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A Bizarre Claim of Right to Try

By ARTHUR CAPLAN, KELLY MCBRIDE FOLKERS, and ANDREW MCFADYEN DONALD TRUMP, RIGHT TO TRY

A patient with glioblastoma recently received an experimental cancer vaccine at the University of California, Irvine. Notably, this is being hailed as the first case of someone utilizing the Right to Try Act of 2017. ERC-USA, a U.S. subsidiary of the Brussels-based pharmaceutical company Epitopoietic Research Corporation, says it provided its product, Gliovac, to the patient at no cost. The vaccine is currently undergoing Phase II clinical trials. A handful of people in Europe have received access to it through “compassionate use.” This patient did not qualify for ongoing clinical trials in the U.S. The patient, who remains anonymous, is the first known individual to receive an experimental medicine that has not been approved by the FDA, as permitted under the federal right to try law.

Glioblastoma is a nasty cancer – John McCain and Ted Kennedy passed away after battling the disease for just over a year. We believe that patients with terminal illnesses, like those with glioblastoma, should have every reasonable tool at their disposal to treat their disease.

That being said, we’ve argued before that right to try laws are not the best way to help desperate patients. They still aren’t. The number of cases claimed to date is exactly one. And, further examination of what we know about this case does not make a strong argument for the widespread usage of the right to try pathway.

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Health in 2 Point 00, Episode 63 Walgreens & Fedex partnership, Verily’s adherence program, & more!

Today on Health in 2 Point 00, Jess and I get festive for the holidays. In this episode, Jess asks me about Walgreens and its new partnership with FedEx for next day prescription delivery and with Verily to help patients with prescription adherence. She also asks me about blockchain startup PokitDok getting its assets acquired by Change Healthcare. Lots of job changes are happening as well. Amy Abernethy, the chief medical officer at Flatiron Health, was named Deputy Commissioner of the FDA. Rasu Shrestha, who was previously at the University of Pittsburgh Medical Center, is the new chief strategy officer of Atrium Health. Finally, Zane Burke, who recently stepped down as president of Cerner, was just hired as Livongo’s new CEO, while Glen Tullman remains executive chairman of the company. Dr. Jennifer Schneider was also promoted from the company’s chief medical officer to president. We have one more episode of Health in 2 Point 00 for 2018, so be on the lookout for our year-end wrap-up. —Matthew Holt

Last Month in Oncology with Dr. Bishal Gyawali: November 2018

Keynote speech

There was a very sobering piece in NEJM by the FDA last month in which the authors try to explore what went wrong with the Keynote-183, Keynote-185 and checkmate 602 trials testing PD-1 inhibitors combinations with pomalidomide or lenalidomide and dexamethasone in multiple myeloma. Interim analysis of Keynote 183 and 185 revealed detrimental effects on overall survival (OS) with hazard ratios of 1.61 and 2.06, not explained by differences in toxicities alone. The checkmate 602 trial was also halted in light of these findings and also showed higher mortality in the nivolumab combination arm.

In the thoughtful NEJM piece, the authors make at least three important points. First, they question why these PD-1 inhibitors were tested in combination despite their having limited single-agent activity. In fact, a couple of years ago, Vinay Prasad and I asked the same question: why are novel cancer drugs being tested in combination despite having limited activity as a single agent? We found that these drugs, even when ultimately approved, provide relatively low value and recommended that drugs with poor single agent activity not be tested in combinations unless there are specific reasons to expect synergy.

The second important point in the article is that many cancer drug approvals are lately based on durable response rates in single arm trials without a control group, a situation in which it is difficult to evaluate the safety and efficacy of drug combinations. Indeed, without an RCT, the oncology community would never have known these signals of detrimental effect. If the FDA had approved these PD-1 inhibitors in multiple myeloma on the basis of non-randomized trials, which it often does in other oncology contexts, who knows how long it would have taken to recognize the increased mortality in patients—and at what cost. This is another reason why we need RCTs more now than ever. Finally, the authors point out that these PD-1 inhibitors in multiple myeloma were directly advanced to phase 3 trials after phase 1 trials were completed, without phase 2 information. Indeed, in a recent paper, Alfredo Addeo and I showed that a substantial percentage of drugs that fail in phase 3 trials do not have supporting phase 2 data.
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Surrogate End Points Ain’t all that Bad

By CHADI NABHAN MD MBA

Dr. Chadi Nabhan, MD, MBA

Life is busy, yet we somehow find time to stay engaged on social media, remain engrossed in the 24/7 news cycle, and continue our futile efforts to resist clickbait. While social media can allow us to mindlessly scroll through feeds, it also provides an avenue to provoke vigorous dialogue, however diverse, controversial, or even rooted in unfettered biases. These exchanges have served as the primordial soup for a virtual friend or foe-ships. Tense and argumentative Twitter exchanges are especially entertaining given the challenges in justifying a position in fewer than 280 characters. Thus, tweetorials have emerged to explain a point of view via a thread of comments since it is not always easy to do so in 1 or 2 tweets. The longer the tweetorial, the more heated the debate. What I am trying to get at here, somewhat obtusely, is the concept of surrogates.

I have already suggested a surrogate. Length of a tweetorial is a surrogate for degree of controversy of the topic. Meaning, length is a surrogate, a proxy. We are surrounded by surrogates. Longer wait lines at restaurants and bars imply a hipper joint or tastier menu. My child being extra nice to me is a surrogate for him wanting more time on electronics. Not a day goes by without folks arguing about surrogate endpoints. I wanted to dig deeper into surrogates and since I am a physician, I’m focusing on surrogates in medicine. Apologies to those who thought I would be discussing restaurants or exotic trips.

I want to make sure my definition of surrogates is accurate: Merriam-Webster dictionary for enlightenment. The first use of the word “surrogate” was in 1533, B.T. (“Before Twitter”). A surrogate is defined as “one appointed to act in place of another” or “one that serves as a substitute”. We use surrogate endpoints in clinical trials as a substitute for other end points.

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Our Guide to Pre-Approval Access to Drugs For Both Doctors & Patients

By ALISON-BATEMAN HOUSE

In April 2016, I published guidance, in the form of a mock case study, on how to access a drug before it has been approved by the FDA—what’s known as pre-approval (or expanded or compassionate) access. This is an updated version of that guidance, reflecting multiple important changes in the pre-approval landscape over the past year. In particular, the FDA rolled out a new, streamlined form for single-patient requests, and Congress passed the 21st Century Cures Act, which, among many other things, mandated that certain pharmaceutical companies provide public information about their pre-approval access policies.

Patients (and physicians) trying to access an unapproved drug outside of a clinical trial can feel as though they’re navigating uncharted waters. Many physicians don’t know that the FDA permits the use of unapproved drugs outside of clinical trials; those who do know often have no idea how to access such drugs for their patients. Those physicians who know about pre-approval access are largely specialists in certain areas—often, oncology or rare diseases—and they are generally self-taught: they didn’t learn about pre-approval access in medical school or in their residencies. Thus, while some physicians have become very accustomed to requesting pre-approval access to drugs, the majority lacks this knowledge. In this essay, I use a fictional case to trace the process for requesting access to an unapproved drug. I hope to explode several myths about the process, especially the beliefs that the FDA is the primary decision-maker in granting access to unapproved drugs and that physicians must spend 100 hours or more completing pre-approval access paperwork.

Imagine you are a physician, and you have a pregnant patient who has tested positive for the Zika virus. She is only mildly ill, but she’s terrified that the virus, which has been linked with microcephaly and other abnormalities, will harm her unborn child. She’s so concerned that she is contemplating an abortion, even though she and her husband have been trying to have a child and were overjoyed to learn she was pregnant.

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The “21st Century Cures” Draft Bill: A Step Away From Transparency

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There is optimism that Congress will soon pass the 21st Century Cures bill. The draft bill proposed by the House Energy and Commerce Committee aims to foster medical innovation by streamlining the FDA regulatory process and increasing NIH research funding by $10 billion. The draft bill has overwhelming bipartisan support and will benefit patients, medical researchers and pharmaceutical companies. However, it also includes a passage, which aims to amend the Sunshine Act and exempt pharmaceutical companies from reporting the payments they make to physicians for continued medical education (CME) programs. The supporters of this change argue that physicians learn about the latest developments in medical science through CME programs and that requiring the disclosure of these payments would discourage pharmaceutical companies from financially supporting educational programs. Ultimately they believe it could inhibit the diffusion of medical innovation among doctors.

I took a look at the data released by CMS on the financial transactions between the pharmaceutical companies and individual physicians. In the last five months of 2013, more than $120 million were paid to physicians who participated (as faculty or speakers) in CME programs. The payments constitute 26 percent of the total financial transactions between pharma and individual physicians. The proposed change essentially allows pharmaceutical companies to hide more than a quarter of their payments to physicians. Exempting the pharmaceutical companies from reporting the largest part of their financial relationship with doctors will not help to foster medical education, rather it will add to current suspicions about the unjustified impact of such payments on the drugs that physicians prescribe to their patients.

If CME programs legitimately increase the awareness of physicians about the latest medical innovations and provide them with unbiased information about new drugs, then both pharmaceutical companies and those physicians who serve as speakers and faculties of such programs should be extremely proud of their role as champions of innovation and envoys of the latest knowledge in the medical community. If that is the case, one would wonder why they wouldn’t embrace and support the efforts that shed light on their noble role.

Patients heavily rely on the recommendations of their doctors to make any kind of decision regarding their health and thus have the right to be informed about the possibility that their doctors have a conflict of interest. Congress should refrain from amending the Sunshine Act and avoid jeopardizing the patients’ right to have access to information.

Niam Yaraghi is a fellow at the Brookings Institute Center For Technology Innovation. His posts appear regularly on THCB and on the Brookings Institute Tech Talk blog, where this post first appeared. This post also appeared as an opinion column on the US News and World Report site.

Those New Neighbors

Daniel GarrettLook at who is entering the New Health Economy: Amazon, with digital health applications; Intel, with a home health gateway; Google, with a fit platform, not to mention the news out of Cupertino last week.

Why? According to the 2013 PwC Global Innovation Survey, nearly half of drug and device companies are focusing on traditional product innovation rather than on breaking their efficacy and safety mold. And the stakes are high: As patients become value-seeking consumers, they want quick and easy technology connections to their health source.

It appears that the biggest barrier to transforming traditional healthcare business is culture. Most (89%) of the drug and device CEOs surveyed by PwC view technological advances as the global trend to follow. Yet three-quarters of these executives cite an inability to grasp new information technologies.

Many of these firms invested heavily in social media in 2012 and 2013, but then retreated, possibly awaiting further guidance from the FDA on what is acceptable conduct for “socializing” with consumers.

In fact, the FDA released draft guidance this spring outlining rules for interactive promotional media, including blogs, social networking sites, online patient forums, and podcasts. Some companies, such as Qu Biologics, already use social media to enhance trial recruitment. Companies can scan social media for information about adverse events related to their products. A recent study showed that social media had three times more adverse-event reports for 23 commonly used prescription medications than the FDA did during the same time period.

Any cultural transformation should begin at home. Although drug and device companies say they value social media as an important accelerator of innovation, the evidence is scant on how these firms use technology to promote internal communications that can better connect employees across traditional silos—from R&D to commercial business units.

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Are Federal Regulations Stifling Disruptive Healthcare Technologies in the US?

Screen Shot 2014-08-28 at 11.38.01 AMIn the past few years, we’ve seen headline after headline marveling at the advancements of medical technology. From wearable tech and micro sensors to 3D printing and health-oriented apps, it’s evident that technology and medicine have merged into an industry that’s pushing healthcare to a new level.

Yet many in the health tech industry are also voicing concerns about government regulators and their standards for healthcare technology. Some have even gone as far as accusing the FDA of “stifling” the creativity of healthcare tech and hindering the value these devices and apps could bring to the public.

In early 2014, legislation was introduced in an attempt to redesign the regulatory framework for certain types of technologies and lessen the FDA’s control over this growing industry. But are the FDA’s standards and actions so bad?

I’m in the tech field myself, and while I’ve heard many arguments against the FDA’s regulations, I strongly feel that it’s completely within its rights as a regulatory agency to place limits on medical technology. The FDA’s standards are put in place to protect consumers and to correct disingenuous manufacturer claims — an alarmingly frequent trend in today’s digital world.

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Informed Consent 2.0

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Is healthcare going to the dogs?  In at least one way, it probably should.

While not often spoken of together, physicians and veterinarians share an otherwise unique position of helping people make healthcare decisions in the awkward and charged space between risk, benefit and cost.  Both share an ethical requirement to provide the information necessary for informed decision making. Before starting a treatment or procedure, patients (and pet owners) need to understand the potential risks and benefits of their care, as well as the reasonable alternatives.

But veterinarians often share some other important information, information that physicians seldom share, or even know – that being: exactly what will it cost.

When our family dog recently became very sick, my veterinarian shared not only about the diagnosis, her recommended treatment, its risks, benefits and the plausible alternatives, but she also provided a detailed estimate of what Cosmo’s care was going to cost me.

Isn’t it crazy that when it comes to our own healthcare, we don’t get the same information?

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Pseudo Innovation

Screen Shot 2014-08-01 at 2.06.25 PMFew people know that new prescription drugs have a 1 in 5 chance of causing serious reactions after they have been approved. That is why expert physicians recommend not taking new drugs for at least five years unless patients have first tried better-established options and need to. Faster reviews advocated by the industry-funded public regulators increase the risk of serious harm to 1 in 3. Yet most drugs they approve are found to have few offsetting clinical advantages over existing ones.

Systematic reviews of hospital charts by expert teams have found that even properly prescribed drugs (aside from misprescribing, overdosing, or self-prescribing) cause about 1.9 million hospitalizations a year. Another 840,000 hospitalized patients given drugs have serious adverse reactions for a total of 2.74 million. Further, the expert teams attributed as many deaths to the drugs as people who die from stroke. A policy review done at the Edmond J. Safra Center for Ethics at Harvard University concluded that prescription drugs are tied with stroke as the 4th leading cause of death in the United States. The European Commission estimates that adverse reactions from prescription drugs cause 200,000 deaths; so together, about 328,000 patients in the US and Europe die from prescription drugs each year. The FDA does not acknowledge these facts and instead gathers a small fraction of the cases.

Perhaps this is “the price of progress”? For example, about 170 million Americans take prescription drugs, and many benefit from them. For some, drugs keep them alive. If we suppose they all benefit, then 2.7 million people have a severe reactions, it’s only about 1.5 percent – the price of progress?

However, independent reviews over the past 35 years have found that only 11-15 percent of newly approved drugs have significant clinical advantages over existing, better-known drugs. While these contribute to the large medicine chest of effective drugs developed over the decades, the 85-89 percent with little or no clinical advantage flood the market. Of the additional $70 billion spent on drugs since 2000 in the U.S. (and another $70 billion abroad), about four-fifths has been spent on purchasing these minor new variations rather than on the really innovative drugs.

In a recent decade, independent reviewers concluded that only 8 percent of 946 new products were clinically superior, down from 11-15 percent in previous decades. (See Figure) Only 2 were breakthroughs and another 13 represented a real therapeutic advance.

Spokesmen for the pharmaceutical industry point out that therapeutically similar drugs have advantages. First, physicians need some choice within a therapeutic class because some patients do not respond well to a given drug. This is true, but after about three choices, there is little evidence to justify a 4th , 5th, or 6th in a class.

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