Pharmaceutical Equivalence: Opportunities, Challenges, and Solutions for ANDA and 505(b)(2) Ajaz S. Hussain, Ph.D., Insight Advice & Solutions LLC [email protected]2 nd Annual Symposium on Development of Generics & 505(b)(2 ): ‘ New Frontiers for Complex Drug Products and BCS Based Biowaivers ’ DoubleTree Hotel Somerset , NJ Ajaz S. Hussain | Insight Advice & Solutions LLC 1
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Keynote New Frontiers for Complex Drug Products and BCS based Biowaivers
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Pharmaceutical Equivalence: Opportunities, Challenges, and Solutions for ANDA and 505(b)(2)
Ajaz S. Hussain, Ph.D., Insight Advice & Solutions LLC
Greetings from Toronto, Canada; sincere apology for not being with you in person to deliver this talk. At IGPA later today we will be discussing Building a Culture of Quality; a topic that is also relevant to the audience in NJ
Why I firmly believe that for Complex Generics it is “Pharmaceutical Equivalence” that is the ‘Elephant in the Dark’ ?
What I have learned specifically that reaffirms the Why? Examples while at FDA, Examples from Sandoz (Omnitrope® - US
505(b)(2), Generic Enoxaparin and Glatiramer acetate), other examples
How many companies fail to leverage this “billion(s) dollar” opportunity?
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Our “generic” paradigm:
Interchangeability with confidence
Pharmaceutical Equivalence
Bio-
equivalence
Practices > Confidence
Therapeutic Equivalence
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This paradigm has been tested and “knocked on its head”
“It still is solid” but in need for attention –particularly in the realm of complex generics
“Knocks on the head” Generic Drug Scandal
Failures to detect obvious errors/flaws
Recent failures and manufacturing challenges
Tested – numerous prospective studies to assess therapeutic equivalence
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“Knocks on the head” erode confidence and increase nocebo effects!
“Knocks on the head” have occurred When we failed to appreciate a systems approach to development,
review, process validation, and inspections (GLP/GCP/CGMPs)
When we ignored to ask the ‘right question’ and in the ‘right sequence’
When we did not question assumptions we take for granted
Most of these relate to Pharmaceutical Equivalence PE = dosage form (irrespective of color, shape, mechanism of
release,….);
A clear liquid in a bottle is a “solution”: e.g., cyclosporine micro emulsion, and low-permeability excipients (e.g., sorbitol)
Consider current examples….ER failures and AB to BX downgrades
Our incorrect thinking – “BE is the pivotal evidence”; instead of integrating PE,BE, Practices – as in a system
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“Pharmaceutical Equivalence” that is the ‘Elephant in the Dark’
Q1/Q2
Q1/Q2/Q3, ……
Today … Color, Shape,…..moving towards same mechanism of release?
Today we are back to “subjectXformulation” interaction – once again in healthy subjects?
Isn't this just an assumption? Which, politely, is not a part of “our elephant” but what comes out of it when we don’t pay attention to PE!
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
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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.
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Put R back in R&D & recognize it is a “complex” product and process!
Invest 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
Ability to justify measured RLD variability is relevant to development of the proposed generic
Exquisite regulatory communication strategy
This is not a ‘complicated process’ for which typical ‘good practices” work (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 to anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications
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Please see past presentations @ http://www.slideshare.net/a2zpharmsci/