Regulatory Approval Scenario of Biosimilars in Pediatric Patients in the United States and European Union.

Regulatory agencies of the USA and European Union (EU) have introduced multiple guidelines in the last decade to standardize and accelerate biosimilar development. As a result, a large number of biosimilars are being approved in the USA and EU. In the present review, we identified the biosimilars and their corresponding reference biologics approved for pediatrics in the USA and EU, and then assessed their approval details. In the USA, a biosimilar applicant needs to submit an initial pediatric study plan under the Pediatric Research Equity Act (PREA). We found that the PREA requirements of a pediatric assessment for biosimilars were waived where the reference biologics were not approved for one or more pediatric age groups for an indication. The PREA requirements of a pediatric assessment were deferred if the indication was under orphan drug exclusivity or a pediatric formulation was not available. Excluding the waiver and deferral scenarios, biosimilars were approved for the same pediatric indications as those of the reference biologics based on scientific justification extrapolation from the pediatric information of the reference biologics to biosimilars. The applicants were asked to submit a pediatric assessment in the deferred indication and/or develop a dedicated formulation that can ensure accurate dose delivery in pediatric population, as applicable. In the EU, pediatric assessments were not required for biosimilars; hence, all biosimilars (except rituximab) have been approved for the same indications as those of the reference biologics. Biosimilar developers need to be aware of the possible requirement of a pediatric study plan, development of pediatric drug delivery devices, and requirement of human factor studies for a device, to avoid delay in approval of biosimilars in the USA.

Bevacizumab for eye diseases - Legal, regulatory, and ethical overview.

Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in the elderly. These drugs are mostly inaccessible due to their high cost. Bevacizumab is a VEGF inhibitor, approved for cancer treatment. Being a cheaper alternative, it is extensively used off-label as an intravitreal injection for the treatment of eye diseases. In this article, we have analyzed similarities and differences between bevacizumab and ranibizumab, and potential long-term safety concerns with off-label use of bevacizumab. We also analyzed legal, regulatory, and ethical background of off-label use and provided recommendations to resolve this issue. Based on the extensive clinical data, actions taken, and recommendations provided by agencies such as the National Institute for Health and Care Excellence, International Council of Ophthalmology, United Kingdom and Thailand regulatory agency, intravitreal bevacizumab has adequate evidence for controlled licensing. Claiming better safety for ranibizumab at the expense of nonaffordability cannot be considered a positive risk-benefit scenario. Intravitreal bevacizumab is being used and will continue to be used off-label, if not regulatory controlled. Licensing will ensure the availability of intravitreal bevacizumab to the patients with eye diseases, without any legal or ethical concerns for the clinicians, and will also assist in generating long-term safety data. Safest delivery formulation and dosage form should be considered for approval. Both the regulatory agency and technical experts should join and take critical decision, which will be a big step forward to making a cost-effective drug available to the public.