ASIAN PHARMA ON TRIAL

After years of relentless change that has steadily driven up the stakes and challenges of clinical development, the pharmaceutical industry is heaving a collective sigh of relief in knowing that at least one element is unlikely to change in the decade ahead: its ability to rely on Asia as a preferred location for clinical trials.

With a population of four billion people, Asia is home to 60 percent of the global population and a huge untapped market for medicines. Meanwhile, the factors that prompted the migration of studies to cities like Shanghai and Mumbai have intensified.

It now takes US$900 million and up to 16 years to shepherd a drug from laboratory to licensure, with nine out of 10 compounds failing to go the distance.

Double-digit growth in studies for biologic products is increasing development complexity and costs, which exceed those of the average small-molecule drug by about US$400 million. Meanwhile, a whopping 86 percent of studies fail to recruit patients on time, resulting in costly delays.

Under growing pressure to increase productivity and cut development costs, trial sponsors have embraced the myriad challenges of conducting clinical trials in Asia in exchange for the rewards of cost savings and rapid patient recruitment.

China and India, which ranked as the most attractive off shore clinical sites in a 2006 survey, have come to dominate the clinical trial experience in Asia. The experiences, positive and negative, of study sponsors and clinical supply chain managers in these countries will undoubtedly inform plans for Asian clinical trials in the decade to come.

CHINA LEADS

In a nation of 1.3 billion potential patients, government reluctance to accept foreign trial data in granting marketing approval for new drugs would be suffi cient incentive for conducting in-country studies. Add ease of patient recruitment and the relatively low cost to conduct trials, and it’s easy to understand why China is likely to continue its reign as the top-ranked, Asian clinical trial location.

In the United States, where virtually nine out of 10 trials are delayed a year due to insufficient patient enrollment, physicians recruit a mere third of study subjects. By comparison, Chinese physicians enroll virtually all study patients at modest cost. The average investigator grant of US$1,000 for a cancer study, plus an additional US$2,000 to cover laboratory tests, make Chinese clinical trials among the most cost-eff ective in the world.

Benefits notwithstanding, there are hurdles to overcome in conducting clinical trials in China, the most formidable of which is bureaucracy. A complex web of national, regional and local government policies and regulations can trigger jurisdictional disputes over documentation. This may delay shipments of temperature-sensitive materials sitting on the tarmac and slow the start of trials, all of which must take place in state-run hospitals, by as much as a year.

While patient recruitment is inexpensive, logistics can be costly in Asia’s largest country, where infrastructure has failed to keep pace with economic growth. This is a special challenge for the growing number of trials involving high-value biologics, which must be shipped and stored in the cold chain at controlled temperatures. For example, more than 25 percent of Fisher Clinical Services’ projects currently involve biologics, a proportion that is increasing steadily.

Other concerns involve ethics and safety, which have attracted widespread coverage by global news media. Language remains another barrier in a country where Mandarin, the official language, is spoken amongst thousands of dialects. While the importance of Mandarin is expected to grow along with China’s clout, it’s worth noting that China has the world’s largest number of English language students.

Some recommended practices for clinical trials in China:

• Understand the local and regulatory environment. Be aware of regulations, which can be a moving target. Navigating China’s regulatory environment efficiently saves time and resources, not to mention frustration.

• Minimize ethics and contamination concerns with professional supply chain management. It’s essential to have a high standard of control in dosage manufacture and packaging assembly, as well as thorough and complete documentation. Compliance with Good Distribution Practice (GDP) ensures that material integrity and efficiency are uncompromised. Work closely with clinical sites to ensure that storage locations are controlled and secure, especially with respect to temperature-controlled drugs.

• Use centralized and regional distribution centers. Doing so improves distribution and logistics effi ciencies, limiting the times when trial drug must clear customs, which can be a time-consuming process. Careful local coordination of customs transit is another critical factor for successful supply chain management. Keep in mind that trial drug shipped from the US or Europe takes time to arrive and additional time to be processed once it reaches China.

INDIA ISSUES

India, which has established a reputation as a global hub for clinical trials, is likely to continue to be the second leading Asian location for conducting global studies. According to one estimate, 15 percent of all global clinical patients will reside in India by 2011.

The reasons are threefold: time, people, and cost. India has a study-start approval process of 12 weeks, which is appealingly short to study sponsors anxious to cut development time. Its population of 1.1 billion offers a large, treatment-naïve patient pool, with subjects able to be quickly recruited for studies of tropical diseases, as well as chronic conditions of the industrial world. Like China, conducting a clinical trial for a standard drug in India is a relative bargain; about 60 percent less than the US$150 million price tag to do so in the United States.

This is not to say that there aren’t shortcomings to conducting clinical trials in India. For example, intellectual property protection in India has lagged. Be that as it may, the 2005 signing by India of the WTO’s Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement provided some relief. It’s important to note, however, that the TRIPS agreement excludes patentability for derivatives of known substances, unless it can be shown that the efficacy is significantly greater than the original substance. Some study sponsors remain concerned about the lack of guaranteed protection.

Others express misgivings about trial safety and ethics in India, which have come under close scrutiny since the 2006 deaths of 49 infants during clinical trials conducted at the governmentowned All-India Institute of Medical Sciences.

Logistics also require special attention in sprawling India, whose government has been struggling to improve its infrastructure by building more roads, generating more power, and overhauling congested ports and airports. Conditions mean logistics service providers have difficulty handling the volumes and diverse distribution networks pharmaceutical sponsors require. Surprisingly, the country’s IT infrastructure is still based on manual systems, so the risk of record-keeping errors is increased.

The steamy climate also increases the challenges to supply chain managers, particularly with regard to transporting and holding temperature-controlled materials in the cold chain. Some recommended practices for clinical trials in India:

• Consider an Asian clinical supply strategy. Packaging clinical trial materials in India off ers genuine speed and cost advantages. In 2007, Fisher opened a full packaging facility in Ahmadabad, located within a Special Economic Zone (SEZ) – an import-restriction-free areas that allows for free movement of goods. In essence, this means that clinical bulk drug can be received and packaged prior to completion of the study approval process, removing these activities from the critical path. Similarly, materials packaged in the SEZ can be exported to all other Asian countries with tax or export restrictions.

• Use current Good Manufacturing Practice-compliant facilities equipped with global inventory systems. Such facilities are capable of tracking material at motion and at rest.

• Employ best-in-breed IT. Move beyond phone/web support to incorporate next-generation technologies, including radio-frequency identification and global positioning system tracking devices.

• Meet labeling requirements. Labels must be written in English and are required to bear the drug name and strength, batch number, expiration date, protocol number, storage condition, and manufacturer’s address. They must also be clearly marked for clinical trial use only, and include cautions and directions for use based upon the protocol.

• Know the documentation rulebook. Know exactly what documents are required for import license applications and for imports, since customs delays in India are commonplace. In addition, it’s critical to be aware of site or location-specific requirements. State import requirements differ in West Bengal, for example. Since these requirements evolve over time, it’s wise to stay tuned in to changes.

POINTS FOR PLANNING

After years of laser-like focus on China and India, the number of clinical trials taking place in all of Asia continues to rise rapidly. Korea and the Philippines top the list of countries where trials are expected to increase most. In Japan, where recent regulatory changes significantly reduced barriers to clinical trials, such substantial growth prompted Fisher to open its newest facility in Tokyo Bay in early 2010.

The move into more challenging countries is certain to create complexity at all levels, including that of the clinical trial supply chain. Every country presents unique issues to decipher, understand and ultimately address. Here are some considerations to keep in mind when planning the next decade of trials in Asia:

• Address the issue of overages. How to reduce product overages is a hot topic in these fi nancially constrained times. Traditionally, trial materials have been packaged and labeled before being shipped to a specific country for use, but this reduces flexibility. At Fisher, supply chain managers are engaging the strategy of product postponement, or late-stage customization, as an alternative.

It works this way: materials are packaged as required across all Fisher facilities and can be shipped in small lots to individual countries and trial sites, as they are needed. This permits supply chain managers to be highly responsive to needs, lower overages and can reduce cycle time to as little as five weeks. To deploy these services requires strong supply chain management, accurate forecasting tools and rigorous monitoring so managers will know in real time exactly where drug is and how it is being used.

• Know the language, spoken and unspoken. Knowing the language and understanding what is being communicated are essential, as there can be a difference. In some countries, such as China and Japan, a high level of cultural courtesy makes it impolite to say no, so being able to read between the lines to understand the meaning of what is being conveyed is essential.

• Be there with a local presence. To properly manage clinical trial supply chain in Asia requires being on the ground. Nothing substitutes for a brickand- mortar local facility and a staff that speaks the language to manage the intricacies of customs clearances and stay on top of changing regulations.

• Keep in mind that all facilities are not created equal. A secure facility with high GMP standards removes the risk from the supply chain for study sponsors. Ideal facilities are those that are part of a global network capable of maintaining consistent standards of quality across all markets, developed and developing.

• Consider centralized distribution. Generally, a regionalized “hub” approach provides flexibility in shifting drug to support actual trial enrollment, rather than a more restrictive countryspecific approach. Some countries may benefi t from a local drug repository to avoid potential delays with regulatory approvals. Here again, all depots are not created equal; prior validation of depot capabilities is critical, particularly for those that handle temperature-controlled materials.

• Enlist the “eyes” of electronic visibility. Electronic inventory systems enable clinical supply chain managers to know at all times where inventory is, both in motion and at rest, reducing risk of stockout.

• Choose logistics providers based on actual performance. Ground handling is a highly vulnerable point in the supply chain, particularly with respect to temperature-controlled materials. Use real, rather than published, performance metrics to select the right logistics companies as a means of ensuring reliable, on-time delivery.

• Address clinical staff skill levels. At clinical sites, novice staff may be new to requirements for receiving and returning investigational drugs. Provide additional training, as necessary, to avoid problems down the road. Consider it an investment in the future.

• Finally, pay close attention to details. That’s where the devil lurks.

Sean Smith is Vice Presdent, Clinical Supply Chain, Fisher Clinical Services.

-----------------------------------------------

DELIVERING WITH CLINICAL EFFICIENCY

To ensure effective clinical trials, pharma companies need to understand and address the key logistics challenges.

by Sue Arden

As Asia’s attractiveness as a centre for conducting clinical trials (CT) grows, so do the challenges. For both pharmaceutical companies and Contract Research Organizations (CROs) keeping trials on track, on time and on budget is critical to their global competitiveness. Given that new drug development takes an estimated seven to 15 years, from conception to commercialization, and at an average cost of between US$100 million to US$1 billion, every element of a CT process is critical – and that includes logistics.

Research shows that the top 10 pharmaceutical manufacturers each spend approximately US$20 million on transportation per annum on their research or trial programs. And a growing percentage of the US$20 million is being spent in Asia.

Of the four phases of a CT study, patients in the field are typically most heavily involved in phases three and four. During these three to five years, CT materials need to be safely and cost eff ectively transported to and from patients for the entire study period. In order to obtain data for regulatory approval prior to commercialization, the visibility and transparency of the logistics chain is crucial to the success of the CT.

GLOBAL VISIBILITY

Despite improving local and regional infrastructure and a plethora of local and international logistic companies, CT and medical service solutions can still be fragmented, patchy and not costeffective.

The best way to address the logistic issues involved in a long-term CT project is through a solution that provides global, real time visibility across the whole supply chain, with a product code that allows standardized global processes, global invoicing, and trained and dedicated staff to coordinate activities worldwide.

To achieve this, innovative solutions have to be found in four key CT logistic problem areas: operational, technology, packaging solutions, and regional warehousing.

Customer service agents need to understand the language and importance of the CT business. This is to instill confidence and react to escalated issues appropriately when dealing with trial investigators and/or clinics. Product code identification is crucial because it encompasses all global service standards for operations, escalations, specific handling requirements, and billing criteria between all parties involved in the trial.

Global visibility at a trial level is important for the chain of custody and an important element when dealing with the regulatory authorities like US FDA, when filing trial data prior to commercialization. Logistics companies need to provide an unbroken chain and technology enables this.

SPECIALIST STORAGE

While catering to a chain of control and visibility, logistics companies must understand the specialist packaging requirements of handling biological products and the needs of CT project managers to be able to provide eff ective solutions and results. As handling and delivery experts, logistics companies understand how to optimally pack materials for transit to protect the contents.

Customized solutions can provide temperature controlled packaging in varied shapes and sizes with delivery to investigators before the trial starts. Coolant materials from gels to dry ice need to be assessed for optimum performance during transportation and storage from pick-up to delivery.

With the rapid growth of life-sciences across Asia, the supply of specialist warehousing and warehouse services for CT and healthcare products is lagging behind demand. As a result, logistics companies are filling the gaps, especially for the handling of temperature sensitive products requiring either controlled ambient or more stringent temperature monitoring.

Specialist logistics hubs or competency centers designed especially for CT and medical shipments are helping improve service, increase visibility and efficiency. They are designed to address the needs of the industry, providing pharmaceutical companies with a supply chain solution that offers warehouse management, transportation and a distribution services.

Flexibility of logistics services allow for customized and cost-effective solutions for priority and non-priority deliveries. Urgent samples are moved using an express network, while slower bulky shipments that are non-urgent items (such as standard trial folders) travel via airfreight or supply chain facilities to capitalize on both the inbound and outbound trial flows. And value added services like labeling and/or postponement that increase costefficiency are a draw for cost-conscious and informed CT project managers.

Sue Arden is vice president, Asia Pacific, life sciences & healthcare, Global Customer Solutions, DHL.