In June 1981 I graduated from law school. One month after that an article appeared in the New York Times with the headline “Rare Cancer Seen in 41 Homosexuals” on page A20. These two events would end up pretty much defining the rest of my life. I became the chairperson of a group of lawyers volunteering time to provide legal help to people with this new disease and later became the Director of Legal Services at the Gay Men’s Health Crisis (GMHC) where I provided wills and advocacy on insurance and immigration matters, landlord/tenant issues, and discrimination in jobs and public accommodation. I also emerged as the spokesperson for the agency on important public health policy matters both at GMHC and in the 1990s at AIDS Project Los Angeles. This included commenting on important milestones such as actions by legislatures (or lack thereof), regulatory matters, and high profile developments such as Rock Hudson, Greg Louganis, Brad Davis and Magic Johnson, and more. In short, I got to know media and communications in the face of an emerging pathogen. During past outbreaks of emerging pathogens, I have written postings on this topic. As I watch the media report on the new Wuhan coronavirus, there are some lessons from that time that bear noting and repeating.
Facts are low; speculation is high – In the earliest reporting on Wuhan, human to human transmission was regarded as a low likelihood though transmission is now regarded as more likely than either SARS or MERS. So little in the earliest stages of an emerging situation that there is necessarily a good deal of speculation, often on which opinion gets based. Early reporting referenced the fact that mortality seemed concentrated in the elderly with co-morbidities, but news outlets also reported the deaths of young medical workers. In short, speculation or casual observation is often presented as fact and policy actions are sometimes based on that. But the only fact is that we don’t know much about this and only time and experience will tell.
Numbers don’t mean a lot – The number of Wuhan cases reported climbed dramatically within only a few days. In the early days of an epidemic, numbers are frequently subject to change. The number of diagnoses represent only those people infected who are showing symptoms, not the number of people infected who may not be symptomatic but who may be able to transmit. Second, the method and nature of counting (and testing) can change, as it did for COVID-19 when the methodology for counting cases caused a spike in the numbers. Third, there is always under-reporting. A communications focus should rely less on numbers than on solid principles of public health and on the business facts that are at hand. Numbers are indicative, but not certain.
Points of reference will change – In the earliest days of the AIDS epidemic the disease was referred to as GRIDS (Gay-related Immune Deficiency Syndrome) and then AIDS. When finally discovered, the virus was HTLV-III and then became called HIV. In short, it takes time for the nomenclature and framework to become established, which can add to confusion. The situation can remain very fluid well into an epidemic. The coronavirus became COVID-19. It will be essential to monitor and educate stakeholders, both internally and externally, in any organization.
Fraud potential is high – Not only will homespun remedies emerge, but on a more unpleasant note, there is a high potential for products to appear accompanied by unapproved claims. There is also a high potential for the emergence of counterfeit products. This is where FDA and FTC have a role to play.
Policy can ham-fisted – With so few facts in hand, policymakers often react in ways to make it appear that something is being done to address an outbreak when in fact, policies being enacted may not support public health goals, necessitating vigilance in monitoring and considerations for how organizations respond. Some may be benign while others may be truly ill-advised.
Under fast changing circumstances, it is difficult to get a good grasp of the total picture along with all the nuance represented therein. As events unfold, and there is a greater demand for communications from stakeholders such as public officials, companies and health authorities, it is important to keep in mind some truisms during the early days to help us keep our bearings and develop perspectives.
FDA Web Page – Outlines FDA actions with respect to COVID-19 and other important links
World Health Organization – Multiple resources and up-to-date situation reports with a focus that is both global and localized
There are a lot of important facts on the FDA’s Web Page set up to provide information about the novel coronoavirus (2019-nCOV) outbreak, now dubbed COVID-19. But there are three sobering statements that stand out:
There are no FDA-approved diagnostics for COVID-19
There are no FDA-approved vaccines to prevent COVID-19
When we think of an epidemic, we naturally think of the obvious concern – the safety of ourselves and those we care about. But there are consequences in store beyond that for many industries – most obviously the travel industry. And there are also dynamic concerns for the industry that makes our medicines.
API – First there is the potential for disruption of the production of medicine due to a lack of active pharmaceutical ingredients (API), a large portion of which are manufactured in China. While there are non-Chinese API producers, many of them are in China and it stands to reason that disruption is a distinct possibility. That would have an impact on everyone relying on medicine not only to treat infections, but also to treat chronic conditions such as diabetes, blood pressure and cholesterol levels.
Manufacturing Disruption – In the event of a widely spread contagion, it stands to reason that social isolation practices – i.e., not coming to work – could become necessary and thereby interrupting the actual manufacture of finished medicines. While API can be obtained from various sources, the manufacture of many medicines is specific to established sites.
Medical Meetings – The effects of the outbreak on large meetings is already becoming apparent with high-profile companies pulling out of the Mobile World Congress set for Barcelona this month resulting in the cancellation of the meeting. At the very time when collaboration is essential, there may be a disruption to medical meetings commonly held around the world at which clinical data is presented and cutting edge research is discussed. A disruption in the course of research-related discourse could impact the speed of development of new medicines.
Regulatory Oversight – Media reports this week mentioned that visitors to the campus of the Food and Drug Administration were being asked upon entry about foreign travel. Social distancing also means that regulatory meetings such as FDA Advisory Committee meetings may be put on hold – as well as the review process itself – considerably slowing down the approval of new medicines.
Blood Supply – As anyone connected with the early days of the AIDS epidemic can attest, when you have a communicable disease where there are no diagnostics for screening, the blood supply becomes particularly vulnerable, resulting in the potential for severe shortages to emerge.
These concerns are not new with COVID-19. The circumstances were very similar during the Avian flu outbreak during the first decade of the 2000’s and extensive planning around the supply chain was undertaken by the pharmaceutical industry. We find ourselves again with an imperative to not just plan appropriately but to consider how to effectively, accurately and compassionately communicate what needs to be considered in a time of crisis. In that way, industry can minimize some of the potential side effects that are possible as we see our way through this.
The World Health Organization puts out daily situation reports that are highly detailed and comprehensive. You can access them here.
There is a policy interest in driving the biosimilar market. Among other reasons, increasing the number of generic drugs and biosimilars on the market addresses another policy priority – having an impact on the high cost of medicine. The approval of generic drugs has been at record highs the past few years, and FDA is also doing all that it can to facilitate the market for biosimilars. This is one of the few things FDA can actually do to address the issue of price, even if in the totality of things it is only nibbling away at the edge of a much larger issue.
So far in 2020, FDA has taken a series of actions designed to enhance the market for biosimilars.
The approval and marketing structures have been primed by FDA to facilitate approvals and uptake of biosimilars. But there are certainly other impediments. For example, currently due to patent issues, several of the biosimilars that have been approved are not brought to market. A study published last year in the AMA Journal of Ethics (AMA J Ethics. 2019;21(8):E668-678. doi: 10.1001/amajethics.2019.668) of the 17 biosimilars approved, only 7 had made it to market. It is an example of only one of many issues that have consequences for uptake.
The more on the market, the merrier (for price). For generic drugs, the rule of thumb has been that the more that are on the market to treat a particular condition, the lower the price for treatment. But for biosimilars, we are not yet a point where there are enough on the market to have a significant impact on pricing. When it comes to biosimilar entries impacting price, we are looking at a process, not an event. FDA has worked to facilitate the process. The effects, however, would appear to be something for which we should be prepared to wait.
In the meantime, there are more near-term consequences for biosimilar marketing. The joint announcement by FDA and FTC not only sets up the guardrails for communications in the industry, it also is a signal of intent. The agencies will be watching closely and likely looking for a circumstance by which enforcement can stress the existence of the guardrails even more keenly. Despite the fact that enforcement by FDA with regard to promotional communications has been at historic lows, they agency seems to be saying pay attention. So pay attention.
Has FDA been holding enough AdComms? There have been a large number of drugs approved in the past year, but there has not been a corresponding increase in the number of advisory committees staged by FDA. Late in 2019, I had a posting about the fact that it looked like FDA was headed to a year where it held fewer FDA Advisory Committees than it had in years past. However, it was premature. FDA did manage to squeak in a few more meetings in December and brought the total up, though it was still well below the number of meetings held during many of the years between 2012 and 2019.
More about the volume of meetings in a moment. First let’s look at those that were held – what they considered and what the outcomes were. How man meetings, how many about drug approvals and how often was FDA in agreement with committees – and more…
There were a total of 28 meetings for the 2019 calendar year
Of the 28 meetings, 23 were held to consider an approval of a medicine, seven of which were sNDAs or sBLAs while the balance were NDAs or BLAs – the other five meetings were to discuss specific issues of safety or policy issues
Of the 23 NDA/BLA/sNDA/sBLA meetings, committees recommended approval for 17 medicines, did not recommend approval of 5 and 1 of the meetings was cancelled;
Of those 17 drugs that Advisory Committees approved during 2019, FDA approved 12 of them; however three of them that got committee approval were instances where FDA decided against the recommendation of the committee and did not approve the application; and there are two applications where a decision has not been announced;
In fact, there were a total of 4 examples of FDA going against the recommendation of the committee – 3 where FDA declined to approve against a recommendation (mentioned above) and 1 where FDA approved the drug in spite of the committee’s recommendation against approval – that would mean FDA disagreed with the Advisory Committee recommendation just over 14 percent of the time
Four of the meetings involved joint sessions with the Drug Safety Risk Management Committee, only one of which was to consider an NDA for a new product
The committee that met the most was the same as in 2018 – the Oncologic Drugs Advisory Committee met six times this year, though that was down from nine last year; the next highest level of activity was also the same as last year – the Antimicrobial Drugs Advisory Committee met five times (three of them product-related) down from six meetings last year.
It is time to look back at enforcement for the 2019 year. It is still possible that FDA could post another letter, as there is a lag time between the time a letter is sent and the time it is posted to the web site, but let’s hope the Office of Prescription Drug Promotion (OPDP) did not send one out as a holiday greeting.
Comparing this year to other recent years, the enforcement actions taken by OPDP was not as sluggish as it has been, but neither was it robust. Long gone are the kinds of years where the agency would issue well over 100 enforcement letters for each and every violation that appeared. Instead now, the agency appears to have areas of concentration where enforcement is focused.
During 2019, as of this writing FDA issued a total of 10 enforcement letters, addressing communications carried in 11 different communications vehicles. While interesting warning letters went out from FDA outside of OPDP – for products containing CBD, for example, our focus is solely on promotional communications. Here are the highlights from this year:
Communications Vehicles – Violations were just about evenly divided between digital communications vehicles and traditional ones. On the digital side, there were 5 violations – the most frequent communications cited involved statements made on a website (4), and one letter sent regarding an email. On the traditional side of communications, there were a total of 6 – almost all DTC videos (4)- one of a DTC video involving a patient testimonial – one of the riskiest areas in promotional communications to my thinking. (I categorize DTC video in the traditional category rather than digital). On the traditional side there was also a banner ad and a print DTC ad involved in enforcement.
Treatment Area – No single treatment area dominated enforcement. In the broad category of CNS-related treatments, there were two violations, two in oncology, two in erectile dysfunction. In short, there was nothing to indicate that the agency is focused on a treatment area with enforcement.
Companies – Small companies watch out. The trend continues for OPDP to aim its enforcement mostly at companies that are generally not considered household names in the industry. This year was almost no different with the notable exception of the inclusion of Alkermes (more on that below). It is unclear whether large established companies have gotten highly adept over the years at scrubbing their communications to the point that they are more compliant with regulations or if FDA is finding that smaller companies provide good examples of violations the agency is concerned about.
Warning versus Untitled Breakdown – Untitled Letters – also referred to as Notice of Violation (NOV) letters are considered the less serious of the two categories of regulatory action letters sent by OPDP, while Warning Letters are reserved for those violations FDA regards as more serious. This year, three out of the ten letters issued were Warning Letters. That is on par with a look at the cumulative rate over the years – in my database going back to 2004 that profiles over 330 letters from OPDP, about one in three letters are Warning Letters. So the proportion did not change this year. So even though FDA seems to be reserving its regulatory actions for violations it deems most noteworthy, that does not appear to alter the traditional approach to Warning Letters.
Violations and Focus – There were 21 violations cited in the 10 letters issued this year. As per usual, by far and away, the most common violation cited by FDA is one that you would think might be the easiest area for compliance – the inclusion of risk information. This involved nine violations – nearly every letter issued by the agency this year. The other violations were for making a superiority claim (3), unsubstantiated claim (3), unapproved use (1) and promotion of an unapproved drug (2). That last one is noteworthy. While promotion of an unapproved drug was numerically low, it is proportionally high. Historically promotion of an unapproved drug has been an rather uncommon violation, having occurred only 19 times by my count since 2004, but 14 of them have been since 2012 and 11 since 2015, indicating it is a high area of interest for the agency in recent years. So the bottom line – there are two things to watch for in communications – risk information and pre-approval communications – particularly if you are a small-ish company.
Finally, one thing that occurred this year that was highly unusual with respect to enforcement concerning the final letter of the year issued by OPDP on December 2. FDA accompanied the posting of the letter – a Warning Letter – to the website with the issuance of a press release about the letter. That is highly unusual and in fact, I do not recall an instance where the agency brought so much attention to an enforcement action since April 2009 when OPDP (then called DDMAC) issued its misguided set of 14 letters impacting 45 brands. It does no good to second-guess reasoning, but it bears noting that his particular letter involved a drug utilized in an area where all stakeholders, including FDA, have been under scrutiny – opioids. The communications about the medication was lacking important risk information, FDA found. While risk information is obviously an important area of focus in enforcement, it is perhaps even more so for those manufacturers who are operating in the area of pain relief.
My name is Mark Senak. I’m a lawyer and I work at the international communications firm FleishmanHillard in New York. For the past several years, I have been consulting with pharmaceutical and biologic companies that are engaged in the process of bringing new drugs to market.
I am an authority on regulatory aspects of communications and medical products, with particular emphasis on pre-approval communications; strategist to help pharma and biotech companies prepare best case for advisory committee approval; and counselor in issues and crisis management. I am a frequent speaker on various aspects of same - drug development, promotion, reimbursement and new media in a highly regulated environment. Author of books, newspaper and magazine pieces related to drug marketing and promotion as well as HIV specialty pieces. And of course... blogger!
About This Blog
Eye on FDA is published by Mark Senak of FleishmanHillard's Washington, D.C. office. The thoughts and ideas in this blog and postings are strictly my own and are not screened by my employer. Everything posted on this blog is my personal opinion and does not necessarily represent the views of FleishmanHillard or its clients.