Weekly Roundup 6.29.18

Apologies are in order for the interruption in the Weekly Roundup schedule and no postings the last few Fridays. It was partially inspired by the fact that it was a busy  few weeks for me.  Conversely it seemed not so much for FDA despite the issuance of a number of not-so-interesting statements so it seemed a good idea to forego a few Roundup postings.  Things got more newsworthy this week though and hopefully makes up for it.  Included are a few things from weeks gone by.  Next week no posting for July 4, resuming the week thereafter. 

  • OPDP Issues 2nd Letter of the Year!  Just when you think FDA’s OPDP is on permanent vacation, they surprise you. The office of the FDA in charge of promotional enforcement which used to issue dozens and dozens of letters to companies each year has eeked out its second for this year. This one was not a warning, but an untitled letter, and the subject was a video for a product that has a boxed warning on its label. Yet FDA found the video contained absolutely no risk information. The video depicted an interaction between a physician and a patient whereby the patient expressed a speedy and breezy use of the product, which FDA also maintained was not an outcome that was typical for patients who might use the product. You can see the letter here
  • FDA Issues Guidance Clarifying Economic Discussions with Payers – In my last posting I covered new FDA Guidance related to discussions about useful drug information not contained in the label, but nevertheless consistent with the label. A companion guidance also covers discussions with payers and formulary committees about economic information not contained in the label to support decision-making around reimbursement. The audiences for this information include both public and private sectors, formulary committees, drug information centers, technology assessment committees, pharmacy benefit managers, third party administrators and other multidisciplinary entities that make coverage decisions. For approved drugs the information imparted must pertain only to approved labeling. The guidance covers situations where manufacturers are providing healthcare economic information (HCEI) to providers about approved drug products, medical devices as well as unapproved products, and the guidance divides the discussion under those categories. 
  • FDA Approves First Medicine Derived from Marijuana – You would have to live under a rock not to have heard this news, but it is historically significant enough for a number of reasons to mention here. First, the newly approved drug, Epidiolex, a purified form of cannabidiol (CBD) and one of more than 80 active chemicals found in marijuana. The new approval, which lacks the THC component for achieving a “high”, is indicated to treat seizures as a result of Dravet Syndrome and Lennox Gestaut Syndrome (LGS).  Both conditions affect children.  It is the first approval for a drug to treat Dravet. Both conditions can have a dramatic impact on quality of life for those affected and their families. But significance is also derived from the fact that the source material – marijuana – has long been advocated as a potential source of medicine. The study for potential benefits has long been hampered by legal constraints and by dogma but FDA has provided guidance for the clinical study of botanicals. The approval was under Fast Track, Priority Review and the drug has Orphan Drug Status. You can see the FDA press release here, the statement by the Commissioner on the importance of research in this area here and the company press release here
  • More on Patient Input – For a long time now we have heard about FDA transitioning to be more patient-centric, including the development and launch of a Patient Engagement Advisory Committee as well as holding a series of Patient Focused Drug Development meetings covering more than 20 disease areas. And in 2016, patient experience counted in the approval of a drug contrary to the recommendation of an FDA Advisory Committee. This week the agency issued a draft guidance document, the first of four planned, to explain to both patients and drug developers the principles by which FDA will incorporate patient and caregiver experience into the regulatory process. This particular guidance – Patient-Focused Drug Development: Collecting Comprehensive and Representative Input – concentrates on providing methodologies for how to operationalize the collection and use of patient experience data by drug developers. 

Things to Keep an Eye on This Week

Regulatory Developments in Pharma/Biotech/Devices

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A (Slight) Liberalization of Communications with Docs from FDA

What Happened. This week FDA issued a new final guidance related to communications about medical products that, while representing a slight liberalization of regulation when it comes to discussing useful information about a drug and the cleared uses for it, but which may not be included in the label. That said, the guidance does not address the issue of off-label promotions – or discussions that involve aspects of the product for uses in which it has not been cleared. The utility of the new guidance is that it will allow firms to talk about things – such as post-marketing study outcomes – that will enhance the understanding of the on-label use of the product. 

What it Says. To shed light on where the parameters are, the guidance document provides eleven Q&A format discussions to demonstrate the approach that FDA is taking. The first Q of the Q&A covers which products are addressed and the second provides the crux the regulatory approach in answering how FDA determines whether a communication is consistent with the FDA-required labeling. The agency said that it uses three factors to determine compliance and failure to meet any of them results in a communication that is outside of the FDA-required labeling. The first such factor involves the actual information contained in the communication – whether it varies the indication, the patient population, affects the limitations and directions for use and whether it alters the dosing or use regimen. If the answer to any of these is yes – then the communication is not going to be consistent with the label. The other two factors are a bit less objective. The second of the three factors is whether the communications increase the potential for harm and the third factor is whether the directions for use enable safe and effective use under conditions that may be described in the context of the communication in question. 

The balance of the guidance provide specific examples to more sharply define the parameters of how the agency applies the assessment of a communication by the company that is about information not included in the label, but which is not involving an off-label use. 

Implications and Insights for Pharma. In considering how the new guidance may impact the communications by pharma companies, it is important to take into account where violations have occurred in the past. It is notable that FDA has issued this guidance during a time when enforcement by the agency is at a standstill with only a single enforcement letter having been issued by the Office of Prescription Drug Promotion (OPDP) so far during 2018 and following a record low of 6 last year. In reviewing FDA enforcement since 2004, out of the 324 letters issued by OPDP (or under its predecessor name DDMAC – the Division of Drug, Marketing, Advertising and Communications) by my count only 18 letters involved a violation of promotion of an unapproved use. Of those, 7 involved oral statements, mostly by sales representatives, though one involved a company CEO in a media interview.  Other violations almost exclusively involved communications vehicles aimed primarily at physicians, such as Dear Doctor letters, direct mail or sales aids. So while the new guidance pertains to all communications by companies to physicians, because the most common violation occurred in the contest of an oral statement, particular care might be taken by companies to train spokespeople with regard to the parameters of the new guidance, especially for sales people who visit doctor offices or who are speaking with people at medical meetings while staffing exhibit booths. 

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The Back and Forth on Safety Versus Speed and FDA

This week the Commissioner issued a statement related to the proposed modernization of the FDA’s drug review office, also the subject of a blog post by FDA’s head of the Center for Drug Evaluation and Research Janet Woodcock. While focused on the drug review process, they are just the latest pronouncements from the agency to address move to speed up the approval processes for all things – devices, digital health, artificial intelligence interventions, not just drugs.  And with the passage and enactment of the 21st Century Cures Act among other things, there has been policy momentum to change the status quo. The word “modernize” has become code for reducing regulatory process – or sometimes in political parlance “reducing regulatory burden” without compromising safety or the “gold standard of the agency”.  

There are a lot of good reasons to speed things up and to maximize access to new treatments. As Dr. Woodcock noted in her blog posting, the environment is dynamic – things change  – evolving technologies, the emergence of new kinds of therapies – and the way we evaluating them has to change with it. 

The need for changes in the system of approvals was very apparent in the earliest years of the AIDS epidemic when there were no treatments available to patients other than those used to address the opportunistic infections that came about as a result of a compromised immune system – and even those treatments were often without much impact.  The average length of time that it took for a drug approval was much longer than it is today. According to a table developed by the General Accounting Office, in 1987 the average length of time from submission to approval for a new drug was at its longest – 33 months. By 1992 it was 18 months. In short the need was extreme, the ability of the system to deliver was not. 

Though the wheels of progress moved slowly,  as a result of AIDS activism, eventually changes came about that resulted in formalized mechanisms that had been under consideration to expedite drug approvals.  The result were several new mechanisms introduced over a period of years designed to facilitate approval as part of the FDA review process – Priority Review, Fast Track, and Accelerated Approval.   And the most recent pathway for expediting approval came in 2012 with the Breakthrough Therapy Designation.

But speeding approvals were also sometimes associated with at least a perceived sacrifice in safety. In the early 2000s there emerged a public debate about the impact of these programs when several high profile drugs were associated with serious side effects, some of which were eventually withdrawn from the market. Several drugs that had been Fast Tracked were withdrawn either for lack of efficacy or safety reasons such as hepatoxicity and cardiovascular events. 

We are now on the cusp of a good deal of change that is poised to pick up the pace broadly. 

As we approach a new level of a systemic easing the regulatory burden – one that goes beyond what was accomplished in the past in that regard- often coupled with reassurances that FDA’s gold standard will not be compromised – we have to be aware that getting the pendulum in exactly the right spot is likely impossible.  Most of the focus so far has been on the steps being taken to speed up and facilitate the process of approval. But in doing so, we have to also ensure that our methods for evaluating that whether the “gold standard” is being maintained are also modernized so that we keep up with monitoring the effects of so much change.   

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Weekly Roundup 6.1.18

While not the official one, the summer I knew as a kid – the one beginning after Memorial Day – has arrived. Officially I guess we have to wait a few more weeks. Once again a week without an intervening posting apart from the Weekly Roundup, but it has been a busy season and I do have a few in the works on deck. In the meantime, as the stragglers among us get busy planning summer getaways, here is a bit of what happened this week:

  • The Eyes Have It – Designated as a Breakthrough Device, this week the agency announced approval in the U.S. of the first standalone prosthetic surgically implantable iris to be used in patients who have a damaged iris either as a congenital condition or as a result of injury. While the iris is the colored part of the eye, it also serves the function of controlling the amount of light entering the eye. A damaged iris is not only therapeutic, but is also a cause of light sensitivity. The device is made of a thin, flexible silicon and can be customized for the eye color and appearance of the patient. In reporting on the clinical trial, one heard something the agency does not often refer to in clinical outcomes which was reference to improved quality of life in patients. FDA said adverse events were low, but did note several conditions where use of the device would be contraindicated. The device went through the Pre-Market Application process – the most thorough regulatory pathway for devices. 
  • Duchenne Muscular Dystrophy Treatment Gets Negative Opinion in Europe – In 2016 Sarepta was granted FDA approval for its treatment – eteplirsen – for Duchenne Muscular Dystrophy under the rare circumstance (about 10-11 percent of the time by my count) whereby the agency goes against the opinion of an advisory committee recommendation.  This week the company announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had issued a negative opinion on the treatment. The company had previously anticipated the outcome in an earnings call earlier this month and will request a re-examination of the opinion, a process that will take place by year-end. The U.S. decision has been described as controversial. 
  • Gottlieb Statement on REMS and Generics – Commissioner Gottlieb continued his narrative related to the use of REMS by brand name drug makers as a means to block timely generic drug market entry this week by issuing a statement to echo prior statements on the subject and to further outline the agency’s approach and releasing new guidance documents to try to ease the situation. He stated that REMS programs are exploited in two ways to block generics by some players. He stated one occurs at the front-end when a generic manufacturer is seeking sufficient doses of a brand name drug to determine bio-equivalence and cannot get access and the other is at the backend of the process when a generic drugs seeks approval. He announced steps to address the latter. Current law requires that under certain circumstances a brand name and generic drug share a single REMS program and the process for doing so requires negotiation between the companies. He said the agency was issuing two new guidance documents to address potential delays – the first – Development of a Shared System REMS that describes principles and recommendations to improve clarity and efficiency for the development of a single REMS program between companies. The second – Waivers of the Single, Shared System REMS Requirement outlines when and how FDA will consider waiving the requirement. 

Things to Keep an Eye on This Week

Regulatory Developments in Drugs/Biotech and Devices

Photo by Patrick Baum on Unsplash

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Weekly Roundup 5.25.18

It is Memorial Day Weekend!  The opening bell for summer vacations has arrived. It is time to do your wardrobe switch – get out the white shoes, sandals and linen clothing and put the corduroys away until Labor Day. Time to wince about last year’s bathing suit and the fact that it appears to have shrunk while stored away. And sorry to say this was a busy week, leaving no time for an intermittent posting between Weekly Roundups, but will shoot for at least one next week. Meanwhile a bit of what happened in this week as everyone is poised to get away or stay home and usher in the summer with a barbeque:

  • Gottlieb Signals New Facilitation of Gene Therapy –  In a speech given at the annual board meeting of the Alliance for Regenerative Medicine, Dr. Gottlieb stated that we have arrived “at a key point when it comes to cell and gene therapy” – moving from theory to therapy.  He pointed up that the agency has put into place a new policy framework in 2017 putting in place an informed approach for the development of new products through enhanced pathways offered by the agency, in particular providing the means for small institutions efficient means to meet requirements of the approval process. The field is growing rapidly – with three new approvals this past year in gene therapies and more than 500 active investigational new drug applications with the agency now. To facilitate rapid consideration he said that the agency will be issuing guidance documents, among which will be a pathway for accelerated approval endpoints for certain gene therapy products and that the first therapeutic category addressed will be for hemophilia. 
  • Congress Passes “Right to Try” – The House of Representatives passed the “Right to Try” legislation that provides an authorized pathway for patients with a terminal illness to seek direct access to drugs under investigation for safety and efficacy. Need for the legislation was perceived by many to be more political than practical given the already existing process of early access or compassionate use overseen by FDA. The new legislation removed federal oversight and Commissioner Gottlieb in prior Congressional testimony expressed reservations about it. The ultimate decision for expanded access under any pathway is  with the sponsoring pharmaceutical company that is investigating the drug. The bill heads to the White House for signature to become law.

Things to Keep an Eye on This Week

  • Not much going on that caught my eye. Congress is gone, no FDA Advisory Committee meetings. 

Regulatory Developments in Pharma/Biotech/Devices

Photograph by Lynne Bertram


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