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FDA has released three final guidance documents on biosimilars but left for later its regulatory answers on requirements for demonstrating interchangeability of a biosimilar with a reference product and terms for establishing the exclusivity period for pioneer biologics. FDA will address these issues in a separate draft guidance. The agency does not have an estimated timeline for when the document will be released.
The agency released final guidances covering scientific and quality considerations in demonstrating biosimilarity. The document on scientific considerations includes additional information on study design, endpoint selection and appropriate patient populations for a comparative clinical trial. The guidance also clarifies what factors to consider when assessing whether products are highly similar, including expression system, manufacturing process, impurities, reference product and reference standards.
The agency also issued a guidance providing questions and answers on biosimilars, which explain how sponsors can justify extrapolation from a single indication to support approval for additional indications on a reference product's label. The document indicates that sponsors should avoid extrapolation from indications for which the reference product has obtained accelerated approval but has not yet demonstrated clinical benefit in post-marketing trials.
The Q&A also includes FDA's expectations for the submission of pediatric study plans and outlines justification that should be provided by a sponsor to use comparative data with a non-U.S.-licensed product to support an application to FDA.
Yesterday, CDER Director Dr. Janet Woodcock suggested to the Senate health committee hearing on the Innovation for Healthier Americans Initiative that developing new biomarkers and clinical trial networks, among other strategies, could help improve the drug development process.
“There are other areas in which we hope to work with you as well, including modernizing drug manufacturing, encouraging the development of new antibiotics, and improving the processes for FDA review of drug/device combination products,” said Woodcock in her testimony. She also said drug development could be improved by harnessing evidence from clinical experience, such as through FDA’s Sentinel Initiative, and strengthening patient engagement.
Absent from Woodcock's testimony were controversial measures, included in the first draft of the House Cures bill, that would dramatically revamp current clinical trial design and provide new market exclusivity incentives to a broad swath of drug products. These proposals have been sharply criticized by consumer advocates and some congressional Democrats. “As we say in medicine: First do no harm,” Woodcock said. She also warned lawmakers that giving the agency’s drug center a “large number of unfunded mandates” would cause review performance to suffer.
Woodcock suggested using clinical trial networks and master protocols as a way to reduce clinical trial costs. She said: “First, the cost of clinical trials continues to grow and is the greatest source of cost increases in medical product development. Today, developers of a new medicine spend many millions of dollars planning a clinical trial, developing an elaborate trial infrastructure, finding and enlisting investigators, conducting the trials, and managing the trial data. Each time a new drug is tested, the process is repeated, at great expense, only to dismantle the infrastructure when the study is completed.”
She also advocated improving the science of biomarkers, which are used as indicators of health or disease, or in assessing the response to a therapeutic intervention. Biomarkers have many uses in drug development, according to Woodcock, such as performing safety monitoring, selecting appropriate patients for clinical trials, and selecting therapy for treating specific patients. “However, biomarkers based on new scientific understanding have been slow to come into clinical use, largely because the evidence supporting their validity has been lacking.”
Senate health committee chair Lamar Alexander (R/TN) told Woodcock he welcomed her suggestions. “We would like to invite you to give the bipartisan working group that [Sen. Patty Murray (D/WA)] and I have formed specific suggestions from your agencies about what we can do to enable you to do your job. We don’t want to produce a bill that reduces your productivity, we’d like to increase it,” he said, adding the timing for that feedback would be in the next few months. He also said that funding would be discussed by the Appropriations Committee and to some extent in the health committee.
Did Dr. Tim Byers (University of Colorado Cancer Center) present (at the April meeting of the American Association for Cancer Research) “new evidence” that some people get more cancer while on vitamins? On the face of it, this doesn’t sound like a tough question.
At a session entitled “Dietary Supplements and Cancer Risk and Prognosis” Dr. Byers presented information from his 2012 commentary in the Journal of the National Cancer Institute, Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms (May 2012). It’s an interesting and important read – but is it new?
Well, it seems that question depends on who you ask. According to CBS News, “new research finds…” and according to a leading British newspaper, the Daily Mail, “a new study has found …”
The media’s interest in Dr. Byers’ research came about via a standard (and accurate) . How does the University PR representative feel about the success of the story?
Garth Sundem (University of Colorado media relations department) said he was surprised to see that his news release was “immediately and aggressively sensationalized” by the media, and described a “ripple effect, almost like a game of telephone tag, where news outlets, especially in the UK, seemed to give increasingly more sensational accounts of the study without ever going back to the original source.” He described Byers as being “just as horrified as you’d expect any academic researcher would be.”
Does this mean that the 2012 article is irrelevant? Certainly not, but in light of the recent news coverage over GNC’s manufacturing irregularities, the on-going debate over regulating dietary supplements as food, and marketing abuses (particularly online) of structure/function claims, it’s not surprising that the Fourth Estate jumped all over Dr. Byers’ findings branding them as “new” to enhance media value.
But that doesn’t make it so.
Sticking to the facts is what news organizations are supposed to do – making the facts more than they are isn’t journalism – it’s hype. And that serves neither the public nor the public health.
Most dangerous outcome here is that the media hype leads people to stop taking important vitamin supplements.
Facts do not need to be … supplemented.
Per Genervon, what is the position of the patient community?
The ALS Association, appreciates the statement that the FDA released today calling on Genervon “to release all the data from the company’s recently completed trial in order to allow a more informed discussion of the trial findings among ALS stakeholders.”
Stand by for more on this on-going debate.
From the pages of the Kansas City Star …
Well-meaning but erroneous online medical advice can be deadly
The most famous recent source of bad advice, according to a group of prominent physicians, is Mehmet Oz. His critics recently called on Columbia University to drop the talk show host (who is also a cardiothoracic surgeon) from its medical faculty, slamming him for showing a “disdain for science and evidence-based medicine” and manifesting an “egregious lack of integrity by promoting quack treatments and cures in the interest of personal financial gain.”
If a heart attack doesn’t kill you, advice on your Facebook page could.
An old, discredited email has found new life on social media, advising people who are alone during a heart attack to breathe deeply and cough vigorously as a way to save their lives. This supposedly increases oxygen levels and helps blood circulate.
While the advice is well-intentioned, it is wrong. Dead wrong.
Repeated hard coughing could turn a mild heart attack into a fatal one, said Tracy Stevens, a cardiologist at St. Luke’s Mid American Heart Institute. So-called “cough CPR” is only preferable in a hospital under expert supervision.
Better advice: Immediately call 911 and chew a regular-sized aspirin.
The coughing message is but one example of potentially dangerous medical misinformation spread online and through social media.
The most famous recent source of such bad advice, according to a group of prominent physicians, is Mehmet Oz. His critics recently called on Columbia University to drop the talk show host (who is also a cardiothoracic surgeon) from its medical faculty, slamming him for showing a “disdain for science and evidence-based medicine” and manifesting an “egregious lack of integrity by promoting quack treatments and cures in the interest of personal financial gain.”
Specifically Oz has come under fire for hyping “miracle” weight-loss products that were later discredited, warning viewers about arsenic in certain brands of apple juice, announcing that his own children wouldn’t be vaccinated, and for suggesting the Ebola virus could become airborne.
He makes those claims on his syndicated TV show, and word spreads further through social media.
Oz fired back, characterizing the attacks as an ugly “smear campaign” by “rent-a-scientists” working for big corporations.
Regardless of who is the culprit, the problem is growing. Last year the World Economic Forum asked its 1,500 members to identify the main concerns spanning the globe. At No. 10: the rapid spread of misinformation online, with special emphasis on the role played by social media.
Peter Pitts, president of the Center for Medicine in the Public Interest, and a former FDA associate commissioner, called such quickly spreading quackery “insidious and dangerous and, in many ways, life-threatening.”
“I’m excited that more people are getting information about their health online, but I’m concerned that some think everything they read (there) is true,” he said in an interview. “There’s a famous quote by Mark Twain: ‘Be careful about reading health books. You might die of a misprint.’ But that was back when medical information traveled at the speed of cattle boats. Now it travels around the world in milliseconds, with absolutely no quality control.”
People want to believe there are simple solutions to complex problems, he said.
“People like good news, and they all just know their doctor is wrong,” he said. “And since nature abhors a vacuum, there’s social media (and other platforms) with well-intentioned people with bad information.”
Experts urge people to search only at trustworthy sites.
“We tell everyone to go to MedlinePlus, which is produced by the National Library of Medicine,” said Linda Walton, president of the Medical Library Association. “The quality and correctness of the information has been reviewed by medical librarians and other experts.”
But checking responsible sites doesn’t always lead to a safe result. An Internet search for “Can coughing during a heart attack save your life when you’re alone?” returns the WebMD article “Coughing May Help During Heart Attack.”
Catherine Daniel, a WebMD spokesperson, noted that the Cough CPR article was datelined 2003 and clearly marked “WebMD News Archive.” She said the site had more up-to-date information that warned against the technique.
The problem, critics say, is that some readers may not go past the headline. And the article does not note that the advice is now discredited, and potentially deadly.
“That’s very misleading,” said Stevens, the St. Luke’s cardiologist.
These messages circulating in email and online contain more misleading and potentially harmful medical information.
▪ Myth: Various cancers can be cured by pureed asparagus. The message has been circulating online for years.
“There’s no human trials that any food cures cancer,” said Jeanne Drisko, professor and director of KU Integrative Medicine at the University of Kansas Medical Center, who tracks medical misinformation online.
It gets worse. Asparagus can interfere with a drug used to treat acute lymphoblastic leukemia, Drisko said, so eating asparagus actually could make some cancers worse.
▪ Myth: Cancer can be cured by ingesting small amounts of hydrogen peroxide mixed with water. NaturalNews.com, a health and wellness website with more than 1.4 million likes on Facebook, makes this claim for “35 percent food grade” hydrogen peroxide.
“The ‘lame-stream’ mainstream media will tell you how ‘dangerous’ it is at 35 percent, but they won’t tell you that you can drip a couple drops in a glass of water each day and end cancer,” the site says. “Yes, it’s true.”
No it’s not, Drisko said.
“They are absolutely off base,” she said. “It cannot cure cancer.… And it can be very dangerous. You should never drink hydrogen peroxide. It can burn the stomach if the wrong form is consumed,” and kill in larger quantities. “That’s very bad advice.”
▪ Myth: Ticks can be easily removed with liquid soap and a cotton ball. This well-meaning piece of medical claptrap was supposedly shared by a school nurse:
“Apply a glob of liquid soap to a cotton ball. Cover the tick with the soap-soaked cotton ball and swab it for a few seconds (15-20). The tick will come out on its own, and be stuck to the cotton ball when you lift it away.”
Don’t do it, Drisko said. Such folk remedies — which also include painting the tick with nail polish or petroleum jelly, or using heat from a burned match head — not only don’t work, but can make matters worse by actually triggering salivary fluids from the tick, possibly leading to the transmission of disease-causing microbes.
“Your best bet is to not mess around, but to get that tick removed,” Drisko said. “Preferably in the first 24 hours.”
Experts recommend using tweezers to grasp the tick as close to its head and mouth as possible and pull slowly but firmly. If the head remains after removal, seek medical attention.
The challenge of policing medical misinformation is monumental, said Pitts of the Center for Medicine in the Public Interest. “You can’t limit a well-meaning person who wants to share their beliefs.”
That puts the onus on the health consumer. While the Internet has many reputable sites, such as the Food and Drug Administration and the Centers for Disease Control and Prevention, Pitts said, the information they provide is not always written in a way consumers can understand.
“In the U.S. our health literacy is very low,” he said. “The way to increase it is not by throwing textbooks at people. What I say is call your doctor, or talk to your pharmacist.”
Even better, he said: Get more doctors on Facebook and Twitter.
“How many physicians are on social media?” he asked. “Not many. They may be on for personal reasons, but we live in the 21st century, and that’s got to change.”
According to a report in FierceBiotech …
The Wall Street Journal has caught up with the Genervon controversy, recapping a series of events from the last few days that followed the big social media campaign to gain an instant approval for a new ALS drug based on the results of a 12-patient study. FierceBiotech readers will know already that the data for GM604 were questioned by Steve Perrin, president and chief scientific officer of the ALS Therapy Development Institute, and that the FDA followed up a day later with an extraordinary challenge to Genervon to publish the data on a drug that the biotech has touted as a major advance for patients.
The Journal, though, did manage to nail down an answer from the company, run by Winston Ko, about the application the patient community believes has been filed for accelerated approval.
There isn't one.
Genervon tends to prefer email communications these days. And the company told the Journal that it is "at the point of communicating with FDA about whether [the agency] would accept our formal application" for accelerated approval.
Genervon, meanwhile, has already repeated claims to us that it made a "formal request" for accelerated approval, an assertion that dates back at least to last month. The company has stated in releases that it has "met with the FDA and has submitted an Accelerated Approval application." The biotech has also claimed several times that an accelerated approval decision was already in the works at the FDA, and it's done nothing to stop publications like The Washington Post from reporting that an application is at the FDA as it repeatedly prodded dying patients and their families to back calls for a quick approval as their only chance of getting the drug and staying alive.
Back in mid-February, Genervon issued a statement saying that it had met with the FDA and asked for accelerated approval three times during the course of the get-together, then asserted that the agency had 30 to 60 days to respond. That mid-April deadline--which has been repeated by the petition's sponsors--helped trigger a frenzy of petition signing at change.org, which currently has more than 535,000 signatures backing instant approval.
But that's not going to happen, because without an actual application, there is no 60-day response time for the agency to accept or reject the application for review. Given the FDA's challenge to Genervon, and its clear doubts about the data from the tiny study, the company's chances of being received at a wary FDA with open arms lies somewhere between none and zero.
As far as making any public statements about Genervon, though, the agency's hands are tied by federal law.
Patients and their families should know that there is no decision pending at the FDA. They might also ask themselves if Winston Ko and Genervon have been stirring false hope among the dying in an attempt to create a social media campaign that would push the FDA to sanction the drug's sale on questionable data.
It looks like the FDA (and specifically John Jenkins) has had enough and isn't going to take it anymore.
From the pages of Medical Marketing & Media …
FDA takes unusual stance on ALS drug
The FDA said Genervon should supply more data if it wants an accelerated approval.
The FDA took an unusual public stand Friday when it publicly asked Genervon Biopharmaceuticals to release all data from the California drugmaker's recently completed trial for an experimental drug for amyotrophic lateral sclerosis, a neurodegenerative disease also referred to as ALS and Lou Gehrig's disease.
Doing this would allow a more informed discussion of the trial findings among ALS stakeholders for GM604, the FDA said.
“It is certainly not a routine practice,” FDA spokesperson Sandy Walsh told MM&M.
The FDA's request follows a surge of patient activism, including a Change.org petition that is urging the FDA to grant an accelerated approval to the drug based on a Phase-IIa study comprising 12 patients. An accelerated approval would allow the drug to be distributed as is to the general patient population as opposed to using pathways like the FDA's compassionate use provision, which grants patient-by-patient access to unapproved investigational drugs.
The FDA has a history of taking patient lobbying efforts into consideration, such as when it approved Sanofi's Lemtrada for multiple sclerosis.
Steven Perrin, CEO of the ALS Therapy Development Institute, which conducts ALS research, highlighted what he considers problems with the research on his blog. He told MM&M that the data set is far too small for a regulatory decision for reasons that include the size of the clinical trial and because ALS progression differs patient by patient. He said this makes it difficult to back efficacy claims.
Perrin said putting ALS patients on a drug lacking sufficient data could jeopardize other experimental drugs that do have Phase-III data because patients taking GM604 would not be able to take another candidate, be it one that his group supports or one that is backed by another company.
Perrin said he doesn't want to kill the drug but he does want Genervon to “do the right thing” and adhere to traditional regulatory protocols and run a larger clinical trial.
Perrin is not Genervon's only critic. The Washington Post reported earlier this month that one of the researchers involved in the study said more data was needed.
Genervon said in press releases that finding a treatment for the disease requires an unconventional approach. Genervon declined to provide answers to queries including if the company plans to pursue late-stage clinical trials and if it has provided the FDA with all of the information it has on hand. Chief Operating Officer Dorothy Ko referred MM&M to its website.
Genervon said in an April 13 press release that pursuing an accelerated approval has some risks because it would mean exposing this early-stage treatment to “a full spectrum of heterogeneous ALS patients,” rather than if the drug went through traditional testing, which the company described as “a more secure and conservative approach.” Genervon also said drug sales from an accelerated approval would allow the company to fund further development.
The FDA noted in its public request that it is not allowed to release clinical trial data about experimental medications, but the drugmaker can.
Perrin acknowledged that it is easy to understand the appeal of an experimental medication but that choosing a drug that is not scientifically supported can prevent patients from trying one that has more verifiable outcomes. “They are desperate for hope and they want access to stuff, even if there is not a lot of data,” he said.
Genervon told MM&M it is reviewing the FDA's request.
What happened to keeping politics away from science?
Some fine legislators in the World’s Greatest Deliberative Body -- Senators Joe Manchin (D/WVA), David Vitter (R/LA), Shelly Moore Capito (R/WVA) and Tim Kaine (D/VA.) -- have just introduced the so-called FDA Accountability for Public Safety Act. So-called, because these fine legislators do not seem to understand that there is no such thing as a drug that is 100% safe.
Among other items, the legislation would require the FDA to hold advisory committee meetings for all opioids under review and submit a report to Congressional committees explaining why the agency approved an opioid against an advisory committee's vote, including scientific evidence related to patient safety.
Note to fine legislators –“safety” is a relative concept viewed through the perspective of benefit/risk.
The bill also would force FDA to publicly justify its approval of any opioid drugs not recommended by advisory committees for safety reasons. Note to fine legislators – all drugs have risks. Products are not abused because they are “unsafe.”
Many raise the FDA adcomm vote on Zohydro as an example of the agency acting to approve an opioid after a negative committee vote. The soundbite you’ve likely heard is that the vote was against approval of the drug. That’s true. What you probably don’t know is that, by a vote of 11-2, the experts affirmed that there was no evidence to suggest Zohydro had greater abuse or addiction potential than any other opioid.
Note to fine legislators – facts are stubborn things.
The bill also stipulates that the FDA commissioner make a final decision regarding approval of opioids not recommended by the committees due to safety concerns. Note to fine legislators – all approvals are done under the name of the Commissioner – and then testify before Congress if called upon. Really? Can you hear those political sabers rattling?
In addition, the agency would have to disclose any conflicts of interest that may be held by its officials. Do these fine legislators mean the members of advisory committees? If so, this already happens. If they mean FDA staff – then shame on these fine legislators for casting unfair and unfounded aspersions on overworked, underpaid, and deeply committed public health officials.
But wait, there’s more. A sponsor would be prohibited from distributing an approved opioid until FDA submits its report to Congress. After all, these fine legislators are all highly trained scientists capable of judging the issues of crucial importance to the tens of millions of American who suffer from chronic pain.
Perhaps these fine legislators should read the FDA’s “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling” which explains the FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties. It also makes recommendations about how those studies should be performed and evaluated, and discusses what labeling claims may be approved based on the results of those studies.
Besides being a bad idea for opioids – the FDA Accountability for Public Safety Act is a slippery slope towards political interference in the drug approval process. If the FDA must defend its approvals of opioids today, will it have to defend its decisions not to approve cancer drugs tomorrow? Should the agency have to explain its decisions to Congress when it approves a drug via an expedited approval pathway too?
Question to fine legislators: What’s next?
Love him or hate him (and many people do both), Dr. Richard Pazdur -- director of the FDA's Office of Hematology and Oncology Products-- is the world's most important cancer drug regulator.
In an exclusive web interview, Dr. Pazdur tells BioCentury why the agency is racing to approve new cancer drugs. He says new targeted drugs and immunotherapies with unprecedented efficacy are the payoff from 20 years of basic science. He calls for greater patient engagement in drug development, says compassionate access should be improved, and predicts rapid uptake of biosimilars.
The four-part interview contains the segments:
· Cancer "Rocket Docket" – How the FDA is racing to approve new drugs because it is seeing unprecedented efficacy.
· Patient Power. Why the patient voice is critical to improving cancer drugs.
· Precision Medicine. How the agency is trying to make precision medicine a reality for cancer patients.
· Compelling Case. The case for doing more to create better cancer drugs for kids.
The complete video interview can be found here.
Ever heard of the Precautionary Principle? It’s basic premise is that you shouldn’t do anything new until you know everything about how it works or what it’s impact will be. Not a good theory on paper – and even worse in practice. For example, if you believe in this concept, you wouldn’t allow any new life-saving medicines on the market before you knew everything about how it would impact patient lives.
When it comes to science, innovation involves a careful balancing of benefits and risks based on the best possible scientific information. And it should not come at the cost of doing harm to public health by slowing down the availability of new and better technologies.
Now consider the case of neonicotinoid pesticides (aka, “neonics”) and the health of honeybees. Neonics were introduced in the late 1990s without incident as a less toxic replacement for the mass spraying of organophosphate and pyrethroid pesticides, which are both known to kill bees and wildlife.
You’ve likely seen the hysterical headlines about the “Bee-pocalypse” caused by neonics. That’s not the Precautionary Principle – that’s a total misrepresentation of the scientific reality.
But bee deaths are nothing new. The current “crisis” prompting the EU’s reaction is an age-old problem in the bee world: unpredictable bee deaths. They’ve occurred periodically for more than a century. And it’s so easy to blame evil pesticides. Unfortunately, that’s not the case. As an article in Forbes commented, “Activists often coalesce around an issue and then come up with a simple but sometimes simplistic narrative to frame it. Strident opponents of modern agricultural technology initially blamed GMOs for bee deaths, and some still make that claim, although there is zero evidence to back it up. When that didn’t get traction, the focus switched to neonics.” Publications ranging from Mother Earth to Mother Jones jumped on the “ban neonics bandwagon.”
Alas – it’s not nice to try to pull a fast one on your mother. Here are the facts.
In December 2013, the European Commission banned the use of neonics, for two years. The moratorium (driven by the precautionary politics that today dominates so-called science-based regulation in Europe) took effect just as numerous new studies shed increasing doubt on the belief that neonics play a central role in bee health. Scientific American’s Francie Diep noted in a recent article sub-headlined “why colony collapse disorder is not that big a deal anymore,” North American honeybee colony numbers have been stable for years at about 2.5 million even as neonics usage became more widespread.
And a brand new study (published in the March 18, 2015 journal PLOS ONE), shows that neonics do not harm honey bees at real-world dosage levels. According to the paper, ““Everyone is pointing the finger at these insecticides. If you pull up a search on the Internet, that’s practically all anyone is talking about,” said Galen Dively, emeritus professor of entomology at UMD and lead author of the study. “This paper says no, it’s not the sole cause. It contributes, but there is a bigger picture.”
And the US Agriculture Department and the EPA convened a working group to address that very question. Their report concluded that neonics, while a contributor, were way down the list of possible causes.
"It seems that the White House is following the same path. Staffed by many environmentalist "true believers," the Obama administration has already implemented both product testing and labeling requirements for neonics before it's own Taskforce on Pollination completes its recommendations."
Alas, the EPA just announced a couple weeks ago that they’re halting new use approval on chemistries that have already been approved until new studies can be done, essentially a precautionary move. The implications of moving to the precautionary principle doesn’t just mean new, innovative technologies don’t get approved, it means innovators may question their desire to pursue and invest in new technologies. Embracing the Precautionary Principle has serious and deliterious implications for feeding a growing planet in a cheaper, safer, and more sustainable manner -- with no guarantee of improving pollinator health at all.
That’s just bee-ing and nothingness.