Understanding Regulatory Pathway in India from Manufacture to

Market for Biosimilars

S. R. Rao, Advisor, DBT, and Member- Secretary, Review Committee on Genetic Engineering

Government of India, India

CONFERENCE DAY 1 [ 4 March 2015 ] Pune

Release of Guidelines on Similar Biologics by DBT the sidelines of BIO2012, Boston,.

Scope

Similar biologics that contain well characterized proteins as their active

substance, derived through modern biotechnological methods

such as “recombinant DNA technology.” The demonstration of similarity depends upon

detailed and comprehensive product characterization, preclinical and clinical studies carried out in comparison with a reference biologic.

The guidelines are applicable for similar biologics developed in India or imported into the country

Research and Commercialization of Biotech product Governed By;

Environment (Protection) Act, 1986; - •Rules, 1989 of EPA • Industries (Development & Regulation) Act, 1951 - New Industrial Policy & Procedures, 1991 - EXIM Policy

• Drugs & Cosmetics Act, 1940 - Rules 1945 • Patent Act, 1970 • Consumer Protection Act, 1986 • Biodiversity Act, 2002 - Rules of Biological Diversity , 2004 • Safety and Standards Act, 2006, 2011, 2012 • Pharmaceutical Policy 2002

Regulatory frame work - Scope…… Statutory Bodies

National

Level

Genetic

Engineering

Appraisal

Committee (GEAC)

Final Approval for

environmental

release

Ministry of

Environment

and Forests

National

Level

Review Committee

For Genetic

Manipulation

(RCGM)

Scientific risk

assessment of

plants, animals,

biopharma,

microbes and

Guidelines

Ministry of

S&T

Department of

Biotechnology

Institute

university

/company

level

Institutional

Biosafety

Committee (IBSC)

with Nominee of

RCGM

R&D and Contained

Experiments

Ministry of

S&T

Department of

Biotechnology

Proposal

Institutional Biosafety Committee with DBT Nominee

RCGM’s approvals, based on the pre-clinical data,

RCGM conveys its recommendations to the applicant (copy to the DCG (I) for further n.a. and to GEAC for information)

RDAC/DCG(I) approves the protocol and recommends for conducting human clinical trials;

DCG(I) Examines the Human Clinical Trials data and Recommends to GEAC directly

GEAC approval for Environmental/Commercial Release

Regulatory clearance pathway for biosimilars in India

Early R&D

Import

per

mis

sion f

rom

RC

GM

for

GM

O

(Form

30/2

9)

Process

Development

Start of Pre-

Clinical

Studies/

Approval of

Toxicity studies

Per

mis

sion

fro

m R

CG

M t

o s

tart

toxic

ity

stu

die

s

(F

orm

C3)

Appro

val

of

tox

icit

y s

tudie

s fr

om

RC

GM

(

form

C4)

Phase –I

CT

Per

mis

sion

fro

m D

CG

(I)

to s

tart

Cli

nic

al

Tri

al

(Form

44)

ND

AC—

Tec

hin

cal

com

mit

tee –A

PE

X-

Ap

pro

val

Phase –II

CT

Su

bm

issi

on

of

Ph

ase

-I d

ata

in

form

44 t

o D

CG

I

To s

eek

per

mis

sion

fo

r P

hase

II/

II

(F

orm

44)

For B

iosim

ilars P

hase-II

may n

ot b

e not req

uired

Phase –

III

CT

Licensure PMS/

Phase-IV

and PAC

Mark

etin

g A

uth

ori

zati

on

fro

m D

CG

(I)l

(F

orm

46)

S

tate

FD

A i

ssues

MF

G. L

icen

se u

nder

Fro

m 2

8-D

For V

accin

es CD

L relea

se

is requ

ired fo

r Clin

ical tria

l use

NO

C f

rom

DC

G(I

) an

d M

an

ufa

ctu

rin

g o

f

tria

l b

atc

hes

un

der

form

29

For n

on

-recom

bin

an

t pro

du

ct,

perm

ission

un

der fo

rm 1

0/1

1 is

requ

ired

Su

bm

issi

on

of

PM

S d

ata

to

DC

GI

Per

mis

sion f

rom

RC

GM

to c

arry

out

R&

D a

ctiv

itie

s

Early R&D

Regulatory pathway for approval in India.

Stage Agency

Involved

Application Approval

Manufacturing license for test,

analysis and examination

State FDA/

CDSCO

Form 30 Form 29

Preclinical studies permission RCGM Form C3 Form C4

Submission of preclinical

study report

RCGM Form C5 Form C6

*#Clinical trial CDSCO, Form 44 Permission letter

*Manufacturing and marketing

permission

CDSCO Form 44 Form 45/ 46

(Finished product)

Manufacturing license State FDA/

CDSCO

Form 27 D Form 28 D

Registration and Import

license

CDSCO Form 40/ Form

8

Form 41/ Form 10

*The CTA and MAA shall be forwarded for SEC (Subject Expert Committee) approval.

#The clinical study proposal shall be forwarded to HMSC (Health Ministry Screening Committee) approval.

Selection of Reference Biologic

• Should be licensed in India and should be innovator product. The reference biologic should be licensed based on a full safety, efficacy and quality data. Therefore another similar biologic cannot be considered as a choice for reference biologic.

• If it is not marketed in India, the reference biologic should have been licensed and widely marketed for 4 years post approval in innovator jurisdiction in a country with well established regulatory framework.

• The same reference biologic should be used throughout the studies supporting the safety, efficacy and quality of the product (i.e. in the development programme for the similar biologic)

• The dosage form, strength and route of administration of the similar biologic should be the same as that of the reference biologic.

• The active substance (active ingredient) of the reference biologic and that of the similar biologic must be shown to be similar

Background about the nature of the product with appropriate references

Molecular biology details of the GMOs/LMOs employed

Standardization of fermentation/production procedures

Downstream process for purification

Product/protein characterization

Formulation and stability studies

Efficacy of the product

Acceptability criteria of the bulk and the formulated material wherever ready for preclinical or safety studies

Proposed work plan for preclinical & Immunogenicity or other safety studies

Proposed containment facility as well as measures

Decontamination and disposal mechanisms

Risk management (Emergency plan)

Any other relevant information

Data requirements for PCT Studies of Bio-Pharma

Summary of the products characteristics and process of development

List of preclinical study protocols approved by RCGM

Preclinical study reports

Measures taken for containment

Measures taken for Containment

Decontamination and disposal mechanisms

Risk management (Emergency plan)

Any other relevant information

Data requirements for PCT Studies of Bio-Pharma

Data requirements for for Clinical Trial Application

Pharmacokinetic Studies

Pharmacodynamic Studies

Confirmatory Safety and Efficacy Study

Safety and Immunogenicity Data

Measures taken for Containment

Extrapolation of Efficacy and Safety Data to other Indications

Market Authorization Application

Post-Market Data for Similar Biologics

Pharmacovigilance Plan

Adverse Drug Reaction (ADR) Reporting

Post Marketing Studies (Pms)

0

5

10

15

20

25

2011-12 2012-13 2013-14 2014-15

Products

Companies

Products approved for pre-clinical studies

Our Performance

Products recommended to DCG(I) for appropriate phase of human clinical trials

0

2

4

6

8

10

12

14

16

18

2011-12 2012-13 2013-14 2014-15

Products

Companies

Our Performance

Similar Biologics Investigational

New Drug (IND)

IND

Veterinary

Biologicals

Therapeutics Monoclonal

Antibodies

rh-GCSF, PEG-rh-GCSF rh-FSH Infliximab r-HPV vaccine

rh-PTH (1-34) Romiplostim Adalimumab Polysialylated erythropoietin Oil adjuvant

TSOL18

rh-IFN-alpha 2a,

PEG-IFN- alpha 2a

Pegylated L-

Asparaginase

Bevacizumab Pneumococcal Conjugate

Vaccine Formulation – I & II

rh-IFN-alpha 2b,

PEG-IFN-alpha 2b

PEG-EPO Rituximab

r-Lysostaphin

rh-IFN-beta 1b Cetuximab r-HSA

rh-Insulin,

Insulin-Aspart,

Insulin-Glargine

Ranibizumab r-Streptokinase,

r-Clot Specific Streptokinase

Tenecteplase (TNK-tPA) Trastuzumab r-Hepatitis B monovalent

vaccine

Rabies-G VLP vaccine Denosumab r-Hepatitis B pentavalent

vaccine

Etanercept Golimumab r-PvDBPII

Darbepoetin alfa Live recombinant vaccine of

Vibrio cholerae

rh-PDGF-BB r-Human Menopausal

Gonadotropin

r-HCG beta

Products approved for pre-clinical studies and recommended to DCG(I) for appropriate phase of clinical Trials

Task Assigned by RCGM/GEAC Secretariat

Chief Scientific Officer (F)

Biologicals Agriculture Scientist (Biologicals ) Scientist (Agriculture )

Scrutiny & Evaluation of Dossier/Application

Report Preparation

Presentation before the RCGM to facilitate regulatory decision making

Scientist- Pharmacology Toxicology Biochemistry Microbiology Veterinary Pharmacology Molecular Biology/Genetics Fermentation Technology Pharma. Biotechnology Drug Regulatory Affairs Analytical Chemistry

Future plans : reforms in current system

Internal Risk Assessment unit to assist statutory bodies

The manufacturing processes for Biosimilars will always be different from those for originator biologics

Martin Kuhlmann, and Adrian Covic Nephrol. Dial. Transplant. 2006;21:v4-v8

Checklist for data requirement for PCT application of Biopharma products [Similar Biologic and Investigational New Drug (IND)]

Checklist for data requirement for PCT report of Biopharma

products [Similar Biologic and Investigational New Drug (IND)]

Engagement with stakeholders

PARAMETERS SIMILAR

BIOLOGICS

IND

A General Requirements A1 Whether the application contains table of contents, pages serially

numbered and annexure(s) separated with separator sheets

YES YES

A2 Copies of approval(s) accorded so far, by the RCGM for the

product under investigation

YES YES

A3 Justification to select the product as reference biologic/ innovator YES NO

A4 Background about the reference biologic/ innovator [includes

product name, active ingredient(s), therapeutic indication(s),

existing treatments for the proposed indications, mode of action,

strength, formulation, dosages, route of administration and

known side effects, if any] along with appropriate references

YES NO

A5 Background about the proposed product [includes product name,

active ingredient(s), therapeutic indication(s), existing treatments

for the proposed indications, mode of action, strength,

formulation, dosages, route of administration and envisaged side

effects, if any]

NO YES

Checklist for data requirement for PCT application of Biopharma products [Similar Biologic and Investigational New Drug (IND)]

Chairperson, BRAI & 2 full time & 2 part time members

Inter-Ministerial Governing Board

National Biotechnology Advisory Council

Environment Appraisal Panel Product Ruling Committee

Chief Regulatory Officer, Industrial & Environmental Applications

Division

Regulatory & Policy Unit

Scientific Advisory Panels (as needed)

Chief Regulatory Officer, Agriculture, Fisheries & Forestry

Division

Regulatory & Policy Unit

Scientific Advisory Panels (as needed)

Scientific Advisory Panels (as needed)

Regulatory & Policy Unit

Chief Regulatory Officer, Human & Animal Health

Division

Cross-Sectoral Offices

National & International Policy Coordination Unit

Communication & Outreach Unit

Legal Unit

Monitoring, Compliance & Accreditation Unit

Capacity Building & Training Unit

Economic Analysis Unit

Biosafety Bill - to establish Biotechnology Regulatory Authority of India

Risk Assessment Unit State Biotechnology Advisory Committee

Core Characterization: Molecular Biologist; Microbiologist; Chemist; Toxicologist; Bioinformatics; Statistics Animal Biotechnology: Physiologist; Pathologist; Nutritionist; Animal Breeder; Veterinary Scientist; Fisheries/aquaculture scientists Plant Biotechnology: Physiologist; Pathologist; Entomologist; Agronomist; Plant Breeder Human Health Biotechnology: Immunologist; Epidemiologist; Pharmacologist; Clinical scientist Industrial & Environmental Biotechnology: Ecologist; Environmental biologist; Industrial microbiologist; Analytical chemist

My Group

DR RajaLaksmi, DR Nitin Jain Dr Amit Parikh and Mr Sunil of DBT

Websites : www.igmoris .nic.in

www.dbtbiosfaety .nic.in

Indian GMO Research Information

Indian GMO Research Information System (IGMORIS) is a web

based database on activities involving the use of GMOs and

products thereof in India.

make available objective and realistic scientific information

relating to GMOs and products thereof under research, trials and

commercial use pertaining to

agriculture, pharmaceuticals, environment and industrial

products to all stakeholders including

scientists, regulators, industry and the public in general.

Thanks