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Frequently Asked Questions

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1. What is the Safety Review Committee (SRC) and who are its members?

  • Novartis chartered an external SRC to provide independent, objective and thorough scientific review of the reported post-marketing adverse events in comparison to relevant events seen in the Phase III HAWK & HARRIER registration trials that were the basis of the approved prescribing information.
  • The SRC is composed of global retina and uveitis specialists, and imaging experts, as well as ophthalmology experts from two separate external data monitoring committees.

2. How is the Safety Review Committee (SRC) analysis different from the previously published HAWK & HARRIER data?

  • The data previously published for the HAWK & HARRIER trials is based on the adverse events reported by investigators during the course of the trials using preferred terms from an international standardized medical coding dictionary.
  • The SRC review, triggered by the new safety signal based on post-marketing reports, was a focused, unmasked, post-hoc assessment of IOI-related cases of the HAWK & HARRIER trials.

3. Do the Safety Review Committee (SRC)-reported adverse events result in an increase in vision loss?

  • The overall rates of moderate and severe vision loss (≥ 15 ETDRS letter loss) remain similar between the brolucizumab (7.4%) and aflibercept (7.7%) treatment arms at week 96 in the HAWK & HARRIER trials.
  • The SRC analysis also provided insights into the overall incidence of moderate and severe vision loss specifically related to retinal vasculitis and/or retinal vascular occlusion.

4. Will the full analysis from the Safety Review Committee (SRC) be published?

  • The SRC has committed to share their findings in future peer-reviewed publications.

5. Why are there different rates and numbers being reported and shared?

  • Adverse events are reported from both clinical trials and post-marketing cases, therefore the data varies between them.
  • During clinical trials, all adverse events are captured by investigators throughout the study in the database. Once a medicine is marketed, patients, treating physicians and other healthcare professionals can voluntarily report adverse reactions to the company marketing the product (Novartis) and/or local Health Authorities.
  • Clinical trial investigators, patients, treating physicians and other healthcare professionals report adverse events in their own words to appropriately describe diagnosis, symptoms, signs and investigation results. An international standardized medical dictionary is used to code these events based on standard terminology used across the pharmaceutical industry and health authorities.
  • Additionally, there are several limitations to post-marketing reporting systems, which can include under-reporting, incompletely documented cases and cases without imaging information. Some of the investigations remain ongoing, and therefore the information is subject to change. 

6. Were the reported post-marketing adverse events also observed in HAWK and HARRIER? Why are the new terms being used now?

  • Cases of intraocular inflammation and retinal occlusive events were observed in the brolucizumab Phase III trials (HAWK & HARRIER).
  • Healthcare providers and clinical trial investigators report what they diagnose or observe. In a clinical trial submitted to Health Authorities, the terms reported by investigators are mapped to the closest terms found within an international standardized medical coding dictionary.
  • Similarly, in post-marketing reports, events are sometimes referred to using terminology not found in the medical coding dictionary. The SRC and Novartis agreed that the best match for these reported post-marketing events in the medical coding dictionary is retinal vasculitis and/or retinal vascular occlusion.

7. Why did we report adverse events per 10,000 injections rather than per patient?

  • Unlike in clinical trials, where the number of injections each patient receives is recorded by investigators, in marketed use, the company knows how much of the medicine has been distributed but does not know the exact number of injections administered. Therefore, post-marketing events rates are calculated per 10,000 per injections distributed.

8. What is the incidence of vision loss associated with brolucizumab in HAWK and HARRIER?

  • In the HAWK & HARRIER trials the overall rates of moderate and severe vision loss (≥ 15 ETDRS letter loss) were similar between the brolucizumab (7.4%) and aflibercept (7.7%) treatment arms at Week 96.
  • Approximately 10% of this moderate and severe vision loss (≥ 15 ETDRS letter loss) in the brolucizumab arms was observed in patients with IOI who had signs of retinal vasculitis and/or retinal vascular occlusion.

9. Are the reports of retinal vasculitis and/or retinal vascular occlusion associated with vision loss?

  • In the HAWK & HARRIER trials, approximately 22% of brolucizumab patients with IOI, who showed signs of retinal vasculitis and/or retinal vascular occlusion, had moderate and severe vision loss (≥ 15 ETDRS letter loss) at Week 96.
  • In a cumulative review of brolucizumab post-marketing cases performed until 25 September 2020, 36% of cases reporting retinal vasculitis and/or retinal vascular occlusion also reported vision loss (as assessed by Novartis based on reported visual acuity test results).

10. Why are you updating the label and when do we expect it to happen?

  • We are working with regulatory authorities worldwide to ensure information available for healthcare professionals and patients reflects our latest understanding of these adverse events and helps them make informed decisions on the use of Beovu.
  • Regulatory timelines vary by geography and we cannot speculate on regulatory actions.
  • The US Food and Drug Administration (FDA) approved an update of the Beovu prescribing information (PI) on June 9, 2020. The update includes characterization of the adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of intraocular inflammation noted in the original prescribing information.
  • The EMA, based on a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) has approved an update to the Beovu Summary of Product Characteristics on September 3, 2020. The update to the EU label includes the addition of retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation. The label notes that patients developing these events should discontinue treatment and the events should be promptly managed.
  • The Swiss Health Authority (Swissmedic) approved an update of the Beovu PI on June 12, 2020. The Swiss PI has been updated to state that retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. In most cases intraocular inflammation was also present.
  • The Australian Health Authority (TGA) approved an update of the Beovu PI on June 25, 2020. The Australian PI has been updated to state that retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. Concomitant intraocular inflammation was reported, but not in all cases. Prior treatment was not reported for all cases, however, some patients had previous intravitreal VEGF inhibitor therapy.
  • The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) approved an update of the Beovu product information on July 13, 2020. The approved amendment to the product information reflects the implementation of a safety labeling change for ‘retinal vasculitis’ and ’retinal vascular occlusion’ which have been reported with the use of Beovu.

11. What should I do if a patient develops IOI, retinal vasculitis or other?

  • Before injecting, physicians are encouraged to look for signs of intraocular inflammation, which may include examination by slit lamp or posterior segment imaging. If active intraocular inflammation is present, you must not perform an intraocular injection and should treat the intraocular inflammation according to medical practice. Please instruct your patients to contact you immediately if they notice any changes in visual acuity or any signs of inflammation, such as eye pain, floaters, discomfort or ocular hyperemia.
  • You are encouraged to continue to report any observed or suspected adverse events according to local country requirements. You can also make a report to Novartis at https://www.report.novartis.com

12. What is the difference between retinal vasculitis, retinal vascular occlusion, retinal artery occlusion and retinal occlusive vasculitis?

  • The definitions of these terms are as follows. Depending on the blood vessel involved and the severity of the inflammation, any of these conditions can lead to significant loss of visual acuity in some patients.
    • Retinal vasculitis: Inflammation of retinal blood vessels. It can be a specific diagnosis or as a part of localized or systemic inflammatory disorder.
    • Retinal vascular occlusion: A blockage of the small vessels that carry blood into or away from the retina, causing blood or other fluids to build up and sometimes preventing the retina from properly functioning, which can result in a sudden loss of vision.
    • Retinal artery occlusion: Blockage of a retinal artery due to any number of causes, including inflammation. Retinal artery occlusion is a subset of retinal vascular occlusion.
    • Retinal occlusive vasculitis: A blockage of any retinal blood vessel due to inflammation. Also referred to as occlusive retinal vasculitis. Healthcare professionals sometimes report this term, but as it is not in the international standardized medical coding dictionary, we have chosen to use the terms retinal vasculitis and/or retinal vascular occlusion instead.