BA and BE Studies

Bioavailability (BA): The amount of drug that reaches the systemic circulation from an administered dosage and the rate at which the drug appears in the systemic circulation are referred to as bioavailability. The extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, allowing it to reach the site of action, is referred to as bioavailability. The qualities of the dosage form, which are partly dictated by its design and manufacture, play a big role in a drug's bioavailability.

Because differences in bioavailability among medication formulations can have clinical implications, it's critical to determine whether they're equal. Chemical equivalency means that medicine goods contain the same active chemical in the same proportion and meet current government requirements; nevertheless, drug products' inactive constituents may differ. When given to the same patient in the same dose regimen, bioequivalence means that the drug products produce similar drug concentrations in plasma and tissues.

Therapeutic equivalence means that drug products have the same therapeutic and unfavorable effects when administered to the same patient in the same dosing regimen. Therapeutically, bioequivalent products are expected to be the same. When patients who have been stabilized on one formulation are offered a non-equivalent alternative, therapeutic non-equivalence (e.g., more side effects, less efficacy) is frequently observed during long-term treatment. Despite discrepancies in bioavailability, therapeutic equivalency is sometimes feasible. Penicillin, for example, has such a large therapeutic index (the ratio of the minimum dangerous concentration to the median effective concentration) that modest changes in plasma levels due to bioavailability variances in penicillin products have little effect on efficacy and safety. Bioavailability discrepancies, on the other hand, might create significant therapeutic non-equivalence for medicines with a limited therapeutic index.

What is Bioequivalence(BE) Studies?

Bioequivalence (BE): When delivered at the same molar dose, bioequivalence of a drug product is attained if the extent and rate of absorption are not statistically significantly different from those of the reference product. Bioequivalence studies examine two medications or two formulations of the same drug to show that their bioavailability and PK/PD parameters are substantially comparable.

These studies are frequently conducted for generic medications or when a drug's composition is altered during development. Typically, what is needed to demonstrate equivalence from a regulatory viewpoint is to show that the experimental drug's PK profile falls within 20% of the reference drug. The 20% is an arbitrary number but is satisfactory for the majority of drugs. In some cases, for drugs with a narrow therapeutic index such as warfarin, 20% may be too large. Practically, what this means is that the upper limit of 95% confidence interval for the experimental drug must fall below 125% of the reference drug and the lower limit must fall above 80% of the reference drug. A value of 125% is used because the difference between 125 and 100 is 20% if one uses 125 as the denominator. Confidence interval is used because it is important that the drug is less than 20% different. If point estimate is used without confidence intervals, then a drug with very wide variability that on average is within 20% of the reference drug but quite often falls outside of that could be considered to be equivalent.

Applicants requesting authorization to conduct BA/BE studies with various pharmacological dose formulations on Indian subjects have been submitting applications to the office of the Drugs Controller General (India) at CDSCO (HQ) FDA Bhawan in New Delhi. The DCG (I) office would like to ensure that generics may be compared to innovator medications in terms of safety and tolerability, in order to ensure that they are equivalent and safe for human consumption. A study of "in vivo equivalence" or "bioequivalence" is used to assess "interchangeability" between the investigational and innovator products (BE). In light of the foregoing, the DCGI office would like to ensure that the documents submitted to this Directorate for review and approval of BE-NOC for export are consistent with the provisions of Schedule Y of the Drugs and Cosmetics Act 1940 and Rules 1945, as well as Indian Good Clinical Practices (GCP) guidelines.

• Application in Form-44 duly signed, by the Authorized signatory with details of name and designation along with relevant drugs details and utilization. 
• Treasury Challan (TR–6)/Bharatkosh receipt of Rs. 25000/- (Medical and Public Health Account: 0210). 
• Application in Form-12 duly signed, by the Authorized signatory with details of name and designation along with relevant drugs details and utilization, if required.
• If needed, a Treasury Challan (TR–6)/ Bharatkosh receipt in the amount of Rs. 100/- (Medical and Public Health Account: 0210). 
• Originally signed on firm letterhead by the Principal Investigator (PI) as per Appendix VII of Schedule "Y" of Drugs and Cosmetic Regulations.
• A copy of the BA/BE Centre permission letter from DCG(I), New Delhi, together with information on the number of beds available at the center (CRO), including ICU beds, for appropriate care of SAEs in emergency situations.
• Authorization letter from the Sponsor, signed on firm letterhead by the Authorized Signatory.
• Study procedures, Informed Consent Form (ICF) or Patient Information Sheet (PIS), audio-visual recording device, and copy of protocol approval from the IEC, if applicable, as per Schedule Y recommendations.

No fee shall be payable for conducting a bioavailability or bioequivalence study in human subjects by an institution or organization owned or funded wholly and partially by the Central Government or a State Government.