title: Differences between post-authorization adverse drug reactions of biopharmaceuticals and small molecules.
abstract: BACKGROUND
  The nature of adverse drug reactions observed post-authorization for biopharmaceuticals differs from that observed for chemically synthesized, small molecules (SMs). However, it remains unclear how much of the observed differences can be attributed to differences in authorized indications of the two product groups.
  
  
  OBJECTIVE
  To investigate if the nature of adverse drug reactions identified post-authorization for biopharmaceuticals differs from those of SMs within the same anatomical therapeutic chemical (ATC) group.
  
  
  METHODS
  We analyzed safety issues included in post-authorization, changes to the Summary of Product Characteristics of centrally approved products in the European Union classified in the ATC main group of 'antineoplastic and immunomodulating agents'. Generics and biosimilars were excluded. All issues identified during 2004-2011 were analyzed for differences in nature and timing between biopharmaceutical and SM products, at different ATC levels.
  
  
  RESULTS
  A total of 747 adverse drug reactions were identified; 361 for biopharmaceuticals and 386 for SMs. Within the sub group of immunosuppressants, neoplasms (20 % vs 2 %, p < 0.01) and infections and infestations (22 % vs 9 %, p < 0.01) occurred significantly more frequent for biopharmaceuticals. Adverse drug reactions of SMs were more often renal and urinary disorders (7 % vs 0 %, p < 0.01), blood and lymphatic system disorders (10 % vs 3 %, p = 0.04), and vascular disorders (7 % vs 1 %, p = 0.02). In the subgroup of antineoplastics, immune system disorders occurred more frequently for biopharmaceuticals, (6 % vs 1 %, p = 0.04). With the exception of immune system disorders and renal disorders, the overall differences between biopharmaceuticals and SMs were mostly caused by products authorized as immunosuppressants. For the subset of products authorized after 2004, the median time to the first safety issue was 18 months (95 % CI 12.4-21.5) for biopharmaceuticals and 17 months (95 % CI 12.5-21.5) for SMs and did not differ significantly within subgroups.
  
  
  CONCLUSIONS
  Even within a group of medicinal products approved in the same indication, differences were observed in the nature of adverse drug reactions between biopharmaceuticals and SMs. The considerable differences in the nature of adverse drug reactions between biopharmaceuticals and SMs were not associated with differences in the timing of regulatory actions.
authors: Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80 082, 3508 TB Utrecht, The Netherlands.
authors: Hans C
authors: HC
authors: Ebbers
authors: Esraa
authors: E
authors: Al-Temimi
authors: Ellen H M
authors: EH
authors: Moors
authors: Aukje K
authors: AK
authors: Mantel-Teeuwisse
authors: Huub
authors: H
authors: Schellekens
authors: Hubert G M
authors: HG
authors: Leufkens
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001688:Biological Products / Q000009:adverse effects*; D007155:Immunologic Factors / Q000009:adverse effects*; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data; D054852:Small Molecule Libraries / Q000009:adverse effects*
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D007155:Immunologic Factors; D054852:Small Molecule Libraries