Regulatory Decision Summary for Revolade

The Sponsor submitted this supplemental new drug submission (SNDS) to revise the chronic immune thrombocytopenia purpura (ITP) indication for Revolade in the Product Monograph (PM). The proposed revisions address the changed disease terminology and definition of chronic ITP; specifically the revisions were to remove the words "chronic" and "purpura" and to add the text "lasting 6 months or longer from diagnosis".

ITP can be defined by disease duration, and the terms "acute" and "chronic" have been used to categorize patients based on the length of time from initial diagnosis. Historically, "chronic" disease referred to the persistence of symptoms beyond 6 months and "acute" was used to describe a self-limited form of the disease, consistent with disease definitions established by American Society of Hematology (ASH) in 1996 and British Committee for Standards in Haematology (BCSH) in 2003. The most recently established guidelines have recommended replacing "acute" with "newly diagnosed" for all cases at diagnosis, "persistent" to define the period between 3 and 12 months after diagnosis, and "chronic" to describe patients with ITP lasting beyond 12 months. The updated guidelines also emphasized the uniform application of the acronym "ITP" to stand for "immune thrombocytopenia." It was advised to avoid the terms "idiopathic" and "purpura " in light of the immune-mediated mechanism of the disease and the absence of purpura in the majority of ITP cases. Results from some of the patients in the Revolade adult and pediatric ITP studies indicated that they did not always present with bleeding symptoms.

In the 5 pivotal and supportive studies for the adult ITP indication, patients diagnosed with chronic ITP for at least 6 months were enrolled as per the inclusion criteria. The percentages of patients with a time since ITP diagnosis of 6 to 12 months represented 2% to 19% of the Revolade treated patients in studies RAISE, REPEAT and EXTEND. The pivotal pediatric ITP study (PETIT2) only enrolled patients in accordance with the updated IWG 2009 guidelines, and therefore, eligible patients had chronic ITP >12 months in duration. The supportive study (PETIT) enrolled patients with chronic ITP for at least 6 months, as per the inclusion criteria, and 17.8% of the patients treated with Revolade had a time since ITP diagnosis of <12 months.

The analysis that evaluated the use of Revolade in a real world setting show that among the patients in the two databases receiving treatment with Revolade a large proportion initiated treatment prior to 12-months after their index ITP diagnosis.

Upon review of the data provided in the current submission and those provided in support of the approval for the adult and pediatric chronic ITP indication, the Sponsors proposal to remove the word "chronic" and to add the text "6 months or longer from diagnosis" for the ITP indication were not recommended. This is because the pivotal study (PETIT2) was conducted only in patients who had confirmed diagnosis of chronic ITP for at least 1 year and very few pediatric patients with a diagnosis of 6 to 12 months were studied in the single supportive study (PETIT). Furthermore, a benefit for those patients without a diagnosis of chronic ITP according to the "new" definition (i.e. more than 12 months duration) was not observed. "Chronic immune thrombocytopenia" was therefore kept in the indication.

The provided analysis in this SNDS, which evaluated the use of Revolade in a real world setting, showed that among the patients in the two databases receiving treatment with Revolade, a large proportion initiated treatment prior to 12-months after their index ITP diagnosis. Based on the analysis, from July 1, 2010 through December 31, 2013, 58% to 65% of the patients on Revolade initiated it at ≤ 12 months after their index diagnosis, and amongst these patients, approximately 62% of them initiated Revolade treatment at 0 to ≤ 3 months after the diagnosis. These data show that Revolade was prescribed and treatment was initiated in a large proportion of the patients prior to 12 months after their ITP diagnosis even at the time when the new definition of chronic ITP had been published (2009) and adopted in certain Clinical Guidelines, and where the indication statement in all of the Revolade labels (United States USPI, Canadian PM and European SmPC) clearly stated that it was for use in "chronic" ITP. Therefore, the use of the wording "chronic" in the PM and the new definition of "chronic ITP" did not hinder the use of Revolade in those patients who had received an ITP diagnosis between 6 and 12 months prior to initiation of treatment, as in the patient population studied in the ITP studies that led to original approval of Revolade for adult ITP.

It was also recommended that the Sponsor maintain the word "chronic" when referring to ITP throughout the PM.

Given the patient population studied in the adult ITP studies included patients diagnosed with chronic ITP for at least 6 months as per the inclusion criteria, the Sponsors proposal to specify "at least 6 months from diagnosis" was acceptable in the CLINICAL TRIALS section in describing "chronic" when referring to those patients with ITP for the EXTEND study. It was recommended to the Sponsor to also consider adding the information in the CLINICAL TRIALS section that patients diagnosed with chronic ITP at least 6 months prior to screening were enrolled in the other adult ITP clinical trials: TRA100773A, TRA1001773B, RAISE, and REPEAT. The Sponsor implemented this revision by adding this information in the paragraph describing the patient demographics for these studies under the CLINICAL TRIALS section of the PM.

As the recent guidelines from the IWG also advised avoiding the terms "idiopathic" and "purpura" in light of the immune-mediated mechanism of the disease and the absence or minimal presence of bleeding symptoms (purpura) in a large proportion of ITP cases, the Sponsors proposal to remove the word "purpura" in the indication and throughout the PM and the word "idiopathic" throughout the PM was considered acceptable. Review of the data in the Revolade ITP studies found that some patients had a World Health Organization (WHO) bleeding scale grade of 0 at baseline, indicating "no bleeding", at the start of the study and throughout the study.

There is no change to the overall benefit-harm-uncertainty for Revolade for the approved indications as a result of the PM changes in this SNDS, given that the revisions to the wording for the chronic ITP indication statement did not change the patient population indicated for chronic ITP.