Complexity of Retention Samples Selection in non-traditional Bioequivalence studies

Transcription

1 Complexity of Retention Samples Selection in non-traditional Bioequivalence studies Nageshwar R Thudi Ph.D. Director-Clinical R&D Teva Pharmaceuticals

2 Disclaimer The views expressed herein are the views of the presenter only and not those of any company, employer, or organization associated with the presenter 2

3 Background on Retention Samples- FDA Guidance for Industry 3

4 FDA Retention Sample Guidance (Do s and Don ts) As per US FDA May 2004 guidance Handling and Retention of BA and BE Testing Samples Study sponsor should not Separate out the reserve samples of the test and reference before sending the drug product to the testing facility. Why To ensure that the reserve samples are in fact representative of the batches provided by the study sponsor for the testing. What study sponsor should do Send batches of the test and reference to the testing facility. What test facility should do Randomly select samples to maintain as reserve samples. Maintain in the sponsor s and/or manufacturer's original container. 4

5 Rationale Beyond FDA Guidance To eliminate the possibility of sample substitution by the study sponsor and/or drug manufacturer To prevent the alteration of any reserve samples from a study conducted by a contractor before release of drug product samples to the FDA FDA investigators conduct inspections of clinical and analytical sites that perform BE studies During these inspections FDA inspectors collect the retention samples from sites for further evaluation by FDA Lab 5

6 FDA Current Requirements on Retention Samples Reserve sample retention is the responsibility of the organization that conducts the BA or BE study The quantity of reserve samples should be sufficient to permit the Agency to perform five times all of the release tests required in the application or supplemental application. For solid oral dosage forms (e.g., tablets, capsules), an upper limit of 300 units each for the test article and reference standard can be considered sufficient to meet the five times quantity rule. 6

7 Challenges faced by the Study Sponsors Blinded studies with 2:2:1 or 3:3:1 design Multi center studies Multiple studies for complex products In-vitro population BE and Microbial kill rate IVRT and IVPT PK and CE studies Vasoconstrictor and CE studies In-vitro population BE, PK and CE studies 7

8 Challenges faced by the Study Sponsors...Continued Shortage/Limited reference product Multiple RLD lots for in-vitro population BE study Multiple lots because of expiry date when randomization is 3:3:1 when cost of the RLD is high!!! (up to 1000 USD per unit) Large number of subjects (up to 1800) When more than 2 shipments per site involved When number of sites are high (sometime 80 or more) When more than 1 unit dispensed for each visit 8

9 A Case study on cost Impact of Reference Product in a CE study Total cost (500 per unit) Total cost (750 per unit) # Patients # Visits # Sites # Shipments # Blocks Total RLD Block size (2:2:1) $ 210,000 $ 315,000 Block size (2:2:1) $ 300,000 $ 450,000 Block size (3:3:1) $ 315,000 $ 472,500 Block size (3:3:1) $ 450,000 $ 675,000 Excluding the cost for retention samples or additional studies needed 9

10 A Case study on cost Impact of Shipments Packaging facility 50 to 60 shipments Investigator sites 50 to 60 shipments Central repository If study is conducted in multiple countries, multiple central repositories needs to be used for retention samples because of customs issues. If retention facility is in US, it is easy to ship to FDA facility 10

11 Certain Exceptions Allowed by FDA for Inhalation Products Dose content uniformity or spray content uniformity release tests alone usually require 30 units (canisters or bottles) per batch. Performance of other release tests requires additional units. The number of reserve sample units required for three batches of T and R could exceed 1000 units (up to 250 units for each batch of T and R) based on the fivetimes-quantity requirement. The Agency has determined that in lieu of the five-times-quantity requirement, the quantity of inhalant (nasal aerosol or nasal spray) test article (T) and reference standard (R) retained for testing and analyses be at least 50 units for each batch. 11

12 Alternate Proposals on Retention Samples and its Quantity by Sponsors To reduce the unnecessary wastage of Investigational Products (IPs), we propose the following options All the IPs will be packed at packaging facility (SMO-1) and shipped to independent facility (SMO-2) to randomly pick out the total retention samples needed for the study at one go and then ship the required IPs to investigators. This way sites do not have to pick up the retention samples for every shipment. To allow the maximum retention quantity of 50 units for all multiple site studies involved with multiple usage containers like for ointments, creams, suspensions etc. (similar to nasal products i.e. more than 30 actuations) 12

13 Alternate Proposals on Retention Samples and its Quantity by Sponsors...Continued Retention samples only at certain (e.g. 25%) sites and final storage at central 3 rd party repository Only one time release testing quantity???? Retention samples from only first shipment Only 1 RLD lot when multiple RLD lots needs to be used Any other proposal? 13

14 Thank You.