Post-market Surveillance Lab Investigation

Wenlei Jiang, Ph.D.

Senior Science Advisor

Office of Research and Standards (ORS)Office of Generic Drugs (OGD)

CDER/FDA

November 18, 2016

FDA JHU-CERSI workshop: Substitutability of Generic Drugs: Perceptions and Reality

Disclaimer: The views expressed in this presentation are those of the speaker and not necessarily those of the Food and Drug Administration (FDA).

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Challenges in Post-market Surveillance of Generic Drugs

• High market entry and multiple ANDA manufacturers

• Limitations of passive surveillance methods, e.g., FAERS

• Public skepticism about generic drugs

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Post-market Surveillance and Post-market Research of Generic Drugs

Lab Investigation

Office of Testing and Research (OTR) and

other FDA labs

Generic Drug Post-market Surveillance

Generic DrugPost-market Research

Surveillance Method

development

Patient and Physician

perception

Therapeutic equivalence evaluation in

patientsIn-depth Signal Evaluation

Office of Surveillance and Epidemiology

(OSE)

Identify Potential Safety Signal

Office of Generic Drugs Clinical Safety and Surveillance Staff

(CSSS)

Root Cause Analysis and Investigation

Conclusion and Regulatory Action

Rigorous analysis of

approval basis Multiple Review

Disciplines

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FDA Lab Investigation

Surveillance

• Perform routine surveillance testing

• Confirm reported issues

• Support root cause analysis

• Help standardize testing procedure

Strengthen FDA Post-market Surveillance and Research Capabilities

Research

• Provide product characterization

• Develop innovative analytical methods

…..

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Classification of FDA Lab Investigation

• Reactive investigation

- Lansoprazole delayed-release orally disintegrating tablet

- Levetiracetam extended-release tablets

• Proactive investigation

- Sodium ferric gluconate complex in sucrose injection

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Lansoprazole Delayed-release (DR) Orally Disintegrating Tablet (ODT)

Issue

• A generic lansoprazole DR ODT has clogged and blocked oral syringes and feeding tubes

• In some cases, patients have had to seek emergency medical assistance and their feeding tubes have had to be unclogged or removed and replaced.

Indication

• Duodenal ulcer, gastric ulcer

Administration option• Oral, with or without water• Oral syringe• Nasogastric tube

administration (>= 8 French)

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Brand and Generic Product Analysis

Formulation analysis

- Generic contains 30% more excipients than the RLD, including the insoluble excipients.

- RLD and generic have different outermost coating which may affect its interaction with the tubing

Lab investigation

- RLD disintegrates faster than the generic

- RLD microgranule size smaller than that of generic

- Generic beads stick to the inner wall of tubes more

In collaboration with Office of Pharmaceutical Quality/Office of Testing and Research

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Regulatory Action and Communication

• The generic firm voluntarily withdrew the product from distribution.

• The FDA recommends not dispense or administer the product to patients who take the drug through an oral syringe or feeding tube.

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Recommendation for Generic Product Evaluation

• Product design- Rationalize the granule particle size, coating material, coating layers,

tablet weight, and insoluble excipients

• Product characterization- Surface properties of the granule particles

- Granule dispersion properties

• Product in-use tests- Dispersibility, recovery, physical observation of drug products with tubes to support labeled routes of administration.

- Demonstrate the in vitro in-use test robustness

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Guidance Updated for Products with Feeding Tube Administration

Drug name Formulation Guidance Updated

Lansoprazole DR Capsule July 2014

Esomeprazole Magnesium DR for Oral Suspension Sep 2015

Esomeprazole Magnesium DR Capsule Aug 2014

Esomeprazole Strontium DR Capsule July 2014

Rivaroxaban IR Tablet Sep 2015

Ticagrelor IR Tablet April 2016

Cysteamine Bitartrate DR Capsule Sep 2015

Lansoprazole DR ODT Oct 2016

Pantoprazole Sodium DR Capsule Oct 2016

Dexlansoprazole DR ODT Oct 2016

Dexlansoprazole DR Capsule Oct 2016

Morphine Sulfate ER Capsule Oct 2016

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Levetiracetam Extended-Release (ER) Tablet

Issue• Patients noticed intact

generic levetiracetam ER tablets in the stool

• Patients did not experience any GI disorders that might have accidentally accelerated the gastric emptying rate

• Anxiety has ensued among patients and clinicians

Indication• Treating partial-onset,

myoclonic, or generalized tonic-clonic seizures in patients with epilepsy

Drug property• Highly permeable and

highly soluble, BCS class I drug

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Brand and Generic Product Analysis

Formulation analysis:

• RLD monolithic device based on slowly dissolving hypromellose

• Generic beads coated by ethylcellulose

Lab investigation:

In collaboration with Office of Pharmaceutical Quality/Office of Testing and Research

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Regulatory Action and Communication

• Generic product label updated

“Patients receiving levetiracetam extended-release tablets may notice an inert matrix tablet passing in the stool. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet”

• Scientific publication in medical journal

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IV iron: iron (III)-oxyhydroxide form stabilized by a carbohydrate complex which leads to nano-sized colloidal structures.

Sodium Ferric Gluconate Complex in Sucrose Injection

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“Issue”

• EMA and FDA have different recommendation about equivalence demonstration

• Iron sucrose similar products marketed outside the US under much less rigorous standards had safety/efficacy concerns

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FDA Proactive Lab Investigation on Marketed Brand and Generic Products

• Physico-chemical characterization

• Cellular uptake

• Bio-distribution in rats

In collaboration with Office of Translational Sciences/Office of Clinical Pharmacology/Division of Applied Regulatory SciencesNational Center for Toxicology ResearchOffice of Pharmaceutical Quality/Office of Testing and Research

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Drug product (Lot #)

Particle Size Distribution by Dynamic light scattering (DLS)

Iron core size byatomic force

microscopy(nm)

Elemental Fe conc. in

formulations (mg/mL)

DiluentZ-average diameter

(nm)

PDI Value

Ferrlecit® (D2C283A)

10 nM NaCl

11.9 0.148 2.2 ± 0.4 12.1

Ferrlecit® (D2C593A)

10 nMNaCl

12.5 0.156 2.6 ± 0.4 12.2

Generic SFG (132296.1)

10 nM NaCl

11.0 0.138 2.6 ± 0.3 12.6

Physico-chemical CharacterizationThermal Stability

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Cellular uptakeComparison of iron uptake in HL-60 cells

Wu M et al. Comparative in vitro Cellular Uptake Study on Reference and Generic Sodium Ferric Gluconate in Mononuclear Phagocyte Systems. 2016 NYAS Conference: Equivalence of Complex Drug Products: Scientific and Regulatory Challenges, New York, NY

• Three macrophage derived cell lines (U937, HL-60, THP-1) were selected to conduct the cellular uptake.

• The overall trends of cellular iron uptake very similar between the generic drug and its reference listed drug (Ferrlecit®) in three human macrophage cell lines.

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Bio-distribution of Colloidal Iron in Rats

No significant difference in overall bio-distribution

Beekman CR et al. Determining the Bio-distribution of Colloidal Iron Drug Products in Rats by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). 2016 NYAS Conference: Equivalence of Complex Drug Products: Scientific and Regulatory Challenges, New York, NY

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Communication

“really impressed by all the work FDA has done to better understand the iv iron and the respective posters presented. I think this is the only way forward to come to a good solution by exchanging our scientific findings..”

Equivalence of Complex Drug Products: Scientific and Regulatory ChallengesWednesday, November 9, 2016 | 8:30 AM - 5:15 PMThe New York Academy of SciencesPresented by the Non Biological Complex Drugs Working Group (NBCD WG), the Nanotechnology Characterization Laboratory (NCL) of the Frederick National Lab for Cancer Research, and the New York Academy of Sciences

Wu M et al. Comparative in vitro Cellular Uptake Study on Reference and Generic Sodium Ferric Gluconate in Mononuclear Phagocyte Systems. 2016 NYAS Conference: Equivalence of Complex Drug Products: Scientific and Regulatory Challenges, New York, NY

Beekman CR et al. Determining the Bio-distribution of Colloidal Iron Drug Products in Rats by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). 2016 NYAS Conference: Equivalence of Complex Drug Products: Scientific and Regulatory Challenges, New York, NY

Matta MK et al. Quantification of Drug Bound Iron, Non-Transferrin Bound Iron, Transferrin Bound Iron, and Total Iron in Serum in a Rat Pharmacokinetic Study. 2016 NYAS Conference: Equivalence of Complex Drug Products: Scientific and Regulatory Challenges, New York, NY

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Summary

• FDA lab investigation is an integral part of post-market generic drug surveillance and research

• Reactive and proactive lab investigations - help ensure only safe generics on the market

- facilitate communication of product knowledge- improve or confirm generic drug review standards

• Enhanced public confidence about generic drugs via diligent surveillance, research and communication to stakeholders

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Acknowledgements

• Office of Testing and Research/Office of Pharmaceutical Quality

• Division of Applied Regulatory Sciences/Office of Clinical Pharmacology/Office of Translational Sciences

• Office of Research and Standards/Office of Generic Drugs

• Clinical Safety and Surveillance Staff/Immediate Office/Office of Generic Drugs

Thank you!

Questions?