SAFETY ASSESSMENT REEVALUATION OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS AS THE IMPERATIVE FOR GETTING RENEWED MARKETING AUTHORISATION APPROVAL (MAA)

EXPERIENCE FROM MEDICIES AND MEDICAL DEVICES AGENCY OF SERBIA-ALIMS

V Stanimirovic1, B Stanimirovic2, D Nikolic3, A Nikolic4, B Stanimirovic5. 1Medicines and Medical Devices Agency of Serbia-ALIMS, Beograd, 11000, Serbia, 2Univ G/O Clinic Narodni front, Beograd, Serbia, 11000, Serbia, 3Clinical Center Bezanijska kosa, Beograd, Serbia, 11000, Serbia, 4Institute for Cardiovascular disease DEDINJE, Beograd Serbia, 11000, Serbia, 5Medical Faculty Beograd, Serbia, 11000, Serbia

A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control.

The primary objectives of nonclinical safety evaluation for pharmaceutical products are to identify potential target organ toxicity, provide a safe starting dose for clinical trials, and establish dose-response relationships. These objectives do not differ in concept for either small molecular weight compounds or biotechnologically derived pharmaceuticals; they are important for both. The complex structural and biological characteristics of biotechnologically derived pharmaceuticals, however, dictate that different approaches to their safety evaluation are needed.

Initial MAA of Gardasil®- the HPV Vaccine (types 6,11,16 and 18) (recombinant, adsorbed), has been performed in Serbia on 2006.year.According to related EU guidelines, and Law on medicines and medical devices of Serbia("The Official Gazette of the Republic of Serbia", 30/2010), biologics license application implied evaluation the clinical, non-clinical, product, and manufacturing data, as well as review the pharmacovigilance plan and determines need for post-marketing studies.

On November 2011.year, Expert of ALIMS gave the negative opinion related to 5 years duration of renewed MAA .The reasons were:1.Reports of Health Concerns Following HPV Vaccination( Vaccine Adverse Event Reporting System CDC FDA) :”Total Gardasil reports to VAERS - 18445 (May 2010): 73 Died, 3771 Not Recovered, 4905 Unknown Recovery, 610 Disabled, 355 Life Threatening, 7858 ER Visit and 1865 Hospitalized”; 2. Regulatory concerns related to :Q/E/S mpurities/Ingredients.Health controversy related to specific anti-squalene antibodies and Squalens Immunologic adjuvants, administered in conjunction with a vaccine, that stimulate the immune system and increase the response to the vaccine; 3. Regulatory Assessor’s Safety concerns .Although in updated non clinical Report: ”Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine – Renewal 2.4 Nonclinical Overview, 20 Apr. 2011”/ mentioned: 5 new toxicological studies performed (single dose toxicity investigated on mice and rat, and local tolerance investigated on rabbit, 2 additional immunogenicity studies of V501 influence on rat male infertility),none of study results of mentioned non- clinical trials have been submitted; 4. EU Summary Product Characteristics (SPC) differed to US SPC : Convulsions and Paresthesia have not been included;5. Gardasil contains Polysorbate 80, which is linked to infertility in mice

Conclusion:Although submitted updated Nonclinical Expert Report (April 20, 2011.), stated that there were no new data that alter benefit-risk assessment, lack of non-clinical safety results, and the risks of serious adverse events including death, reported after Gardasil use in, were 3.4/100,000 doses distributed (the JAMA article by CDC’s Dr. Barbara Slade), provoked the ALIMS\'s evaluator\'s conclusion about close post approval monitoring the safety of HPV vaccines and limitation on MAA renewal on 2 years, instead of 5 years ( as Initial MAA granted).

Key words: biotechnology-derived pharmaceuticals, safety assessment, MAA,Gardasil®