Bioequivalence Frequently Asked Questions

What is Bioequivalence Study? Bioequivalence simply means a generic drug has the same therapeutic effect with that of the originator drug based on clinical tests performed and presented by trustworthy research institutions. Birkett defined bioequivalence by stating that, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards." The United States Food and Drug Administration (FDA) has defined bioequivalence as, "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." There are two graphs in the bioequivalence study. What do they mean?

The Linear Plot-Time versus Plasma Concentration Graph and the Semi-Log Time versus Plasma Concentration are essentially the same. The graphs represent the peak and troughs of both the reference drug and our brand in the system (bioavailability). The Y axis demonstrates plasma concentration and the X axis is the duration. Notice that on the initial phase of the drug intake, the blood levels of our drug (e.g. Amlodine) and the reference drug (e.g. Norvasc) rises at the same pace. This is true for the succeeding hours which demonstrate the clearance and elimination of the medicine. The plots of the reference drug and our brand are not exactly alike. How come we say that they are bioequivalent to each other? Although the plots of the reference drug and our brand are not exactly the same, the difference is not statistically significant. Our study was done using 90% confidence interval. It means that 90% of the time, the reference drug and our brand have the same action in the human body. This is at par with the standard set by U.S. FDA in bioequivalence studies. Who needs Bioequivalence Studies? Pharmaceutical Companies. Bioequivalence studies play a big role in the promotion of especially in the establishment of parity with certain life-saving medicines. Hospital's Therapeutic Committee. This group serves as the gate keepers of the

hospital pharmacy. They evaluate all documentation needed regarding any drug that wants entry in the hospital formulary. Bioequivalence studies enhance the chances of drugs of being accepted by these institutions. Physicians. With the advent of Evidence-Based Medicine (EBM), more and more physicians require evidence before prescribing any type of drugs to their patients. Before any "me-too" pharma company can claim a particular clinical trial for the brand that they are carrying, physicians will first ask if they have bio-equivalence studies. Only then the physician may consider prescribing that brand to his patient with the same profile cited in the clinical trial. Bioequivalence studies also eliminate doubt about the efficacy and safety of the product. Is Bioequivalence Studies required on all products? No. Only products that are included in the List B' (prime) are required by the Bureau of Food and Drugs (BFAD) to submit Bioequivalence Studies. List B' (prime) products usually exhibit problems with solubility and absorption hence requires bioequivalence. These products are compared to the reference or originator drug. These products are: metoprolol, nicardipine, nifedipine, phenytoin, propanolol, pyrazinamide and theophylline. Is Amlodipine Besylate included in the list B' (prime)? No. Amlodipine Besylate is not included in the list because it has no problem in terms of solubility and absorption. Why did we perform bioequivalence if it is not a regulatory requirement? We want to assure our doctors and patients that our products have undergone rigorous research and studies before bringing them out to the market. Where did we conduct our Bioequivalence Studies? We commissioned third-party research institutions from abroad. But the reference drugs used (in this case NORVASC) is the actual product marketed and sold in the Philippines. Some other bioequivalence studies use reference drugs that are marketed and sold in other countries. BFAD does not honor this. They require that all bioequivalence studies, although done abroad, uses the actual product marketed and sold in the Philippines. Why do we need to conduct Bioequivalence Studies abroad? We see to it that the facilities that will conduct the bio-equivalency studies are FDA compliant, because we intend to market our new products outside the Philippines. At present, we are on the process of registering our products in other countries.

How many Bioequivalence Studies do you have? We have five. We have bioequivalence studies for AMLODINE (Amlodipine Besylate), ZIONEL (metoprolol tartrate), GABATIN (gabapentin), VIMETROL (metformin) and LOSARGARD (losartan potassium). Both ZIONEL and VIMETROL are required by BFAD to undergo bioequivalence study. For the other products, we went a step forward to make AMLODINE, GABATIN and LOSARGARD undergo BE studies even if not required by our regulatory. This is to assure doctors and patients that INNOGEN products can be trusted. How much does one bioequivalence study costs? On the average one study costs P1.5M to P2M pesos.