The latest OPDP letter, an untitled letter, came out this week and, as usual, there are interesting aspects to it. Here are links to the letter and the promotional material:
Link to untitled letter: https://www.fda.gov/media/144115/download
Link to promotional material: https://www.fda.gov/media/144114/download
Here are some of the highlights of this letter:
1. The letter, addressed to Azurity Pharmaceuticals which was previously known as CutisPharma and is the parent company of Silvergate Pharmaceuticals which was identified in this untitled letter as the NDA holder at the time of NDA approval.
2. The letter appeared to be prompted somewhat, at least, by advisory comments provided to Silvergate, presumably on launch materials. Those comments were completely redacted in this untitled letter so it is hard to say what FDA's advisory opinion was, exactly. However, the mention of the advisory comments appears to signal that what FDA originally told Silvergate was not currently being followed in promotion of the drug in question, XATMEP® (methotrexate) oral solution.
3. This letter, which dealt with an e-mail sent out by the company to HCPs, has a number of violations, some of which have been mentioned previously by OPDP in letters to other companies. These include:
a. Put the safety information at the bottom of the e-mail below the signature line. OPDP said, as it has previously, that putting safety information below a signature line or other signal that the document has ended minimizes that safety information. In the past they have cited companies for having safety information at the bottom of a long (multipage) e-mail without any pointer to it in the e-mail. They have also cited companies forplacing safety information at the bottom of press releases that had signals (for example, several hastags in succession) above the safety information indicating that the press release content was finished.
b. Had the boxed warning as the only balancing safety information for the claims in this piece. I have seen this with other companies in recent months, thinking the boxed warning was all the safety information they needed to make significant claims about their product. It stands to reason that since boxed warning products require the boxed warning just to have a reminder-like ad (product name only, no claims or representations that could be interpreted as real or implied claims), that you would need more safety information that would be contextual to your claims if, in fact, you had claims in your promotional piece.
c. Not having the right safety information. The is an important violation and one not always cited by OPDP. Azurity made a claim about easy dose titration and OPDP said that this should have triggered inclusion of safety language from the PI saying the drug should be taken weekly and that taking the drug daily could lead to fatal toxicity. This likely came up in the advisory comments, based on the sentence immediately after the redacted section.
d. expanding the indication by shortening it in a succinct claim. They e-mail template said: "I wanted to let you know that Xatmep® (methotrexate) oral solution is available for your patients with Acute Lymphoblastic Leukemia." OPDP opined that this implied that Xatmep had no age limitation on its use and had no limitations on its use, including that the statement, as written, implied that Xatmep could be used by itself and, although the OPDP letter didn't say it, possibly as a first-line treatment. The actual indication says that Xatmep was approved for pediatric patients and as part of a multicomponent chemotherapy treatment regime. OPDP said that presenting the exact indication at the bottom of the e-mail didn't offset the expansion of the PI above, once again stating, as it has in many instances previously, that a company cannot mitigate a false or misleading statement by having correct information somewhere else in a promotional piece, especially if the correct information is minimized in some way (e.g., in a footnote or placed far away from the misleading claim). Most interesting was that the e-mail template, one sentence previously, said "...[I am] a representative for Azurity Pharmaceuticals specializing in pediatric medicine." Apparently OPDP did not consider that the statement that this representative was a pediatric medicine specialist was sufficient to mitigate that the claim did not specifically mention pediatric in its claim language. OPDP has, over the years for varying reasons, clearly stated that expansion of indication can occur from truncating indication language to save space and has ruled in an advisory comment that I am aware of that even when that truncation did nothing to change the meaning of the indication, OPDP wanted the company to use exactly the indication language as it appeared in the approved indication. That advisory opinion is consistent with their opinion in this letter.
No one really knows what Azurity could have done to mitigate risk to avoid this letter but here are some simple suggestions that I think might have helped (changes in strikeout and red) without changing the e-mail language substantially:
1. Use a pointer statement to point to the safety information and define the group the drug is indicated for. An example of how this might have looked would be "I wanted to let you know that talk to you about Xatmep® (methotrexate) oral solution (see Important Safety Information, including Boxed Warning, for Xatmep at the end of this e-mail). Xatmep is available for your pediatric patients with Acute Lymphoblastic Leukemia. It is also the first and only FDA‐approved oral
solution that is available..."
2. Include in the Important Safety Information standard safety information and not just the boxed warning. Normally this would involve inclusion of contraindications and important AND relevant warnings, precautions and use information, in addition to the boxed warning and indication.
3. Be a little more careful with how claims, including the truncated indication, are made. For example, the claim pointed out by the FDA could have said:
"Xatmep may benefit your pediatric patients
- 2.5mg/mL provides easy, once weekly dose titration as body surface area‐based dosing is recommended."
