WHITE PAPER. establishing a regulatory Drug Development Strategy for Asia Pacific

WHITE PAPER establishing a regulatory Drug Development Strategy for Asia Pacific ppdi.com July 2012

EXECUTIVE SUMMARY As the economic power of China and other Asian countries grows, many biopharmaceutical companies are interested in expanding into (or within) this region. A shared challenge is the Asian regulatory landscape, which is heterogeneous, and, until recently, was characterized by unpredictable timelines, varied requirements and limited authoritative documentation of the processes and policies. In the past few years the landscape has improved, with more cooperation between countries; an increasing convergence on priorities, principles and approach; and a deeper awareness of regional and global differences in regulatory policies and practices. Industry has responded to these positive changes and the increasing economic influence of the region by including Asia in global strategic planning more frequently. While challenges still remain, they can be overcome with a comprehensive regulatory strategy in Asia that includes advanced planning, local knowledge and strong professional relationships with regulatory agencies. Establishing a Regulatory Drug Development Strategy for Asia pacific 2

Introduction While more than 60 percent of the world s population lives in Asia (Figure 1, on page 4), 1 until recently, the region has been a fairly low priority for most Western biopharmaceutical companies because of the relatively limited buying power of governments and individual consumers/patients. However, political reforms and economic improvements over the last few decades have made Asia an important global pharmaceutical market. For example, the Chinese middle class, currently larger than the entire United States population, is predicted to grow to 700 to 800 million people (50 to 60 percent of the Chinese population). 2 In India, the middle class is expected to increase to 583 million people (41 percent of the country s population) by 2025. 3 Recognizing this significant economic shift, many biopharmaceutical companies are expanding into (or, for local companies and international enterprises with an established presence in the region, expanding within) this massive market. The shared concern, 3 however, is the Asian regulatory landscape, which is often perceived as having complicated processes, long delays and widely varying requirements between countries. The regulatory environment in Asia is evolving rapidly to accommodate this expansion, but challenges remain, including: + + Limited transparency in decision making + + Little collaboration with industry on new regulations and guidelines + + Unpredictable timelines in some countries + + A cultural emphasis on collaboration and consensus that often slows major decisions and discourages agencies from publishing road maps of upcoming improvements Though the process can be complicated and difficult to navigate, it is manageable with realistic timelines, disciplined project management and access to local resources who have up-to-date knowledge and experience with the regulatory environment and requirements of each targeted country. This paper makes recommendations on planning and executing a successful regulatory strategy in Asia. Establishing a Regulatory Drug Development Strategy for Asia pacific

Figure 1: Estimated World Population by Region, 2010 Africa, 15% Europe, 11% All of Asia, 60% China, 19% India, 18% Latin America, 9% Rest of Asia, 23% North America, 5% Source: United Nations, Department of Economic and Social Affairs 1 Regulatory Development in Asia The current biopharmaceutical regulatory environment in Asia is quite heterogeneous, with each country independently enforcing its unique policies. Up until a few years ago, timelines were unpredictable, requirements varied widely and authoritative documentation of the processes and policies was limited. These issues, coupled with an under appreciation of the region s potential for both clinical development and commercial sales, meant that large pharmaceutical companies tended to view Asia as a place to pick up the slack for trials that needed more participants. Their focus was on getting drugs to market in the U.S. and Europe; other regions, including Asia, were usually an afterthought. Today, the situation has improved with more cooperation between countries and a deeper awareness of the regional and global differences in regulatory policies and practices. Formal regulatory harmonization in the region is unlikely, but there is an increasing convergence on priorities, principles and approach. Larger Asian countries are striving to provide regulatory services at the same level as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and smaller Asian countries are finding that they can play a valuable role within the constraints of their more limited resources. Globally, there is a growing appreciation that there are many paths to the same goal, and no single approach is ideal for all countries. Industry has responded to these positive changes and the increasing economic influence of the region by including Asia in global strategic planning more frequently. Establishing a Regulatory Drug Development Strategy for Asia pacific 4

Figure 2: Percentage of Clinical Studies With Sites in Asia Pacific, 2000 to 2009 4 14 Percentage of Clinical Trials With Sites in Asia Pacific 12 10 8 6 4 2 3.4% 3.8% 5.2% 6.4% 8.3% 11.1% 10.9% 11.2% 11.4% 12.5% 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year Source: Outsourcing-pharma.com 4 Clinical Development in Asia At the beginning of the millennium, only a handful of the global clinical trials listed on the U.S. National Institutes of Health s online registry, clinicaltrials.gov, were ongoing in Asia. By 2009, there were more than 2,900 trials (Figure 2, above), 12.5 percent of the global total. 4 A myriad of factors contributed to this increase. In brief: + + The region s huge pool of mostly treatmentnaïve patients includes many with diseases in key therapeutic areas, such as respiratory and cardiovascular diseases, hepatitis, cancer, diabetes and obesity 5,6 + + Asia is gaining a reputation as an area where efficient, cost-effective clinical development can result in high-quality data acceptable to regulatory agencies worldwide + + A growing number of experienced Asian physicians are considered global opinion leaders + + The population is concentrated in urban areas, where large hospitals can facilitate recruitment by providing a substantial patient pool at a single site + + Many Asian physicians are educated in Western countries, resulting in high rates of English comprehension + + Most investigators in Asia are driven by an interest in research, as their fees are typically used for local research and not as a part of their income + + The respect afforded physicians in Asian cultures results in rapid rates of trial enrollment and participants who are more adherent and less likely to drop out of a study compared with their Western counterparts Establishing a Regulatory Drug Development Strategy for Asia pacific 5

The Asian health care environment, including the testing and licensing of drugs, is as important to the region s regulatory agencies as it is to the biopharmaceutical companies. Asian governments tend to support clinical trials, whether sponsored by domestic or foreign companies, because of their contribution toward excellence in clinical standards and the opportunities for employment and training. Current Regulatory Environment in Asia Many positive changes to the regulatory review process have already been implemented and, in the past 10 years, there has been a noticeable improvement in the regulatory review processes in most countries. Most Asian countries now have defined, realistic review timelines (Figure 3, on page 9), and Southeast Asia, in particular, has made a move toward regional harmonization in some areas. National regulatory agencies tend to be somewhat flexible and frequently welcome industry collaboration in areas where policies and requirements are not well defined. For example, although no guidance exists on how to design and execute regional clinical development programs for a combination cardiovascular product, it is possible to have rational, collaborative meetings with regulatory agencies in some countries that result in a semi-binding consensus on how to approach the issue. Evolution is ongoing, and countries in the region continue to develop their regulatory agencies and processes as resources and expertise permit. Common hurdles are transparency in decision making and collaboration in the development of new guidelines. Regulations often appear with little warning and without an opportunity for public comment, as many Asian authorities have not yet developed robust processes for formal technical consultations with industry and other stakeholders. Timelines in some countries can be unpredictable, with review periods varying significantly for both clinical trial applications and new product licensing submissions. Finally, the emphasis on collaboration and consensus characteristic of Asian cultures means that major decisions often take considerable time and multiple meetings. As a result, most Asian regulatory agencies are reluctant to publish a road map of what they plan to accomplish in the next two, five or 10 years. Changes are coming, but which changes and when can be difficult to predict. Developing a Regulatory Strategy for Asia Given the heterogeneity and evolving nature of regulatory agencies in Asia, the keys to developing a regulatory strategy are advanced planning, extensive local knowledge and strong professional relationships with agencies. The current environment can be complicated and confusing to navigate, but with the right expertise, realistic timelines and disciplined project management, much can be accomplished. Critical factors for success include early planning for the often-necessary local clinical trials, an in-region footprint and/or access to appropriate expertise and a positive relationship with relevant regulatory agencies. Understanding the Environment Developing a regulatory strategy involves consideration of many other significant issues, including intellectual property rights, pricing, supply, health care infrastructure and the government s interest in encouraging and incentivizing local companies to produce high-quality biopharmaceutical products. China, India, Korea and Japan, in particular, have thriving local research and development industries. Before committing to a local/ regional clinical development plan, it is important to think through the likely future availability of the product, government listing and reimbursement, size of the private market, market growth and competition Establishing a Regulatory Drug Development Strategy for Asia pacific 6

from local and multinational companies. These areas are interdependent, and all are evolving rapidly in the Asian market. Access to Expertise Successful strategic planning is not possible without access to people on the ground who have up-to-date knowledge and experience with the regulatory environment and requirements of each targeted country. This team should be tasked with planning, preparing and submitting applications and working with the local authorities to manage any queries, delays or changes to policies or procedures. The considerable variation in regulatory requirements and timelines across the region means that country-specific knowledge is imperative. What works in Singapore will not necessarily work in Taiwan. Relationship with Regulatory Agencies The importance of good professional relationships with the regulatory agencies, characterized by openness, integrity and transparency, cannot be overstated. Many of the regulatory guidelines and regulations in Asian countries are open to interpretation, and knowledge transfer often relies on experience and regular communication with authorities. Pre-submission meetings for clinical trial or new drug applications are available in some Asian countries, and intimate familiarity with the process as well as with the personnel, language and culture makes it possible to move forward more quickly and efficiently. Companies new to the Asian market often choose to outsource regulatory work to a team with extensive, on-the-ground experience with the local authorities. Requirements for Local Clinical Data As a general rule, marketing authorization in some key Asian countries requires clinical trial data, which includes its citizens. Some countries, such as those in Southeast Asia, will accept data from other nations in lieu of a local study, but key countries, such as China, Korea and Japan, expect a degree of local/regional development. For these countries, early inclusion in global development programs will speed local marketing approval. For example, the Chinese State Food and Drug Administration (SFDA) requires both approval in a foreign country and a local China study before any new chemical entity (NCE) that is not developed in China can be given marketing approval and an import drug license (IDL). This can result in a significant marketing approval lag in China compared to rest of world. Ideally, China should be included in strategic planning at the start of Phase II trials, and included in the global Phase III stage of the trial with other Asian countries added as soon as practically possible. For China in particular, this can allow for product launch two to three years earlier (Figure 4, on page 9). Similar strategies in other key Asian countries will also result in earlier launch. Early inclusion in global development is critical. Establishing a Regulatory Drug Development Strategy for Asia pacific 7

Special Challenges and potential solutions for Regulatory Review in China Regulatory affairs in China has always been complex and burdened with long lead times, bureaucracy, understaffing and a lack of transparency. In the past few years, the centralized SFDA has made significant strides toward higher levels of professionalism, more specific regulations and increased participation in regional and global initiatives, such as the Tripartite Forum (China, Japan and Korea) and the International Conference on Harmonisation s Global Cooperation Group (ICH GCG). The environment is evolving and the SFDA has stated its intention to make steady improvements over the next few years. In the meantime, there are potential solutions to some of the significant regulatory challenges in China. Vaccines Phase I Ethics committee NDA IND and NDA content and format Challenge Cannot include China in a global trial if the vaccine is not approved abroad First-in-human studies can only be conducted in China for locally developed products Ethics committees cannot review clinical trial applications until CTA is issued CPP is a prerequisite for submission of an NDA Long timelines, need for a detailed CMC, pre-clinical and clinical data requirements and numerous queries, particularly on CMC data potential solutions + + Assess feasibility of developing the vaccine in China + + File an IND application immediately after CPP is available abroad + + A foreign sponsor with Chinese affiliations and local manufacturing capabilities can conduct Phase I studies as locally developed products + + This policy is evolving rapidly and the SFDA has stated its interest in participating in global drug development programs + + Select sites in advance + + Submit ethics committee applications as soon as the CTA is received + + Apply for a global trial CTA instead of an NDA + + Include China in the global development plan at Phase II or III + + Review submission documents carefully + + Perform a gap analysis in advance + + Keep in close contact with reviewers to address issues early + + Provide quality translations KEY CMC = chemical, manufacturing and control CPP = certificate of pharmaceutical product CTA = clinical trial authorization IND = investigational new drug NDA = new drug application Establishing a Regulatory Drug Development Strategy for Asia pacific 8

Figure 3: Regulatory Timelines in Asia for Clinical Trial Approval China Hong Kong India Indonesia South Korea Malaysia Philippines * Singapore Taiwan * Thailand Vietnam 0 2 4 Months KEY n Ethics Committees n Regulatory Authorities n Ethics and Regulatory Authorities in Parallel n Import License * Import license issued with regulatory authority approval 6 8 10 12 Figure 4: Potential Impact on Marketing Authorization Timelines for NCEs When China is Included in Earlier Phases of Drug Development U.S./EU approval China clinical and regulatory times China approval with Scenario 1 Scenario I: Phase III in U.S./EU first U.S./EU program* CTA review China program IDL review Scenario II: China included in global Phase III Global program including China and other Asian countries* IDL review Opportunity for earlier launch in China -3 years -2 years -1 year 1 year 2 years 3 years 4 years *Trial durations vary by project Establishing a Regulatory Drug Development Strategy for Asia pacific 9

Looking Toward the Future Regulatory strategies must also incorporate contingency planning for the rapid evolution of the Asian biopharmaceutical marketplace that is likely to occur over the next two decades. Changes may include: + + Increase in the quality and capacity of resources at regulatory agencies, with a corresponding improvement in documentation and transparency. This change may result in increased demand from the agencies for documentation and data + + Evolution of a few countries with local R&D, manufacturing and regulatory competence toward status as reference nations for Asia + + Introduction of a rolling/open model for investigational new drug (IND) applications in China in an effort to increase quality, shorten timelines and align to global regulatory systems + + Emergence of different regulatory/development models, particularly for products that treat diseases endemic to Asia + + Growing demand for new biopharmaceutical products from both health care providers and an increasingly affluent population + + Increased regionalization and globalization of Asian companies through expansion, partnerships and alliances + + More stringent enforcement of intellectual property rights belonging to both foreign and domestic companies + + Increased industry interest in outsourcing development and regulatory functions, leading to further growth of clinical research organizations (CROs) and contract houses with the appropriate local experience and expertise Conclusion Asia s huge population and growing economic power are strong incentives for biopharmaceutical companies to expand into (or, for local companies and multinational enterprises with an established presence in Asia, expanding within) this market. Ten to 20 years ago, the Asian biopharmaceutical regulatory environment was extremely heterogeneous, with unpredictable timelines, widely-varying requirements and scarce documentation. The region s regulatory agencies are evolving rapidly, and many positive changes have already been implemented. Developing a regulatory strategy in Asia remains complex and challenging, but success can be achieved with advanced planning and a team of people on the ground who have up-to-date knowledge and experience with the regulatory environment and requirements of each targeted country. Numerous positive changes are expected to continue to improve the Asian regulatory environment in the next decade, more closely aligning Asia with established global regulatory standards. Establishing a Regulatory Drug Development Strategy for Asia pacific 10

References 1 United Nations, Department of Economic and Social Affairs. World Population Prospects, the 2010 Revision. http://esa.un.org/wpp/analytical-figures/ htm/fig_5.htm and http://esa.un.org/wpp/unpp/ panel_population.htm. Accessed 6 June, 2012. 2 CNN Money. China s growing middle class. April 26, 2012. http://money.cnn.com/2012/04/25/news/ economy/china-middle-class/index.htm. Accessed 5 June, 2012. 3 McKinsey Global Institute. The Bird of Gold : The Rise of India s Consumer Market. May 2007. http://www.mckinsey.com/insights/mgi/research/ Asia/The_bird_of_gold. Accessed 5 June, 2012. 4 Taylor N. Global clinical trial activity in the 2000s, visualized. October 6, 2010. http://www. outsourcing-pharma.com/clinical-development/ Global-clinical-trial-activity-in-the-2000s-visualised. Accessed 7 June, 2012. 5 Liou A. The China Proposition. European Pharmaceutical Contractor. Spring 2010. 6 Virk KP. China s clinical trial boom. PharmFocus Asia, 2011;14. Establishing a Regulatory Drug Development Strategy for Asia pacific 11

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