Therapeutic Product Immunogenicity Community

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

We used a full set of clinical samples and tested them in old and new methods to investigate whether the new method (with better drug tolerance) changed the clinical assessment previously done by the old method.

------------------------------
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.Associate Scientific DirectorTakeda

Original Message:
Sent: 11-05-2023 08:44
From: Bonnie Wu
Subject: Discussion on the Need of Cross-Validation for Improved ADA/NAb Methods

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

We used a full set of clinical samples and tested them in old and new methods to investigate whether the new method (with better drug tolerance) changed the clinical assessment previously done by the old method.

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

We used a full set of clinical samples and tested them in old and new methods to investigate whether the new method (with better drug tolerance) changed the clinical assessment previously done by the old method.

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

Hi Bonnie,

it really depends on the stage of the clinical development when these assays are used. For example, if you change them from Phase 1 to Phase 2, you would only conduct the tests that satisfy you as a company. On the opposite end, if you change assay during a pivotal study, you will need to do a lot of comparative tests to show the regulators how the assay has changed. In that case, a rigorous cross-validation including clinical samples would be needed.

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

Thanks @lili and @bonnie.

@lili, while the impact of higher ADA titer with the new method and it's impact on interpretation on PKPD is definitely important, my thoughts are stuck on the logistical aspects of carrying out the immunogenicity study.

Specifically, if the testing had been initiated at site one, using an older method and testing is continued at site two using the improved method, will you now re-analyze all the older samples with the new method, as the titer results no longer concordant? 

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

The cleanliest way to do this is to re-analyze all the older samples with the new method, so that you can answer what the relationship is between old vs new methods (ADA status, titers, transient/persistent) in preparing any future questions from the regulatory agencies.

Typically, only one (improved) method is used to report clinical results unless requested by the FDA that both set of data is needed.

Thanks @lili and @bonnie.

@lili, while the impact of higher ADA titer with the new method and it's impact on interpretation on PKPD is definitely important, my thoughts are stuck on the logistical aspects of carrying out the immunogenicity study.

Specifically, if the testing had been initiated at site one, using an older method and testing is continued at site two using the improved method, will you now re-analyze all the older samples with the new method, as the titer results no longer concordant? 

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

The cleanliest way to do this is to re-analyze all the older samples with the new method, so that you can answer what the relationship is between old vs new methods (ADA status, titers, transient/persistent) in preparing any future questions from the regulatory agencies.

Typically, only one (improved) method is used to report clinical results unless requested by the FDA that both set of data is needed.

Thanks @lili and @bonnie.

@lili, while the impact of higher ADA titer with the new method and it's impact on interpretation on PKPD is definitely important, my thoughts are stuck on the logistical aspects of carrying out the immunogenicity study.

Specifically, if the testing had been initiated at site one, using an older method and testing is continued at site two using the improved method, will you now re-analyze all the older samples with the new method, as the titer results no longer concordant? 

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

I found this reference provided useful information for your consideration: Strategies for method comparison when changes in the immunogenicity method are needed within a clinical program. Johanna R Mora, 2020. Please note that method comparison approaches may vary according to the immunogenicity the risk assessment of the biotherapeutic and operational circumstances.

If you ever want to use the data generated from the old method, using the same PC and clinical samples in both assays to access the (non)comparability is informative. 

The cleanliest way to do this is to re-analyze all the older samples with the new method, so that you can answer what the relationship is between old vs new methods (ADA status, titers, transient/persistent) in preparing any future questions from the regulatory agencies.

Typically, only one (improved) method is used to report clinical results unless requested by the FDA that both set of data is needed.

Thanks @lili and @bonnie.

@lili, while the impact of higher ADA titer with the new method and it's impact on interpretation on PKPD is definitely important, my thoughts are stuck on the logistical aspects of carrying out the immunogenicity study.

Specifically, if the testing had been initiated at site one, using an older method and testing is continued at site two using the improved method, will you now re-analyze all the older samples with the new method, as the titer results no longer concordant? 

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

I found this reference provided useful information for your consideration: Strategies for method comparison when changes in the immunogenicity method are needed within a clinical program. Johanna R Mora, 2020. Please note that method comparison approaches may vary according to the immunogenicity the risk assessment of the biotherapeutic and operational circumstances.

If you ever want to use the data generated from the old method, using the same PC and clinical samples in both assays to access the (non)comparability is informative. 

The cleanliest way to do this is to re-analyze all the older samples with the new method, so that you can answer what the relationship is between old vs new methods (ADA status, titers, transient/persistent) in preparing any future questions from the regulatory agencies.

Typically, only one (improved) method is used to report clinical results unless requested by the FDA that both set of data is needed.

Thanks @lili and @bonnie.

@lili, while the impact of higher ADA titer with the new method and it's impact on interpretation on PKPD is definitely important, my thoughts are stuck on the logistical aspects of carrying out the immunogenicity study.

Specifically, if the testing had been initiated at site one, using an older method and testing is continued at site two using the improved method, will you now re-analyze all the older samples with the new method, as the titer results no longer concordant? 

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------

I found this reference provided useful information for your consideration: Strategies for method comparison when changes in the immunogenicity method are needed within a clinical program. Johanna R Mora, 2020. Please note that method comparison approaches may vary according to the immunogenicity the risk assessment of the biotherapeutic and operational circumstances.

If you ever want to use the data generated from the old method, using the same PC and clinical samples in both assays to access the (non)comparability is informative. 

The cleanliest way to do this is to re-analyze all the older samples with the new method, so that you can answer what the relationship is between old vs new methods (ADA status, titers, transient/persistent) in preparing any future questions from the regulatory agencies.

Typically, only one (improved) method is used to report clinical results unless requested by the FDA that both set of data is needed.

Thanks @lili and @bonnie.

@lili, while the impact of higher ADA titer with the new method and it's impact on interpretation on PKPD is definitely important, my thoughts are stuck on the logistical aspects of carrying out the immunogenicity study.

Specifically, if the testing had been initiated at site one, using an older method and testing is continued at site two using the improved method, will you now re-analyze all the older samples with the new method, as the titer results no longer concordant? 

The improved new method could have higher titer values reported as expected; However, some of the lower levels of ADA detected by the new method may or may not cause additional changes in PK/PD, safety and efficacy clinically. This is one of the key questions for a study team to answer and justify what the differences are between old vs new methods during regulatory submissions. 

All great answers, but please allow me to use this thread to ask a follow up for the "improved" part of the question. 

If the sensitivity of the new method is > the titer precision of the old method, it is highly likely that the incurred sample in the titer tier will fail (sample that titered at 1:64, may now titer at 1:1024). This is not a failure of the method but rather it's success. How do you reconcile?

Ritankar 

Dear AAPS Therapeutic Product Immunogenicity Community Members, 

When an improved ADA/NAb method is developed, do you typically conduct a cross-validation or bridging study to ensure that the new method is comparable or superior to the original method? Any difference in the approach for applying the new method within the same study or for different studies? 

Thank you in advance for your feedback!

All the best,

Bonnie

------------------------------
Bonnie Wu Ph.D.
Associate Scientific Director
Johnson&Johnson Innovative Medicine
Spring House PA
[email protected]
------------------------------