When the U.S. Food and Drug Administration declines to approve a new medicine, its delivers the news to the drug developer in what’s known as a complete response letter.
There may be many reasons why the agency feels a drug is not ready for prime time. The most common ones are that the data the company provided do not make a case that the drug is either safe of effective, but there can be other deficiencies too. This can extend across a range of issues including a lack of data integrity, inappropriate trial design, an inadequate patient population in the studies, issues with non-clinical studies, manufacturing concerns, and more.
In Europe, these letters take the form of the European Medicines Agency’s refusal assessment reports that provide a detailed public record explaining why the agency refuses to approve a particular drug. In the United States, though, complete response letters are considered private communications between the agency and the drug sponsor. The only thing that is made public about these letters is what a drug company chooses to make public because they are viewed as confidential business information.
The issue of complete response letters became top of mind for me because of the recent FDA refusal to approve Akcea’s and Ionis’ experimental therapy Waylivra for familial chylomicronemia syndrome (FCS), an ultra-rare and potentially fatal disease. The FCS Foundation, a patient group, has been critical of the FDA’s decision and is calling on the agency to reverse itself. The wife of one FCS patient has also launched an online petition campaign and, as of September 11, had gather more than 5,600 signatures—more signatures than there are FCS patients worldwide—to say Waylivra needs to be approved.
FCS can be a painful, debilitating, and deadly disease. Patients who participated in the Waylivra clinical trial spoke at an advisory committee meeting at the FDA and expressed the benefits they derived from the drug. In May, the advisory committee voted 12 to 8 in favor of recommending approval. But at the end of August, the agency decided it would not approve the drug.
The patient response isn’t surprising given the seriousness of the condition and the absence of any available therapy. The assumption has been that the issue for the FDA centered on safety concerns about Waylivra because the drug could cause abnormally low platelet counts. But the patients are acting with less than complete information because Akcea, as is its right, has not made public the complete response letter.
“Regarding the CRL, we have stated publicly that the issues raised are consistent with what was discussed at the AdComm and are related to data on managing platelet levels and dosing,” the company said in response to a request for a copy of the letter. “We hope to address this with data from our ongoing Open Label Extension study and/or Early Access Program, but we will not know the specific path forward or if this will be a sufficient approach until we meet with the FDA. We hope to do that as soon as possible.”
One of the issues that the patient community has increasingly focused on in recent years is data transparency. This often centers on the issue of publishing data from clinical trial studies including the ones that fail. Complete response letters, though, are less often an area of focus.
But a 2015 study from staff of the FDA’s Office of Public Health Strategy and Analysis, published in the open access journal BMJ, provides an unusual view into the content of complete response letters and how good a job companies do at communicating their content.
It turns out they don’t do a good job at all. Often companies didn’t even bother to issue a press release when they get a complete response letter. When they did issue a press release, they omitted much of the information contained in the complete response letters.
The researchers examined all of the complete response letters issued by the FDA’s Center for Drug Evaluation and Research between August 11, 2008 and June 27, 2013—a total of 61. They compared all off the statements in the letters relating to the FDA decision to statements in corresponding company press releases.
A total of 87 percent of the complete response letters identified a deficiency in either safety or efficacy of a drug and nearly half of the letters (48 percent) identified deficiencies in both. Only 13 percent cited concerns that did not include either safety or efficacy issues.
For 18 percent of the letters, the company that received them did not issue a press release. In 21 percent of the cases, the press releases that were issued did not match any of the statements in the complete response letters.
Of the 687 statements in the complete response letters in the study sample, the researchers matched them to 93 statements (14 percent) companies made in corresponding press releases, including 30 out of 191 about efficacy (16 percent) and 22 out of 150 about safety (15 percent).
Of the 32 complete response letters that called for a new clinical trial for safety or efficacy, 19 (59 percent) had matching statements in corresponding press releases.
A total of seven complete response letters in the study sample reported higher mortality rates in treated participants in clinical trials, but only one corresponding release mentioned that fact.
“Our analysis of the content of press releases indicates that they are incomplete substitutes for the detailed information contained in complete response letters,” the authors write. “Disclosure of letters would allow the FDA to increase the overall transparency of its regulatory processes, providing greater awareness of the agency’s role in protecting health and combating misperceptions regarding the basis for non-approval of a drug. It would also allow for broader and more informed public discussions by relevant stakeholders (such as patients, clinicians, researchers, and public health advocate) of the scientific and regulatory reasons for the FDA’s actions.”
The U.S. Food and Drug Administration has an obligation to patients. That obligation does not only include approving needed medicines in a timely manner, but also ensuring they are safe and effective. In the absence of access to complete response letters, patients are left with an incomplete understanding of the reasons behind an FDA decision and whether the FDA rejected a drug because it ignored patients, or because patients, in fact, were top of mind.
Investors often makes noise about the lack of transparency that results from the FDA not disclosing the content of complete response letters. Patient advocates would do well to make their voices heard on this issue as well.
September 11, 2018