A total of seven companies received Warning Letters during the last quarter, meaning that one-third of the year’s letters came in the final three months of the year.
What we saw is a mix of large and small companies, with some of the points raised by FDA bordering on esoteric. That said, there were many obvious mistakes as well, such as the omission of any risk information, that are surprising.
Vehicles for the communications cited in the warning letters included a Print Ad, two Professional Sales Aids, a Flashcard, Exhibit Booth Panels, a promotional piece overviewing a hypothetical case study and a Web site.
Lessons to Take Away
- Broadening of Indication – A violation here involved a statement about the effectiveness of a treatment to one section of the eye (the posterior) that was not included in the PI, which refers to treatment of the anterior. Another violation in this category said that making a statement regarding use of the product in patients with the target condition broadly when the product was intended for a narrower population was extending the indication.
- Overstatement of Efficacy – Here one company made a statement that suggested that their drug preserved magnesium levels and therefore may enhance lipi-peroxidation, citing an in vivo study in rats as evidence. The agency deemed that insufficient grounds to make such a link between preserved magnesium levels and this particular outcome. Another manufacturer included a drawing showing that their drug worked better than two other drugs in the class, in the absence of head to head clinical trials demonstrating that point. And another manufacturer made claims that had percentages of patients who responded, without corresponding studies that either contained those specific endpoints or achieved the claimed numbers.
- Unsubstantiated Superiority – A superiority claim made citing a study where the drug against which the claim is being made was studied at a less than optimal dose is not sufficient to make a superiority claim. Another manufacturer’s claim that the product worked better was supported by evidence that demonstrated that the way it worked was more thorough, but there was no evidence to demonstrate that this increased efficiency led to the clinical outcome claimed by the communication. In addition, the use of a claim such as "easier to use" has to be supported by clinical evidence that is direct, not a conclusion drawn from circumstances.
- Omission of Important Risk Information – This was by far the most common issue cited in the fourth quarter warning letters. Two manufacturers cherry picked the information – while including much of the risk information in an ad, did not put in the contraindications, which the agency cited as making the drug appear safer than it actually is. Other manufacturers failed to put any risk information whatsoever into the promotional material. What is promotional material? The panels of an exhibit booth are promotional. The lesson here is risk information must be put on any communication, and must be complete, not partial. If a physician or patient is going to see the communication, put the risk material in. Of note, if you have a boxed warning, it not information that should be skipped when promoting the product!
- Misleading Safety Claim – One manufacturer provided dosing and safety information that was cited to a study, but unfortunately an animal study. It has to be humans.
- Unsubstantiated Claim – One product claimed that it was made to induce better patient compliance, relying on the logic that the taste was improved with flavor enhancers. While that is a logical assumption, without data to back it up, the agency deems it an unsubstantiated claim.
These additions are going to be updated in the column to your left under "Resources by Me" with the entire list of warning letters for 2006, or you can go directly to the FDA’s 2006 Warning Letters page for CDER.