Position of the Medical Products Agency regarding Lucentis and Avastin

Avastin (bevacizumab) is approved for the treatment of metastatic and/or advanced carcinoma of the colon or rectum, breast cancer, non-small cell lung cancer, renal cell cancer and epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The Company Genentech has developed both Lucentis and Avastin while Novartis (Lucentis) and Roche (Avastin) are marketing authorisation holders in Europe. There is no marketing authorisation application concerning Avastin for ocular use.

The free prescription right in Sweden means that medicinal products are could be used off-label if the use is justified by scientific reasons or by valid experience.. However, in view of extensive ocular use of Avastin, a position is now issued by the MPA. This is a scientifically based position.

• The MPA advocate the use of approved products when available.
   
  - A marketing authorisation application includes detailed documentation making it possible to evaluate the strength and weaknesses of the studies performed and consequently also the strength and weaknesses of the medicinal product.
   
  - A marketing authorisation approval means that an adequate quality, efficacy and safety profile leading to a positive benefit-risk balance for a specific indication has been demonstrated.
  
  - At the time of approval, decisions regarding the content of the information to prescribers and patients as well as how the safety of the product should be monitored are made.
   
• Lucentis is an approved medicinal product with a formulation and quality specifications making it suitable for intraocular use.
   
• In the treatment of oncological diseases, Avastin is supplied as a solution for single use since it is devoid of preservatives. When to be used intravitreally, the solution is repackaged to smaller aliquots for use to more than one patient. This leads to an increased risk of bacterial contamination.
   
• The documentation regarding ocular use of Avastin available to the MPA consists mainly of published studies and abstracts. The strength of these studies cannot fully be concluded upon since detailed information is missing.
   
• Only one parallel evaluation (the CATT-study) of the efficacy of Lucentis and Avastin is available. The study included subjects with neovascular AMD. The results of this study show effects of a similar magnitude. There are no comparative efficacy data in subjects with DME and RVO.
   
• The knowledge on the safety profile of Avastin in relation to that of Lucentis is inadequate with regards to subjects with AMD and nonexistent in DME and RVO:
   
  - No conclusions can be drawn from the CATT-study due to its limited size.
   
  - The Medicare studies that include subjects with neovascular AMD have to be interpreted with extreme caution since there are uncertainties regarding the included patient population. Further, one of the studies is presented only in the form of an abstract.
   
  - In both Medicare studies however, indications of potentially increased risks of mortalities and stroke were observed. These signals cannot be dismissed.
   
  - In the Medicare study that also evaluated ocular adverse events, an increased risk of intraocular inflammation was observed. In addition, a number of publications report clusters of intraocular inflammation after intraocular use of Avastin.
   
  - No firm conclusions can be drawn based on the spontaneous reporting of adverse events after the use of Avastin. The number of reports is few and the extent of under-reporting is difficult to evaluate, but it is noted that a high proportion of reports concerned serious intraocular inflammation.However, compared to sight-threatening intraocular infection (endophthalmitis), in case of serious intraocular inflammation, recovery of vision is to be expected in the majority of cases.
   
  - Concerning the pharmacodynamic and pharmacokinetic data, it is possible that the longer circulatory half-life of bevacizumab and the larger extent of suppression of circulating vascular endothelial growth factor may lead to an increased risk for systemic adverse events after the use of Avastin.
   
• The MPA cannot assess the value of the clinical experience of Avastin.
   

In conclusion, Lucentis is a medicinal product approved for the treatment of the three above mentioned eye diseases, diseases for which adequate efficacy and safety profiles have been demonstrated. In addition, Lucentis is supplied in a formulation appropriate for ocular use. Regarding the ocular use of Avastin, the knowledge concerning efficacy and safety is far from satisfactory. Available safety data are inadequate but indicate an increased risk for ocular inflammation and potentially also for certain systemic adverse events. Given these concerns, the MPA advocate the use of Lucentis.

In general, the MPA considers that an extensive use of a non approved medicinal product should be within in the frame of clinical trials or in other forms that include a structured follow-up. The MPA emphasise the importance of reporting adverse events.

A background to the above position is available in Swedish.