Accutane

Chronology

1971

Hoffman La-Roche (Roche) develops Accutane, but chooses not to pursue marketing because of its risk of birth defects.

June 1982

The Food and Drug Administration (FDA) approves Accutane for the treatment of severe cystic acne which is unresponsive to other treatments. Shortly after marketing, FDA and Roche receive reports of Accutane-related birth defects.

September 1983

Public Citizen, a consumer advocacy group, petitions FDA for warning labels on Accutane's risk of birth defects and other side effects.

March and October 1984

FDA requires stronger warnings and physician mailings on Accutane's risk of birth defects.

June 1985

Roche amends Accutane's package insert under 'Adverse Reactions' to state:
"The following CNS reactions have been reported and may bear no relationship to therapy - seizures, emotional instability including depression, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy and paresthesias."

August 1986

Roche amends Accutane's package insert to state:
"Depression has been reported in some patients on Accutane therapy. In some of these patients, this has subsided with discontinuation and recurred with reinstitution of therapy."

February 1988

Discussion of an FDA memo previously listed under February, 1988, has been corrected and now can be found under the heading "February, 1998."

May 1988

FDA requires stronger warnings and physician mailings on Accutane's risk of birth defects. FDA also requires additional studies, including follow-up patient surveys. Disregarding an advisory committee recommendation, FDA does not restrict prescribing of Accutane to board-certified dermatologists. Industry contends that FDA lacks the statutory authority to require all such conditions on Accutane's distribution.

1990

In a 1990 memo, FDA concluded that as a result of Accutane's risks of birth defects, "The magnitude of injury and death has been great and permanent, with 11,000 to 13,000 Accutane-related abortions and 900 to 1,100 Accutane-related birth defects."

1996

FDA initiates a MedGuide program to provide patients with drug information leaflets (also known as "patient package inserts" or PPIs). In the past, FDA had established PPIs through independent regulations or through voluntary manufacturer agreement. Where public health warranted, MedGuide would have permitted FDA to develop PPIs without manufacturer consent.

In response to industry objections, Congress enacts an appropriations rider limiting the MedGuide program. Congress permits FDA to develop MedGuides for 40 drugs with serious side-effects, including Accutane.

Roche unsuccessfully seeks in Federal court in New Jersey to suppress public availability of extensive Accutane documents, including adverse event reports, marketing plans and clinical data, relating to Accutane's risk of birth defects.

According to a 1996 press account of FDA documents, "More than 90 percent of females treated with Accutane did not have severe cystic acne."

March 3, 1997

Based on a 1992-94 French study of Accutane's association with depression, French health authorities require Roche to add "suicide attempt" to Accutane's side effects. Roche does not inform the FDA.

May 1997

FDA initiates discussions with Roche concerning reports of serious psychiatric disorders associated with Accutane. FDA is unaware of the new French warning.

August 1997

FDA issues a warning letter to Roche for failing to submit serious adverse event reports in a timely manner. Roche claims its computer systems are responsible for delays of up to eight years in complying with the law.

February 1998

A 1998 FDA memo concludes that Roche "had not acted in good faith to truly and accurately answer questions relating to Accutane use in women and pregnancy exposure." The memo recommends "active consideration of removal of Accutane from the market."

The memo also concludes that: "Given all the pieces of evidence available, it is difficult to avoid the conclusion that Accutane can adversely affect the adult human brain in clinically significant ways and that Accutane use is associated with severe psychiatric disease in some patients."

In response to calls to withdraw Accutane, Roche proposes more intensive patient education on the drug's risks of birth defects, including patient materials and informed consent forms.

February 25, 1998

FDA requires Roche to add the following new bold-face warning to Accutane's physician package insert. FDA is still unaware of the new French warning.

"WARNINGS - Psychiatric Disorders: Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. No mechanism of action has been established for these events."

"ADVERSE REACTIONS - In the postmarketing period, a number of patients treated with Accutane have reported depression, psychosis and rarely, suicidal, ideation, suicide attempts and suicide. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy."

In its press release, Roche claims there is no proof of causation and that "teenagers are at particular risk for depression."

March 1998

The U.K. and Ireland require warnings of Accutane's risk of psychiatric disorders which are similar to those in the U.S.

March 5, 1998

Just two weeks after Roche is compelled to strengthen warnings of Accutane's risks of "depression, psychosis and, rarely, suicidal ideation, suicide attempts and suicide," the FDA is forced to issue a warning letter requiring Roche to cease "false and misleading" advertisements which promote Accutane as an "effective treatment of severe acne... [that] minimizes negative psychosocial effects such as depression and poor self-image."

FDA adds, "This claim is particularly troublesome in light of information recently presented in a Dear Doctor letter that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts and suicide."

FDA charges Roche to "prominently disclose information about the psychiatric disorders described in the warnings section of the revised labeling" in Accutane advertisements.

July 1998

FDA becomes aware that French authorities had already required the addition of an Accutane "suicide attempt" warning in 1997, of the 1992-94 French study associating Accutane with depression, and of Roche's failure to disclose this information to the agency.

December 21, 1999

Roche prepares a "Psychiatric Disorder Issue Work-Up" for FDA, concluding:
"Psychotic Disorders: There are a very small number (3) of reported cases that imply causality between a described psychotic disorder and Accutane administration... Suicidal Behavior: There are no reports amongst the 168 reviewed that would imply causality between suicidal behavior and Accutane."

May 1, 2000

Roche changes the warnings on the package label to include:
"...DEPRESSION, AND RARELY SUICIDAL THOUGHTS, SUICIDE ATTEMPTS AND SUICIDE..."
This is the first time that the actual packaging contains the full psychiatric warnings.

September 18-19, 2000

FDA's Dermatologic and Ophthalmic Drug Advisory Committee holds a meeting on Accutane's risks of birth defects and psychiatric disorders. FDA concludes that from 1982 to May, 2000, Accutane is associated with 147 suicides and hospitalizations for depression.

The Advisory Committee determines that further research is needed to establish Accutane's risks of birth defects and of depression, suicide and other psychiatric disorders – but fails to specifically recommend that FDA require such studies. FDA suggests that such research should be conducted, but does not commit to requiring them.

Roche claims, "The number of suicides observed in the U.S. in the Accutane-exposed cohort is much less than would have been predicted... There is plainly no excess of observed suicidies in the Accutane-exposed population (32) compared to what would be predicted in the age-matched general population."

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