Topic 9: Clinical Trial considerations for different formulations

Question 1

Clinical trial issues for biologic drug formats

Answer 1

• Challenges in assay development (PK, PD, ADA) dosing, FIH calculation and CMC is an issue due to the following factors: Biologic drug format, immunogenicity, drug disposition and routes of administration

Question 2

Disposition characteristics

Answer 2

Note: must be built into phase 1 and 2 clinical trials

• Poor extravasation into tissue/tumors (size and binding site barriers)
• Rapid elimination
• Interaction with the target (TDD), immunogenicity
• Prolonged resistance required due to the adaption of the FcRn process

Question 3

TMDD, how to account for it and effects

Answer 3

• Elimination of a mAB is dependent on the amount of targets and their turn over in the body
• Clinical trials need to take this into account or just dose to avoid it (below saturation of targe threshold).
• TMDD results in non-linear PK profiles. Allometric rules do not work… a flat dose approach is often used.

Question 4

we must answer the following questions for appropriate drug design:

Answer 4

1. What is the projected effective concentration
2. What concentration can we expect non-linear PK
3. How can we minimize the effects of TMDD
4. Can the persistence and T1/2 be adapted to achieved desired target and treatment period

Question 5

Formulation considerations: IV

Answer 5

IV is used during early stages of development as:

• Large amount of drug/volume can be injected
• Rate of infusion can be tightly controlled and matched to immunogenic response
• Known bioavailability
• High maximal concentrations
• Low interpatient variability

Question 6

Formulation considerations: SC

Answer 6

• This requires study in order to determine F and best site of injection
• If IV formulation is already in use a phase 3 clinical trial will not be needed but phase 2 (dose response) will be needed
• Advantages (convenience, compliance) need to be weighed up against cons (variability, 1-2 ml injection volume)
• May increase immunogenic risk, particularly ADA production as the SC route results in absorption via the lymph system

Question 7

Prior to clinical trials there must be, how do you predict the dose

Answer 7

Before trials there must be:

• understanding of the impact of the immune response, development of ADAs and causes of the immune response and if they can be resolved using formulation approaches
• MABEL us used to predict first time in human dosing
• NABS and NNAABS both have the potential to significantly increase the rate of drug elimination

Question 8

clinical trials must ask

Answer 8

1. %of patients which develop ADA
2. What type of ADA
3. Is there a PK profile which promotes the formation of ADA i.e. significant period of little or no drug, patients who achieved a high plasma concentration. This will be mAB, manufacture process and patient population specific!
4. Do ADA positive subject have difference in PK profiles/therapeutic outcomes?

Question 9

When MR trials occur

Answer 9

• after phase 1 and 2 clinical trials as PK, safety, PK/PD are already determined

Question 10

purpose of MR

Answer 10

• adjust the release of the API to ensure concentrations stay close to the target EC50 and reduce the frequency of dosing

Question 11

Minimum clinical trial requirements

Answer 11

– Minimum clinical trial requirement is a bioequivalence study which would then typically be followed by a phase 2 trial in the target population to prove similar therapeutic outcomes

Question 12

PK of MR

Answer 12

• May cause flipflop PK which is where the terminal half-life and absorption half-life swap so the elimination half-life is now the Ka