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Mehul Mehta FDA/PQRI 10/05/15 1

Implementation of BCS Guidance, Analysis of BCS Submissions to

FDA and Guidance Update

Mehul Mehta, Ph.D., FAAPS Director, DCP1

OCP, OTS, CDER, FDA


DISCLAIMER

• Views expressed are mine and

do not reflect official FDA Policy.


OUTLINE I. BCS Based Biowaivers

a) Guidance Highlights b) Implementation c) Results

II. Highlights of the Draft Revision III. Summary IV. Acknowledgements






Guidance for Industry Waiver of In Vivo Bioavailability and

Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics

Classification System

FDA/CDER August 2000


I a) Guidance Highlights i. Biowaivers ii. BCS Class 1 Requirements iii. Additional Considerations


I.a.i) Biowaivers • Initial in-vivo Bioavailability (BA) characterization is

required for NDAs. BCS consideration is not applicable for these studies.

• BCS consideration is applicable for waiver of bioequivalence (BE) studies in NDAs (pre- and post-approval) and ANDAs.

• The drug substance has to be BCS Class 1, the product has to be rapidly dissolving plus the test and reference formulations should be pharmaceutical equivalents and show rapid and similar dissolution.


I.a.ii) BCS Class 1 Requirements • HS: Highest strength should be soluble in 250 ml

or less of aqueous media over the pH range of 1-7.5.

• HP: (a) 90% or greater absolute bio, or urinary recovery, or; (b) permeability greater than the reference compound(s).

• RD: 85% in 30 minutes at pH 1, 4.5 and 6.8 each.


I.a.iii) Additional Considerations

• More than one permeability method • Excipients • Prodrugs • NTI products • Oral cavity absorption • Only IR products






I.b) Implementation CDER BCS Committee

i. Membership ii. Process


I.b.i) Membership • Mehul Mehta (Co-Chair), OCP, OTS • Ramana Uppoor, OCP, OTS • Dakshina Chilukuri, OCP, OTS • Jayabharathi Vaidyanathan, OCP, OTS • Donna Volpe, DARS, OCP, OTS • Lawrence Yu (Co-Chair), OPQ • Ethen Stier, DBE2, OGD • Dale Conner, OB, OGD • Tapash Ghosh (ONDP) • Angelica Dorantes (ONDP) • Pariban Dharnomchitphong, Exec Sec, DBE1, OGD


Always bring this case for

discussion at the BCS committee

Reviewer can choose to bring it to the committee

(but not absolutely necessary)

YES YES NO NO

Consider bringing this to the committee

especially if it fits into BCS class I

Conclude appropriately that there are

inadequate data for BCS classification. No

further action necessary

Did the sponsor ask for BCS class I classification in this submission?

YES NO

Does reviewer feel that there are adequate data to classify the drug

into one of the BCS classes?

Does reviewer agree?

I.b.ii) Process When should one bring application to BCS Committee?


I.b.ii) Process • Primary reviewer submits the summary package to the

committee for review. • Each member has one vote • The choice is yes, no, or insufficient information for BCS

Class 1 classification; decision is by majority. • Official record of each consult is kept which consists of

the summary report, discussion, vote and outcome. • Communication back to the review team and back to the

sponsor via the review division.

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I c.) Results • The committee has met several times a year to

review submitted applications. • Sixty three (63) drug products came up for

evaluation. • 42/63 (67%) were classified as BCS Class 1. • 30/63 were from the New Drugs side.

– 17/30 (57%) got class 1 determination. • 33/63 were from the OGD side.

– 25/33 (76%) were classified as BCS Class 1.

Mehul Mehta FDA/PQRI 10/05/15





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I c.) Results • New Drugs Side: • 30 cases

– 15/30 were at the IND stage • 8 got class 1 determination and agreement on biowaivers • 5 were turned down • 2 had insufficient information

– 15/30 were at the NDA review stage • 9 got class 1 determination and related regulatory relief • 2 were turned down • 4 had insufficient information


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I c.) Results • Generic Drugs Side: • 33 cases

– 25 got BCS Class 1 determination – 6 were turned down – 2 had insufficient information


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I c.) Results • Generic Drugs Side: • ANDAs Approved:

– 71 (57 Approved; 14 Tentative Approval) – #ANDA/Drug ranged from 1 to 14







http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070246.pdf

II. Highlights of the Draft Revision

1. Biowaivers for BCS Class 3 drugs also (with Q1, Q2 restrictions)

2. Addition of ‘very rapid’ dissolution criteria (>85% in 15 minutes)

3. Change permeability boundary from 90% to 85% 4. Change the pH solubility range from 1 – 7.5 to 1 – 6.8

22 Mehul Mehta FDA/PQRI 10/05/15

5. Possibility of changing paddle speed from 50 to 75 rpm. 6. Additional topics / clarification on FDCs (Fixed Dose

Combinations), ODTs (Orally Disintegrating Tablets), MR (Modified Release ) products.

7. Update the list of model drugs. 8. Strengthen GI stability requirement.

23 Mehul Mehta FDA/PQRI 10/05/15

II. Highlights of the Draft Revision





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1. BCS guidance is founded on sound scientific and regulatory bases.

2. CDER has created a centralized BCS evaluation process to assure consistency and transparency across all therapeutic areas and generic drugs.

3. Since the issuance of the guidance in 2000, FDA has reviewed 63 drug products across NDAs and ANDA, of which 42 (67%) were given BCS Class 1 determination indicating wide application of the BCS principles in drug development and evaluation.

III) Summary


26

4. In vivo studies are used and relied upon extensively for permeability classification of drug substances.

5. In vitro permeability studies can provide pivotal information. They are also very helpful many times to resolve uncertainties from in vivo data.

6. Appropriate reporting of all necessary information (e.g. GI stability, method suitability) will help timely evaluation of BCS classification submissions.

III) Summary


27

7. The BCS guidance has been revised and proposes to allow biowaivers for BCS Class 3 drugs also; additional changes are also being proposed which allow rational expansion of the current criteria; this will also lead to greater international harmonization.

8. Comments have been received on the draft guidance and are under evaluation; the revised final guidance should be issued in the very near future.

III) Summary





II. Guidance Updates being Considered III. Summary IV. Acknowledgements

29

Ramana Uppoor Jaya Vaidyanathan Duong (Diane) Nhu

IV) Acknowledgments



Thanks!!

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