THE GLOBAL PHARMACEUTICAL INDUSTRY - The Decision Points 1.5.1.1 Decision Point I

The Decision Points 1.5.1.1 Decision Point I

1.6 THE GLOBAL PHARMACEUTICAL INDUSTRY

HARMONIZATION AND PARTNERSHIPS

Due to increasing international focus on manufacturing and clinical trial activities, globalization has become a matter of importance to the pharmaceutical industry. International regulators have increasingly recognized that international partnering enhances the pharmaceutical market and facilitates the regulation of health products in a sustainable way. The NRA has a shared global approach, as they align their initiatives to reduce limitations in actualizing this process. Globalization and harmonization have resulted in several initiatives. The following are some examples:

the establishment of TRIPS and agreement of the World Trade Organi- zation play prominent roles in international pharmaceutical regulation.

TRIPS was formed in order to promote the intellectual property rights and to subject it to common international control. The Regulatory Co- operation Council unifies the Canada–United States regulatory systems for across the border operational gain and efficiencies in trade, eliminat- ing unnecessary differences and repetitions to sustain appropriate levels of oversight of their products. A vehicle to harmonization, the MRA, en- ables pharmaceutical products that have been inspected and certified in a member nation to be recognized within the MRA countries. The MRA taps into the value of reciprocity allowing each sovereign nation to recog- nize standards within the other participating nations. MRA also promotes trade and market access within the European Union, the United States, Canada, Japan, Switzerland, Australia, New Zealand, and Israel. EMA sup- ports the European Commission’s collaboration with China, India, and Russia. This can be found at http://www.ema.europa.eu/ema/index.

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listing_000233.jsp&mid=WC0b01ac05801f0a04. A memorandum of un- derstanding is a common agreement platform that promotes greater global cooperation. The International Organization for Standardization (ISO), the International Conference on Harmonisation of Technical Require- ments for Registration of Pharmaceuticals for Human Use (ICH), and the International Cooperation on Harmonisation of Technical Requirements

for Registration of Veterinary Medicinal Products (VICH) all contain regulatory guidelines that are collectively recognized internationally.

There is an increasing focus toward harmonization as it has been dem- onstrated to promote effective globalization of the pharmaceutical sector, which is the key aim of establishing the ICH documents.

1.6.1 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

1.6.1.1 Scope

ICH is the harmonized format for drug registration applications for new pharmaceutical products, biologicals, the abbreviated (abridged) applications. ICH represents a point of convergence to straighten the uneven global regulatory landscape. Thus, it was created in an attempt to address the unilateral development of requirements and to reduce time and resources needed to compile applications and enhance reviews, communication, and exchange between regional countries.

The International Conference of Drug Regulatory Authorities (orga- nized by the World Health Organization (WHO), attended by delegates from Japan, the European Union, and the United States and observers from WHO, the European Free Trade Association, and Canada, took place in 1989. Other participants were trade associations: European Federation of Pharmaceutical Industries Association, Pharmaceutical Research and Man- ufacturers of America, and Japan Pharmaceutical Manufacturers Associa- tion. A consensus was reached and it led to the launch of the International Conference on Harmonisation of Technical Requirements for the Reg- istration of Pharmaceuticals for Human Use. Guidelines for active pharmaceutical ingredients (API), by the ICH, and GMPs now apply in the European Union, Japan, and the United States, and also in other countries (e.g., Australia, Canada, and Singapore), which adopt them for the manufac- ture and testing of active raw materials.

The United States, Europe, Japan, and Canada are the major trade group- ings that are the signatories to ICH. Other regions are Asia Pacific, Latin America, Africa, Russia, Australia, and New Zealand. These nations incor- porate the dossier requirements for quality, preclinical and clinical studies for developmental healthcare products and drug master file (Figure 1.2).

According to Figure 1.2, module 1 is region specific while modules 2–5 are common to all the applicable regions.

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The ICH Global Cooperation Group comprises representatives from the regional harmonization initiatives, which are: Asia-Pacific Economic Cooperation, Association of the Southeast Asian Nations, Gulf Cooperation Council, Pan American Network for Drug Regulatory Harmonization, and Southern African Development Community. Certain non-ICH countries are now major contributors/consumers of the global pharmaceutical market. The regulators forum that started in 2008 includes representatives from Australia, Brazil, China, Taiwan, India, Russia, Singapore, and South Korea most of which are not part of harmonization initiatives and are focusing on the API, GMP, clinical trials, and pharmacovigilance. While promoting the efficiency and integrity of clinical trials, increasing reforms are bringing ap- preciable impact on globalization due to its widening scope and geographical coverage. The evolutionary changes and international harmonization endeavors are opening avenues for collaboration among the national regulators to facilitate faster “time to launch” while mitigating the regulatory burden. Continual cooperation among the NRAs is a priority and essential toward the moving forward of the regulatory agenda.

ICH terminology used in the Quality Safety and Efficacy Classification Systems:

ICH-Q: Quality. This pertains to pharmaceutical quality based on GMP risk management.

ICH-S: Safety. This pertains to risks like carcinogenicity, genotoxicity, and reprotoxicity.

Figure 1.2 Structure of the ICH Document.

ICH-E: Efficacy. This pertains to effective design, conduct, safety, and reporting of clinical trials and processes pivotal for demonstrating efficacy including the use of pharmacogenetics/pharmacogenomics.

ICH-M: Multidisciplinary. This pertains to topics outside the quality, safety, and efficacy categories. It includes the ICH medical terminology, the CTD, and the development of Electronic Standards for the Transfer of Regulatory Information.

1.6.2 Government Regulations: Prospects for Multinational Clinical Trials

Outsourcing some aspects of pharmaceutical research and development (R&D) has been a cost-saving mechanism for many international sponsors.

For example, conducting international clinical trials in less industrialized or less developed countries usually brings less expenditure for the sponsor.

But to the middle to low income country or geographical region that is indisposed to meet the legal standards, regulatory compliance has been a challenge. Continual regulatory reform is streamlining processes in multinational clinical trials to help bridge the gap and promote its effectiveness.

1.6.2.1 Pharmaceutical Regulations in Asia

Asia is a rapidly growing pharmaceutical market that attracts drug development projects and marketing opportunities. However, incremental regulatory demands and reformations tend to mitigate the success opportunities for the affected companies. Thus, modernization of the pharmaceutical regulatory systems that have taken into consideration these economic barriers has played a major role in shaping the effectual multinational pharmaceutical R&D operations. This strongly elicits the strengthening of the global pharmaceutical marketplace – a crucial need for the industry and human health.

In Japan, the adoption of the ICH “Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data” (E5) in 1998, and the approval of the new “Basic Concepts for International Joint Clinical Trials” in 2007 by Japan’s PMDA, relaxed the regulations that now permit pharmaceutical companies to accept clinical data from outside Japan. This has reduced the lengthy timelines for projects resulting from limitations in clinical trial studies performed in Japan. Prior to the recent regulatory changes, approval for new drugs in Japan could take up to 4 years longer than in the United States or Europe because of the difficulty of conducting trials in Japan.

China’s population explosion (over a billion people) is an advantage for pharmaceutical manufacturers, as it attracts clinical trials and markets for

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emerging therapies, but these trials often have longer timelines. With increasing investment in R&D by foreign companies, the regulatory demands for multinational clinical trials performed in China have made it difficult for foreign drug sponsors and multinational sponsors to proceed with clinical trials in the country. On December 2, 2011, China’s State Food and Drug Administration (SFDA) issued the Guiding Principles for Administration on Phase I Clinical Trials on Drugs (for Trial Implementation), in order to streamline Phase I clinical trials in China that has now enhanced multinational clinical trials in the country. In drafting the previously mentioned principles, the SFDA referred to British Pharmaceutical Industry and EMA clinical trials guidelines. The guidelines are found in the Association of the British Pharmaceutical Industry’s Guidelines for Phase I Clinical Trials. The EMA’s Guideline on Strategies to Identify and Mitigate Risks for First- in-Human Clinical Trials with Investigational Medicinal Products. EMA’s Guideline for Good Clinical Practice. China Issues New Guidelines on Phase I Trials [18].

One significant regulatory change is that Certificates of Analysis (COA) must be issued locally for the ingredients in drugs to be tested in China. The COA requirement may now be waived for chemical-based products not registered for sale in China. This further widens the scope of multinational trials, providing a better opportunity for Chinese patients seeking new medicines. In October 2007, China’s SFDA issued new timetable guidelines that have reduced the pharmaceutical review time by 1–2 months [19,20].

1.7 MODERNIZATION OF THE GLOBAL PHARMACEUTICAL

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