21 st Expert Committee on the Selection and Use of Essential Medicines Application for the deletion of bevacizumab (Avastin ) on the WHO Model List of Essential Medicines Submitted by F. Hoffmann-La Roche Ltd. 2 December 2016 F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124 4070 Basel, Switzerland 1
Table of Contents 1. Summary Statement of the proposal for inclusion, change or deletion 3 2. Name of the focal point in WHO submitting or supporting the application 3 3. Name of organization(s) consulted and/or supporting the application 3 4. International Nonproprietary Name (INN) and ATC code of the medicine 4 5. Formulation and strength proposed for inclusion 4 6. Whether listing is requested as an individual medicine or a pharmacological class 4 7. Treatment details (requirements for diagnosis, treatment and monitoring). 4 8. Information support the public health relevance 4 9. Summary of comparative effectiveness in a variety of clinical settings 4 10. Summary of evidence on safety 4-5 11. Summary of available data on comparative cost and cost-effectiveness 5 12. Summary of regulatory status of the medicine 5 13. Availability of pharmacopoeial standards 6 14. References 6 15. Attachments 6 2
1. Summary statement of the proposal for inclusion, change or deletion F. Hoffmann-La Roche Ltd. (Hereafter referred to as Roche) proposes the deletion of bevacizumab from the WHO Model List of Essential Medicines (EML) under the category of ophthalmological preparations. Bevacizumab (brand name Avastin ) is indicated for the treatment of multiple types of cancer through intravenous infusion. This product was not developed nor manufactured according to the quality standards for drugs to be injected intravitreally. These quality standards are different from those required for drugs given as intravenous infusion (Refer to Section 13). Bevacizumab has never been reviewed or approved by any regulatory authority for ophthalmic use. For unapproved ophthalmic use, a single-use vial of bevacizumab is often compounded for multiple injections. Lack of preservative and the compounding process may lead to loss of sterility. There have been reports of adverse events, such as serious intraocular infections, after the injection of compounded bevacizumab into the eye. Such infections have, in some cases, resulted in permanent blindness (Refer to Section 10). As the use of bevacizumab in the eye is off-label, Roche does not endorse or promote in any way its use for ophthalmology indications. The risks of this off-label use have been clearly stated and communicated in the bevacizumab Prescribing Information. Alternative treatment options, ranibizumab (Lucentis ) and aflibercept (Eylea ) are approved worldwide by national Health Authorities for the treatment of wet age-related macular degeneration and other ophthalmology indications for which bevacizumab is currently recommended in the WHO EML, while the aforementioned approved products are not recommended in the WHO EML. Roche thereby proposes: the deletion of bevacizumab from the WHO EML for ophthalmic use, or if WHO continues to recommend the use of bevacizumab for ocular use, then, as the Marketing Authorization Holder for bevacizumab, we request that clarifying language be added to the WHO EML itself with the purpose of reminding prescribers that this product has not been developed nor approved by regulatory authorities for ocular use and that inappropriate handling and storage can directly lead to harmful outcomes for patients. Roche has raised concerns directly with the WHO Secretariat regarding the off-label listing of bevacizumab on the WHO EML in respect to patient safety risks in letters dated September 2013 and June 2016 (Refer to Attachments 1 and 2). WHO responded in July 2016 (Refer to Attachment 3) and acknowledged that ensuring prescribers are appropriately informed of the safe use and administration of intravitreal bevacizumab is of great importance. WHO expressed that as the 2013 and 2015 WHO Technical Report Series acknowledge formulation and safety issues relating to intravitreal administration of bevacizumab and address the importance of appropriate compounding and quality measure that our concerns have been satisfactorily addressed. However, we believe that this inclusion within the Technical Report Series is insufficient, as we continue to receive patient safety reports. Therefore, the medicine should be deleted from the WHO EML or clarifying language on the WHO EML itself is necessary. 2. Name of the WHO technical department and focal point supporting the application (where relevant). 3. Name of organization(s) consulted and/or supporting the application. F. Hoffmann-La Roche Ltd. 3
4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine. INN: Bevacizumab ATC: Not applicable 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate). Roche proposes the deletion of bevacizumab (25 mg/ml, concentrate for solution for infusion) from the WHO EML for ophthalmic use. Alternatively, if WHO continues to recommend the use of bevacizumab for ocular use, then, as the Marketing Authorization Holder for bevacizumab, Roche requests that clarifying language be added to the WHO EML itself with the purpose of reminding prescribers that this product has not been developed nor approved by regulatory authorities for ocular use and that inappropriate handling and storage can directly lead to harmful outcomes for patients. 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class 7. Treatment details (requirements for diagnosis, treatment and monitoring). 8. Information supporting the public health relevance. 9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings. 10. Review of harms and toxicity: summary of evidence on safety. In order to use bevacizumab in the eye, a compounding pharmacy (that Roche has no responsibility for) must withdraw repeatedly with an intravitreal syringe a low amount of solution from the same single-use vial of bevacizumab and aliquot into multiple syringes. The single-use vial of bevacizumab does not contain preservative. Consequently, during the compounding process its sterility can be compromised with the result that infections such as endophthalmitis are possible. As the Marketing Authorization Holder for bevacizumab, Roche has received reports of serious patient safety risks associated with the adaptation of the product for the off-label use in the eye. In the past two years, we have been alerted to three incidents of multiple usage from a single-use vial, in which 43 patients reported adverse events, ranging from ocular irritation to unilateral blindness. In March 2015, Roche received a report from Iran in which 15 patients were treated from a single vial of bevacizumab. Within 24 hours all treated patients experienced infectious endophthalmitis. Bacterial cultures from each of the 15 patients grew gram-negative bacilli. In January 2016, Roche received a report from India relating to 15 patients who experienced eye problems following intravitreal administration of bevacizumab. A 4
representative of Roche India visited the institution in which these patients had been treated. The physician with whom the representative spoke confirmed that the institution did not aliquot multiple doses from a single vial but rather returned on multiple occasions to the vial as each patient was treated, but ensuring that the vial was used only on the day on which it had been opened. The media coverage of this incident appears to have prompted further interest and two subsequent reports were also noted in Indian media outlets. Neither of these were particularly well documented but it was noted that 7 patients had been overdosed and also that the vial from which they were treated was positive for gram-negative bacilli. The reported adverse events ranged from vision impairment to unilateral blindness. As a direct result of these reports of complications following intravitreal administration of bevacizumab, the Indian Directorate of General Health instructed on January 21, 2016 that bevacizumab not be used for the treatment of ophthalmological conditions. State inspectorate staff were also advised that they should consider monitoring distribution of bevacizumab and its use in ophthalmology. In considering the use of bevacizumab in ophthalmology, the Indian Ministry of Health and Family Welfare referenced the addition of bevacizumab to the WHO s EML. Plans were initiated following this consideration that the All India Ophthalmological Society and Vitreo Retinal Society of India formulate guidelines for safe and effective use of bevacizumab for ophthalmic use (Refer to Attachment 4). In Egypt in February of 2016, a physician reported on more than 20 patients who were treated from a single vial of bevacizumab on a single day. Of these 20, 13 reported untoward occurrences of eye bleeding, vision loss and blindness. Therefore, the majority but not all patients treated with the suspected vial developed adverse events. It is highly probable that a violation of sterile precautions resulted in intravitreal administration of locally contaminated bevacizumab. Similar to the situation in India, these reports also prompted action on the part of the Egyptian Ministry of Health. Roche Egypt was advised that a hold on the distribution of bevacizumab was likely in the absence of action on the part of Roche Egypt to actively address the ongoing use of bevacizumab via the intravitreal route, despite the adverse events experienced by these patients being accurately described in the local Egyptian Prescribing Information. Subsequently, A Direct Healthcare Provider Letter was provided to the Egyptian Ministry of Health for circulation and the Central Administration for Pharmaceutical Affairs ordered a ban on the distribution of bevacizumab to ophthalmology hospitals (Refer to Attachment 5). Promotion of off-label use of bevacizumab runs the risk of encouraging its use in ways not supported by robust, scientifically verified data approved by regulatory authorities. Listing off-label bevacizumab for use in ophthalmology indications with no supporting context, as is currently the case with the WHO EML, does not provide physicians, healthcare providers and patients with transparent and complete information about safe and effective treatment options and misrepresents the regulatory approval status of bevacizumab, leading in some instances to unfavourable outcomes for patients, as described above. 11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group. Not applicable 12. Summary of regulatory status of the medicine. Bevacizumab is not approved by any Health Authority for the treatment of wet age-related macular degeneration or any other ophthalmology indication. 5
13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia). The pharmacopoeial standards for the manufacture of intravitreal injections are different from those for intravenous administration with respect to the amounts of subvisible particles permitted. The United States Pharmacopoeia (USP) manufacturing requirements for intravenous drug formulations (USP 788) 1 permit higher subvisible particulate counts than that for ophthalmic solutions (USP 789) 2. Bevacizumab is manufactured to meet the requirements of particulate matter in injections (USP 788). Bevacizumab is not manufactured to meet the more stringent requirements for particulate matter in ophthalmic solutions (USP 789). 14. Reference list. 1. USP 39/NF 34. Chapter <788> Particulate Matter in Injections. 2. USP 39/NF 34. Chapter <789> Particulate Matter in Ophthalmic Solutions. 15. Attachments 1. Attachment 1 Roche Letter to WHO September 2013 2. Attachment 2 Roche Letter to WHO June 2016 3. Attachment 3 WHO Letter to Roche July 2016 4. Attachment 4 India 5. Attachment 5 Egypt 6