totality of evidence & theraputic equivalence 15 october 2016

05/01/2023 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1

Totality of Evidence & Therapeutic Equivalence: Lessons from a Case Study of Bioequivalence Evaluation of a Locally Acting Nasal SprayAjaz S. Hussain, Ph.D.

National Seminar, Controlled Release Society,

India ChapterSciTech Centre, Mumbai

(West)

15th October 2016

CLINICAL APPROACH FOR DRUG DELIVERY

SYSTEMS ADHERENCE TO REGULATORY

REQUIREMENTS


Presentation Outline

Answers: To

questions

Questions: We

should ask

• Why risk of development failure?

• How to reduce complexity & uncertainty?

• What steps mitigate risk and create competitive advantage?

Challenges: Efficient Developme

nt

• Complexity & uncertainty

• Confidence for the patients we serve

• Efficiency of development and regulatory review

Background:

Therapeutic Equivalence

• Complex Generics; US FDA Classification & Totality of Evidence

• Case example: Generic Nasal Spray

• Summary of the FDA’s review chronical


Complex Generics:US FDA Classification points to where the “complexity” lies

Complex Active

Ingredients

LMWH, peptides, complex mixtures,..

Complex Formulations

Complex Route of Delivery

Complex Drug-Device

Combinations

Liposomes, iron colloids, nanomaterials, emulsions

Locally acting drug products

DPI, MDI, nasal spray, transdermal system

Complex Drug Release Profile

Modified release drug products (some)


Generic enoxaparin (USA); Biosimilar (EU)

Moreover, this approval presents a major development in the review and approval of complex drug products in the FDA that may have implications for regulatory assessments in other jurisdictions (Box 1). It further illustrates that progress in the analytical characterization of macromolecules, as well as in product and process understanding, permit demonstration of sameness for some complex drug molecule(s) coupled with adequate assessment of the immunogenicity risk. As a result of these scientific advancements and increased knowledge, unnecessary in vivo testing in animals and humans can be eliminated.

All of these [EMA, ISTH, & SASAT] three guidelines advocate and rely primarily on clinical studies to establish comparability of clinical effectiveness and safety of biosimilar and innovator LMWHs.

Box 1 Other regulatory guidelines on LMWHs


Totality of Evidence:

An emerging standard in need for clarity & consistency


Selected Case Study

Draft Guidance on Mometasone Furoate Monohydrate (US FDA; September 2015)

FDA/CDER/SBIA/Chronicle: FDA Embraces Emerging Technology for Bioequivalence Evaluation of Locally Acting Nasal Sprays (19 May 2016)

FDA Disclaimer: This communication is consistent with 21CFR10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed


Draft Guidance on Mometasone Furoate Monohydrate

DOSAGE FORM: Metered, spray; nasal

US FDA, September 2015

The generic product formulation is recommended to be qualitatively (Q1) and quantitatively (Q2) the same as the RLD product.

The generic product is recommended to deliver the same number of doses as the RLD product, and the device should be similar in shape, size, and external operating principles to ensure substitutability with the RLD product without additional need to retrain patients upon use of the generic product.


Weight of Evidence or Totality of Evidence

In vitro, pharmacokinetic, and pharmacodynamic or clinical endpoint studies

Collectively provide sufficient information to conclude equivalence in systemic exposure and local drug delivery between two products

Equivalence assessment in vivo provides information about safety of the test product


The weight-of-evidence approach

The AAPS Journal, Vol. 15, No. 3, July 2013

Locally Acting Nasal Spray and Nasal Aerosol Products


Evidence Architecture

Integrative thinking and execution


FDA/CDER/SBIA/ChronicleInterview with Dr. Bing Li, Acting Director, Office of Generic Drugs, Division of Bioequivalence I

How long did it take for FDA to approve the ANDA for Mometasone Furoate

nasal spray?• This application was submitted in

December 2008 and was approved in March 2016 - about 8 years of work!

• The application history included a refuse-to-receive determination, a dispute resolution, and a significant number of amendments…a long way to reach its approval!

• Nevertheless, this approval is a great example of commitment and collaboration between CDER staff and industry to overcome challenges and embrace new technology in bringing a generic product to the American public.



What makes this generic approval so special?

• The first generic mometasone nasal spray made available in the US market

• The review was extremely complicated and involved many amendments, many internal and external meetings, and a formal dispute resolution

• The review of this application involved a coordinated and collaborative effort of disciplines within OGD, the Office of Pharmaceutical Quality, and the Office of New Drugs.

• This was a very timely approval – during allergy season.



What were some of the specific challenges encountered along the way?

• The clinical endpoint BE study was unacceptable to FDA because it used API manufactured from a site that was not intended for the manufacture of the commercial batch. The two API batches showed a certain level of difference in terms of their particle size distribution.

• The PK endpoint BE studies were challenging, as they always are with locally acting drugs. As I mentioned earlier, locally acting drugs lead to a low systemic drug concentrations in the blood and therefore require a sensitive analytical method. The PK endpoint BE study is one of the elements of the weight-of-evidence approach and demonstrates the comparative systemic exposure of the drug. It is considered a critical element for the overall BE evaluation



What were some of the specific challenges encountered along the way?

• In vitro BE studies were also challenging and were repeated multiple times. There are a total of six in vitro BE tests recommended for this drug product. The firm first conducted all six tests using API manufactured by a single site. As the firm later switched to API manufactured by a second site (for batches intended for commercial use), they had to repeat some of these in vitro studies.

• The generic used an [anhydrous] API, whereas the innovator used a monohydrate API. [Anhydrous] and monohydrate drug substance have different hydration levels. Typically, a generic firm uses the same form as that of RLD. In this case, XYZ chose to use a different form. Since the [anhydrous] form of the API and the monohydrate form may undergo inter-conversion, we required adequate evidence to demonstrate that the final drug formulation remain [anhydrous] throughout the shelf life.



You mentioned that the use of new technology sets a precedent for change.

What does this mean for future approvals of the same class?

• FDA accepted the in vitro particle size data from MDRS in lieu of the clinical endpoint BE study, deemed unacceptable due to its API manufacturing site issue. This is a first in OGD history. Clinical BE determinations are expensive and time-consuming. Pharmaceutical companies face huge challenges with recruiting patients, and the results are unpredictable in many cases. Simple, accurate in vitro studies can therefore greatly enhance ANDA reviews. This application opened the possibility for in vitro appraisals of BE to be used in the review of future ANDAs submitted to the FDA.


Morphologically Directed Raman Spectroscopy

Separation and identification of species in a mixed system;

analysis of micron-scale particulates with chemical specificity

Raman spectroscopy is sensitive to the unique polymorphic forms of a

substance, and can be used to identify and investigate single or

specific particles to measure size and morphology and to monitor long-term stability of a product



Answers: To

questions

Questions: We

should ask





nt




Background:






Complexity & Uncertainty

FDA & much of Generic Industry is ill prepared to address the challenges posed by increasing complexity of products and manufacturing processes

The paradigm for development of complex generics and for that for review of such products must evolve and mature quickly

FDA has recently instituted changes in its organization structure and added emphasis on “One Quality Voice”; this will take time to progress, thus regulatory uncertainty will remain high for the foreseeable future


Confidence for the patients we serve

Focus on the crucial human factor!

Confidence is a critical quality attribute Confidence in generic drugs is built upon an optimal

integration of evidence derived from formulation and process design, analytical characterization and, when necessary, in vivo assessment

Pharmaceutical Equivalence (Bioequivalence)


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, 13:17336 % 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.

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


Efficiency of development and regulatory review

Several programs in OPQ, One Quality Voice

Need for additional quality regulation to “better assure quality in an increasingly

globalized industry“.

“First Generics” Public Health Priority GADUFA goal date (15 months – to shorter)

GDUFA research funding prioritizationNeed for research; Research to policy to practice - time and effectiveness.

GDUFA II negotiations a pre-ANDA process

Submission quality - Multiple review cycles (on average 4)



Answers: To

questions

Questions: We

should ask





nt




Background:






“Pharmaceutical Equivalence” Six blind men & the Elephant or ‘Elephant in the Dark’

Q1/Q2/Q3, …… Today … Color, Shape,…..moving towards same

mechanism of release? We lack consensus on a set of principles to integrate

across multiple, orthogonal, analytical characterization tools for physical attributes and physical performance (e.g., size, shape, charge, flow, plume, …)

This is a “billion dollar” opportunity; but only for certain companies


Characterization of Brand Copaxone

Thorough understanding of reference listed drug (Copaxone) required. Review available scientific, patent, and regulatory literature on Copaxone. Characterization by more than 60 physicochemical, biological, and immunological methods. Multiple lots (up to 50 for some attributes) were studied over several years probing the range and diversity of the commercial lots, as well as evaluating the effects of lot aging.

Demonstration of Equivalence of Glatopa and CopaxoneEquivalence of starting materials and basic chemistry. Equivalence of structural signatures for polymerization, depolymerization, and purification. Equivalence of physicochemical properties. Equivalence of biological and immunological properties.

Example: Equivalence considerations for Glatopa® and Copaxone®http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf (accessed 16 September 2015)

http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf


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

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

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


Steps to mitigate risk and create competitive advantage

Put R back in R&D & recognize It is a “complex” product and process!

Invest smartly in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration

Get to know the RLD – multiple lots; open the door with large sample size

Build capability to justify measured RLD variability is relevant to development of the proposed generic/biosimilar

Exquisite regulatory communication strategy This is not a ‘complicated process’ for which typical “good

practices” will work seamlessly (e.g., typical project management approach); this is a complex process – with multiple interactions and “emergent properties”

Treat it as it is - a complex process and plan; anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications


Presentation Summary

Answers: To

questions

Questions: We

should ask





nt




Background:






Thank you!

Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom. Viktor E. Frankl

Between regulatory query and response there is Design Space. In that space is our comparability protocol…

will be to arrive where we started and know the place for the first time.

T. S. Eliot

We shall not cease from exploration, and the end of all our exploring …….

totality of evidence & theraputic equivalence 15 october 2016

Education