Complexity of Retention Samples Selection in non-traditional

Bioequivalence studies

Nageshwar R ThudiPh.D.

Director-Clinical R&DTeva Pharmaceuticals

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”

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Background on Retention Samples- FDA Guidance for Industry

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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.WhyTo ensure that the reserve samples are in fact representative of the batches provided by the study sponsor for the testing.What study sponsor should doSend batches of the test and reference to the testing facility. What test facility should doRandomly select samples to maintain as reserve samples. Maintain in the sponsor’s and/or manufacturer's original container.

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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

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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.

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– 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

Challenges faced by the Study Sponsors

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– 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

Challenges faced by the Study Sponsors....Continued

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– Excluding the cost for retention samples or additional studies needed

A Case study on cost Impact of Reference Product in a CE study

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# Patients # Visits # Sites # Shipments # Blocks Total RLD

Total cost (500 per

unit)

Total cost (750 per

unit)Block size (2:2:1) 1000 3 35 2 70 420 $ 210,000 $ 315,000Block size (2:2:1) 1500 3 50 2 100 600 $ 300,000 $ 450,000Block size (3:3:1) 1000 3 35 2 70 630 $ 315,000 $ 472,500Block size (3:3:1) 1500 3 50 2 100 900 $ 450,000 $ 675,000

A Case study on cost Impact of Shipments

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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

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 five-times-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.

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– 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)

Alternate Proposals on Retention Samples and its Quantity by Sponsors

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– Retention samples only at certain (e.g. 25%) sites and final storage at central 3rd 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?

Alternate Proposals on Retention Samples and its Quantity by Sponsors....Continued

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Thank You.