Sorting it Out – FDA AdComm Review for 2018

Looking back at FDA Advisory Committee meetings (AdComms) held during any given year requires a bit of patience given that some of the approval results don’t come in for a while after each meeting is held. And in fact, there are still some drugs that were considered by advisory committees during 2018 for which there is still no FDA decision. But we are going ahead with a look-back anyway.

FDA holds advisory committee meetings in order to get input from experts and from the public regarding the approval of new products and has a fleet of advisors serving on those committees. For Human Drugs there are 18 committees with varied subject matter jurisdiction. Not every new drug application goes through the advisory committee process, but for those that do, from a communications perspective, it is often where the branding of a medicine takes its first breath.

That is because when there is an advisory committee meeting held it does bring more transparency to the approval process because there is a publicly open scrutiny of the application. This, in turn, has communications ramifications. While the application milestones and clinical study outcomes have largely been public, the bulk of attention has been paid in trade and scientific journals. When there is an AdComm, there is a shift to mainstream media coverage. And while the filing of the new drug application and the acceptance of that application are important milestones, it is when FDA posts the briefs of the professional reviewers within FDA that result in headlines in mainstream media. And because reviewers are citing their perceptions of the strengths and weaknesses of the drug in question, the comments in those briefing documents generate the first real round of headlines about the medicine. The second wave comes as a result of the meeting discussion and vote. And as we know, the vote is a recommendation to FDA which the agency may or may not follow.

All that said, how did 2018 stack up in terms of Advisory Committee activity and how did it compare to the year before? Last year, FDA approved a record number of new molecular entities (59). In addition there were approvals of biosimilars and approvals of drugs that were not new molecular entities, as well as label expansions.

More Meetings. There were more meetings held last year than the year before. In all there were 34 meetings of advisory committees last year, but only 27 of them involved the consideration of New Drug Applications (NDAs) or supplemental New Drug Applications (sNDAs). That is slightly higher than last year when there were 29 meetings, 23 of which were considering NDAs for approval, two of which ended up not taking place.

Most New Treatments Considered. In 2017, the Oncologic Drugs Advisory Committee came in at a whopping 9 meetings to consider drugs, but in 2018 met only once. The committee with the most meetings in 2018 was the Analgesic Drugs Advisory Committee with 7 meetings, indicative of the activity around pain. Also in 2018, the Antimicrobial Drugs Advisory Committee met 6 times.

Voting Patterns/No Votes. In 2017, the Committee that had the highest number and proportion of negative outcomes was the Arthritis Drugs Advisory Committee, voting down 2 out of 3 NDAs, while in 2018, it was the Analgesic Drugs Advisory Committee that voted down 2 out of 7. In 2017, the Advisory Committees voted to recommend approval 71.4 percent of the time; in 2018 it was 66.6 percent.

Disagreement in Outcomes Between FDA and AdComm. As is noted in every press release about an AdComm vote, FDA may or may not follow the recommendation of the committee. That naturally raises the question – how often does FDA go against the advice of an advisory committee. Consulting my own database that tracks outcomes, I have found that FDA goes against the advice of the committee about 11 percent of the time. In 2017, there were 21 recommendations and FDA went counter to the recommendation of the committee in 3 of them (14 percent). In 2018 there were 27 votes and FDA appears to have gone against the recommendation 4 times (15 percent). There is still one FDA decision still pending where FDA has extended the PDUFA date for the investigative treatment for postpartum depression Zulresso(TM) from Sage Therapeutics. If FDA’s decision ran counter to the AdComm recommendation of approval, would change these numbers slightly.

For your reference here is a table comparing the activity of the past two years. The first column denotes the number of meetings/medicines considered by each committee, the second the number of approvals voted, the third the number of times FDA had a different outcome from the recommendation.

Comparison of FDA AdComm Activity 2017-2018

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What They Said – A Review of FDA Press Statements for 2018

Periodically it is a good idea to take the pulse of what FDA is saying. This is not by looking at each press release individually, though of course that is important, but rather to look at the aggregate of what is being said – and how does it compare to the past? Utilizing a database created to track and characterize the output by the agency, I did a look-back at the end of 2017. Time to do so again. There are some interesting results.

Undoubtedly, this has been a banner year for FDA in many respects. There were more approvals of new molecular entities by the agency than ever and more approvals of generics. Communications is no exception when it comes to volume. This past year, FDA issued a total of 289 releases, a healthy increase over the 164 of 2017 and the 122 of the year before that. In short, FDA has had more to say – a lot more.

More Approvals – Fewer Approval Announcements. Given that there were more new molecular entities approved than ever, you might thing that the increase in approvals led the increase in communications. It did not. In fact, the number of press releases about new approvals actually declined during 2018. There were 74 releases about new approvals in 2018 compared to 77 in 2018, with a smaller proportion of those (47) being about drugs or biologics compared to 2017 (52) – that despite the fact that more drugs were approved in 2018. So more approvals, fewer press releases on that front.

What was the driver of the huge increase? It was, after all, a 76 percent increase (by the way I had Wolfram Alpha do the math). The primary reason for the increase was the number of “Statements from the Commissioner”. Last year he sent out 36 statements. This year he increased it to 126.

What is he talking about? Everything it turns out. A good deal of his focus was the enunciation of policy change for the agency that included departures from the past and setting up new regulatory frameworks – from the use of animals in laboratory testing to modernizing the regulatory process for the development of targeted therapies to new steps in the implementation of FDA’s pre-cert program. And related, he sometimes announces the issuance of new guidance documents. and has focused on marking progress and milestones respecting some particular issues, notably various aspects of the opioid misuse epidemic and FDA steps taken to address it. But there were also clearly issues that rose to the top – those he cared about personally (opioids and e-cigarettes) and where he was perhaps demonstrating that the agency was taking some issues seriously and acting upon them – including

  • e-cigarettes about which there were 4 statements over a two-month period;
  • food safety – 4 statements about the Romaine lettuce safety issue from this year in addition to several more on food safety procedures in general;
  • medical device regulatory approaches and approvals about which there were 6 statements;
  • kratom – 3 statements about various actions around kratom, which is related to those he made about opioids;
  • opioids – 11 more statements involving some aspect addressing opioid misuse and abuse – from new steps FDA was taking to new treatment approaches and much more

Certainly the Commissioner Statements allow the luxury to provide more context, background and reasoning than does a normal press release, and it was clear that there were a number of issues where he felt adding that context was helpful to explain to key stakeholders, most certainly including policy makers, not only why the agency is doing things, but seeking to underscore the announcement to demonstrate progress.

What Did FDA Talk About? When the communication wasn’t in the form of a Commissioner’s Statement, there were some definite increases in activity by the agency in some categories. For example, there were a much larger number of alerts about public health matters with 12 this year (romaine lettuce, e.g.) than last year with just 3. And there were a lot more announcements related to legal actions – seizures, warnings and the like this year (32) compared to last (19).

A Comparison of FDA Press Releases by Category 2017-2018

Note that the Guidance category does not include at least 5 Commissioner Statements that were in regard to new guidance documents the agency was issuing.

Much has changed at the agency over the past year and a half. There has been a concerted effort at policy change. But not to be overlooked, and a point made in a prior blog posting, is that communications is among those changes. It certainly seems worth keeping an eye on it.

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Happy New Year – and FDA Statement on Government Shutdown

Happy New Year. On a personal note, I have been on a hiatus or shutdown myself to take time while undertaking a move. With that behind me, I am back at it and will be posting again with intermittent content and Weekly Roundups. And while I’m back, the government is not, having experienced a shut down just before the Christmas holiday. FDA has issued a statement on how the partial government shut down would be affecting the agency. In addition, the agency posted a Q&A for employees. The description of activities is not dissimilar to those outlined during the government shutdown of October 2013.

The statement provides an outline of activities that will continue, but there remains some vagueness about what functions will continue during what is referred to as the “lapse period”. The following are areas mentioned specifically:

  • Vital activities” to the extent permitted by the law, critical to ensuing public health and safety – however what exactly constitutes vital and what the law permits are not entirely clear.
  • Maintaining core functions to handle and respond to emergencies – such as monitoring for and quickly responding to outbreaks related to food borne illness and the flu, supporting high-risk food and medical product recalls when products endanger consumers and patients – presumably this means that the core capabilities will continue to function, however, efforts such as recalls require coordinated communications efforts from the agency and it is not clear if this component is available from the statement.
  • Pursuing civil investigations when we believe public health is imminently at risk and pursuing criminal investigations, screening the food and medical products that are imported and addressing other critical public health issues and surveillance for significant safety concerns with medical products continues – This sounds like it covers a lot of ground but turns somewhat on how terms like “critical public health issues” are interpreted
  • Support of activities funded by carryover user fee balances – It is somewhat uncertain as to what the term “support” means in this case. For example, advisory committee meetings to consider new drug applications would presumably be a user fee activity. An examination of the FDA advisory committee calendar during the shutdown of 2013 shows that meetings considering new products did take place. However, meetings that were not involving new product considerations were postponed. FDA has an advisory committee meeting on January 11 to consider an sNDA. See Dr. Gottlieb’s tweets noted below for more information in this regard.

Noted FDA activity and inactivity since the shutdown:

  • No new press releases issued, no FDA Voice Blog postings and remarkably, no Statements from the Commissioner
  • Federal Register notices from FDA have continued to be published, though at a diminishing rate and publication might represent material already in the pipeline
  • No new warning letters issued out of any office
  • Updates and clarification are being provided by some key personnel on Twitter. While some have only tweeted excerpts from the official statement, Dr. Gottlieb has been using Twitter to provide clarification on finer points on his Twitter feed.
  • Some of Dr. Gottlieb’s pertinent tweets:
    • From December 28 – We have questions re: drug review work that’s not user fee funded and won’t continue during shutdown. CBER will pause non-emergency work on whole blood, blood components for transfusion, allergenic extracts and HCT/Ps regulated solely under sec. 361 of the PHSA.
    • For our Center for Drug Evaluation and Research this also includes pausing all OTC monograph drug activities. Only emergency work related to these products will continue.
    • The 30-day review clock for any pending, non-emergency IND for a medical product that is not covered by a user fee program will be suspended during the lapse period. The clock will resume when the lapse period is over.
    • However, new emergency INDs and IND amendments that relate tot he safety of individuals who are participating in clinical trials will continue to be reviewed during the government shutdown, even for products that are not covered by a user fee program.
    • Many asked if FDA can accept new medical product applications during the shutdown. The FDA can’t collect FY 2019 user fee payments during the shutdown, which means we can’t accept new application for products under user fee programs: PDUFA, GDUFA, BsUFA, MDUFA, ADUFA, AGDUFA.
    • FDA retains limited carryover balances for 21st Century Cures and opioids funding. These balances will only be spent on activities for which the funds are authorized. FDA carryover user-fee funds also allow the agency to continue work on existing user-fee related applications. (emphasis added by me)

Will endeavor to keep you posted on new developments. Happy New Year to all.

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Weekly Roundup 11.9.18

So much to talk about, so little time. The election (thankfully) is over. The days are shorter, darker, wetter and altogether more lean. Thanksgiving is but a few short weeks away and Christmas decorations are already sneaking their way into stores and our psyche. There is a rush to finish all that needs to be finished before the end of the year, and perhaps it is no different at FDA where there has really been a good deal of activity over the calendar year, much of which we will visit in some year-end look-backs. In the meantime, here is what happened this week. 

  • FDA and Expanded Access – Expanded access to drugs under clinical study is important on many levels – access for the patient, protecting the integrity of clinical trials, and of course patient safety. In a statement this week, FDA Commissioner Gottlieb announced improvements to the expanded access program that streamline the process even further by requiring less documentation and involving fewer individuals in the approval process. The agency also clarified how adverse events experienced through the expanded access pathway would be considered in the context of the review process for investigational treatments. In addition, changes have been made to improve the usability of the expanded access website, reducing duplication and adding new pages of commonly requested information. The statement also clarified that this program is distinct from the “Right to Try” legislation signed into law earlier this year and that FDA is in the process of considering what steps are needed to implement that legislation. 
  • OTC Asthma Medicine Returns – Commissioner Gottlieb and CDER Director Janet Woodcock issued a joint statement this week about the return to market of a new version of Over-the-Counter Primatene Mist, the only OTC metered-dose inhaler for use in providing temporary relieve to mild, intermittent symptoms of asthma. It is approved only for persons who have been diagnosed with asthma by their healthcare provider. While there was a former version of OTC Primatene Mist, it was removed from the market in 2011 due to the fact that it contained chlorofluorocarbons (CFC) propellants known to be harmful to the earth’s ozone layer. In the wake of the removal, the two said that there were considerations as to whether having an OTC asthma product improved access for patients or actually caused patients to forestall needed treatment. They acknowledged that there is a narrow population of people diagnosed for whom an OTC asthma inhaler would have benefit, but that appropriate use needed to be reinforced. 
  • Deadline Today on FDA Response to Senator Inquiries on Pre-Cert Program – On October 10, 2018, Senators Warren, Murray and Smith sent a letter to Commissioner Gottlieb and to CDRH Director Jeffrey Shuren containing a long-list of inquiries about the nature of the FDA pre-certification program for software being used in medical devices. The letter included nearly two dozen questions on a range of topics including particulars about the legal underpinnings of some of the aspects of the proposed pilot program that FDA is developing to allow specific manufacturers to facilitate the pathway to market for software used in some medical devices. The deadline for FDA’s response was today, November 9. 

Things to Keep an Eye on This Week

Regulatory Developments in Pharma/Biotech/Devices/Food

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Weekly Roundup 11.2.18

We are shifting gears as we head into the year’s end, with two months to wrap everything up and we kick it off by ending Daylight Saving 2018 this weekend – so remember to set your clocks back (Fall Back) this weekend. In the meantime, it was a week of long days and travel for me, precluding some intervening postings. That said, several things happened on the FDA front and here are a few of them:

  • FDA Approves New Opioid – If you wondered whether or not it would be possible for another opioid medicine to be approved in the current climate, today FDA provided an answer. In his statement regarding the approval of the AcelRx compound Dsuvia (sufentanil sublingual tablet 30 mcg) for the management of acute pain severe enough to require an opioid analgesic in adult patients in certified medically supervised healthcare settings, Commissioner Gottlieb stated that in balancing the needs of pain patients with the risk considerations of the category, it is important to consider whether “new opioids are sufficiently better than existing drugs to justify their addition to the market in the context of the current crisis of abuse.” He described the unique approach taken with this particular opioid – that it is restricted in its use to certified medically supervised health care settings such as hospitals and administered by a health care professional using a pre-filled, disposable, single-dose applicator delivering the dose under the tongue. He stated that in addition to weighing each drug application on the merits of the individual drug, that in the case of opioids, FDA will use its new authorities with regard to post-marketing decisions and to require unit dose packaging and dispensing systems. He also cited, but did not limit himself, to the consideration of key questions in evaluating a new entry to this market – here in paraphrased form – (1) does an additional opioid benefit public health due to its properties; (2) does it create aded risk of diversion or misuse or other concerns; and (3) is there differentiation that will benefit certain groups of patients?  His statement is lengthy and worth the read. 
  • OPDP Issues 7th Letter of the Year – After spending most of the year in regulatory slumber, the Office of Prescription Drug Promotion (OPDP) seems to be using this last quarter to play catch-up. This one was a Warning Letter, the second of the year, and involved two products (one for the treatment of schizophrenia and one for sleep/wake disorder) but only one communications vehicle – a web page. Earlier this year, the head of CDER, Dr. Janet Woodcock indicated that the agency would likely be reserving enforcement for violations that were the most egregious. What might that mean?  In this case, it means a web page regarding a medicine that has a Boxed Warning, but which contained no risk information whatsoever. It its noteworthy that nearly all of the letters issued this year involved products with Boxed Warnings. The number of regulatory action letters for this year now surpasses last year’s low of five letters issued, but falls far short of the eleven from 2016. However in that year, OPDP issued six of them in the month of December – so given the recent spate of letters, let’s keep our eyes open.  And if you are involved in communications for a product with a Boxed Warning, be alert.
  • Recall of Test Strips to Monitor Blood Thinner Levels – It has not been a good year for cardio patients. First the recall of a major blood pressure medication and now a Class 1 recall announced for test strips used to monitor levels of warfarin in the blood stream for patients with blood clots at-home or in the doctor’s office. According to the FDA release there are millions of Americans who take warfarin to thin their blood, prescribed for patients who have certain types of irregular heartbeats, blood clots or who may have certain implant devices. FDA warned patients that they should not rely on the results of the tests from certain lots of the strips issued during 2018 and stated that use of the strips can result in serious errors in medication dosage as a result that could bring serious harm to patients using them. The agency stated that they are working with the company to ensure swift removal and replacement with corrected strips as soon as possible. 

Things to Keep an Eye on This Week

Regulatory Developments in Pharma/Biotech/Devices/Food


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