshot of all this is that we continue to lack a robust, comprehensive and modernized computer-based system in the US to detect problems with drugs once they come on the market. That is a big gap. Arguably, it’s a gap that is more important than ever to fill as the new administration in Washington and new FDA chief, Scott Gottlieb, intend to accelerate the approval of drugs.

Sentinel is at the cutting edge of the big-data revolution, and, as a concept, still has tremendous value and promise. The initial vision was a good one. But the FDA now needs to move much faster to deploy Sentinel to quickly identify unsafe drugs and adverse effects that consumers must be informed about.

Recent Drug Approval Highlights Less Stringent FDA Criteria

The FDA’s March approval of Noctiva (desmopressin) is an example of the agency approving a drug where the risks outweigh the benefits, two physicians argue.

Noctiva was approved to treat nocturia, a condition characterized by frequently waking up in the middle of the night to urinate. Michael Fralick, MD, and Aaron S. Kesselheim, MD, say that nocturia is a symptom rather than a disease, and nocturia itself can be a side effect of a medication or an indication of a more significant health problem.

Writing in a JAMA op-ed piece, Fralick and Kesselheim, who are both affiliated with Brigham and Women’s Hospital and Harvard Medical School in Boston, note that the benefit of desmopressin was moderate. Yet, the drug was approved with a “black box” warning — the most severe the FDA can require — on potentially life-threatening hyponatremia, a condition where the sodium level in the blood is too low, leading to swelling in cells.

Incidentally, desmopressin is not a new drug at all. It was approved back in the 1970s to treat bedwetting in children.

Desmopressin was tested in several clinical trials. In 2 of them, Fralick and Kesselheim say that the drug failed to work in terms of reducing the number of trips to the bathroom. In 2 other trials, they noted that researchers excluded many patients the drug would likely be used on, including those with diabetes, congestive heart failure, poor kidney functioning or hyponatremia.

“It is becoming increasingly important for physicians to critically examine the underlying data and communicate the totality of the expected benefits to patients,” the pair wrote.

Can You Trust a New Drug?

The US prides itself on the fact that the FDA is arguably the best drug regulatory organization in the world. Yet in less than 5 years of being on the market, 32% of new drugs have bad enough side effects and adverse events that the FDA has had to send doctors warnings about safety and/or put “black box” labels on the drugs. And this was after drugs were on the market a median of 4.2 years.

A new study from the Yale University School of Medicine published in JAMA looked at the 222 new medicines that the FDA approved from 2001-2010. Of those drugs, 3 had to be withdrawn from the market because of safety concerns, about 20% received safety communications from the FDA, and 20% had “black box” warnings slapped on their label, the FDA’s most serious warning. Some drugs received both black box and safety communications, most often for different safety issues.

Are we safe taking new drugs? Pretty much. The good news is that few drugs get pulled from the market because they aren’t effective. The bad news is that we don’t know what the actual health risks are from new drugs. We don’t know what new side effects are or even if adverse events can be caused because the length of clinical trials is short and the number of people the drug is tested on is usually small.

Short Trials With Relatively Few Patients

Most new drugs are tested for only 6 months and on fewer than 1,000 people. Consider that a side effect considered “common” would happen in 1 in 100 people. If there were 700 people in a trial, 7 would have to complain of the same side effect. If it was an “uncommon” — but not “rare” — side effect, then 1 person in 1,000 might report it, and there aren’t even 1,000 people in many trials. That’s why so many side effects are found after the medicine is approved.

There might be a way to predict which new drugs are most likely to have safety problems — which was the goal of the study. If we could predict problem drugs, than patients could be warned of the likely possibility of unknown safety issues and follow-up studies could be more rigorous.

The researchers were able to classify most of the drugs that had postmarket safety events into 4 categories. They are drugs that received:

  • “Priority Review” status: Drugs with that designation have to be reviewed within a 6-month window rather than the standard 10-month time frame.
  • “Accelerated Approval” status: Drugs being developed for a serious unmet medical need can get this designation and use surrogate markers of disease in their clinical trials instead of actual outcomes (true endpoints). Surrogate markers have been helpful, but can be misleading. For example, Vytorin, a combination of Zocor and Zetia used to lower cholesterol, was shown to decrease LDL (bad) cholesterol and C-reactive protein, both considered “markers” of heart disease. Vytorin was approved based on this surrogate marker. The true endpoint is survival, and out in the real world it was found that patients using Vytorin did not live longer, even though their LDL was lower.
  • “Orphan Drug” status: Drugs that treat a rare disease gain a longer period of exclusivity in the marketplace, which prolongs a generic competition. For this study, researchers examined if a drug received an orphan designation for the indication for which it was initially approved.
  • Near-Regulatory Deadline Approvals: The FDA has strict deadlines for approving drugs. Those drugs that were approved within 60 days of the deadline were more likely to end up with postmarketing safety problems.

Drugs used to treat psychiatric illnesses or ones known as biologics (genetically-engineered proteins derived from human genes instead of chemical components) had more frequent safety events than others.

Increasing Drug Review Time

We need to consider taking more time to review drugs. Notice that 2 of the red flags have to do with rushing the drug through the review process: Priority Review and Near-Regulatory Deadline Approvals. The difference between a thorough, considered review and one that leads to expensive and time-consuming drug fact label changes and warnings is only days.

A third (Accelerated Approval) allows for shorter study times because of the use of surrogate markers in place of true endpoints.

We need to have rigorous and ongoing postmarket studies of drugs. It’s the only way to keep people safe and to give doctors the information they need to prescribe appropriately.

As for your own health, ask your doctor how long a drug has been on the market. When you consider taking a medicine to improve your health, don’t ask for the newest drug on the block. Unless there is a compelling reason to use a new drug, you may well be better off with older medicines that have proven themselves safe over time.

Can Pregnant Women Be Trusted to Make Their Own Medical Decisions?

Flash advice from the FDA! Avoid putting your infant under sedation for 3 hours or more. But if medically necessary, go right ahead.

Question: Who is going to put a child younger than 3 years old under a lengthy surgical procedure without medical necessity?

Answer: Doctors everyone should avoid.

The FDA is alerting parents and doctors that more than 3 hours of anesthesia can “cause widespread loss of nerve cells in the developing brain; and studies in young animals suggested these changes resulted in long-term negative effects on the animals’ behavior or learning.” (Note: Animal studies are often, but not always, predictive of human responses.)

Sometimes even small children need surgery. A heart problem can’t be put off or a cleft lip has to be addressed very early in life so that the infant can feed properly. In those cases, the new guidelines might help prepare parents for future cognitive and behavioral challenges. The FDA’s warnings about nerve cell damage won’t likely be a deciding factor when the stakes are life or death. It may encourage parents of children who need surgery for non-life threatening deformities to wait as long as possible.

Labels Dissuading Pregnant Women?

The same animal studies raised identical concerns about long exposure to anesthesia in the last trimester of pregnancy, which is when most of the fetus’ brain growth occurs. The label mentions pregnant women, but the warning is specific to infants up to 3 years old.

The medical news site, STAT, noted that, “Some experts had raised concerns that the labels would dissuade pregnant women from undergoing necessary medical procedures, and FDA officials said the revisions came from ongoing discussions with experts.”

The suggestion that information should be withheld from women for fear that women won’t make a medical decision that the doctor doesn’t agree with is something I find deeply disturbing. Hopefully, it’s not true. If so, my message to the FDA and to doctors is please allow pregnant women the same courtesy and respect you should to all patients. Informed consent is cornerstone of good patient care and women are perfectly capable of making the right decision for herself and her fetus.

Why Drugs Should Take a Long Time to Get to Market

Why NOT rush a drug to market when it might save lives? Here are 2 reasons. First, it could harm more people than it helps. And second, people might take a useless, harmful drug rather than get medicines or care that could help.

Whether the drug works or not (efficacy) can be proven fairly quickly, but side effects and adverse events take time to happen and high numbers of people to identify.

  • Drug companies object to extending the length of drug trials so that the effect of drug accumulation in the body can be measured.
  • Drug companies often don’t test on multiple subgroups that would ascertain if women, minorities, babies or seniors respond differently than the primary target group the companies are required to test against.
  • Drug companies don’t test the drug on people with multiple health issues. In trials, diabetes drugs, for example, are tested on those who have diabetes only, not additional health issues that might commonly co-occur with diabetes (or whatever the test drug targets), like depression or anxiety or heart problems.

During drug trials, patients are carefully watched. However, once the drug is in the general marketplace and is being taken by people with many different health issues, drugs may act differently than in the trials. Why? People in the “real world” are not like carefully selected test subjects. They may have underlying medical issues, or are taking other medications, vitamins or dietary supplements that can interact with the drug and can lead to side effects.

In the big, wide world outside of carefully conducted drug trials, it can be difficult even for a doctor to determine if a side effect or a death happened because of a new drug or an outside factor. Once being used in the marketplace by thousands (millions!) of people, the system for gathering information on side effects and adverse events is clunky and inefficient.

Side Effect Patterns Take Time to Appear

So it takes a while for patterns to start to appear and make clear that some drugs are worse than the disease. In the meantime, what is the cost to human lives and comfort? Too-fast approvals and testing that is too limited to singular groups or health factors are both reasons why so many drugs get pulled off the market a matter of years after approval.

It takes a while for patterns to start to appear and make clear that some drugs are worse than the disease.

Prescribed drugs, when used as directed, seriously harm many people each year. Despite this, many drugs are given a “Fast Track” designation by the FDA, shortening the time to market. Patients demanding medical miracles and pharmaceutical companies promising breakthrough cures that may or may not work are demanding that the road to market be made quicker and less expensive. And some politicians are supporting this push for faster, easier access to drugs.

What happens when a pharmaceutical company puts a drug on the market knowing it might harm people or that it is not as effective as they claim it is? The drug is withdrawn and the company is fined a lower amount of money than what the profits were for that drug. Sounds like a business model. Put a flawed product on the market, make millions of dollars, pay 50% of that back in fines. Pull another drug off the shelf and do it again.

A History of Harmful Drugs

Is it possible I’m exaggerating? Painting an unfair picture? Here are links to articles on multiple drugs that the pharmaceutical companies seemed to know of potential harm or that it didn’t work as well as published.