Black Americans face a disproportionate amount of gun violence

According to Everytown, a nonprofit advocating for gun control, Black Americans are disproportionately subjected to gun violence. The statistics are astounding: with ten times the gun homicides as compared to white Americans, eighteen times the gun injuries, and three times the fatal police shootings, Black Americans face a horrific threat of gun violence. 

Apart from the obvious trauma inflicted by guns, firearm violence deteriorates the wellbeing of entire communities. The constant threat compounds an individual’s cumulative stress load, leading to chronic health conditions even if one isn’t directly victimized by gun violence. The problem intensifies in historically underfunded cities, correlating with deep inequities in resources, support, and economic instability. 

It gets even trickier when considering mental health – over half of suicides in the United States involved a gun, and the vast majority who attempt suicide with a gun are successful in their attempt. Suicide rates, specifically amongst young Black men, are on the rise, leading some experts to posit that higher rates of gun ownership are connected to higher rates of self-inflicted gun violence.

Hospital staff get traumatized too

It can feel like we are in a never-ending cycle of firearm trauma. From Tyre Nichols to the six mass shootings in California just last month, it can feel endless. The damage ranges from mass shootings to domestic violence to self-harm to police brutality, and it doesn’t just impact victims and their families. Hospital staff are subjected to devastating cases time and time again, especially staff who work in emergency departments in metro areas. 

Seeing so many cases of needless gun violence takes a toll. Depression, PTSD, and anxiety can all emerge from repeatedly treating victims and having hard conversations with their families. Quickly moving on to the next patient feels empty of empathy yet is expected. Hospital staff are struggling more than ever and repeated instances of gun violence can be triggering – especially for Black staff who feel the extra burden of racialized gun and police violence.  Black hospital workers may feel the impacts even deeper when working with Black victims. It’s traumatizing to try and save a gun or police violence victim with the knowledge that you personally belong to the group being targeted.

Just ask our Board member Dr. Selwyn O. Rogers, Jr., M.D., M.P.H., a surgeon, public health expert, and founding director of  the University of Chicago Trauma Center. In an article published in NEJM last month, Dr. Rogers describes the trauma he carries from treating victims of gun violence day after day.

“In reality, I harbor and carry the burden of suffering within me. The piercing screams, the severed limbs, the brain matter exuding from the temporal lobes haunt me. Many evenings on the drive home, I know that my inner battery is spent, that I have no more strength to shoulder the hurt. I have nothing left to give. Sometimes when I get home, I cry like a baby on my wife’s shoulder. My wife, my three sons, my friends, and my faith — a belief in things not seen — recharge me.”

From Grief to Hope

While the nation continues to cycle through gun violence-related grief, healthcare workers are still standing up for their patients and communities. People in healthcare can leverage their unique knowledge and experience to advocate for gun control and police reform as they continue to heal victims. In recent years, clinicians have been stepping up and speaking out about firearm violence, declaring “This is our lane.” Collective power, especially from a highly trained and vital workforce like that of healthcare, is the way forward. 

Just as recovery after violence provides hope in the ER, recovery from our social conditions is possible and can provide hope for a better future. As Dr. Rogers wrote in his NEJM piece, “Despite the uncountable victims, the howls of pain, the repeated sadness, such moments give me hope — hope that if such a patient can recover and find joy and communion, perhaps someday our society can too.”

Do you know a clinician leading the way in preventing firearm violence? Nominate them for a BLASR!

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Preterm birth (defined as delivery before 37 weeks) impacts one in ten births in the US, and accounted for 16% of infant deaths in 2020. However, there are significant racial disparities. According to the CDC, the rate of preterm birth among Black women was 14.8% in 2021, much higher than the rate among white (9.5%) or Hispanic women (10.2%).

Given the devastating consequences of preterm birth, it’s tempting to want to take any action possible to fix it. If there is a chance that a drug could reduce premature births and racial disparities in infant death and disability, shouldn’t we take that chance? Those who approve drugs for serious conditions are not immune to the desire for hope in treating these conditions — it’s what drove approval of the recent ALS drug, for example.

But the Makena case shows how the logic of “What do we have to lose?” falls apart when you look at the evidence. From approval to withdrawal, the story of Makena shows some of the major pitfalls of the FDA’s drug approval process.

What is Makena?

Makena is a compound version of a synthetic hormone called hydroxyprogesterone caproate that was first developed in the 1950s. For decades, doctors thought the drug might reduce preterm births, but there was no evidence to show it worked. Bristol-Myers Squibb marketed the drug as Delalutin until the FDA issued a warning in the 1970s about the lack of effectiveness and safety issues, and BMS took it off the market.

A 2003 trial brought the hormone back into the public eye. The National Institute of Child Health and Human Development conducted a randomized trial of hydroxyprogesterone caproate for women with a history of spontaneous preterm birth. They found a significant difference in rates of preterm birth and low birth weight, although there were no differences in infant mortality or morbidity.

Seems promising, but researchers noted some concerning methodological issues. For one, the placebo group had higher rate of preterm birth before the trial, indicating that the randomization was not done correctly. Another issue was that a large proportion of trial participants were from a single site, so the study results may have been confounded (ie. something particular about that site is driving the results, not the effect of the drug). The FDA statistical review noted these limitations and concluded that the evidence wasn’t strong enough to approve Makena based on a single study.

Accelerated approval

Despite these concerns, K-V Pharmaceuticals (which owned Makena at the time) was still able to gain approval for the compound through the FDA’s accelerated approval process in 2011. Accelerated approval allows for drugs to be greenlit without evidence that they improve meaningful clinical outcomes, as long as they prove effective on a “surrogate endpoint” (a metric that is “reasonably likely to predict clinical benefit”).

In the case of Makena, the drug was approved based on reduction in delivery before 37 weeks, a surrogate endpoint for infant mortality associated with premature birth. The company was required to conduct a “confirmatory” trial to ensure that the drug was indeed effective.

Cut to 2019 when the new trial results came out. The PROLONG trial showed no significant difference in frequency of preterm birth or infant mortality for those taking Makena. In 2020, an FDA advisory panel voted to withdraw Makena from the market, but Covis pharmaceuticals, the private equity-backed new owner of the drug, demanded a hearing with the FDA before withdrawal. That hearing didn’t happen until October 2022.

What’s at stake?

Between the time it took to conduct the follow-up trial and the delay for the hearing, Makena was on the market for 11 years. That’s more than a decade of giving pregnant people a drug with an unclear benefit.

It’s also an immense cost to the system. Although hydroxyprogesterone caproate was first developed 80 years ago, after the FDA approved it, K-V pharmaceuticals marked up Makena 75 times the generic price. Medicaid, which covers about half of all births in the US, spent $700 million on the drug since 2018. Advocates have pointed out that this $700 million could have been used on other interventions to improve birth outcomes, such as funding birth centers and cultural competency training for medical professionals.

Makena is just one example of the waste generated by unproven drugs greenlit through the accelerated approval pathway. According to a recent report from the Office of the Inspector General, Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for accelerated approval drugs with incomplete follow-up trials past their original due dates.

What’s next?

Covis’ “hail mary” hearing didn’t work, but that doesn’t mean Makena is off the market instantly. The FDA will deliberate for a few months before deciding whether to remove the drug. The Makena saga provides an important lesson for the FDA and the drug approval process: An ounce of prevention is worth a pound of cure.

We could save so much time and money by ensuring that evidence supports the approval of drugs in the first place, rather than approve them and wait for the evidence. Makena is not an anomaly in terms of drugs approved through the accelerated pathway that later prove ineffective. A 2019 study found that out of 93 cancer drug indications granted accelerated approval, only 19 (20%) had confirmatory trials that demonstrated a benefit in overall survival. The case of Makena should urge the FDA to raise the bar on evidence for accelerated approval.

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The FDA green-lit Aduhelm using their “Accelerated Approval” process, which allows the agency to approve drugs based on their performance on surrogate markers. Surrogate markers are metrics that are not generally meaningful on their own, but correlate with clinical benefits that matter to patients. In the case of Aduhelm, the drug did not meaningfully improve patients’ ratings on a clinical dementia scale, but it did reduce amyloid plaques in the brain, which are associated with Alzheimer’s Disease.

The accelerated approval pathway is meant to help get treatments for life-threatening diseases on the market more quickly. However, research has shown that this process is often abused when it comes to cancer drug approvals. Most cancer drugs approved through this process don’t show meaningful results in later clinical trials and surrogate markers for new cancer drugs are often used without being vetted. While manufacturers are required to conduct a post-marketing clinical trial to prove effectiveness on a clinically meaningful outcome, these typically take years to publish (if the studies are ever conducted at all).

The approval of Aduhelm has brought many of these issues into the spotlight, leading to new legislative proposals. One of these proposed bills, called the Accelerating Approval Integrity Act of 2022, would add new requirements for drug companies to ensure that post-approval studies are conducted in a timely way. The Act would require these studies to be designed before approval and could require companies to start these trials at the time of approval. If the studies are not conducted “with due diligence” or if they do not find a clinical benefit, there could be fines for drug companies and their drug approval would be withdrawn.

These commonsense changes would go a long way toward achieving the intended purpose of the accelerated approval pathway. However, another piece of proposed legislation, the “Accelerating Access for Patients Act of 2022,” warrants attention as well. This bill would broaden the accelerated approval pathway to take into account the “severity, rarity, or prevalence of the disease or condition and the availability or lack of alternative treatments” when evaluating the effectiveness and safety of new drugs.

This seems like an important consideration to make, as patients suffering from terminal illnesses like ALS likely have different risk-benefit considerations than do patients with less severe illnesses. However, exceptions made in order to give patients the “right to try” or “provide hope” for those with fatal conditions seems to be partly what got us into the Aduhelm mess in the first place. Any legislation proposed to broaden the already fairly-lenient accelerated approval pathway should not be taken lightly.

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Researchers and activists — including the FDA’s own advisory panel — responded with concern to Aduhelm’s approval, given the low level of evidence behind it, and the implications for future drug trials, health system costs, and patient safety.

Experts also were surprised that the FDA originally approved Aduhelm for anyone with Alzheimer’s, although the trial only included people with mild cognitive impairment or dementia. The FDA eventually revised their label to narrow the indication to those in the mild stages of disease. However, the population for which Aduhelm is approved still differs from the trial participants in a very important way — the FDA did not exclude patients that are at higher risk of side effects from the drug, who were excluded from the original trials.

The side effects of Aduhelm include swelling (edema) or bleeding (hemorrhage) in the brain, headache, falls, and diarrhea. According to the drug trials, 1% more patients taking Aduhelm experienced a serious adverse event that researchers attributed to the drug, compared to patients taking placebo (0.7% of placebo group vs 1.7% of Aduhelm group). The Aduhelm group also reported higher rates of headache (19.6% vs 15.2%), falls (14.1% vs 11.8%), and diarrhea (8.2% vs 6.8%), compared to the placebo group.

The Aduhelm trials specifically excluded patients with certain conditions that would make them more susceptible to these side effects, including patients 85 or older; patients with certain chronic conditions such as heart disease, blood clots, and kidney disease; and patients taking antiplatelet drugs or blood thinners.

Researchers wanted to know: How many Medicare beneficiaries fall under these exclusion criteria? In a recent JAMA article, Dr. Timothy Anderson at the Beth Israel Deaconess Medical Center and colleagues took a look at Medicare data to find out. They discovered that among Medicare beneficiaries with Alzheimer’s Disease, more than 90% would have been excluded from the original Aduhelm trials. Most beneficiaries met two or more of the exclusion criteria.

The types of patients that were excluded from trials are the same ones that are at higher risk of side effects from Aduhelm, the study authors point out. However, these patients aren’t excluded from taking Aduhelm under the FDA’s criteria. This disconnect between trial and drug approval criteria puts millions at risk of harm from side effects, and must be resolved. As Dr. Anderson wrote on Twitter, “CMS should strongly consider restricting coverage of Aducanumab for trial ineligible populations until clinical trial data on safety and efficacy in these groups is published.”

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The evidence behind the approval

The path to approval for aducanumab was anything but straightforward. In 2015, Biogen started two randomized controlled trials, called EMERGE and ENGAGE, to test the effectiveness and safety of aducanumab. At an interim look at the data in 2019, Biogen shut the trials down, declaring that the drug was not proving to be effective, and that further study would be “futile.” However, data continued to come in from trial participants, and a few months later, Biogen did a reanalysis and found that EMERGE was showing positive results for patients taking a high dose of aducanumab.

“These kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.”

Dr. Jason Karlawish, in StatNews

Experts were skeptical that this result was enough proof for Biogen to seek FDA approval. For one, the FDA generally requires two controlled trials to approve a new drug, and Biogen had positive results from only one trial. Second, although the trial results were statistically significant, it’s not clear that the results actually show clinical significance– that is, that the drug makes a noticeable difference to patients or their families. The primary endpoint of the trials was change on the Clinical Dementia Rating Scale (CDRS). The range for this scale is from 0-18, with a higher score indicating more severity of illness. Among those taking a high dose of aducanumab in the EMERGE trial, the average decrease on the scale was 0.39 points, according to the Institute for Clinical and Economic Review (ICER) report.

Given the negative results of ENGAGE (as well as the many previous negative trials of drugs that similarly target brain amyloid), the positive results of EMERGE may have been due to random chance as much as anything else. But even if the result is “real,” that doesn’t mean we should rush to approve the drug. In a recent StatNews op-ed, Dr. Jason Karlawish, professor of medicine at the University of Pennsylvania’s Perelman School of Medicine, argued that “these kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.”

After looking at the evidence, the FDA’s own advisory panel voted overwhelmingly that the trials were not “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease.” It’s not uncommon for the FDA to vote against the recommendation of its advisory panels, but this was the first time in many years that the FDA overruled such a decisive vote by a panel. Many of the panel members were shocked by the FDA’s approval of the drug, and as of June 11, three have resigned.

Implications for future drug approvals

So why did the FDA approve aducanumab, given the low level of evidence shown by the trials? It appears that their decision was based mostly on the drug’s performance on a surrogate marker, how well it cleared beta-amyloid plaques from the brain. Surrogate markers are metrics that are not generally meaningful on their own, but correlate with clinical benefits that matter to patients.

In the FDA’s statement, director Dr. Patrizia Cavazzoni wrote, “Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain. The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer’s—is expected to lead to a reduction in the clinical decline of this devastating form of dementia.” 

The FDA’s “Accelerated Approval” pathway allows the agency to approve drugs based on their performance on surrogate markers for serious or life-threatening illnesses, on the contingency that the company does a confirmatory clinical trial to show improvement on meaningful outcomes.

“A general signal being sent to the rest of the drug industry is: If you can get uncertain, maybe suggestive data…we may approve your drug.”

Dr. Peter Bach, in Axios

The use of accelerated approval in recent years has been highly problematic, leading to approval of many cancer drugs based on unproven surrogate markers, that don’t show improvement in survival in post-approval trials. However, the aducanumab approval takes accelerated approval to another level, by bringing a drug to market that applies to a very broad population — about 6 million Americans are living with Alzheimer’s, and 500,000 are diagnosed with the disease each year. Although the trials included only patients with mild dementia, the FDA declined to limit the drug’s indication to patients at a particular stage of the disease. This means that anyone affected by Alzheimer’s could be eligible for treatment with aducanumab.

The FDA’s approval of aducanumab sets a dangerous precedent, because it may become more common for the FDA to approve drugs without proof they are effective and ask for confirmatory trials, rather than waiting for evidence before approving. The FDA rarely holds drugmakers accountable for conducting postmarketing trials to validate drug effectiveness. A 2019 review of 93 cancer drugs approved through accelerated approval found that only 15 of the approvals later had confirmatory trials that showed improvement in overall survival.

“A general signal being sent to the rest of the drug industry is: If you can get uncertain, maybe suggestive data and a post-hoc analysis — get that threshold to us — we may approve your drug,” said Peter Bach, a drug researcher at Memorial Sloan Kettering Cancer Center, in Axios.

Potential for patient harm

Aduhelm’s approval also has implications for patient harm if it becomes widely used. In the combined drug trials, according to the ICER summary report, 1% more patients taking aducanumab experienced a serious adverse event that researchers attributed to the drug, compared to patients taking placebo (0.7% of placebo group vs 1.7% of aducanumab group). If all 6 million Americans diagnosed with Alzheimer’s each year took the drug, that would result in 60,000 more serious adverse drug events each year.

The aducanumab group also reported higher rates of headache (19.6% vs 15.2%), falls (14.1% vs 11.8%), and diarrhea (8.2% vs 6.8%), compared to the placebo group. Applied to 6 million potential aducanumab users, this would result in 252,000 more cases of headache, 84,000 cases of diarrhea, and 138,000 more falls each year.

Implications for health system spending

The reimbursements for Aduhelm infusions and related scans are potentially a gold mine for clinics offering this treatment–not to mention the billions that Biogen is expected to make in profits. But these profits come at a high cost for Medicare and the health system as a whole. The wholesale price for the drug is $56,000 per year, far higher than ICER’s recommended price range of $2,560 to $8,290 based on the drug’s effectiveness. Not only is the cost of the drug itself expensive, but the costs of brain scans to monitor previously mentioned side effects adds an estimated $30,000 per patient.

The introduction of a new expensive drug that could be given to millions of people has serious implications for the cost of health care nationwide. If the Centers for Medicare and Medicaid (CMS) decide that Medicare should cover the cost of aducanumab, this could add hundreds of billions of dollars to Medicare spending.

CMS may decide to limit Medicare coverage of aducanumab through their National Coverage Determination (NCD) process, in which CMS would independently review the evidence around the drug and determine for which beneficiaries the drug should be covered. Without the NCD, other insurers and regional Medicare Part B contractors could still decide to set coverage limits for aducanumab. But even with these limits, aducanumab’s approval will likely strain Medicare’s budget and result in higher insurance premiums.

Conflicts of interest

Finally, the approval of Aduhelm confirms that pharmaceutical companies’ strategy of funding patient advocate groups is working. The Alzheimer’s Association received at least $1.4 million from from Biogen and Eisai since fiscal year 2018. The group has been ardent supporters of Aduhelm, sending letters to the FDA urging approval of the drug (without disclosing their conflicts). The pattern of pharmaceutical funding for patient advocate organizations — which exceeds what pharma companies spend on federal lobbying — is likely to continue, if not increase.

Similarly, the relationship between the FDA itself and pharma should be taken into account. As Shannon Brownlee and Jeanne Lenzer wrote in the Washington Post, the FDA is in many ways a “captive agency” of industry, write Brownlee and Lenzer. The FDA relies on industry fees for 35% of their budget, and many of the scientists that work at the FDA either come from industry or later go on to work in industry (a phenomenon known as the “revolving door”). As a result, the FDA sees drug and device companies as its primary customers, not patients. This cozy relationship may explain why the FDA offered Biogen and Eisai accelerated approval for aducanumab, and did not push them to do additional trials before approval.

A strong response

The pushback from the scientific community against the FDA’s approval of Aduhelm has been strong; so far, three of the FDA advisory panel members have resigned in protest. Even pharma industry insiders say that the FDA should not have approved Aduhelm, and that it’s not worth the high price. Hopefully the FDA will reexamine their decision and take in this lesson for the future.

If nothing else, this episode and its implications will make it clear the issues with lax FDA regulation, and with the accelerated approval pathway especially. As Dr. Vinay Prasad, Associate Professor in the Department of Epidemiology and Biostatistics at the University of California-San Francisco, wrote on Twitter, “We have five or six aducanumabs a year in oncology.” Hopefully, the strong public outcry from the scientific community will make the FDA take notice, and push President Biden to appoint a new FDA commissioner who will priority drug safety and efficacy over speed.

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The increasing use of surrogate endpoints is a significant driver of these approvals. Surrogate endpoints (also known as “surrogate markers”) are metrics that are not generally meaningful on their own, but correlate with clinical benefits that matter to patients. Examples of surrogate markers include tumor size or progression-free survival in the case of cancer drugs. Another example: In a recent trial of hydroxychloroquine for Covid-19, researchers measured “viral load,” a supposed surrogate marker for survival.

If the FDA is not approving drugs based on the right evidence, they could be sacrificing effectiveness for speed.

In the FDA’s “accelerated approval” program, rather than prove a cancer drug has a beneficial clinical outcome, such as improved survival or better quality of life, the drugmaker just has to prove that the drug improved a surrogate endpoint, making it much quicker to develop these drugs and bring them to market. But if the FDA is not approving drugs based on the right surrogate markers, they could be sacrificing drug effectiveness for speed.

It would make sense if the FDA only approved drugs based on surrogate endpoints if 1) The endpoint is strongly correlated with overall survival or quality of life, or 2) The endpoint has been previously used in treating the condition. However, according to a recent study in JAMA Internal Medicine, the FDA has frequently approved cancer drugs based on a surrogate endpoint that had never before been used for that type of cancer.

Oncology researchers at Oregon Health and Science University Emerson Chen, Alyson Haslam, and Vinay Prasad examined 194 cancer drug approvals based on surrogate endpoints that occurred from 1992-2019. They found that about one-third of these approvals were based on a surrogate endpoint that had not been previously used for that specific cancer.

Among the 64 new surrogate marker-based approvals, only 4 had a relatively strong correlation with meaningful outcomes.

If the FDA approved these drugs based on a new surrogate marker, it must be because those marker were proven to correlate with clinical outcomes…right? Not exactly. Among the 64 new surrogate marker-based approvals, Chen et al. found that only 4 had a relatively strong correlation with meaningful outcomes. This means that over the past few decades, a full quarter of cancer drug approvals based on surrogate endpoints were not based on validated surrogates or previous regulatory standard.

The authors conclude that “the FDA is steadily accepting more surrogate measures over time, which are not justified by scientific validity or adherence to regulatory precedent.” This pattern is especially concerning, because the FDA rarely holds drugmakers accountable for conducting postmarketing studies to validate the effectiveness of drugs approved based on surrogate markers. The method by which new cancer drugs are approved seems to only benefit drugmakers, allowing them to get drugs to the market faster with little evidence of benefit. Meanwhile, patients are taking on the increased risks of financial cost and potential side effects without having the confidence that these new drugs will improve the outcomes that matter most to them.

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What is a REMS?

When the Food and Drug Administration (FDA) wants to approve a medication that has the potential for misuse, abuse, or other risks, they can require a Risk Evaluation and Mitigation Strategy (REMS) for that drug. A REMS is a drug safety program designed to mitigate certain serious risks, by making sure the medication is being used safely. A REMS may require health care professionals to undergo training or certification before prescribing, patient education or dissemination of informational materials, confirmation of a certain diagnosis or condition before prescribing, limits on where the drug administered, and or other interventions.

When the Food and Drug Administration (FDA) approved fentanyl sprays and lozenges, products that are 100 times as potent as morphine, they recognized the potential danger for misuse and overdose, so they required a REMS. Prescribers and patients were informed that the product was only to be used for “breakthrough” cancer pain to patients who had developed a tolerance to opioids. Drug companies and the FDA would monitor prescribing to make sure that only this small subset of patients received the fentanyl, and drug companies were supposed to cut any providers who prescribed the drug inappropriately.

Unfortunately, that’s not how the REMS program worked in practice, as a JAMA study earlier this year revealed. Researchers at Johns Hopkins School of Public Health reviewed the FDA’s REMS documents from 2012 to 2017 and found that between 34.6% and 55.4% of patients who were prescribed fast-acting fentanyl were not meant to receive it. Although there was documentation that providers were prescribing fentanyl inappropriately, the drug makers did not revoke certification from any of them, allowing them to keep giving out the drug. 

This may not come as a surprise to those who followed the trial of opioid-maker Insys CEO John Kapoor. The trial revealed extremely unethical practices, such as encouraging employees to lie about a patient’s condition to approve insurance coverage of their fentanyl spray. Insys was in charge of monitoring and reporting non-compliant prescribers according to the REMS, but in practice they did the exact opposite, encouraging doctors to give out fentanyl inappropriately. 

The REMS drug safety system is clearly broken. It relies on the drug manufacturers to monitor how the REMS program is going, submit assessment reports to the FDA, and recommend any changes. The FDA’s role is to review the REMS assessment reports, determine if the REMS is meeting its goals, and if the REMS plan should be modified. The drug manufacturers have no incentive to strictly regulate the prescribing of their drug, because their goal is to sell as much of the drug as possible. In fact, drug companies spend millions to market their drug to doctors and patients, and to suggest off-label uses for drugs.

The REMS cycle

The intention to safely monitor the use of potentially dangerous drugs is a good one. However, some worry that the REMS system is being used to justify the approval of drugs for which the harm outweighs the benefit. For example, earlier this year, the FDA approved esketamine for treatment-resistant depression, which can have serious side effects and has a high potential for abuse. In fact, FDA panel members expressed significant concern about the potential for diversion (patients selling or giving away the drugs to others) and misuse.

What swayed these FDA panel members was the promise of a strict REMS program that would require esketamine to be administered only in a health care setting, so patients would not sell the drug to someone else or potentially overdose. Now that the Department of Veteran’s Affairs has approved the use of esketamine at VA clinics (a decision that has alarmed some politicians and VA officials), the strict REMS program promised by the makers of esketamine will be put to the test in the real world. 

Another recent example of REMS justifying an FDA approval was the approval of opioid painkiller Dsuvia, which is ten times more powerful than fentanyl. Although some FDA panelists and others noted that Dsuvia could easily be prescribed inappropriately or diverted illegally, the FDA approved it based on its “unique features” that would be useful on the battlefield. In response to criticism, FDA commissioner Scott Gottlieb “insisted the risk management program, known as a REMS, will ensure the drug is only used in a medically supervised settings.”

It is evident that the REMS system is not robust enough to combat the forces pushing for inappropriate use. The FDA should be in charge of developing REMS, monitoring prescriptions, and given real methods of enforcement. Drug companies should not be policing themselves; we cannot keep putting the fox in charge of the henhouse. And there should be restrictions on drug company marketing for any drug that requires a REMS, including giving money to doctors for speaker fees or continuing medical education. 

Without substantive changes to the REMS program, we will continue with the cycle of dubious drug approval, non-enforced REMS, immense harm, then promises from drug companies to do better. Rinse, repeat. After what we know happened with fentanyl, can we really make the same mistake again and again? 

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While the accelerated approval program has led to a greater number of cancer drugs being approved in a short period of time, some oncologists and researchers argue that the process has merely created more profit for drug companies, without corresponding clinical benefit for cancer patients. For example, using surrogate endpoints shortens the time it takes to conduct a clinical trial and bring a drug to market, but these endpoints often fall short of predicting real clinical benefit.

Now, two studies in JAMA Internal Medicine provide more evidence to suggest that the FDA isn’t holding newly approved cancer drugs to high enough standards. Dr. Bishal Gyawali, Dr. Spencer Phillips Hey, and Dr. Aaron Kesselheim of the Program on Regulation, Therapeutics, and Law (PORTAL) at Harvard Medical School/Brigham and Women’s Hospital, analyzed the results of confirmatory trials for all cancer drugs granted accelerated approval from 1992 to 2017. 

If the accelerated approval program is working as intended, these confirmatory trials should show that approved drugs indeed offer a clinical benefit. However, that’s not what Gyawali et al.’s research found. Out of 93 cancer drug indications granted accelerated approval, only 19 (20%) had confirmatory trials that demonstrated a benefit in overall survival. For another 41% of approved indications, confirmatory trials showed improvement using a surrogate outcome, but not in overall survival. The rest of the approvals had not been confirmed yet because trials were delayed or in process. It appears that confirmatory trials are not working as a safeguard against drug manufacturers are using less rigorous evidence to get cancer drugs to market faster.  

Another study by Dr. Emerson Chen, Dr. Vikram Raghunathan, and Dr. Vinay Prasad at Oregon Health and Science University examines the use of response rate as a surrogate endpoint in cancer drug trials. Many cancer drugs are approved through the accelerated pathway based on response rate, which the authors define as “the percentage of patients whose tumors shrink beyond an arbitrary threshold.” Response rate is a surrogate endpoint; it correlates with overall survival, but does not have an inherent benefit to patients (hence “arbitrary threshold”). If drugs are being approved based on response rate, one would expect that the response rate would have to be pretty outstanding, especially if there is no control group in the trial. However, that’s not always the case, as Chen and colleagues found out.

Out of 85 cancer drug indicates that were approved from 2006 to 2018 based on response rate, the median response rate was 41%, meaning that, in the typical trial, fewer than half of patients saw their tumors shrink. One third of approved cancer drugs showed response rates less than 30%. Out of drugs that were approved through accelerated approval but had yet to conduct a confirmatory trial, the typical response rate was just 28%. 

What do these findings mean for patients? The lack of evidence of clinical benefit for new cancer drugs is frustrating for patients and families trying to make treatment decisions. Patient advocate Sally Schott wrote in the American Journal of Medicine that caring for her brother with advanced cancer was made more frustrating by the lack of controlled data for the treatments they gave him. “For my brother and me, we wanted more information, not just more choices,” she writes.

What we need is more randomized controlled trials of new drugs, that measure outcomes that patients care about, not just surrogate endpoints. Unfortunately, as long as the FDA continues to reward drug companies with accelerated approval for surrogate outcomes and low response rates, it is unlikely that manufacturers will conduct RCTs, which take longer and are more expensive.

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“Should we be making it easier for companies to bring new tests to market, rather than having a process that is so complicated and expensive that they give up? Have we set up a system so complex that we’re inadvertently stifling diagnostic innovations and possibly endangering the health of our nation?”

Wolf paints a picture of dozens of life-saving tests held back from doctors by a tangle of red tape. But is that really what diagnostics regulation at the FDA is like? We’ve written extensively about the FDA’s lax regulations of medical devices. What you may not know is that the protocol for approving diagnostic tests is just as minimal. 

No real test for diagnostic tests 

Here’s a brief summary of how it works. Tests that analyze human samples (blood, tissue, etc) that are created for commercial sale are called “In Vitro Diagnostics” and are regulated by the FDA using the same process as medical devices. IVDs that are Class I (lowest risk) do not need premarket review. IVDs that are Class II or III and are shown to be “substantially equivalent” to an existing test can be approved through the 510(k) pathway. Tests that are approved this way do not need to have been tested in humans through a clinical trial to prove effectiveness and safety, which has caused significant patient safety issues around the world. 

Diagnostic tests that aren’t equivalent to a predicate have to go through “premarket approval,” where the FDA evaluates whether “scientific evidence shows that the possible benefits to health from the intended use of a device outweigh the possible risks.” However, there are some exceptions to premarket approval, including “De Novo” classification, which are device types that have not been marketed in the US but have been used in other countries and are “reasonably well understood.” Devices can also be exempt if they are for diagnosing “orphan” diseases, diseases that affect fewer than 4,000 patients a year.

An explosion of genetic tests

If a diagnostic test was developed, manufactured, and used only within a single laboratory, it is redefined as a “Laboratory Developed Test” and is not subject to FDA approval. According to a report from the Congressional Research Service, when the LDT designation was created in 1976, it mainly covered genetic tests developed by academic or research laboratories to diagnose rare diseases. But over the past few decades, the use of the LDT designation has dramatically increased as development of genetic tests has become more popular. Now, there are more than 10,000 LDTs now on the market, none of which are evaluated for clinical validity before being used. 

This is no small danger. The FDA knows that faulty LDTs may have caused “patients being over- or undertreated for heart disease; cancer patients being exposed to inappropriate therapies or not getting effective therapies; incorrect diagnosis of autism; unnecessary antibiotic treatments; and exposure to unnecessary, harmful treatments for certain diseases such as Lyme disease.” 

The FDA has attempted to regulate LDTs over the past few years, but has faced significant pushback from companies that sell genetic tests. The most the FDA has been able to do is issue a non-enforceable “discussion paper” on how they would like LDTs to be regulated. Legislators on both sides of the aisle are working to try and pass legislation that would allow the FDA to regulate LDTs (while further streamlining approvals for low-risk diagnostic tests), but it is unclear when this bill will be passed.

Do we need fewer “roadblocks”?

Wolf’s argument that the FDA’s red tape is preventing important diagnostic tests from getting to market contains several holes. She wants some diagnostic tests to be approved based on “Right to Try” or “coverage with evidence,” policies that would allow unapproved tests to be marketed and used, for the purpose of getting more evidence on whether the test works. These would expose many patients to harms of inaccurate tests and dangerous overtreatment, a outcome nearly guaranteed by the fact that this is happening with unregulated LDTs. Wolf also does not specify how “Right to Try” for diagnostics would work, given that this designation is typically reserved for drugs for terminal illnesses.

On social media, doctors and policy experts countered Wolf’s argument. Former FDA commissioner Robert Califf tweeted, “While i’m in favor of reducing unhelpful bureaucracy, this is way off base. We need is better evidence so we can have confidence that new tests actually provide value.” 

While i’m in favor of reducing unhelpful bureaucracy, this is way off base. We need is better evidence so we can have confidence that new tests actually provide value. @dukeforge Diagnostic innovations are slowed by bureaucratic roadblocks https://t.co/aApORH9gLT via @statnews — Robert M Califf (@califf001) January 19, 2019

The FDA’s protocol for approving diagnostic tests is no more stringent than their approval process for devices; in many ways, it is dangerously lenient. As Califf wrote, we need evidence of value before approving diagnostic tests, not less.

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