Emerging Biomarkets

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Several smaller-market countries in the Asia–Pacific region are looking to biotechnology as a significant driver for their economic growth. Some present themselves as wide open to foreign investment, hoping to attract partners or contract clients from overseas. Others are working to develop homegrown industry through local research and financing. A few have banded together in an Asian “light” version of the European Union.

ASEAN Countries

The Association of Southeast Asian Nations (ASEAN) is a geopolitical and economic organization of 10 countries in SE Asia. Formed in 1967 by Indonesia, Malaysia, the Philippines, Singapore, and Thailand, ASEAN has since added Brunei, Burma (Myanmar), Cambodia, Laos, and Vietnam. In 2010, the combined GDP of ASEAN nations was US$1.8 trillion. As a single country, they would be the ninth largest economy in the world and the third largest in Asia.

Ian Taylor, editorial director at Espicom Business Intelligence, said in 2008 that the countries of SE Asia present both a growing market and a research-driven development environment too often overshadowed by commercial interest in China and India. He forecast the market to climb to US$3.1 billion by 2013, about twice the growth rate of pharmaceuticals in general but at a slower pace than the global average. From ~7.7% of the Southeast Asian pharmaceutical market in 2008, Espicom expects biopharmaceuticals to increase as a proportion to 10% by 2013. Diabetic treatments and recombinant vaccines are the main types of products ASEAN patients will be looking for.


 

“The simple truth is that many biopharmaceuticals, such as oncologics, are too expensive for widespread distribution in countries with low healthcare expenditure,” Taylor warned. “The market will be focused on local market demand (insulins, hepatitis B vaccines, tropical disease vaccines), and access to the more expensive treatments will continue to be restricted until they come off patent and cheaper biosimilars become widely available.”

It is worth noting that after a late 1990s economic boom during which Asia led the world in growth, the region was hit by an infamous financial crisis that in many ways foreshadowed the deep global recession that took place about a decade later. As Ames Gross, president of Pacific Bridge Medical, said at the 2001 annual conference of the Regulatory Affairs Professional Society, “The Asian crisis was mainly a result of runaway, over-leveraged financial institutions that gambled ‘hot money.’” SE Asia was hardest hit: ASEAN countries collectively lost 9.3% of their GDP, with the worst effects seen in Thailand (–10.2%) and Indonesia (–13%).

Did that experience prepare them for what was to come? “The stock prices of emerging markets fell more than [those of] the developed markets late last year,” David Hunkar wrote for the financial web-zine Seeking Alpha in 2009. “However, they have recovered much faster and are now leading the developed market indices.” Those most dependent on outsourcing and exports to the West were hardest hit this time, and tourism dropped dramatically as well. But the biomedical industry overall was less affected — and as developed nations have begun looking for less costly options for research, development, and manufacturing, Asian countries are stepping up. Recognizing the main obstacles standing in their way, ASEAN is addressing their regulatory systems and manufacturing capabilities.

The ASEAN Consultative Committee for Standards and Quality-Pharmaceutical Product Working Group met in May 2009, hosted by the Philippines Bureau of Food and Drugs (BFAD). There, the respective drug regulatory agencies agreed to harmonize standards and regulations of pharmaceutical products. In June of that, the Asia Medical eNewsletter reported that their three principal aims were to create a transparent regulatory process, standardize regulation requirements, and remove the need for duplicate studies, thus allowing drug companies more time and resources to use for research and development. The ultimate goal is for a single set of regulatory requirements covering all ASEAN countries.

Editor Phil Greenfield wrote in the 2010 Scrip Asia 100 that ASEAN countries “need to get their regulatory systems in line before they can compete on the global stage.” The first big step forward came when ASEAN countries implemented their common technical dossier (ACTD) in 2009, following an approach similar to the ICH common technical document with agreed-upon requirements (ACTR) for quality, safety, and efficacy of drugs. According to Greenfield, “Their regulators are now planning to streamline the registration process for pharmaceutical products to improve patient access to new medicines.” He said the results of those discussions should amend existing drug registration guidelines and make the ACTD and its requirements compulsory for registering pharmaceutical products throughout the ASEAN region.

That’s not going to be easy. When the ACTD was adopted, only 5% of the drug industry in the Philippines was compliant with its requirements. Still, the ASEAN committee hopes that synchronization of standards will lower costs and increase the quality and availability of medicines for countries in SE Asia. Meanwhile, ASEAN wants to fortify rules on importing drugs to obtain high-quality medicines from the outside.

“Countries must adhere to international standards and not create their own,” says Martin Hutagalung, regional director of the US–ASEAN Business Council. “We know it is important, and we see efforts to harmonize, but progress is slow.” Along with Singapore (elsewhere highlighted in this supplement), Malaysia leads SE Asia in working toward these goals.

In general, ASEAN healthcare systems are not as highly developed as those of wealthier Asian countries such as Japan. Their standards are evolving. Currently the cost of clinical research in these countries is less than half of that in the West, largely due to lower wages for clinical personnel. Language Connections, a translation service in Boston, MA, wrote in 2008 about the great diversity of languages and cultures in SE Asia: “Presently Indonesia, Malaysia, Philippines, and Thailand are the most common locations for clinical trials, with Malaysia being the most dominant. Approval processes in these countries are relatively quick, and hospital infrastructure and regulatory environments are gradually improving. Despite the prevalence of English as a second language, generally only the educated populations in Southeast Asia speak English fluently. Other native languages include Malay, Thai, Tagalog, Indonesian, and various other dialects of each respective country and region. Thus, the issue of native language translation and integration of cultural factors in clinical data management must once again be taken into account.”

A report published by the College of William & Mary’s Mason School of Business at the end of 2010 identified several other trends in SE Asia of interest to both multinational and local pharmaceutical companies. Foreign direct investment as well as public and private investments are making healthcare more accessible to rural populations in remote regions, which o
stensibly expands the market. But increasing government intervention into drug pricing combines with limited intellectual property (IP) rights recognition to make extension of a company’s reach into such areas a risky proposition. Even relatively underdeveloped Cambodia, however, is making strides against unregistered and counterfeit drugs.

Indonesia has weathered the global financial crisis relatively smoothly because of its heavy reliance on domestic consumption to drive economic growth. Increasing investment by both local and foreign investors is also helping. Although the economy slowed in 2009, it did not contract, and by 2010 the growth rate had returned to 6%. During the recession, Indonesia outperformed most of its regional neighbors.

Most of Indonesia’s biotechnology interests are aimed at agricultural applications. The pharmaceutical market has much growth potential due to a stable political system and growth of the already large population. But that population is relatively young, and that government is known for relatively high levels of corruption. Many Indonesian patients who can afford it seek medical treatment abroad.

Salman Bokhari provided a SWOT analysis in the 2010 Scrip Asia 100 special issue. He listed other Indonesian strengths as seen from the outside: a well-established domestic manufacturing industry and long-term presence of most multinational pharmaceutical companies as well as relatively high drug prices with no formal controls in place. Among weaknesses, Bokhari identified corruption manifesting as the Indonesian regulatory system’s tendency to favor local companies and local physicians’ tendency to expect incentives. GMP standards are being implemented by the local industry, and modernization of the healthcare sector could increase health spending — even as the government seeks to reduce prices.

“Local companies’ dominant market position might make some of them attractive acquisition targets for international firms,” Bokhari wrote.

Ian Taylor of Espicom Business Intelligence estimated the Indonesian biopharmaceutical market at $101 million in 2008 and forecasted that it would rise to $148 million by 2013. But Indonesia’s share of the biopharmaceutical market in SE Asia was expected to slip from 5.4% to 4.7%.

Bokhari reported that most originator companies regard Indonesia as not yet fully compliant with the World Trade Organization’s Agreement on Trade-Related Aspects of Intellectual Property Rights (WTO-TRIPs). “Many drugs marketed in Indonesia today are lowcost copies which circumvent patents,” he wrote. “Original brand-name drugs are estimated to comprise less than one-third of the total number of drugs sold, with >70% being accounted for by locally made generic equivalents. Relatively long regulatory approval lead-times (on average up to two years) are also often cited as one of the major challenges.” He said that the Indonesian regulatory authority hopes that greater use of the electronic review system now being developed will help it meet 80–90% of targeted registration timelines in 2011.

Malaysia has transformed itself since the 1970s from a producer of raw materials into an emerging multisector economy. The country wants to achieve high-income status by 2020 and move farther up the value-added production chain by attracting investments in finance, high-technology, biotechnology, and services. Its famous Petronas Towers, however, are named after the state oil producer — emphasizing the continuing importance of fossil fuels as the country’s main economic engine. A well-developed financial regulatory regime limited Malaysia’s exposure to riskier investments and protected it somewhat from the recent global financial crisis. Nevertheless, decreasing worldwide demand for consumer goods did hurt the country’s exports and economic growth in 2009 — both of which showed signs of recovery in 2010.


 

As a member of the WTO, Malaysia has acceded to the TRIPs agreement, so patents are registered and copyrights are protected. A relatively speedy and efficient drug-approval process makes the country an attractive market for pharmaceuticals in general. However, Malaysia is home to a significant counterfeit industry and despite harmonization efforts presents challenges in applying process patents. The recent Mason School report said that a “lack of data exclusivity and generally poor regulatory enforcement will continue to pose major drawbacks to multinationals interested in Malaysia.”

In 2008, Espicom Business Intelligence estimated the Malaysian biopharmaceutical market at $75 million and forecasted it to reach $132 million by 2013 as the country’s share of the regional biopharmaceutical market shows a marginal increase from 4% to 4.2%. In 2005, Ames Gross and Rachel Weintraub of Pacific Bridge Medical valued the Malaysian healthcare industry at $1 billion and identified the United States, Japan, and Germany as major drug importers to the country. Late in 2010, Asia Medical eNewsletter reported that Malaysia ranks second only to Vietnam in healthcare spending among ASEAN nations (third in Asia overall). Its local industry has shown higher profitability over others since 2000, according to the World Health Organization.

Malaysia currently seeks international sponsors and manufacturers to boost its local industry. And to grow the local clinical research environment, policy changes are being implemented to make it attractive for phase 2–4 trials. The country has also adopted its own version of the ICH guidelines for good clinical practice (GCP).

Owned by the Minister of Finance Incorporated, BiotechCorp is a Malaysian government agency under the purview of the Ministry of Science, Technology, and Innovation. It is governed by a Biotechnology Implementation Council and advised by an international advisory panel, both chaired by the prime minister of Malaysia. Intending to serve as a “one-stop shop” for the Malaysian biotechnology industry, BiotechCorp both nurtures and accelerates growth of local companies and actively promotes foreign direct investments.

Ahmad Ibrahim, a fellow of the Academy of Sciences in Malaysia, wrote in 2007 for the New Straits Times that Malaysia had set aside about $100 million for “various biotech activities,” including money for research and development, funding to buy technologies, and allocations to promote investment. Dozens of companies given BioNexus status received benefits including tax incentives and access to grants for R&D from about $30 million in seed funding, loans, and other grants to be distributed over five years. Ibrahim added, “We also have to be judicious and selective about which biotech investments to support. There have been instances in the past of Malaysia being preyed on by pseudotechnology companies from abroad bent on making quick bucks. There is no substitute for proper due diligence to avoid such things happening.”

InnoBiologics is a Malaysian government-owned contract manufacturer for monoclonal antibodies and therapeutic proteins with a state-of-the-art GMP manufacturing facility about 150 miles from Singapore. The company delivered its first batch of clinical-grade mate
rials to Indian biosimilars company Avesthagen Ltd. in late 2010. Headed by CEO Dato Mohd Nazlee Kamal, InnoBiologics has in-licensed technology from Boehringer Ingelheim.

Alpha Biologics, another Malaysian CMO biomanufacturing specialist, built an $18 million 5,000-ft2 mammalian-cell–based biomanufacturing plant at Penang Biotech Park in April 2010. The company also conducts R&D and process development work at facilities in the United Kingdom, where it opened a new complex in November 2010.

The Philippines GDP grew 7.3% in 2010, spurred by consumer demand, a rebound in exports and investments, and election-related spending. The country weathered the 2008–2009 global recession better than most of its regional peers through minimal exposure to troubled international securities, lower dependence on exports, relatively resilient domestic consumption, large remittances from several million overseas workers, and a growing business process outsourcing industry. Weak tax collection exacerbated by new tax breaks and incentives has limited the government’s ability to address major challenges. But the current administration vows to focus on improving tax collection efficiencies rather than imposing new taxes.

Transparency International has given this country the second-lowest score (2.4) for public perceptions regarding corruption, meaning the second highest corruption rate of any country scored. By way of comparison, the United States, United Kingdom, and Japan score around 7.6–7.7; China and India 3.6 and 3.4, respectively; and the lowest score (highest corruption) goes to Russia (2.2). Some people consider bribes and other forms of corruption as analogous to taxes or even as useful means of expediting transactions. But most reputable businesses are loathe to participate in such dealings, not the least because they’re hard to justify in accounting! Ruslan Stefanov, economic program coordinator at the Center for the Study of Democracy in Bulgaria, was quoted in Scientific American’s “WorldView” supplement as saying “Corruption is a tax, and it’s a tax that doesn’t return public value.” So high levels of corruption translate to much waste in a given economy.


 

All that said, the Philippines was the first ASEAN country to initiate a biotechnology regulatory system, with establishment of its National Committee on Biosafety of the Philippines (NCBP) in 1990 — primarily concerned with agricultural applications of the technology. The country’s biosafety regulatory system follows strict scientific standards and has become a model for other ASEAN nations seeking to become producers of biotechnology crops. Like Indonesia, the Philippines have committed more to agricultural biotechnology than any other form.

In 2005 Gross and Rachel Weintraub (of Pacific Bridge Medical) valued the Filipino pharmaceutical market at ~$300 million. It’s largely served by imported products. The United States has a limited presence in drugs, though, holding less of the market share than either the United Kingdom, Germany, France, or Switzerland (each with ~10%). About that time, the Filipino Bureau of Food and Drugs adopted US Pharmacopeia standards, clearing the way for US chemical entities at least. “Companies such as Pfizer, Wyeth, and Eli Lilly all have a presence in the Philippines’ drug market,” wrote Gross and Weintraub.

Thailand: With a developed infrastructure, a free-enterprise economy, generally proinvestment policies, and strong export industries, Thailand enjoyed steady growth from 2000 to 2007 as it recovered from the late-1990s Asian financial crisis. But the recent global recession severely cut its exports, with most sectors experiencing double-digit drops. In 2009, Thailand’s economy shrank 2.2%, but in 2010 it expanded again 7.6% (the most since 1995) as exports rebounded. Business and investor sentiment remained buoyant, and Thailand’s stock market grew nearly 5% during March–May 2010.

Back in 2008, Ian Taylor of Espicom Business Intelligence reported that the Thai government was keen to restore investor confidence and promote investment in targeted industries, so those efforts appear to be working. Although biotechnology is one of those designated industries, Thailand’s compulsory licensing of pharmaceuticals complicates the business environment for life sciences. The country lags behind some others in SE Asia for promoting biotechnology, but many Thais are optimistic that the situation can be improved by their country’s relative wealth of skilled personnel.

Phil Greenfield pointed out in the 2010 Scrip Asia 100 special issue that Thailand has one of the slowest patent registration processes in Asia, usually taking six to eight years. Processing applications for some drugs can take ≤10 years, and some have taken >15. Such delays complicate matters for innovator companies if their patents are not granted by the time products are ready for market launch. Without enforceable patent rights, such products are not protected.

A 2010 report by the Office of the US Trade Representative (USTR) listed Thailand among countries having the “most onerous or egregious” practices and policies with the biggest negative impact on US products. And the Pharmaceutical Research and Manufacturers of America (PhRMA) claims that pharmaceutical and biotech companies are excluded from “meaningful” participation in reforming Thailand’s healthcare system. According to Greenfield, key issues of concern include that lack of sufficient stakeholder engagement as well as weak IP protection and anticounterfeiting, and discriminatory government procurement policies. South Korea

South Korea joined the trillion-dollar club of world economies in 2004 and currently ranks among the world’s 20 largest economies. The Asian financial crisis of 1997–1998 exposed longstanding weaknesses in its development model, including high debt/equity ratios and massive short-term foreign borrowing. After adopting numerous economic reforms following that crisis — including greater openness to foreign investment and imports — the country was able to recover fairly quickly from the global recession (during which its own economic growth had nearly stopped but not reversed). Long-term challenges include a rapidly aging population, inflexible labor market,and overdependence on manufacturing exports to drive economic growth

In 2008, Ian Taylor of Espicom Business Intelligence pointed out that South Korea’s close proximity to China and Japan makes it “well-placed as a gateway to two of the world’s most powerful economies.” But the country has a strong research base of its own. Since 1986, >30 new drug candidates and related technologies developed by Korean companies have been licensed to the major players in the pharmaceutical industry, according to Espicom. South Korean inventors rank 12th for biotechnology patents filed with the US Patent and Trade Office, and they account for 1% of USPTO patents related to stem cells, comparable to those filed by British and French researchers.

South Korea implemented its own GCPs in 2002, and it has one of the most recently established regulatory systems in SE Asia
for foreign-sponsored clinical trials. But its regulatory system moved rapidly to meet growing demands and has served as a model for others. A well-developed healthcare systems and new regulatory standards comparable to those of developed nations in the West makes it possible for high-quality clinical research to be performed at reduced cost here.

According to Gross, the Korean FDA is responsible for nearly every stage in the local drug regulatory process. “It establishes safety and quality standards for pharmaceuticals and medical devices, and it oversees the approval process to ensure that new pharmaceuticals and devices conform to their standards.” To ensure compliance, the KFDA conducts its own scientific testing on products submitted for approval. Its drug evaluation department operates within the drug bureau to ensure quality and standardization. For products already on the market, KFDA regional offices carry out postmarket surveillance and inspections. The pharmaceutical and medical devices research department is responsible for evaluating product safety. The KFDA’s Risk Violation Central Investigation Agency performs criminal investigations and doles out punishments in the event of violations. And in addition to regulatory functions, the agency develops research, study, and analysis methods for pharmaceuticals and medical devices.

A 2010 Research and Markets report said the South Korea pharmaceuticals market generated total revenues of $9,603.3 million in 2009, with a growth rate of 7% for 2005 – 2009. By comparison, the Chinese and Japanese markets grew with CAGRs of 20.1% and 2.3% respectively over the same period. Cardiovascular sales were most lucrative for South Korea in 2009, generating total revenues of $1,804.1 million (18.8% of the total market). Alimentary/metabolism sales generated revenues of $1,335.7 million (13.9%).

Many of us first learned about biotechnology in South Korea in 2004–2005, when former professor of Seoul National University Hwang Woo-suk falsely reported in the journal Science that his lab had created human embryonic stem cells through cloning. After his infamous exposure and dismissal, an indictment followed in 2006. By 2007, he had lost government financial and legal support and the South Korean government had barred Hwang from conducting human cloning research. He was given a two years suspended prison sentence on 26 October 2009 for embezzlement and bioethical violations, but cleared of fraud. CNN reported that he admitted faking his findings. His conviction was upheld by an appeals court in December 2010, but his sentenced was shortened by six months. Hwang now leads research creating cloned pig embryos to make embryonic stem-cell lines at Sooam Bioengineering Research Institute.

Hwang, however, is far from all there is to say about South Korean biotechnology. The KoreaBio trade association boasts ~250 member companies. Like the US Biotechnology Industry Organization, it came about through unification of other biotechnology associations in November 2008. In addition to supporting its members and partnering with the government, KoreaBio actively participates as a member of the international bioindustry community and develops training and policy-making programs.

As indicated by the licensing-out of so much technology, many South Korean companies are engaged in research. For example, CHA Biotech was established in September 2000 by Pochon CHA University College of Medicine and CHA General Hospital Group to create a central, multidisciplinary research facility where scientists and physicians could focus their efforts on developing stem cell, gene therapy, and regenerative medicine technology. The company recently entered a joint venture with Advanced Cell Technology, Inc. of Worcester, MA, to develop stem cell therapies under a new company named Allied Cell Technology.

Another biotechnology company based in South Korea, PanGen Biotech is a contract developer of animal cell lines (particularly Chinese hamster ovary cells) and producer of proteins and antibodies. To cut the time and costs of recombinant gene expression, the company uses patent-pending technology and its own expression system. PanGen makes proteins and cell lines for industry, academia, and governmental organizations to use in high-throughput screening, in vivo studies, diagnostics, research reagents, and therapeutics. It also partners with multinational corporations. New Zealand

Although Australia is the nearest major country to New Zealand (and a fellow member of the “continent” of Oceania), the two are separated by >1,000 miles of the Tasman Sea. New Zealand is actually closer to the Pacific island nations of New Caledonia, Fiji, and Tonga (about half as far to the north of it). The country’s remote location is widely considered to be its largest economic challenge.

Like many countries in SE Asia, New Zealand’s biotechnology presence is much stronger in agriculture and the environment than in the therapeutic realm. Unlike Indonesia and the Philippines, however, its agricultural interests lie in forestry and animal husbandry rather than crops — most particularly, cattle and sheep. Most of New Zealand’s healthcare successes thus far have occurred in the realm of medical devices and cell technologies.

However, the country has a “gold standard” regulatory regime and conforms to the highest international ethical standards for clinical testing. Most products on its market are EMA and US FDA approved. Transparency International gives New Zealand the highest score (9.4) for public perceptions regarding corruption, meaning that its business and government are the least corrupt of any country’s.

New Zealand’s per-capita income rose for 10 consecutive years through 2007, then fell in 2008–2009 as part of the global financial crisis. The country has experienced a series of “brain drains” since the 1970s that continue today. Nearly a quarter of its highly skilled workers live overseas (most in Australia and Britain), the most from any developed nation. But a recent “brain gain” has brought in educated professionals from Europe and less-developed countries.

Remoteness has kept New Zealand free of transmissible animal diseases such as bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. This makes it one of a diminishing number of sources for the safest animal sera, which are vital to many legacy cell culture products as well as research use around the world.

Research in 2009 showed that New Zealand’s human therapeutics industry generates revenues of $200 million each year and could contribute $300–450 million per year within the next decade. In 2009, Scientific American Worldview ranked New Zealand in the top 10 countries for biotechnology innovation, particularly agricultural applications. Some current research activities and achievements include animal genomics and reproductive technologies; asthma and tuberculosis research, including the patenting of an asthma vaccine; bioprocessing and biomaterials research; development of new foods and flavors; and nutritional supplements and natural-sourced bioactives.

Researchers at Victoria University are using a form of selective breeding called “directed evolution” to make enzymes with new or improved functions. For example, the laboratory is developing one as a cancer treatment: It activates a prodrug, which releases a toxic metabolite, causing cells to die. And since 2000, other scientists at AgResearch Ltd. (New Zealand’s largest research institute) have been successfully creating transgenic cows that make modified milk with therapeutic proteins to treat human diseases.

Based in Auckland, Innate Therapeutics Ltd. has designed and manufactured an immunomodulator microparticle that can be used to induce the human immune system to fight cancers and infections. It can also turn off immune mechanisms that lead to autoimmune disease. The s
ame technology is being used in vaccine design.

And Living Cell Technologies (LCT), a developer of cell implants to treat diabetes, is marketing a groundbreaking diabetes treatment called Diabecell through a Russian subsidiary. It’s the first registered porcine-cell implant therapy, which is administered through a simple laparoscopic procedure using LCT’s Immupel encapsulation technology. Meanwhile the company is conducting phase 2 trials at home in New Zealand with patients suffering from unstable type 1 diabetes. Because the product works by self-regulating and efficiently secreting insulin in the patient’s body, patients receiving the Diabecell implant do not require immune suppressing drugs.

Late in 2009, BioSpectrum Asia reported that the newly elected NZ administration is interested in bringing back a proposal dropped in 2007 by the previous government. It intends to streamline the regulatory environment for businesses operating on both sides of the Tasman Sea by forming a joint drug regulatory scheme with Australia. An official agreement between the two countries remains in place, so postponed negotiations to establish an Australia New Zealand Therapeutic Products Authority (ANZTPA) could resume soon. Strength in Diversity

When it comes to bioprocessing in the Asia–Pacific region, much attention is being directed toward China and India. They’re big countries, and they’re doing big things. However, the region covers much of two continents: the world’s largest (Asia) and the world’s smallest (Oceania). As such, it is home to a vast and diverse population divided into a wide range of political entities implementing a number of economic philosophies within numerous religious and cultural traditions. The ASEAN organization seeks to create strength from some of that diversity, and even distant New Zealand realizes that close relations with its neighbors are key to a great future.

 

About the Author

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Cheryl Scott is senior technical editor for BioProcess International

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