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

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By BISHAL GYAWALI MD 

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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GAO: FDA Can’t Monitor Device Recalls

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By MERRILL GOOZNER

The Government Accountability Office has weighed in on the failure of the Food and Drug Administration to properly monitor medical device recalls. Its review of the 3,510 recalls between 2005 and 2009 — 40 percent of which were cardiovascular radiological or orthopedic devices — found:

Several gaps in the medical device recall process limited firms’ and FDA’s abilities to ensure that the highest-risk recalls were implemented in an effective and timely manner. For many high-risk recalls, firms faced challenges, such as locating specific devices or device users, and thus could not correct or remove all devices.

“The gist of this report is that the FDA can’t tell if recalls of high-risk devices were carried out successfully because it lacks criteria for assessing device recalls and doesn’t routinely review recall data,” said Sen. Charles Grassley, R-Ia., who along with Sen. Herb Kohl, D-Wis., called for the report. “Recalls are typically voluntary, and patients would be better served if the FDA took a thorough approach to post-market surveillance of medical devices.”

 

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FDA Mobile Medical Applications NPRM

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By JOHN HALAMKA, MD

Many have asked me for an analysis of the new FDA Mobile Medical Applications NPRM.

The FDA will not seek to regulate mobile medical apps that perform the functionality of an electronic health record system or personal health record system.   However, the FDA defined a small subset of mobile medical apps that may impact the functionality of currently regulated medical devices that will require oversight.   Here’s a thoughtful analysis by Bradley Merrill Thompson of Epstein Becker Green, which he has given me permission to post:

“Today, FDA published the long-anticipated draft guidance on the regulation of mobile apps—more specifically, what the agency calls “mobile medical apps”.  This draft reflects significant efforts by FDA in a fairly short amount of time, and we applaud that work.  Much of the framework of the FDA guidance is consistent with the work the mHealth Regulatory Coalition (MRC) published on its website earlier this year (www.mhealthregulatorycoalition.org).  While FDA has done a good job getting the ball rolling, there are a number of areas that require further work.  We all (including FDA) recognize that this draft guidance is certainly not the end of the story.

The regulatory oversight recommended in today’s draft guidance applies only to a small subset of mobile apps, which FDA defines as any software application that runs on an off-the-shelf, handheld computing platform as well as web-based software designed for mobile platforms.  To be regulated, as a first step the app would have to first meet the definition of a medical device and then as a second step either (1) be used as an accessory to another regulated device or (2) “transform” the handheld platform into a device, such as by using the platform’s display screens or built-in sensors.

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Is There an Independent Unbiased Expert in the House?

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By SHANNON BROWNLEE

Last week, U.S. Food and Drug Administration Commissioner Margaret Hamburg told the advocacy group Public Citizen that the FDA may loosen conflict-of-interest rules for experts who serve on the agency’s advisory panels. These panels wield considerable power when it comes to FDA decisions about approving drugs and medical devices, and for pulling them off the market when evidence surfaces that they may cause patients harm.

Why loosen the rules? Commissioner Hamburg said the agency is having trouble finding experts to fill its advisory panel slots. In other words, anybody expert enough to be on an FDA panel undoubtedly has a conflict.

Or maybe the FDA just isn’t looking very hard. In 2008, Jeanne Lenzer — an independent journalist — and I created a list of more than 100 experts in fields ranging from epidemiology to neurology to emergency medicine, every one of them independent from industry conflicts of interest. We made the list available to our fellow journalists at the website, Healthnewsreview.org, a site that grades health stories. Dozens of journalists from top news outlets, including the New York Times,Bloomberg, and the Wall Street Journal, have requested the list, and used it to find sources for their stories — or at least we hope they have.

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Pfizer Pioners New Ways to Frustrate Generics

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By Merrill Goozner

The best-selling drug in pharmaceutical industry history, Pfizer’s cholesterol-lowering Lipitor, lost its patent protection Thursday. But the huge savings that consumers, insurance companies and the government usually realize when generic versions of a best-selling pill hit the market are still six months away, and, consumer advocates fear, may never come to pass.

The reason is the unprecedented series of side deals that Pfizer has signed in recent months with some insurers and pharmacy benefit managers to offer lower-priced versions of Lipitor, known generically as atorvastatin. They also are offering consumers $4 co-pays – comparable to prices paid at discount outlets like Walmart and Costco – so they’ll continue buying the brand name version of the drug.

Government officials fear the full cost of the drugs might then be passed along to insurers and Medicare, although the companies involved say that won’t happen.

The goal of the maneuvers is to keep as many of the estimated 8 to 10 million Americans who take Lipitor ($7.2 billion in U.S. sales in 2010; $10.7 billion worldwide) on either the branded product or on an “official” generic, which in Lipitor’s case will be marketed by Watson Pharmaceuticals. They will sell for about half the price of the branded product for about six months, when a number of generic makers are expected to hit the market. Their versions of atorvastatin could sell for as low as $50 a month, which is less than a tenth its current price and comparable to other generic statin drugs already on the market.

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Food Safety: It’s Déjà Vu All Over Again

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By Marion Nestle

In preparation for the holiday season, Secretary of Health and Human Services Kathleen Sebelius and Agriculture Secretary Thomas Vilsack held a press conference to promote the departments’ efforts on food safety.

They announced release of the administration’s progress report from its Food Safety Working Group.

They also highlighted additional places to get government information about food safety at home:

I didn’t pay much attention to these announcements until I read the slightly snarky account in Food Chemical News (December 22).

The Obama administration patted itself on the back today with a new report that both lists the accomplishments over the past three years of its Food Safety Working Group (FSWG) and identifies the group’s top priorities for the coming year.

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The Economics of Reimplantation

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By Dr. Wes

From The Annals of Internal Medicine doctors from the US have shown that ICDs can be safely resterilized and re-used for indigent patients in another country. In their study, Pavri et al collected 106 ICDs with three or more years of estimated battery life from either deceased patients or patients having devices explanted because of “upgrades” or infection and implanted then in 81 patients in a single hospital in Mumbai, India. From the Methods section of their paper:

We deleted all identifying patient information and lead information; programmed them to nonpacing mode, when possible, or lowered the outputs to the minimum possible values; turned off all sensing and therapies for ventricular tachycardia (VT) and ventricular fibrillation (VF); and deactivated all ICD alerts (auditory and vibratory). When a sufficient number of devices were collected, they were transported to India in batches. Transport was most often done by physicians (or friends and family members of physicians) who were traveling from the United States. The devices were placed in checked-in baggage in a clear plastic bag, and 2 letters were placed in prominent view. The first letter was signed by the donating physician, stating that the devices were of no commercial value and that they were being donated for reuse in patients who could not afford such devices. The second letter was signed by the Chief Executive Officer of Holy Family Hospital, stating that the hospital was expecting the devices for donation to such patients. Contact information for all physicians was provided in the letters.

Attempts at sending explanted devices by courier or mail proved difficult; without precedent, it was simply not possible to describe the purpose and nature of the shipment to shipping authorities or to insure the contents. We finally resorted to carrying the devices during travel to India in our personal baggage, as described. Some difficulties (requiring lengthy explanations) were encountered during baggage screening and, especially, at Customs in Mumbai.

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Surrogate End Points Ain’t all that Bad

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By 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

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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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By NIAM YARAGHI

Screen Shot 2015-05-18 at 10.25.01 AM

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.

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