complex generics developing defensible statistical analyses and acceptance criteria

Assessing the Equivalence of Conventional Drugs Containing Complex APIs: Developing Defensible Statistical Analyses and Acceptance CriteriaAjaz S. Hussain | Insight Advice & Solutions LLC

Symposium: Improved Statistical Approaches for Comparability/Equivalence Assessments of Biosimilars and Complex DrugsAAPS Annual Meeting 2015 | 27 October 2015, Orlando, Florida

10/27/2015 Ajaz S. Hussain | Insight Advice & Solutions LLC 1

Thank you Charles DiLiberti

• For the kind invitation and for suggesting the title of this talk• Assessing the Equivalence of Conventional Drugs Containing Complex APIs:

Developing Defensible Statistical Analyses and Acceptance Criteria

• This talk focuses on ‘defensible’ and is, in part, a reflection – a decade ago –when I had, among others, the responsibility for the Sandoz’s development portfolio of biosimilar and complex generic products

• This talk builds on the experience gained during development of generic enoxaparin – which was done in collaboration with Momenta Pharmaceuticals

• Acknowledging Prof. Ram Sasisekharan (MIT) and Dr. Ganesh Venkataraman Kaundinya (Momenta)


Symposium description

• The assessment of equivalence between two drug products containing complex active pharmaceutical ingredients (APIs) and the assessment of comparability as part of the demonstration of biosimilarity, share the common goal of comparing two or more large multivariate data sets comprising measurements obtained using a wide variety of different analytical technologies. Historically, such comparisons have been mostly univariate in nature, comparing results from one type of measurement at a time. Although simpler technically, this univariate approach tends to ignore much of the information content inherent in these large data sets. Increasingly, multivariate approaches have been considered to maximize the useful information derived from these rich data sets. This session will highlight the similarities and differences between the statistical approaches used for the equivalence comparisons of complex “small molecule” products and those used for the comparability assessments of biosimilars, with an emphasis on cutting edge multivariate methods, and as illustrated with case studies.


Outline US Pathway for Generic Enoxaparin (a complex generic not

biosimilar)— Required an epistemological rethink to instigate a paradigm shift from

the traditional interpretation of Pharmaceutical Equivalence

A New Era: Clash of Chemometrics?— “Society and medicine treat us all as members of populations, whereas

as individuals we are all unique, and population statistics do not apply.” Craig Venter

For generics of complex API’s it is derived from designing the API process and proving it is Pharmaceuticals Equivalent

— Representative sample size to estimate variability in the RLD API— Analytical characterization integrated with process understanding

A Major Development

DefensibleStatistical

Analyses and Acceptance

Criteria?

Confidence in Therapeutic Equivalence

Defending this Paradigm Shift


“A major development in the US regulatory science and policy….”

Generic Enoxaparin

Ajaz Hussain. Reducing technical and regulatory uncertainty in biosimilar development (2014)

Biosimilar


http://www.slideshare.net/a2zpharmsci/reducing-technical-and-regulatory-uncertinty-in-biosimilar-development-20140307-a

A Major Development?

What

Why

How

Demonstrated US FDA‘s ability to bring a systems approach to reduce complexity and mount a strong legal defense

A path leading to totality of evidence concept for biosimilars and also for several complex generics

Integrative assessment of Pharmaceutical Equivalence and Bioequivalence to ensure Therapeutic Equivalence

Defending this approach poses new challenges


Defensible Statistical Analyses and Acceptance Criteria?

Scientific

Morally defensible

Legally defensibleComplicated

[Simple]

Complex

Emerging practices

Good practices (CGMPs)

[Best practices]

Process understanding

Control strategy

Reducing uncertainty & complexity (in variability)

An epistemological rethink is needed to instigate a paradigm shift from the traditional Pharmaceutical Equivalence interpretation that has dominated the pharmaceutical sector, to an appraisal of complexity that includes both holism and reductionism… (adapted from Fulvio Mazzocchi 2008)


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246621/

A New Era: Clash of Chemometrics?

Clash of Chemometrics

Development & Approval of Generic Enoxaparin

Analytical scrutiny of ‘sameness’ with new analytics

Representativeness of analysis &

Clinical/Therapeutic relevance?


Continued scientific scrutiny; as expected For example:

Mourier, Pierre AJ, et al. "Analytical and statistical comparability of generic enoxaparins from the US market with the originator product." Journal of pharmaceutical and biomedical analysis 115 (2015): 431-442.

Results were compared by statistical approaches using multivariate analysis with a partial least squares discriminant analysis methodology. The variations were statistically significant and allowed a clear distinction to be made between the enoxaparin batches according to their manufacturer.


Continued scientific scrutiny; as expected For example:

Guerrini, Marco, et al. "Differentiation of Generic Enoxaparins Marketed in the United States by Employing NMR and Multivariate Analysis." Analytical chemistry 87.16 (2015): 8275-8283.

Chemometric analysis of the NMR spectra, utilizing both 1H and 1H–13C HSQC NMR experiments, of Lovenox and Enoxaparin, the latter being the generic version of the former, revealed that Lovenox and the four Enoxaparin compounds produced by Sandoz (Enoxaparin and Fibrinox), Winthrop, and Amphastar exhibit dissimilarities in terms of their composition. All of the collected samples had expiry dates between 2012 and 2015.


Defensible Statistical Analyses and Acceptance Criteria?

Scientific

Morally defensible

Legally defensible

Clash of Chemometrics

Development & Approval of Generic Enoxaparin

Analytical scrutiny of ‘sameness’ with new analytics

Representativeness of analysis (estimate of lot-lot

variance in API) & Clinical/Therapeutic

relevance?


The best defense

Do all approved ANDA’s

have the necessary

& sufficient controls?

Science is legally

defensible

Technology and knowledge transfer to ensure adequate control— Life-cycle approach to process validation and continued process

verification

Science-based review integrated with life-cycle approach to process validation – the new OPQ paradigm at US FDA

— Minimizing regulator heterogeneity

Design, integration or synthesis of process understanding — Sufficiently large data set generated based on characteristics of raw

materials and underlying reaction mechanisms and understanding — Integration via a structure based bioinformatics; not black-box

multivariate statistical package


Often overlooked

RLD ProductSample size Representativeness

RLD API

lot-lot variability


Summary

Building consensus slow/difficult — Stakeholders need conclusions— Regulator heterogeneity — Scientific scrutiny is open-ended— Need to defend ANDA approvals — Uncertainty expected to increase— Complexity often underestimated

Complex Generics: Enoxaparin— A major development — Recognition & emphasis on PE— Scientific scrutiny; as expected— Totality of evidence concept— Biosimilar review paradigm— OGD/OPQ open to discuss science— Analytical characterization— Process understanding— Life-cycle approach to PV— Continued process verification — Integrated CMC - CGMP

Challenges

Opportunities

Representativeness of analysis

(estimate of lot-lot variance in API) &

Clinical/Therapeutic relevance?


generics are for minor but not serious illnesses;… and poor people are forced to ‘settle’ for generics.

What do people really think of generic medicines? A systematic review and critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Medicine 2015, 13:173

36 % of the patients reported negative experiences after medication substitution

89 % of pharmacists reported receiving patient complaints regarding use of generic medicine, although 64 % suggested that this was due to a nocebo effect

Only 50.2 % of the surveyed pharmacists agreed that all products that were approved as generic equivalents can be considered therapeutically equivalent.

Just 6 % of pharmacists considered that dry powder inhalers were interchangeable.

While acceptance of generic medications is improving, substantial mistrust and lack of confidence remains, particularly within the patient and, to a lesser extent, physician groups.

Nearly half the patients stated they would refuse generic substitution when it became available if this was just to save the health authority money.

Generic medicines were considered to be poor quality and treated with suspicion.

Ajaz S. Hussain | Insight Advice & Solutions LLC 1510/27/2015

http://www.biomedcentral.com/1741-7015/13/173/additional

“Society and medicine treat us all as members of populations, whereas as individuals we are all unique, and population statistics do not apply.” Craig Venter


complex generics developing defensible statistical analyses and acceptance criteria

Leadership & Management