Article

Regulatory Perspective for Entering Global Pharma Markets

T. Ramesh, D. Saravanan and Dr. Praveen Khullar* * Senior Director, Development Centre, Sanofi-Synthelabo (India) Limited, Goa

Introduction
The value of the global pharmaceutical market is expected to grow 5-7 percent in 2011, to USD 880 billion according to IMS Health. The pharmaceutical industry is one of the highly regulated industries, to protect the health and well being of the masses. The structures of drug regulation that exist today i.e. drug laws, drug regulatory agencies, drug evaluation boards, quality control laboratories, drug information centers, etc., have evolved over time in response both to the increasingly sophisticated pharmaceutical sector, and to the apparent needs of society. In some countries, the passing of comprehensive drug laws was a result of crisis-led change, when public demand led to the adoption of more restrictive legislations to provide stronger safeguards for the public. While drug laws provide the basis for drug regulation, regulatory tools such as standards and guidelines equip drug regulatory authorities with the practical means of implementing those laws. Though the world pharmaceutical regulations are in continuous process of harmonization, they can be divided into four major categories based on the region, development strategy, regulations and marketing interest. North America (US, Canada) Europe (Europe Union, Eastern Europe) Rest of the World (Asia Pacific minus Japan, ANZ, GCC, LATAM, CEE, CIS) Japan (LATAM: Latin America; CEE Central East Europe; CIS Commonwealth Independent States; ANZ Australia, New Zealand; ROW Rest of World) Based on the economy and regulatory control of the countries, these are grouped into Regulated markets (US, EU, Japan, ANZ) or Emerging Markets (ROW excluding ANZ). They not only differ by their region, but also in various other aspects like: how they regulate the pharmaceuticals, the

different guidelines for registering the drugs, requirements to maintain the registrations, registration fee, patent regulations and so on. In this article, we will briefly touch upon the different regulatory perspectives of these regions mainly emphasizing on US and EU and its effect on the pharmaceutical manufacturers.

New Drug Applications (ANDA) and the mix of both which is widely called as 505 (b)(2) Applications. Fig. 1 illustrates the different kinds of routes available to get the registration of pharmaceuticals in US under the Section 505 of the Federal Food Drug and Cosmetic Act. Till 1980s, mostly innovators dominated the US pharma market. The introduction of Drug Price Competition and Patent Term Restoration Act of 1984 i.e. HatchWaxman Act can be termed as birth of generic industry in US which helped generic companies to flourish in US.

North America
Both USA and Canada are the major markets in the pharma industry. The US enjoys the largest player tag in terms of value in the pharma sector. It is valued approximately at USD 300 bn in 2009. The US has evolved from no regulation in the 18th century to one of the highly admired, favorite regulatory authority in the world. The Food and Drug Administration (FDA) within the U.S. Department of Health and Human Services, regulates the drug approval system in United States with the help of six product centers including Center for Drug Evaluation and Research (CDER) and Center for Biologicals Evaluation and Research (CBER). The drug registration procedure in US is majorly categorized into three parts, New Drug Applications (NDA), Abbreviated

505(b)(1) or New Drug Application (NDA):

This route is mainly used to get the approval for New Chemical Entities (NCE) which contains full reports of investigations of safety and effectiveness (Pre-clinical, Phase I to Phase IV study reports). NDA is preceded by the Investigational New Drug Application (IND).

505(b)(2) Application:
This application is same as full NDA, except that this NDA is based on investigations relied on by the applicant

Fig. 1 Different Applications in USA

*Email id: Praveen.Khullar@sanofi.com Pharma Times - Vol. 43 - No. 09 - September 2011 15

for approval of the application and for which the applicant has not obtained a right of reference or use. The applicant majorly relies on published literature, FDAs Federal Register. This route is often used for changes to an approved drug (Change in dosage form, strength, indication etc.)

formulation, method of manufacture, labeling or recommended route of administration. An SNDS must also be submitted to HPFB if the manufacturer wants to expand the indications (claims or conditions of use) for the drug product.

Medicines Agency regulates the medicinal products marketing authorization through various committees. The particulars of the different authorization procedures available in Europe and the committee responsible are tabulated below in Table (2).

505(j) or ANDA or Generic Drug Application:

This section is used for obtaining marketing authorization of exact or close copies of already approved drugs. The application is submitted under any of the below subsections of 505(j) of Federal act given in table (1).

Europe
Different procedures in Europe:
A medicinal product may only be placed on the market in the European Economic Area (EEA) when a marketing authorisation has been issued. The marketing authorisation holder must be established within the EEA. European

Different legal basis for the applications in Europe:

The eligibility and requirements are set in the commission regulation (EC) No 726/2004 and defined in the Article 8 and 10 are of the Directive 2001/83/EC. The Article 8 (3) and 10 are for full applications (NDA) and other applications respectively as illustrated in Fig. 2.

Table (1): Different types of ANDA applications in US

Subsection of 505(j) Paragraph I Products type

Fig. 2 - Different Applications in Europe

For the products for which no patent information is available in the orange book Paragraph II Used for the products for which all the applicable patents are expired Paragraph III Used for the products for which the some or all the applicable patents are valid and the applicant confirms that the product will not be placed in the market till such patents are expired Paragraph IV Used for the products for which some or all the applicable patents are valid and applicant try to file the product which does not infringe those patents or applicant invalidates the granted patents. On successful outcome, the generic applicant enjoys the six month exclusivity in the market In Canada, the manufacturer may seek authorization to sell the product in Canada by filing a New Drug Submission with Health Products and Food Branch(HPFB). A New Drug Submission (NDS), typically contains scientific information about the products safety, efficacy and quality. It includes the results of both the pre-clinical and clinical studies. An Abbreviated NDS (ANDS) is used for a generic product. The generic product must be shown to be as safe and efficacious as the reference product usually established with bioequivalence studies. A Supplemental NDS (SNDS) must be filed by the manufacturer if certain changes are made to already-authorized products. Such changes might include the dosage form or strength of the drug product, the

Table (2): Type of procedures in Europe

Agencies responsible Procedure Type Products Applicable Mandatory scope (Article 3(1)) (EC) No 726/2004 Developed by biotechnological processes New active substance for AIDS, Cancer, Diabetes, Neurodegenerative disorder, Autoimmune disease, Viral disease Orphan drugs Optional Scope (Article 3(2) & 3(3)) (EC) No 726/2004 New chemical, biological or radiopharmaceutical active substance An isomer, mixture of isomers, a complex or derivative or salt Significant therapeutic, scientific or technical innovation Generic/Hybrid of applications (Article 3(2)) Certain medicinal products for pediatric

EMA / CHMP Centralized Procedure

RMS / CMD(h) Decentralized procedure For drugs which does not fall in the mandatory /CHMP ( D C P ) a n d M u t u a l scope of Centralized procedure Recognition Procedure (MRP) Member States (MS) National Marketing Authorization For drugs which does not fall in the mandatory scope of Centralized procedure

EMA - European Medicines Agency; CHMP- Committee for Medicinal Products for Human Use RMS - Reference Member States; CMD(h) Co-ordination Group for Mutual Recognition and Decentralized Procedure (Human)

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Centralized procedure:
European Council lays down a centralized procedure for the authorization of medicinal products, for which there is a single application, a single evaluation and a single authorization allowing direct access to the single market of the Community of 27 countries. Article 3 of Regulation (EC) No 726/2004 defines the eligibility of applications through which medicinal products must (mandatory scope) or may (optional scope or Generic/Hybrid) be authorized by centralized procedure.

main duties and functions of the Ministry: it handles clinical studies, approval reviews and post-marketing safety measures i.e. approvals and licensing. Application forms from both Japanese New Drug Application (J-NDA) and Japanese Abbreviated New Drug Application (JANDA) for approval to market drugs are usually submitted to the PMDA. When application forms for new drugs are received by the PMDA, an approval review of the application data is done in consultation with experts from the PAFSC. PMDA also does the compliance review of GCP/GMP on-site inspection, and the team prepares a review report. This report then refers to MHLV which evaluates the application for medical needs, social issues in addition to scientific review and issues the final decision for approval. The flow chart (Fig. 3) illustrates the various authorities function on the approval of drug applications.

Moreover, intense competition among major players in the regions has fuelled growth. A favorable regulatory environment in these countries has also allowed easy entry of foreign companies. In the ASEAN regions, the applicant can comply with the common requirements set in the ASEAN Common Technical Dossier (ACTD) to get approval in the member countries (Indonesia, Malaysia, Philippines, Singapore, Thailand, Brunei, Myanmar, Cambodia, Laos and Vietnam). Almost the same documents can be used for the national approval in the non member countries of Asia pacific region with simple amendments. The GCC pharmaceuticals industry accounted for nearly 1% of the global pharmaceuticals industry in 2009. The sector is still in a nascent stage compared with international standards. To compete with the global pharmaceuticals industry and meet increasing healthcare demand,

National authorizations:
Member states are responsible for granting marketing authorizations for medicinal products which are placed on their markets, except for medicinal products which are authorized through centralized procedure. In order to obtain a national marketing authorisation, an application must be submitted to the particular Member State.

Decentralized procedure:
If no marketing authorization has been granted in the Community, the applicant may make use of a decentralized procedure and submit an application to all the Member States where it intends to obtain a marketing authorization at the same time, and choose one of them as reference Member State (RMS). Based on the assessment report prepared by the reference Member State and any comments made by the concerned Member State, marketing authorisation should be granted.

Fig. 3 - The approval procedures in Japan

Mutual recognition procedure (MRP):

If the applicant has marketing authorization in one member state and wishes to obtain the same in other member states, MRP is followed. This procedure is based on the mutual recognition by concerned Member State(s) of a national marketing authorization granted by the reference Member State. At the end of both mutual recognition and de-centralized procedure with a positive agreement, a national marketing authorization will be issued in individual Member States. The detailed timetable for each procedure is available in the EMA websites.

Emerging Nations: Rest of the World:

This region consists of mainly the countries from Asia pacific, Latin America, Eastern Europe, Africa and Gulf countries. While countries from Asia pacific and Gulf have almost harmonized their regulatory environment through The Association of Southeast Asian Nations (ASEAN) and Gulf Co-operation Council (GCC) organizations, rest of the regions are yet to come up with the harmonized regulations in their respective regions. The Asia Pacific market is expected to grow from USD 187 billion in 2009 to nearly USD 275 billion in 2013, at a CAGR of 13%. This is mainly owing to low cost availability of medicines, rising income levels, and growth of business and health insurance schemes, ensuring sales of branded drugs.

GCC is undergoing a massive change by implementing reforms, simplifying government regulations, and upgrading and expanding healthcare infrastructure. The GCC pharmaceuticals market depends primarily on imported pharmaceutical drugs and therapeutics. Nearly 80% of total drugs consumed in the region are imported. Ministry of Health of GCC states (Bahrain, Kuwait, Oman,Qatar,Saudi ArabiaandUAE) are regulatory authorities for the regional pharmaceuticals sector. They also regulate prices of pharmaceutical products. To bring about reforms of harmonization of varying prices and consolidation of the regulatory process, the GCC implemented a centralized system, Gulf Central Committee for Drug Registration (GCC-DR) in May 1999, which currently runs parallel to the regulatory regimes in the region. In May 2010, the UAE has

Japan
Japan is the worlds second largest market next to the US. With USD 52 billion drug market, it represents 11% of global sales. The Ministry of Health, Labour, and Welfare (MHLW) is in charge of pharmaceutical regulatory affairs in Japan and the Pharmaceutical and Medical Devices Agency (PMDA, KIKO) undertakes

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revealed formation of Middle East Generic Association (MEGA) to promote proper regulatory and bioequivalence testing and advance generic drug sales in the region. The Latin American markets are forecast to grow at a robust 10% CAGR from USD 37.6 billion in 2009 to USD 62 billion in 2012, due to changes in regulatory policies and increased manufacturing base for generic drugs by the US drug makers. Strong economic growth in these countries will drive lucrative growth in these markets. The regulatory regime in LATAM countries can be divided into three categories i.e. Countries which have established regulations (Brazil, Mexico, and Venezuela) to demonstrate the efficacy, safety through clinical trials and therapeutic equivalence studies with the proper drug approval systems. The countries like Argentina, Chile, Columbia, Ecuador, Paraguay too have the regulations to register a new drug or generics but not as stringent as the first category. The last category of countries (Guatemala, Barbados, Bolivia, Nicaragua, and Peru) have imperfectly formed drug regulations for the approval of drugs. This variety causes difficulty in the characterization of markets and can generate fictitious segmentations.

Table (3): Exclusivities available in major regions

Type of exclusivity Data exclusivity USA 5 years data exclusivity for NCE / 4 years in case of Para IV / 505(b)(2) application 3 years Europe Union 8 years Japan 8 years

Marketing exclusivity Exclusivity for additional indications / changes to existing product

2 years 1 year

6 years for new delivery routes or for other significant changes / 4 years for new indications and for other relatively insignificant changes

Orphan drug exclusivity Pediatric exclusivity Exclusivity for first to file generic application through patent challenge

7 years 6 months 6 months

10 years -

10 years -

Other factors for consideration:

Patents Scenario
All developed nations (US, EU, Japan, ANZ) have established a product patent which runs for 20 years from the date of patent filing. In US, Japan, Australia the original patent term can be extended by a maximum of five years, if undue delays take place during the regulatory approval. In case of Para IV application in US, it is mandatory for the manufacturer to notify the original patent holder, who can take up to 45 days to bring an infringement suit against the manufacturer, if he feels his patents are being violated. However, if no such action is taken within the stipulated period, certification of the ANDA applicant will be accepted by the FDA. If an infringement action is brought in time, FDA suspends approval of the ANDA until the date of courts decision or up to 30 months. If the courts decision goes in favor of the patent owner, FDA suspends the approval till expiry of the patent. In EU member states, an extension of the patent term is obtained by seeking a supplementary protection certificate (SPC). The SPC regime came into force in the European Community on 1 January 1993 but has not been uniformly implemented by all European countries. The SPC takes

effect for a maximum of 5 years after the expiry of the original patent term; however, the exact length of the extension granted under the Regulation is determined by national law. Applications for the SPC must be filed on a country-by-country basis. There is no unitary European SPC. In developing regions, countries like Brazil, Argentina, Canada, China, India, Malaysia, Russia, Taiwan, and South Africa have 20 years of patent term. The term can be extended up to 5 years in some of these countries.

Exclusivities
Data exclusivity is a period granted to the innovator companies in which no other company can file any type of application for that particular molecule. There are other exclusivities available to promote the company which engages in the innovation or incremental innovations. table(3) summarizes the various exclusivities available in three major regions. It is very critical to understand the data exclusivities in various regions in order to estimate the filing timelines of applications as well as to determine the marketing strategies.

The CTD is organized into five modules. Module 1 is region specific and Modules 2, 3, 4 and 5 are intended to be common for all regions. Rest of the region / countries insist on following ICH region for some data like stability, clinical trials though it follows majorly its own regulations. For instance, the ASEAN countries require data as per ASEAN CTD (ACTD) which is same as ICH CTD for data requirements organized in Parts. The brief contents of CTD and major requirements for various regions are tabulated in Table (4).

Indian Regulations
India being the leading supplier of API and generic drugs to the world, it is important to understand the Indian requirements and regulations associated with pharmaceuticals. When the applicant intends to develop and export the pharmaceuticals, it is necessary to comply with regulations set forth in the Drugs and Cosmetics Act 1940 and Rules 1945. There are some necessary licenses to be obtained as mentioned in the table (5) for developing and exporting the drug products.

Components of regulatory filing and Data Requirements

The US, EU and Japan are a part of International Conference on Harmonization (ICH), hence the technical requirements for registration of Pharmaceuticals follow the ICH recommendations. These countries require data as per the requirements of Common Technical Document (CTD).

Conclusion
Planning forward towards getting marketing approval includes various junctures such as getting drug substances from approved vendors, finished product development, clinical studies, plant inspection, dossier writing and finally submission to authorities. Hence it is critical to plan and co-ordinate all the activities for successful launch of product

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Table (4): Contents of Common Technical Document (CTD)

ICH CTD Module 1 - Regional and Administrative Information Module 2 - Overall Summary Part II Module 3 - Quality ASEAN CTD Part I Description This module contains documents that are specific to each region. This module is not part of CTD. Basically consists of administrative documents like Application form, legal documents (GMP, Licenses etc.), labeling etc. This module summarizes the Module 3, 4 and 5. It includes Quality Overall summary, Non Clinical Overview and Summary and Clinical Overview and Summary. The summary provides reviewer the abstract of documents provided in the whole application The documents related to Chemistry, manufacturing and Control of both Drug Substance and Drug Product is included in this module. Part III Non Clinical Study Reports Data on pharmacologic, pharmacokinetic, and toxicological evaluation of the pharmaceutical product is provided in this module. Clinical Study Reports - Applicant provides a critical assessment of the clinical data and related reports in this module. Remarks Required for generics and New Drug

Required for generics and New Drug. For generics summary on Quality part only required Required for generics and New Drug Not required for generics

Module 4 - Safety

Module 5 Efficacy

Part IV

Not required for generics except Bioequivalence study

in the market on time. The diagram (Fig.4) illustrates the various elements involved in obtaining marketing authorization of pharmaceuticals. Since the world is divided in the drug approval procedures as described above, it is important for the manufacturers, specially the generic companies, to carefully assess the market interest, cost of development, target regions, regulatory requirements before the development of drugs. By looking at the different regulatory environment, it is impractical to get global marketing approval at same time and launch in all the regions at one go. Hence, one should carefully understand and define the clear regulatory strategy by looking at the target regions, different patent terms and its extension, various application possibilities, data requirements, potential timeline for marketing launch in different regions. This eliminates unnecessary studies, minimizes the delay in drug approvals and subsequent launch, and reduces over all cost of development.

Fig. 4 - Components of Regulatory Filing

Table (5): Various Licenses required from Indian regulatory authority

License Test License Form Form 29 Description To be obtained for developing a new drug. To import API and Reference Samples for comparison To import API for commercial purposes To conduct Bioequivalence studies in India To manufacture commercial batches Granting Authority SLA. Sometime it warrant NOC from DCGI DCGI DCGI DCGI

References

http://www.fda.gov/ http://www.ema.europa.eu http://www.ich.org http://www.pmda.go.jp http://www.hc-sc.gc.ca/ http://www.hma.eu/cmdh.html http://www.asean.org http://www.drugterm.com http://www.tga.gov.au http://www.cdsco.nic.in http://www.anvisa.gov.br/eng/index.htm http:// www.hsa.gov.sg http://www.sgh.org.sa/registration.htm http:// www.mccza.com http:// www.paho.org

Import License Import License NOC for BE Manufacturing License

Form 11 Form 10 Form 46 Form 25/ Form 28

SLA. Sometime it warrant NOC from DCGI NOC No Objection Certificate; DCGI Drugs Controller General (India); SLA State Licensing Authority

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Table (6) Data requirements of different regions

Europe Audit by any member states of EU Zone I & II 25 2 C 60% 5% RH
0 0 0 0 0 0 0 0

Requirements Yes Audit by PMDA of both FP and API sites Zone II 25 2 C 60% 5% RH 30 2 C 65% 5% RH 30 2 C 65% 5% RH Zone IVa & IVb Zone IVa Accepts FDA/EU/PICs approval for FP site. Audit by GCC member countries of FP site Yes Yes Yes

USA

Japan

ASEAN

GCC

LATAM Major countries do audit. (Brazil, Mexico, Colombia) Zone II & Zone IVb Brazil: 300 20 C 75% 5% RH Colombia, Peru, Ecuador: 300 20 C / 65% 5% RH Others: 250 20 C 60% 5% RH

Site registration

Yes

Plant GMP approval

US FDA Audit of both API and FP manufacturer

0

Stability Zone

Zone I & II

Stability requirements

25 2 C 60% 5% RH

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2 pilot scale + 1 lab batch 3 pilot scale 3 pilot scale 3 pilot scale 3 pilot scale ICH 6 months Against European Reference Product (ERP) in any country. Fed, Fast and Steady state required. Against Japan reference drug in any country 12 months 12 months ICH ASEAN GCC 12 months Against US /EU/Australia reference drug in any Country. ANVISA and ICH 6 12 months Brazil: Against Brazil reference drug in any CRO approved by ANVISA. PE to be done in Brazil Mexico: Against Mexican reference, in Mexico Only. Others: The BE for Brazil /Mexico is normally accepted. Obtaining Certificate of Pharmaceutical product (CPP) may delay the process, Administrative procedures in individual countries, time delay in approval Stand alone development, QbD in practice, translations, generic acceptance CTD 18-24 months ACTD 24-36 months Delay in registrations. Administrative issues with local regulatory and country laws. CPP, Legalizations, Translations, GMP audits, local requirements, time delay Against US /EU/Australia reference drug in any Country except Thailand, where BE to be done locally. PE to be done against local reference product in some countries. Patent noninfringement, GMP audit, high cost of registration, maintenance of registration, Administrative procedures for each member states. CTD As per the procedure (DCP, MRP) schedule, Usually 12-18 months CTD 24-36 months Country specific Varies from 7 days in Peru to 24 months in Brazil

No. of submission batches

One pilot scale or minimum 100,000 units whichever is higher

Stability guidelines reference

ICH

20

Stability data

3 months

BE Study (for Generic)

Against US reference listed drug (RLD) in any country. To refer BE recommendation in FDA site for guidance.

CRO should be approved by USFDA

Major holdup

Patent noninfringement, FDA audit, competition

Dossier Format

CTD

Registration time

12-24 months

FP Finished Product; CRO- Contract Research Organization; QbD Quality by Design; PE Pharmaceutical Equivalence