Patient Rep Reverses Position On SSRI Black-Box Warning

Needless to say, 2004 was not a very good year at the FDA. Griffith recalled that the first public hearing to address the potential link (and her first public meeting as a patient representative) was held February 2, 2004. That hearing, which included the Psychopharmacologic Drugs Advisory Committee (PDAC) as well as the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee, ultimately led to the agency's decision to contract with suicidology experts at Columbia University. The Columbia team was asked to reanalyze clinical trials data involving antidepressant medications and reclassify all the adverse events that occurred in children and adolescents as definitely representing a self-harm event, possibly representing self-harm, or not involving self-harm at all. That analysis proved cumbersome, painstaking, and time consuming.

When the Columbia team submitted its completed analysis to the FDA in late summer 2004, FDA officials moved ahead with an in-house analysis of Columbia's reclassified adverse events by the Office of Drug Safety to determine if suicidal thoughts and behaviors were still more prevalent in children and adolescents taking antidepressants compared with patients taking placebo in the controlled clinical trials.

The FDA announced the completion of Columbia's reclassification of adverse events in August 2004 and presented its own analysis at a second joint public hearing of the two advisory committees on September 13-14, 2004.

The week before the second public hearing, FDA officials testified before a congressional committee investigating its handling of the antidepressant/suicide issue. The agency had come under increasing public and government scrutiny, and agency officials were said to be anxious to provide hard evidence of the FDA's rigorous attention and analysis of the data.

“At this point you've got an atmosphere that is emotionally charged,” Griffith remembered. “The FDA is `soiled' in the public's mind, and here we were headed into the second hearing.”

Griffith believes that the typical format of the public hearings is fatally flawed. Most hearings involve presentations by various FDA officials, scientists, and safety officers and a comment period for the public, in which interested parties are allowed to enter a brief statement into the record.

During the September PDAC/Pediatric public hearing, more than 60 public witnesses testified. The majority were family members of patients who had committed suicide while taking antidepressants. In addition, a number of physicians entered their own comments regarding the potential link—some supporting a link, some discounting any link. Many of the same witnesses had testified at the February hearing as well.

“Trotting out members of the public to air emotionally devastating, personal, and anecdotal stories and having those stories sit as evidence for the committee amounts to a barrage that can't help but sway how you feel and how you look at the data you are seeing,” Griffith said.

“Intellectual analysis does not happen [under those circumstances],” Griffith continued. “It is an emotional exercise. After a day's worth of personal and anecdotal accounts—some pro, some con—if the committee could then be sequestered and thereby have the opportunity to fully examine the data in light of what we'd heard, then I think you would have some confidence in the notion that a scientific effort had been made to render a decision.”

As it was, she added, “it was just a show, a very public show. And it was tragic to sit there—not once but twice—and have people tell you that the committee had the blood of their children on its hands.”

Although Griffith did not receive death threats, other members of the committee did, she said. “I did get a lot of really nasty e-mails,” she added, particularly after the September hearing and again following the APA press conference.

By the morning of September 14, 2004—the second day of the contentious advisory committee hearing—FDA officials were looking for some way to redeem themselves, Griffith believes.

“The only option [FDA officials] put on the table was a black-box warning,” she said.

The FDA needed to show that critics of the agency were wrong about the FDA's ignoring or minimizing an important safety concern, she said. They seemed to believe that the agency needed to move forward with strong warnings about antidepressants and suicidality that were based in science and in the best interest of the public health.

PDAC/pediatric advisory committee members, including Griffith, asked about other options.

“At one point I said, `Why not simply go with an informed-consent document?' I felt that by requiring a formal written informed consent, the FDA would in a way force the prescriber to sit down with the patient and engage in a discussion about the risks and the benefits.”

The patient or the patient's parent would have to sign the document, acknowledging that he or she had been informed and understood the risks and benefits of antidepressant medications.

According to Griffith, FDA officials discounted a formal written informed consent as “too cumbersome” and as “dictating the methods by which the doctor/patient conversation transpires.”

“I have to say, that really angered me. If you have to get informed consent for something as superficial as a Botox injection, then why don't you have to when the issue is as serious as antidepressant medications?”

PDAC members also asked agency officials whether any data were available indicating the public's response to the controversy since it first hit the media in May 2003. That's when U.K. regulators questioned a potential increased risk of suicidal thoughts and behaviors in clinical trials data involving paroxetine (Paxil).

FDA officials responded that the most recent prescribing data were available only through March 2004. Those data—which spanned the period since the start of the controversy nine months earlier in the U.K.—indicated that antidepressant prescription rates up to the weeks following the first advisory committee meeting were continuing to increase, Griffith said.

“You could almost see the committee members' relief,” she recalled. “We had a false sense that the public understood the risks” associated with taking antidepressants and could cope with the risks in light of the benefits. “So we thought that if we leaned toward the black-box warning, it might not be the worst thing after all.”

Other options ranged widely in their potential impact on prescribing of antidepressants, from making no change in existing labeling or availability of the drugs to removing all SSRIs from the market. The committee members searched for the best alternative to balance safety concerns with the critical need to keep antidepressant medications widely available to patients who needed them.

In the end, Griffith believed that committee members left the hearing thinking that the only viable course of action was to add a black-box warning to all antidepressants' labeling about the potential for increased risk of suicidal thoughts and behaviors in children and adolescents taking the drugs. She said that committee members believed that such a warning would sufficiently prompt a candid dialogue between prescribers and patients about the drugs' risks and benefits while not actually restricting physicians' ability to prescribe them based on clinical judgment.

Reality, however, took a different turn. The data released in the weeks following the September hearing showed significant decreases in antidepressant prescribing rates as the controversy unfolded between the first and second PDAC/pediatric committee hearings (Psychiatric News, October 15, 2004).

At the conclusion of the September hearing, the PDAC/pediatric advisory committee members voted 15-8 in favor of the black-box warning. Griffith now believes she voted the wrong way.

“In my heart of hearts, I was not in favor of the black-box warning, and I didn't want to vote for it,” she said. “I felt as though I was betraying my instincts [by voting in favor], yet I also knew that I was there as a patient representative. My vote represented a larger constituency.”

Because of her role as the mother of a teenager who nearly succeeded in completing suicide while on antidepressant medications, Griffith understands all too well both sides of the argument.

“Blaming the medications is a simplistic answer to the question of why children attempt suicide,” Griffith said. “And you know, if my child had died, and all of the data had come out regarding increased suicidal behaviors and thinking, I might very well have been one of the people on the other side. Grieving parents feel they have no place to turn but to blame the pharmaceutical companies and their products.”

Yet, Griffith believes, the data linking the medications to increased suicidal thoughts and behaviors remain very weak.

“I don't think the reason for the increase has been examined very closely, but it's my suspicion that any time a kid is talking about his or her feelings in a therapeutic setting amid depression, he or she is going to be talking about self-harm. It simply goes hand in hand with the diagnosis: depression is a suicide illness.”

In the end, Griffith said, “I think it's important for me, having come through all of these experiences, to maintain an independent and unbiased voice. It's important for me to use that voice to support the overriding message along with APA and AACAP. Really, APA and AACAP need to engage the consumer, the family member, to get that message out: untreated depression carries a phenomenal risk, but that risk far outweighs the risk of treating depression with medications. We need to open a dialogue with the public and translate the rapidly advancing science. It's critical.” ▪