A monthly look at FDA Warning Letters and Untitled letters for Rx drug advertising and promotion.
For our inaugural installment of Enforcement Action of the Month Club, we'll take a look at one of my favorite topics...drumroll please...Press Releases!
Wait a minute...FDA doesn't regulate press releases, do they?
"You know, even if they do, press releases don't need copy approval. Senior management already approved this one."
"Its just the principal investigator's expert opinion--we can't delete that quote. [Insert VIP name] put that sentence in, so you can't touch that either."
"What's wrong with those data? We explain that it's an exploratory endpoint in paragraph 15, right after the safety results in paragraph 14."
I'm sure you've never heard words like those before. Press releases can be tricky of course. Historically, FDA reserves the right to regulate press releases and seeks to do so with little or no limitations. It can do so under 21 CFR 312.7 if it believes that a press release about investigational information is false or misleading or contains inappropriate conclusions about the safety and efficacy of an investigational drug (or investigational use of an approved drug). Press releases can be purely promotional, and FDA simply can regulate these under its advertising or labeling regulations, or they can be purely investigational and non-promotional. More often than not, press releases lie in the "purely" gray space in between. Most attempt to be "non-promotional" while also being juicy enough to get attention and media pickup. It's "breaking news" after all. The public must be apprised of the truth about our drug.
1997 Untitled Letter for Press Release(s) for Estrasorb
For this month's post, I've picked an older press release, partly to make some points about how FDA finds justification to enforce against press releases, but also to point out how FDA's enforcement approaches and interpetations may have changed over the years. In 1997, FDA's DDMAC (now OPDP) issued an untitled letter to Novavax Inc. for its product ESTRASORB (estradio micellar nanoparticles). You can read the letter here. DDMAC explained that a press release dated June 26, 1997 contained false and misleading statements about the drug. FDA's objections related primarily to the fact that the company had issued press releases making efficacy claims (that Estrasorb was found to reduce hot flashes in postmenopausal women) that were derived from a small pharmacokinetic study in 10 subjects. In addition, according to the DDMAC's letter, the company had also used the term "approved" inappropriately to characterize FDA's review and approval of a study protocol as approval of the dosages used in the pharmacokinetic study. FDA/DDMAC viewed this as a false and misleading characterization of FDA's study protocol reviews (presumably during the IND stage of development).
Request for Advisory Comments ...or not...
To make matters worse, according to the circumstances described in the letter, there was an existing request to provide advisory comments on the press release as well. However, according to DDMAC's letter, the company issued the press release before FDA completed its comments. I probably would not have done that. On the other hand, I think it's a bit hard to be too snarky here, as there are frequently any number of frustrating and unknowable circumstances behind these letters. Also, because the letter dates back to before FDA posted the violative content for it's enforcement actions, we're left with only partial context when reviewing this letter.
The Basics of DDMAC's Letter
All that said, at least according to the details of the letter, its easy to see what the company should have avoided:
Don't make efficacy claims based on small pharmacokinetic studies
Don't mischaracterize FDA "approval" or non objection to study protocols as approval of the product's characteristics (in this case, dosing)
Don't ask DDMAC/OPDP or APLB for advisory comments and then issue the content while they're working on comments to tell you which parts they object to. Predictably, this will annoy the enforcement agency (emphasis on "enforcement"). Did I mention that DDMAC/OPDP is an enforcement agency?
FDA's Own Substantiation of Its Legal Authority Has Evolved
Another interesting thing about looking at older letters is the format and style of the letters. Over time, for a number of reasons, including, periodically, the requirement for legal review by FDA's Office of Chief Counsel, FDA's enforcement actions more explicitly justify their objections by citing the specific requirements of the law. In the case of this letter from 1997, however, FDA only explains to the company that "The press releases issued were false or misleading, in violation of the U.S. Food,Drug and Cosmetic Act..." FDA does not cite the specific sections of the Act or the specific sections of the labeling, advertising, or IND regulations (something they would undoubtedly do today). On the other hand, if you look at this untitled letter to Cornerstone Therapeutics over a decade later, DDMAC is much more meticulous about explaining where, specifically, in the law and regulations, it gets its authority from. Damn those First Amendment lawyers.
I rarely review and approve press releases that are uncomplicated
FDA reserves the right to cite press releases even though they may not be defined as "advertising," "labeling," or "promotional material." In cases where press releases relate to unapproved uses or investigational information, it is impossible for that information to be defined as labeling or advertising, because you cannot have labeling or advertising for uses for which there is not FDA-approved labeling (unless a company does something extraordinarily unfortunate and actually publishes an advertisement for an unapproved use). Companies then issue press releases under 21 CFR Sec. 312.7 (at least they do so if they're doing so consciously). This provision comes from the IND regulations and allows companies to share truthful and non misleading information about unapproved uses as long as they do not make conclusions of safety or efficacy or otherwise commercialize the drug prior to FDA approval.
Now, what makes a communication "false or misleading" in this context is a bit of a gray area, primarily because there is really no evidence standard. Inherently, the content relates to a use for which there is no "substantial evidence." That is, the product is still under investigation. You are sharing pieces of the research that will be part of the body of evidence that FDA considers for approval (typically). Also, since the "fair balance" requirement is specifically related to advertising in 21 CFR Sec. 202.1, there isn't that requirement either. A press release, is not an "advertisement." Nonetheless, FDA usually expects to see risk information under the premise that risks are "material information" that must not be omitted. So, while "fair balance" is not a technical requirement, material disclosure of relevant risk information is. Tomato..."toe-mahh-toe."
What we typically see when FDA takes action against press releases or other information in the IND stage, are factors that make the communication conclusive, overly selective, overly positive, or lacking material disclosures. Other issues include failure to adequately acknowledge the investigational nature of the information, or simply giving an overwhelming impression that the efficacy and safety (benefits) are a done deal, or that FDA approval is a foregone conclusion.
I like to go through each press release and ensure the following:
Make sure the investigational nature of the drug or research is evident from the beginning (including the headings and initial paragraphs).
Somewhere prominently in the release, the company should explicitly acknowledge the need for FDA review and approval of the investigational drug/data. Some of these things you can accomplish through creative use of quotes. Something like "We look forward to submitting these data in our application to FDA later this year for their review," according to Michelle McSuperstar, CEO of American Wonderceuticals, Inc.
Accurately describe the patient population of the research. If the study was in second-line, stage 4 renal cell carcinoma, don't call it a drug under investigation for, simply, kidney cancer. Look out for the phrasing of investigator quotes and stuff like that. Make sure nothing could be misconstrued to expand the target patient population or use beyond that which was studied.
Exclude conclusory statements of safety or efficacy, including inherently comparative statements (e.g., "first" or "only" words or words of similar meaning). "first and only phase 3 study with XYZ endpoint" may be ok. On the other hand, "First and only drug to demonstrate efficacy for XYZ endpoint" is probably not.
Accurately describe the results within the hierarchy of the study design and evidence standard. Leading with the non-adjusted secondary endpoints (maybe because they're unique) instead of leading with primary or more statistically valid endpoints is usually a bad idea.
Don't make failed studies look positive. Look. If you fail your primary endpoint and then go on to just emphasize the positive secondary or post hoc sub analyses, FDA is more than likely going to find that to be misleading in and of itself. Also, they'll cite a failure to adequately disclose the material fact that the data are from a failed study (thereby, substantiating little else than the need to redo the study or redesign a new hypothesis for another study).
Disclose any material risk information. If your product is already an approved product, FDA would expect that the same risk information that is used in promotion (your Important Safety Information) is used (at a minimum). Material disclosure of the most common adverse reactions from the research, the most common reasons for discontinuation, and/or the most common or most serious adverse reactions should be considered for disclosure.
Disclose the results of the control arm. Duh. I must admit, this is one that baffles me. I often see press releases and other materials where an an agency does not include the results of the control arm for certain endpoints. Particularly in a research context, the results of the control arm are critical to understanding the observed effects, including rates of adverse reactions. Don't mess this one up. It's a layup for an FDA objection.
Avoid statements that you know wouldn't fly in a promotional context. I understand that press releases for investigational information are not regulated, technically, under FDA's advertising regulations, but don't say dumb stuff that you know FDA finds objectionable. For example, avoid things like tying your novel mechanism of action or chemical structure to efficacy or safety.
Disclose the approved uses of the drug, if any, and provide a reference and link to the approved PI, if any.
This is where I disclaim that this isn't "everything." But it is a good start. I think.
The End
Ok, that's all I got for this one. I'm tired. You're probably bored, and it may even be Friday wherever you are. Thanks for reading the inaugural installment of EAMC.
John