1 Current Issues for Conduction of BE Studies in Pakistan 1 st Symposium on Bioequivalence and Bioavailability Studies April 2014, Lahore, Pakistan Dr. Zeba Ahmed Shuja TECHNICAL DIRECTOR SCHAZOO ZAKA Pvt. Ltd. Lahore, Pakistan

BE Studies Current Issues 1. BE Study Regulatory issues 2. Selection and arrangement of comparator product and Reference Standard 3. BE Study Volunteers issues 4. BE Study Organizational issues 5. BE Study Costing issues 6. Ethics Committee issues 2

3 1. Currently BE Studies rule not enforced at the time of registration of Generic Drugs by Drug Regulatory Authority Pakistan, MOH 2. No procedure in place for Contract Research Organizations Public/Private inspection and approvals 3. Similarly currently BE study Protocols not being approved by MOH. BE Study Regulatory Issues

4 4. According to the drug act 1976, Section 11 point 5(g) page 37 Provincial Quality Control Board: The following shall be the powers of the Provincial Quality Control Board…… g) Identify and accredit on payment of fee other laboratories in the province with suitable facilities and expertise BE Study Regulatory Issues ….

5. Health Department Punjab has adopted BE studies as compulsory for Bid evaluation for the procurement of drugs/medicines for the financial year ? A, Center for BE Studies and Bioassay Research Institute University of Karachi B, University of Veterinary Animal Sciences Lahore C, Dow University of Medical & Health Sciences Karachi D, Faculty of Pharmacy Islamia University Bahawalpur 5

6 1. WHO recommended comparator product should be used to conduct BE study from ICH countries (EU, Japan, UK) 2. On line pharmacies not reliable: delivery and storage condition problems 3. Government support needed in duty free custom clearance. Selection and Arrangement of Comparator Product

7 Arrangement of Reference Standard 1.An authenticated analytical reference standard of known identity and purity should be purchased either from USP, WHO & EP or from well reputable source like Sigma etc. should be used to prepare solutions of known concentrations

8 BE Study Volunteers Issues 1. There is no proper system of volunteers insurance. 2. Difficult to arrange healthy volunteers for initial screening. Women do not volunteer in Pakistan. Generally 24 volunteers are essential for any single cross over study according to WHO guidelines. Studies using volunteers are also conducted.

BE Study Volunteers Issues…. 3. Difficulties in blood sampling due to lack of trained stuff resulting in blockage of cannula during blood sampling causing Direct sampling, Less volume sampling & Haemolysis, leading to Volunteer discomfort Problem related to volunteers next follow up visit, Time punctuality & no show problems 4. Problem related to volunteers next follow up visit, Time punctuality & no show problems 4.. 9

10 BE Study Organizational Issues 1. Lack of proper standard operating procedures i.e., weak documentation in case of deviation from Protocol. 2. Lack of resource like skilled Phlebotomists / Analysts, calibrated and qualified analytical instruments i.e., HPLC/LCMS instrument 3. Non availability of validated bio-analytical methods. No studies done on the stability of the analyte in the plasma indifferent storage conditions

BE Study Organizational Issues…. 4. BE center’s do not meet the international WHO current Good Laboratory Practices, and Good Clinical Practices requirements 5. No timeline commitment for bioanalytical method development, bioanalytical method validation, protocol preparation, study execution and report preparation in the Centers 11

BE Study Organizational Issues…. 6. Insufficient stock of Chemicals, analytical columns and guard columns etc. 7. Documents eg. like Case Report Form not filled and signed on time 8. No Quality Assurance System established or followed properly. 12

13 Estimated cost / BE study in Pakistan is Approx. 20,000 US $. Internationally up to 100,000 US $ 1.Cost of documentation i.e., bio protocol preparation, review and aproval. Report preparation about pages 2.Cost of subject’s recruitment, complete blood and urine testing, ECG, X-RAY, subject’s insurance, follow up and confinement and catering etc. BE Study Cost Issues

BE Study Cost Issues …. 3. No Tax relaxation on the purchase of comparator product from ICH countries Reference Standard from USP/EP, Statistical Experts Cost. 4. Cost of blood collection tubes (cryo tubes), Cost of processing and storage, cost of support staff (phlebotomist, doctor, pharmacist and biochemist etc.) 5. Maintenance of sensitive analytical instruments like LCMS, HPLC ( Chemicals, columns) 14

Ethics Committee Issues…. 1.Should have 5 Members at least. With prime responsibility to verify safety, integrity & human rights of volunteers 2.One Independent Member not linked to the Center and one Physician required. 3.One Community nonscientific member 4.Only independent members should vote on a trial related matter 15

Recommendations : Laws 1.Proper Law under Federal DRAP by consensus of all stake holders Should make guidelines based on Int. Standards to Conduct, Inspect and Approve all Centers for performing BE studies. 2.System of getting BE Protocol approved in fast track before start of any study for a minor fee. 3.Duty free and fast track purchase to be allowed of Comparator Product from ICH countries & Reference Standard from EP /USP. 16

Recommendations : Laws 1.Encourage Centers to get ISO certification so that a minimum quality standard of testing is maintained. Financial subsidy or refund of cost? 2.Encourage The Pharma Industry by giving a reasonable timeline of 3-5 years for Compliance to registration of Generic Drugs with authentic BE Studies or Biowaver Dissolution Studies. Similar criteria to be followed for registered Antibiotics and Life saving drugs. 3.System of getting BE Protocol approved in fast track before start of any study for a minor fee. 4.Duty free and fast track purchase to be allowed of Comparator Product from ICH countries & Reference Standard from EP /USP. 17

Recommendations : BE Centers 1.Staff ( Phlebotomists, Doctors, Analysts) should be continuously trained to follow international standards for conduction and reporting of BE Studies. Co-operation among Centers. 2. Adequate Number of Qualified staff must be employed & Volunteer rights must be ensured by proper Insurance. 3.Ethics Committee Structure must be as per International Standards with actual powers. 18

Recommendations : Pharmaceutical Industry 1.High time the Pharmaceutical Industry realizes the ethical and moral responsibility of conducting BE studies to ensure Efficacy, safety and Quality of Generic Drug Products in Pakistan. 2.Financial benefits of Opening doors for export of Generic Drugs to ICH countries with highest expenditure on Health Care. 3.All stakeholders must co-operate with each other to achieve any success. 19

20 Thank You