Intended use of reference products & who international standards or reference reagents
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The document provides an overview of biosimilars and non-innovator biotherapeutics in India. It discusses that India has a large population with limited access to expensive biologic drugs. This has led Indian companies to develop "copy" or non-innovator versions of biologics through an abbreviated approval process. Over 50 such products are now approved or in development. The regulatory process in India differs from WHO and EMA guidelines by not requiring comparative clinical trials or testing against reference products. Non-clinical and Phase III clinical trials are required. The biologics industry in India is an important supplier of more affordable versions of biologics to address healthcare needs.
![Biologicals 39 (2011) 321e324
Contents lists available at ScienceDirect
Biologicals
journal homepage: www.elsevier.com/locate/biologicals
Biosimilars and non-innovator biotherapeutics in India: An overview of the
current situation
Hemant Malhotra*
Division of Medical Oncology, SMS Medical College Hospital, C-70 Ram Marg Tilak Nagar, Jaipur 302004, India
a b s t r a c t
Keywords:
Biosimilar products
Non-innovator products
Copy products
India
Developing country
Globally, a large number of blockbuster biotherapeutic molecules are going off patent in the next few
years. For emerging economies, like India, it is imperative to be able to provide safe and cost effective
drugs for its huge, non-insured and poor population. India has a robust pharmaceutical industry
including the biopharmaceutical sector which is actively engaged in the production and marketing of
‘non-innovator’ or ‘copy’ biotherapeutic products These products are approved through an abbreviated
route which relies on limited safety and efficacy data enabling the local companies to keep the
production costs low and pass on the price benefit to the patient and make the product affordable to the
masses. Some of the available products may not be truly ‘similar’ and may be of suspect quality. The WHO
[1] and the European Medicines Agency (EMA) [2] have published guidelines for the development and
marketing of biosimilar products. These products, as stated in both guidelines undergo extensive headto-head comparability testing with the reference biotherapeutic product (RBP) to show their similarity to
the RBP in terms of quality, efficacy and safety. Regulators and administrators of different countries need
to strike a balance in cost-to-benefit versus risks that are perceived for these products, keeping in mind
global regulatory issues.
Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the
Publisher permission for the reproduction of this article.
1. Introduction
India is the 2nd most populous country in the world with
a population of approximately 1.2 billion. Only a small minority of
the population of the country is insured or has the economic
capability to afford standard-of-care medical care especially highend, expensive biotherapeutic products. Mass affordability is
a genuine problem in India and other developing countries.
Because of this pressure, the regulatory process reflects a complex
interplay between economics, science, public health and politics.
In terms of volume, India is the world’s 2nd largest supplier of
vaccines and 4th largest supplier of pharmaceuticals. The country
also has a robust biopharma sector with over 100 companies
actively engaged in development or production of copy biotherapeutic products. The emphasis of the Indian biopharma
industry had been directed more toward development of ‘copies’
rather than original molecules because of much lower developmental costs and risks, reduced spending on research and development, reduced time to market and expertise in reverse
* Tel.: þ91 141 262 0600/400 4547; fax: þ91 141 262 2899/510 5589.
E-mail address: drmalhotrahemant@gmail.com.
engineering drug development process. Over 50 different brands of
copy products are approved for more than 20 different biopharmaceutical companies and some of these molecules have
completed a decade of market presence with several thousand
doses already administered. Even though there have been some
concerns and questions that all locally manufactured products are
not truly biosimilars, their acceptance by, both, the prescribers and
the patients has been good [3,4].
Strict guidelines have been laid down by the Indian Regulatory
bodies for the approval of Indian non-innovator/copy products.
These have been published and are available on the website of the
Central Drug Standard Control Organization and the Schedule Y of
the Drug and Cosmetic Rules. These are based on the recommendations of a Task force on recombinant-pharmaceuticals accepted
by the government of India in January 2006 [5].
The Indian guidelines for the approval process of noninnovator/copy products [6] are to some extent different from
the EMA and the recently published WHO guidelines. In the
present review, an attempt will be made to provide the present
status of the non-innovator biotherapeutic industry in India and
the regulatory processes governing the approval of the same. The
difference between the WHO and the Indian guidelines will be
highlighted.
1045-1056/$36.00 Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.
doi:10.1016/j.biologicals.2011.06.018](https://image.slidesharecdn.com/intendeduseofreferenceproductswhointernationalstandardsorreferencereagents-131029232301-phpapp02/85/Intended-use-of-reference-products-who-international-standards-or-reference-reagents-1-320.jpg)
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H. Malhotra / Biologicals 39 (2011) 321e324
2. Non-innovator biotherapeutic industry in India
Table 1B
Non-innovator biotherapeutic products under development in India.
The opportunity for marketing non-innovator products in India
is huge e approximately 50 biologicals patented prior to 1995 are
now marketable in the country. To exploit this demand several
home-grown biopharma industries are now actively developing
and marketing non-innovator products in India.
The intensity of competition can be gauged from Table 1. Presently, there are 16 brands of Erythropoietin (EPO) and 14 brands of
granulocyte colony stimulating factor (G-CSF) available in the
Indian market and new ones are being added every few months [4].
There have been concerns regarding the quality of available
molecules and questions whether these copy products are at all
‘similar’ to the innovator products. Another major concern in India
and other developing countries has been the maintenance of the
cold chain at the stockist level and the viability of the product when
it reaches the consumer.
Global market for Indian non-innovator products was anticipated
to be approximately USD 1.5 billion in 2006 with a compounded
annual growth rate of 27%. It is estimated that the exports of Indian
biopharma products are increasing at the rate of 47% (2008) [4].
Availability of non-innovator products provides major price
advantages to the patients as innovators sometimes drop prices by
30e50%, sometimes 2e3 years ahead of launch of the biosimilar
product. As a generalization, prices of non-innovator products are
approximately 45e75% of the price of the innovator product [4].
In India, there has been good acceptance of non-innovator
products amongst health care professionals and patients. For
example of the total sales of G-GCF, 65% is comprised of noninnovator products by volume and for EPO, these non-innovator
products account for 40% of total annual sales [4].
The Indian regulators are attempting to ensure a high quality of
the products. The recently published and released (August 2010)
6th Edition of the Indian Pharmacopoeia includes product-specific
monographs for 5 biological drug substances including insulin,
interferon, EPO, G-CSF and streptokinase and monographs for other
biologic products are under development [7].
3. Indian regulatory process for non-innovator
biotherapeutic products
Product
Type
Application
Peg IFN-a
Cytokine
IFN-b
Etanercept
Cytokine
TNF Fusion protein
Infliximab
Monoclonal antibody
against TNF (Chimeric)
Trastuzumab
(Herceptin)
Monoclonal antibody
against HER2
(humanized)
Monoclonal antibody
against VEGF
(humanized)
Hepatitis, certain
hematological cancers
Multiple Sclerosis
Rheumatoid arthritis
(RA) and other joint
disorders, Psoriasis
Inflammatory bowel
disease, RA & autoimmune
joint disorders
HER2 expressing
breast cancers
Bevacizumab
(Avastin)
Colorectal, breast,
non-small cell
lung cancers,
Age related macular
degeneration
Used in gonadotropin
deficiency states
Induction of ovulation
Luteinizing
Hormone
Hormone
Human Menopausal
Hormone
Gonadotropin (HMG)
Palvizumab (Synagis)
Monoclonal antibody
Used in children
directed against
at high risk of
respiratory syncytial
RSV infection.
virus (RSV) (humanized)
and committtees involved (Table 2). The regulations for noninnovator products are different from the published WHO and
the EMA guidelines (Table 3). The approval requirements for any
new non-innovator product are shown in Fig. 1. These comprise
physico-chemical and biological characterization, non-clinical
toxicity studies and Phase III confirmatory clinical trials. None of
the assessment includes any comparative testing at all.
The regulatory process has defined protocols for 5 scenarios for
which committee clearances are mandatory. For example, products
without Live Micro-organisms (LMO) could be:
1. Indigenous product Development, Manufacturing & Marketing
(RCGM & DCGI)
2. Import and Marketing (DCGI)
Products with LMO are evaluated under the following heads:
The Indian regulatory system for non-innovator products is
a stand-alone system and is followed for all the biotechnologyderived products since 1996 [5,6]. There are several departments
Table 1A
Non-innovator biotherapeutic products marketed in India.
Product
Launched
(no. of COs)
Pursuing
(no. of COs)
G-CSF
EPO
Peg EPO
Peg G-CSF
Alpha-IFN
IL-2
FSH
PTH
HGH
Rituximab (anti-CD20 monoclonal antibody)
HCG
Streptokinase
TPA
EGRFI Mab
14
16
1
2
06
1
1
1
2
1
1
2
1
1
20
20
2
7
12
2
3
5
8
5
4
2
1
2
CO: Company, G-CSF: Granulocyte Colony Stimulating Factor, EPO: Erythropoietin,
Peg: Pegylated, IFN: Interferon, IL-2: Interleukin-2, FSH: Follicle Stimulating
Hormone, PTH: Parathyroid hormone, HGH: Human Growth Hormone, HCG:
Human chorionic gonadotrophine, TPA: Tissue Thromboplastin activator, EGFRI
Mab: Epidermal Growth Factor Inhibitor Monoclonal antibody.
1. Indigenous product Development, Manufacturing & Marketing
(RCGM, GEAC & DCGI)
2. Import and Marketing (GEAC, DCGI)
3. Import of bulk, for Manufacturing & Marketing (RCGM, GEAC,
DCGI)
Table 2
Indian Regulatory Authorities involved in the approval of biotherapeutic products.
Committee
Department
Responsibility
Review Committee
for Genetic
Manipulation
(RCGM)
Genetic
Engineering
Advisory
Committee
(GEAC)
Drug Controller
General of India
(DCGI)
Food & Drugs
Control
Administration
(FDCA)
Department of
Biotechnology e
Ministry of Science &
Technology
Ministry of Environment
Monitors all researchescale
activity and approval for
non-clinical studies
Ministry of Health
Environmental safety for
large-scale operations of Live
Modified Organism (LMO)
based products
Product safety and efficacy &
Clinical Trial & Marketing
approval for Biotech drugs
State government body, Approves plant & ensures
Under Ministry of Health cGMP.](https://image.slidesharecdn.com/intendeduseofreferenceproductswhointernationalstandardsorreferencereagents-131029232301-phpapp02/85/Intended-use-of-reference-products-who-international-standards-or-reference-reagents-2-320.jpg)
![H. Malhotra / Biologicals 39 (2011) 321e324
Table 3
Key differences between the guidelines published by the WHO and the existing
Indian regulatory system for approval of non-innovator biological products.
Area
Indian Regulatory Expectation
GMP certified facility.
Full cell bank characterization
as per ICH guideline.
Post approval changes warrant
comparability study (as per ICH
Q5E and Post Approval
guideline published by DCGI,
India).
Extractable studies are needed.
Viral validation study is not
mandatory.
Analytical Detailed characterization is
expected (including the Post
translational modification).
Specification needed to be
justified.
CMC requirement as per DCGI
guideline (in line with ICH M4).
Clinical
Comparative PK/PD is not
mandatory.
Comparative CT is not
mandatory.
Scientific advice process is
not in place.
Exploration to other indication
can be obtained.
PMS is mandatory for 4 years
with every 6 months safety
reporting (PSUR) for first 2 year.
Immunogenicity is not
mandatory, but expected.
Process
WHO/EMEA
GMP certified facility.
Full cell bank characterization as
per ICH guideline.
Post approval changes warrants
comparability study (as per ICH
Q5E and Post approval guideline
published by DCGI, India).
Extractable studies are needed.
Viral validation study is
mandatory.
Detailed characterization is
mandatory.
Specification needed to be
justified.
CMC requirement is as per ICH
M4.
Comparative PK/PD is required.
Comparative CT is required.
Scientific advice process is in
place for EMA, not for all WHO
countries.
Exploration to other indication
can only be approved if the
clinical MOA is similar.
PMS is mandatory.
Immunogenicity is mandatory.
[EMEA e European Medicines Agency; GMP e Good Manufacturing Practices; ICH e
International Committee on Harmonization; DCGI e Drug Controller General of
India; CMC e Central Monitoring Committee; PK/PD e PharmacoKinetics/Pharmaco
Dynamics; CT e Clinical Trial; PMS e Post Marketing Surveillance; PSUR e Periodic
Safety Update Report].
3.1. Dossier requirements
The Indian regulatory authorities have specified the dossier
requirements for submission for approvals of non-innovator
biotherapeutic products [6]. The dossier needs to have
323
Table 4
Dossier Requirements for submission of new biological product.
Information
Details
Basic pharmaceutical
information
Name, dosage form, composition, container
closure.
- Classification, indication, patent status.
- Details of GMO (Gene, Vector and Host).
- Cloning details.
- Biosafety measures risk management.
Physico-chemical biological
characterization of the product (Structure,
biological activity and impurities)
- Manufacturing procedure including
parameters.
- In-process controls in the process.
- Raw materials and processing material testing.
- Equipment, machinery facility.
- Consistency of process, process validation.
- Specification of DS and DP.
- Method of analysis of DS and DP.
Clone related information
Product characterization
Process e Drug Substance
(DS) Drug Product (DP)
Quality Control and Quality
Assurance
Stability of DS DP
Pre approval regulatory
inspections
-
All GMP matters.
Review of all the quality systems.
- Review of manufacturing facility (DS, DP QC)
utilities.
- Review of documents submitted in the dossier.
- Process validation, analytical method
validation.
- Cell Bank characterization, stability.
-
considerable information; relevant details are provided in Table 4
and below:
3.1.1. Non-clinical studies
These need to assess single dose toxicity (dose tolerance), repeat
dose toxicity (also with recovery period), local tolerance and
allergenicity and have to be done in at least two relevant species
with route of administration resembling clinics (IV/IM/SC) and with
control animals in each study (vehicle control) [6].
These studies can be non-comparative and comparative study is
not a regulatory requirement but some large companies are performing comparisons.
Fig. 1. Summary of the regulatory pathway for approval of non-innovator biotherapeutics in India. [GLP e Good Laboratory Practices; DCGI e Drug Controller General of India;
CT e Clinical Trial; GMP e Good Manufacturing Practices; DSMD e Data Safety Monitoring Board; CTD e Clinical Trials Dossier; PMS e Post Marketing Surveillance;
PV e Pharmaco Vigilance; PSUR e Periodic Safety Update Report].](https://image.slidesharecdn.com/intendeduseofreferenceproductswhointernationalstandardsorreferencereagents-131029232301-phpapp02/85/Intended-use-of-reference-products-who-international-standards-or-reference-reagents-3-320.jpg)
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H. Malhotra / Biologicals 39 (2011) 321e324
3.1.2. Clinical studies
A confirmatory Phase III Clinical Trial to evaluate safety and
efficacy is mandatory before approval. The trial should be multicentre but can be single-arm, open label and non-comparative with
the originator molecule.
Standard Inclusion and Exclusion criteria and the clinical trials
protocol has to be approved by the DCG(I) Institutional Ethics
committee. The clinical trial needs to adhere to Good Clinical
Practices with evaluation of adequate clinical parameters with
statistical evaluation. Post marketing studies are also required by
the authorities.
4. Summary conclusions
With more and more innovator/RBP going off patent, urgent
attention is required to regulate the increasing number of copy
biotherapeutics. New non-innovator biotherapeutics should be
made available as soon as patent protection is over so that the
economically compromised patients who cannot afford the high
cost of the originator molecule have an option to opt for the
cheaper copy versions. Reducing the cost of drugs is now a global
priority rather than just being a major issue in developing economies [8]. Biopharma industry in many developing countries is
ready and capable of manufacturing world-class non-innovator
biotherapeutic products. However, it is imperative that the local
regulatory authorities ensure that the manufacturer maintains the
quality and consistency of the finished product across batches over
time [9]. This can be a major challenge especially in developing
countries [10,11].
The costs associated with conducting comparative clinical trials
should not be so high that the new manufacturer is unable to
perform the trial or passes on the cost of the trial to the patient
making the non-innovator product out of economic reach for the
majority of patients. Efficacy and safety of non-innovator products
should be ensured by the national regulatory authorities.
Developing specific guidelines is important for approval of copy
biotherapeutics in India. Like guidelines for vaccines, productspecific guidelines for biosimilar products are needed. These
should include various aspects e.g. quality of the product, pharmaco vigilance, cold chain maintenance etc.
Conflict of interest
Author has disclosed no potential conflicts of interests.
Disclaimer
The views expressed in this article are purely those of the author
and his interpretation of the published guidelines and literature.
These should not be regarded as stating the official position of the
government of India or any Drug Regulatory body of the country.
References
[1] Guidelines on evaluation of similar biotherapeutic products (SBPs): http://
www.who.int/biologicals/publications/trs/areas/biological_therapeutics/
guidelines_biotherapeutic_products_final_hk_ik_12_june.pdf
[2] European Medicines Agency (EMEA) scientific guidance for human medicinal
products/biologicals guidelines, http://www.emea.europa.eu/htms/human/
humanguidelines/biologicals.httm; 2008.
[3] An introduction to the Indian Pharmaceutical Industry by the Boston analytics,
http://www.bostonanalytics.com/leading_thoughts_research/ba_indian_
pharmaceutical_market_research_report_10_07.pdf; 2007.
[4] Indian biogeneric companies on the threshold of globalization. Biospectrum
June 2007;5(6), http://www.biospectrumasia.com/content/130808ind6791.
asp.
[5] The Mashelkar Committee report on recombinant pharmaceuticals: http://
cdsco.nic.in/html/Final%20Report%20mashelkar.pdfug
[6] Biotechnological/biological products e central drug standard control organization guidance document for industry: http://cdsco.nic.in/CDSCO-Guidance
ForIndustry.pdf
[7] The Indian Pharmacopoeia (IP), http://ipc.nic.in/writereaddata/linkimages/
New%20Features%20of%20IP%2020107592310671.pdf; 2010.
[8] Shapiro R. Huge potential savings from biogenerics: http://www.
thefreelibrary.com/Hugeþpotentialþsavingsþfromþbiogenerics%3Aþaþreportþ
byþeconomistþDr.-a0199538731
[9] Brockmeyer C. Binocrit: assessment of quality, safety and efficacy of biopharmaceuticals. EJHP Practice 2009;15:24e40.
[10] Deechongkit S, Aoki K, Park S, Kerwin B. Biophysical comparability of the same
protein from different manufacturers: a case study using Epoetin alfa from
Epogen and Eprex. J Pharm Sci 2006;95:1931e43.
[11] Mody R, Goradia V, Gupta D. How similar are biosimilars in India? A blind
comparative study. Pharma Focus Asia 2009;11:40e9.](https://image.slidesharecdn.com/intendeduseofreferenceproductswhointernationalstandardsorreferencereagents-131029232301-phpapp02/85/Intended-use-of-reference-products-who-international-standards-or-reference-reagents-4-320.jpg)
Intended use of reference products & who international standards or reference reagents
- 1. Biologicals 39 (2011) 321e324 Contents lists available at ScienceDirect Biologicals journal homepage: www.elsevier.com/locate/biologicals Biosimilars and non-innovator biotherapeutics in India: An overview of the current situation Hemant Malhotra* Division of Medical Oncology, SMS Medical College Hospital, C-70 Ram Marg Tilak Nagar, Jaipur 302004, India a b s t r a c t Keywords: Biosimilar products Non-innovator products Copy products India Developing country Globally, a large number of blockbuster biotherapeutic molecules are going off patent in the next few years. For emerging economies, like India, it is imperative to be able to provide safe and cost effective drugs for its huge, non-insured and poor population. India has a robust pharmaceutical industry including the biopharmaceutical sector which is actively engaged in the production and marketing of ‘non-innovator’ or ‘copy’ biotherapeutic products These products are approved through an abbreviated route which relies on limited safety and efficacy data enabling the local companies to keep the production costs low and pass on the price benefit to the patient and make the product affordable to the masses. Some of the available products may not be truly ‘similar’ and may be of suspect quality. The WHO [1] and the European Medicines Agency (EMA) [2] have published guidelines for the development and marketing of biosimilar products. These products, as stated in both guidelines undergo extensive headto-head comparability testing with the reference biotherapeutic product (RBP) to show their similarity to the RBP in terms of quality, efficacy and safety. Regulators and administrators of different countries need to strike a balance in cost-to-benefit versus risks that are perceived for these products, keeping in mind global regulatory issues. Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article. 1. Introduction India is the 2nd most populous country in the world with a population of approximately 1.2 billion. Only a small minority of the population of the country is insured or has the economic capability to afford standard-of-care medical care especially highend, expensive biotherapeutic products. Mass affordability is a genuine problem in India and other developing countries. Because of this pressure, the regulatory process reflects a complex interplay between economics, science, public health and politics. In terms of volume, India is the world’s 2nd largest supplier of vaccines and 4th largest supplier of pharmaceuticals. The country also has a robust biopharma sector with over 100 companies actively engaged in development or production of copy biotherapeutic products. The emphasis of the Indian biopharma industry had been directed more toward development of ‘copies’ rather than original molecules because of much lower developmental costs and risks, reduced spending on research and development, reduced time to market and expertise in reverse * Tel.: þ91 141 262 0600/400 4547; fax: þ91 141 262 2899/510 5589. E-mail address: drmalhotrahemant@gmail.com. engineering drug development process. Over 50 different brands of copy products are approved for more than 20 different biopharmaceutical companies and some of these molecules have completed a decade of market presence with several thousand doses already administered. Even though there have been some concerns and questions that all locally manufactured products are not truly biosimilars, their acceptance by, both, the prescribers and the patients has been good [3,4]. Strict guidelines have been laid down by the Indian Regulatory bodies for the approval of Indian non-innovator/copy products. These have been published and are available on the website of the Central Drug Standard Control Organization and the Schedule Y of the Drug and Cosmetic Rules. These are based on the recommendations of a Task force on recombinant-pharmaceuticals accepted by the government of India in January 2006 [5]. The Indian guidelines for the approval process of noninnovator/copy products [6] are to some extent different from the EMA and the recently published WHO guidelines. In the present review, an attempt will be made to provide the present status of the non-innovator biotherapeutic industry in India and the regulatory processes governing the approval of the same. The difference between the WHO and the Indian guidelines will be highlighted. 1045-1056/$36.00 Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article. doi:10.1016/j.biologicals.2011.06.018
- 2. 322 H. Malhotra / Biologicals 39 (2011) 321e324 2. Non-innovator biotherapeutic industry in India Table 1B Non-innovator biotherapeutic products under development in India. The opportunity for marketing non-innovator products in India is huge e approximately 50 biologicals patented prior to 1995 are now marketable in the country. To exploit this demand several home-grown biopharma industries are now actively developing and marketing non-innovator products in India. The intensity of competition can be gauged from Table 1. Presently, there are 16 brands of Erythropoietin (EPO) and 14 brands of granulocyte colony stimulating factor (G-CSF) available in the Indian market and new ones are being added every few months [4]. There have been concerns regarding the quality of available molecules and questions whether these copy products are at all ‘similar’ to the innovator products. Another major concern in India and other developing countries has been the maintenance of the cold chain at the stockist level and the viability of the product when it reaches the consumer. Global market for Indian non-innovator products was anticipated to be approximately USD 1.5 billion in 2006 with a compounded annual growth rate of 27%. It is estimated that the exports of Indian biopharma products are increasing at the rate of 47% (2008) [4]. Availability of non-innovator products provides major price advantages to the patients as innovators sometimes drop prices by 30e50%, sometimes 2e3 years ahead of launch of the biosimilar product. As a generalization, prices of non-innovator products are approximately 45e75% of the price of the innovator product [4]. In India, there has been good acceptance of non-innovator products amongst health care professionals and patients. For example of the total sales of G-GCF, 65% is comprised of noninnovator products by volume and for EPO, these non-innovator products account for 40% of total annual sales [4]. The Indian regulators are attempting to ensure a high quality of the products. The recently published and released (August 2010) 6th Edition of the Indian Pharmacopoeia includes product-specific monographs for 5 biological drug substances including insulin, interferon, EPO, G-CSF and streptokinase and monographs for other biologic products are under development [7]. 3. Indian regulatory process for non-innovator biotherapeutic products Product Type Application Peg IFN-a Cytokine IFN-b Etanercept Cytokine TNF Fusion protein Infliximab Monoclonal antibody against TNF (Chimeric) Trastuzumab (Herceptin) Monoclonal antibody against HER2 (humanized) Monoclonal antibody against VEGF (humanized) Hepatitis, certain hematological cancers Multiple Sclerosis Rheumatoid arthritis (RA) and other joint disorders, Psoriasis Inflammatory bowel disease, RA & autoimmune joint disorders HER2 expressing breast cancers Bevacizumab (Avastin) Colorectal, breast, non-small cell lung cancers, Age related macular degeneration Used in gonadotropin deficiency states Induction of ovulation Luteinizing Hormone Hormone Human Menopausal Hormone Gonadotropin (HMG) Palvizumab (Synagis) Monoclonal antibody Used in children directed against at high risk of respiratory syncytial RSV infection. virus (RSV) (humanized) and committtees involved (Table 2). The regulations for noninnovator products are different from the published WHO and the EMA guidelines (Table 3). The approval requirements for any new non-innovator product are shown in Fig. 1. These comprise physico-chemical and biological characterization, non-clinical toxicity studies and Phase III confirmatory clinical trials. None of the assessment includes any comparative testing at all. The regulatory process has defined protocols for 5 scenarios for which committee clearances are mandatory. For example, products without Live Micro-organisms (LMO) could be: 1. Indigenous product Development, Manufacturing & Marketing (RCGM & DCGI) 2. Import and Marketing (DCGI) Products with LMO are evaluated under the following heads: The Indian regulatory system for non-innovator products is a stand-alone system and is followed for all the biotechnologyderived products since 1996 [5,6]. There are several departments Table 1A Non-innovator biotherapeutic products marketed in India. Product Launched (no. of COs) Pursuing (no. of COs) G-CSF EPO Peg EPO Peg G-CSF Alpha-IFN IL-2 FSH PTH HGH Rituximab (anti-CD20 monoclonal antibody) HCG Streptokinase TPA EGRFI Mab 14 16 1 2 06 1 1 1 2 1 1 2 1 1 20 20 2 7 12 2 3 5 8 5 4 2 1 2 CO: Company, G-CSF: Granulocyte Colony Stimulating Factor, EPO: Erythropoietin, Peg: Pegylated, IFN: Interferon, IL-2: Interleukin-2, FSH: Follicle Stimulating Hormone, PTH: Parathyroid hormone, HGH: Human Growth Hormone, HCG: Human chorionic gonadotrophine, TPA: Tissue Thromboplastin activator, EGFRI Mab: Epidermal Growth Factor Inhibitor Monoclonal antibody. 1. Indigenous product Development, Manufacturing & Marketing (RCGM, GEAC & DCGI) 2. Import and Marketing (GEAC, DCGI) 3. Import of bulk, for Manufacturing & Marketing (RCGM, GEAC, DCGI) Table 2 Indian Regulatory Authorities involved in the approval of biotherapeutic products. Committee Department Responsibility Review Committee for Genetic Manipulation (RCGM) Genetic Engineering Advisory Committee (GEAC) Drug Controller General of India (DCGI) Food & Drugs Control Administration (FDCA) Department of Biotechnology e Ministry of Science & Technology Ministry of Environment Monitors all researchescale activity and approval for non-clinical studies Ministry of Health Environmental safety for large-scale operations of Live Modified Organism (LMO) based products Product safety and efficacy & Clinical Trial & Marketing approval for Biotech drugs State government body, Approves plant & ensures Under Ministry of Health cGMP.
- 3. H. Malhotra / Biologicals 39 (2011) 321e324 Table 3 Key differences between the guidelines published by the WHO and the existing Indian regulatory system for approval of non-innovator biological products. Area Indian Regulatory Expectation GMP certified facility. Full cell bank characterization as per ICH guideline. Post approval changes warrant comparability study (as per ICH Q5E and Post Approval guideline published by DCGI, India). Extractable studies are needed. Viral validation study is not mandatory. Analytical Detailed characterization is expected (including the Post translational modification). Specification needed to be justified. CMC requirement as per DCGI guideline (in line with ICH M4). Clinical Comparative PK/PD is not mandatory. Comparative CT is not mandatory. Scientific advice process is not in place. Exploration to other indication can be obtained. PMS is mandatory for 4 years with every 6 months safety reporting (PSUR) for first 2 year. Immunogenicity is not mandatory, but expected. Process WHO/EMEA GMP certified facility. Full cell bank characterization as per ICH guideline. Post approval changes warrants comparability study (as per ICH Q5E and Post approval guideline published by DCGI, India). Extractable studies are needed. Viral validation study is mandatory. Detailed characterization is mandatory. Specification needed to be justified. CMC requirement is as per ICH M4. Comparative PK/PD is required. Comparative CT is required. Scientific advice process is in place for EMA, not for all WHO countries. Exploration to other indication can only be approved if the clinical MOA is similar. PMS is mandatory. Immunogenicity is mandatory. [EMEA e European Medicines Agency; GMP e Good Manufacturing Practices; ICH e International Committee on Harmonization; DCGI e Drug Controller General of India; CMC e Central Monitoring Committee; PK/PD e PharmacoKinetics/Pharmaco Dynamics; CT e Clinical Trial; PMS e Post Marketing Surveillance; PSUR e Periodic Safety Update Report]. 3.1. Dossier requirements The Indian regulatory authorities have specified the dossier requirements for submission for approvals of non-innovator biotherapeutic products [6]. The dossier needs to have 323 Table 4 Dossier Requirements for submission of new biological product. Information Details Basic pharmaceutical information Name, dosage form, composition, container closure. - Classification, indication, patent status. - Details of GMO (Gene, Vector and Host). - Cloning details. - Biosafety measures risk management. Physico-chemical biological characterization of the product (Structure, biological activity and impurities) - Manufacturing procedure including parameters. - In-process controls in the process. - Raw materials and processing material testing. - Equipment, machinery facility. - Consistency of process, process validation. - Specification of DS and DP. - Method of analysis of DS and DP. Clone related information Product characterization Process e Drug Substance (DS) Drug Product (DP) Quality Control and Quality Assurance Stability of DS DP Pre approval regulatory inspections - All GMP matters. Review of all the quality systems. - Review of manufacturing facility (DS, DP QC) utilities. - Review of documents submitted in the dossier. - Process validation, analytical method validation. - Cell Bank characterization, stability. - considerable information; relevant details are provided in Table 4 and below: 3.1.1. Non-clinical studies These need to assess single dose toxicity (dose tolerance), repeat dose toxicity (also with recovery period), local tolerance and allergenicity and have to be done in at least two relevant species with route of administration resembling clinics (IV/IM/SC) and with control animals in each study (vehicle control) [6]. These studies can be non-comparative and comparative study is not a regulatory requirement but some large companies are performing comparisons. Fig. 1. Summary of the regulatory pathway for approval of non-innovator biotherapeutics in India. [GLP e Good Laboratory Practices; DCGI e Drug Controller General of India; CT e Clinical Trial; GMP e Good Manufacturing Practices; DSMD e Data Safety Monitoring Board; CTD e Clinical Trials Dossier; PMS e Post Marketing Surveillance; PV e Pharmaco Vigilance; PSUR e Periodic Safety Update Report].
- 4. 324 H. Malhotra / Biologicals 39 (2011) 321e324 3.1.2. Clinical studies A confirmatory Phase III Clinical Trial to evaluate safety and efficacy is mandatory before approval. The trial should be multicentre but can be single-arm, open label and non-comparative with the originator molecule. Standard Inclusion and Exclusion criteria and the clinical trials protocol has to be approved by the DCG(I) Institutional Ethics committee. The clinical trial needs to adhere to Good Clinical Practices with evaluation of adequate clinical parameters with statistical evaluation. Post marketing studies are also required by the authorities. 4. Summary conclusions With more and more innovator/RBP going off patent, urgent attention is required to regulate the increasing number of copy biotherapeutics. New non-innovator biotherapeutics should be made available as soon as patent protection is over so that the economically compromised patients who cannot afford the high cost of the originator molecule have an option to opt for the cheaper copy versions. Reducing the cost of drugs is now a global priority rather than just being a major issue in developing economies [8]. Biopharma industry in many developing countries is ready and capable of manufacturing world-class non-innovator biotherapeutic products. However, it is imperative that the local regulatory authorities ensure that the manufacturer maintains the quality and consistency of the finished product across batches over time [9]. This can be a major challenge especially in developing countries [10,11]. The costs associated with conducting comparative clinical trials should not be so high that the new manufacturer is unable to perform the trial or passes on the cost of the trial to the patient making the non-innovator product out of economic reach for the majority of patients. Efficacy and safety of non-innovator products should be ensured by the national regulatory authorities. Developing specific guidelines is important for approval of copy biotherapeutics in India. Like guidelines for vaccines, productspecific guidelines for biosimilar products are needed. These should include various aspects e.g. quality of the product, pharmaco vigilance, cold chain maintenance etc. Conflict of interest Author has disclosed no potential conflicts of interests. Disclaimer The views expressed in this article are purely those of the author and his interpretation of the published guidelines and literature. These should not be regarded as stating the official position of the government of India or any Drug Regulatory body of the country. References [1] Guidelines on evaluation of similar biotherapeutic products (SBPs): http:// www.who.int/biologicals/publications/trs/areas/biological_therapeutics/ guidelines_biotherapeutic_products_final_hk_ik_12_june.pdf [2] European Medicines Agency (EMEA) scientific guidance for human medicinal products/biologicals guidelines, http://www.emea.europa.eu/htms/human/ humanguidelines/biologicals.httm; 2008. [3] An introduction to the Indian Pharmaceutical Industry by the Boston analytics, http://www.bostonanalytics.com/leading_thoughts_research/ba_indian_ pharmaceutical_market_research_report_10_07.pdf; 2007. [4] Indian biogeneric companies on the threshold of globalization. Biospectrum June 2007;5(6), http://www.biospectrumasia.com/content/130808ind6791. asp. [5] The Mashelkar Committee report on recombinant pharmaceuticals: http:// cdsco.nic.in/html/Final%20Report%20mashelkar.pdfug [6] Biotechnological/biological products e central drug standard control organization guidance document for industry: http://cdsco.nic.in/CDSCO-Guidance ForIndustry.pdf [7] The Indian Pharmacopoeia (IP), http://ipc.nic.in/writereaddata/linkimages/ New%20Features%20of%20IP%2020107592310671.pdf; 2010. [8] Shapiro R. Huge potential savings from biogenerics: http://www. thefreelibrary.com/Hugeþpotentialþsavingsþfromþbiogenerics%3Aþaþreportþ byþeconomistþDr.-a0199538731 [9] Brockmeyer C. Binocrit: assessment of quality, safety and efficacy of biopharmaceuticals. EJHP Practice 2009;15:24e40. [10] Deechongkit S, Aoki K, Park S, Kerwin B. Biophysical comparability of the same protein from different manufacturers: a case study using Epoetin alfa from Epogen and Eprex. J Pharm Sci 2006;95:1931e43. [11] Mody R, Goradia V, Gupta D. How similar are biosimilars in India? A blind comparative study. Pharma Focus Asia 2009;11:40e9.