A drug already approved by the Licensing Authority mentioned in Rule 21 now proposed to be marketed as a ‘Modified release dosage form’.
When a modified release product is the first market entry of the modified release type both comparative clinical trials and bioequivalence study comparing the modified release formulation with the immediate release formulation is required to be conducted.
When the modified release product is approved and marketed in other major countries, comparative bioequivalence study of the test product versus the innovator’s modified release is required to be conducted.
For modified release dosage form In vivo bioequivalence/bioavailability studies are recommended which should be designed to ensure that:
i . The product meets the modified release label claims
ii. The product does not release the active drug substance at a rate and extent leading to dose dumping
iii. There is no significant difference between the performance of the modified release product and the reference immediate release product administered by same route in multiple doses (of an equivalent daily amount) or to the reference modified release product.
Iv. There must be a significant difference between the performance of modified release product and the conventional release product when used as reference product.
For In vivo bioequivalence/bioavailability studies of modified release doses forms study design will be single dose or single and multiple dose based on the modified release products that are likely to accumulate or unlikely to accumulate both in the fasted and non-fasting state. If the effect of food on the reference product is not known (or it is known that food affects its absorption), two separate two-way cross-over studies, one in the fasted state and the other in the fed state, may be carried out. If it is known with certainty (e.g. from published data) that the reference product is not affected by food, then a three-way cross-over study may be appropriate with:
A. The reference product in the fasting state
B. The test product in the fasted state, and
C. The test product in the fed state.
Modified release formulations which are not likely to accumulate
When the modified release product is the first market entry of that type of dosage form, the reference product should normally be the innovator’s immediate- release formulation. The comparison should be between a single dose of the modified release formulation and doses of the immediate-release formulation which it is intended to replace. The later must be administered according to the established dosing regimen.
When the modified release product is the second or subsequent entry on the market, comparison should be with the reference modified release product for which bioequivalence is claimed.
Studies should be performed with single dose administration in the fasting state as well as following an appropriate meal at a specified time.
Modified release formulations which are likely to accumulate
Studies should be performed with single dose administration in the fasting state as well as following an appropriate meal. In addition, studies are required at steady state.
When the modified release product is the second or subsequent modified release entry, single dose and steady state comparisons should normally be made with the reference modified release product for which bioequivalence is claimed..
The documents required to be submitted for approval of new dosage forms are as follows:
1. Form 44
2. Treasury Challan of INR 50,000 / 15,000 as the case may be.
3. Source of bulk drugs /raw materials.
4. Chemical and pharmaceutical information of API
5. Data on Formulation:
6. Summary of Animal Pharmacology & Toxicological Data
7. A. Summary of Phase I, Phase II & Phase III clinical trials data generated with immediate release formulation of the drug
B. Report of clinical trials carried out with the modified release dosage form
C. Report of Bioequivalence study (ies) carried out with the modified release dosage form
8. Regulatory status in other countries
9. A. Prescribing information and Draft Specimen of label & Carton
10. Copy of License in Form-29
11. Samples and Testing Protocol/s
Dr. Manoj Karwa
Auriga Research Ltd.
Email: [email protected]
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