The benchmark activity detailed in this article demonstrates the degree of harmonization in the general performance and reporting of investigator site audits within the pharmaceutical industry. The vast majority of respondents surveyed confirmed that the audit teams operate to globally standardized processes. Most companies classify the audit findings in terms of severity and they categorize them with respect to impact on specific processes. All companies expect responses to critical and major findings. Seventy-five percent of the companies who responded conduct trend analyses, but their target audience and further utilization vary among the companies. The greatest variation occurred in the mechanism for ensuring that audit findings are considered in the overall process improvement cycle.  

In summary, this benchmarking exercise provides assurance that the pharmaceutical industry has made major steps toward a common approach to investigator site audits. This leads to the benefit of individual sites and studies and to the overall process of clinical development. 

In order to ascertain prevailing practices in the industry, a survey was conducted in the area of clinical quality assurance (CQA). CQA was defined as the corporate department or function with the main responsibility of assessing and supporting compliance of clinical development projects and systems with GCP standards. This specific survey was conducted in order to obtain benchmark data on the consistency of audit practices and the impact of audit findings originating from investigator site audits. 

A questionnaire was developed by a working group within the German Association of Research-Based Pharmaceutical Companies (VFA) Clinical Research/Quality Assurance Committee. This questionnaire was distributed in mid-February 2005 to 38 global companies in order to collect the benchmark data via the Internet. The creation and online submission of the survey and capture of feedback was simplified by the use of Zoomerang online survey products. Feedback was received from 29 companies (14 European, 10 American, four Japanese, and one Australian), which corresponds to an additional response rate of 81%. All responses were valid and used in the overall evaluation of the results. Global QA Heads of GCP or their delegates completed the questionnaire. The results represent a global perspective on general performance and reporting of investigator site audits. 

It should be noted that four of the companies originally contacted merged during the course of the survey. Out of the four companies, two provided a consolidated response and two did not. 

The following results are based on feedback received from the 29 companies. The survey collated information on the following areas: 					

distribution of draft and final audit reports

More than 80% of the companies have a globally standardized audit process in place—i.e., all auditors worldwide are working according to the same audit SOP, audit standard, checklist/worksheets, tools, etc. Global documents and tools in place within the companies are shown in Figure 1. 

 Global Documents/Tools Within Companies			

All participating companies, with the exception of one, assign audit findings to process related categories, such as "informed consent," "study protocol compliance," or "safety reporting." Most companies use similar categories for the critical processes that are subject to an audit (see Figure 2). All companies utilizing such categorizations use the categories "safety reporting" and "informed consent." Approximately 90% use the categories "IRB/IEC," "source documents," "drug supply handling," and "protocol compliance," and approximately 80% use the categories "essential documents," "study personnel and agreements," "monitoring," and "data accuracy/SDV." Each of the 14 categories provided in the survey is used by at least 66% of the companies. Additional categories not specifically listed in the questionnaire—such as "trial management," "training," and "computer validation"—are also used by some companies. 

Main Categories Used for Audit Findings			

Almost 80% of the companies evaluate the significance of each single audit finding and state this in the audit report. The most frequent classifications used are "critical," "major," and "minor." 

In addition, one fourth of the companies have a system or rule to evaluate the significance of each category, stating the overall evaluation of all findings related to each one (e.g., informed consent). 

About 50% of the companies classify the overall outcome of site audits. Half of them use predefined classifications, while the other half provide narratives. If predefined classifications are used, they are similar to those used for single audit findings. 

About 70% of the companies have a multistep reporting process implemented (e.g., draft/final reports); the other companies have a single-step reporting process in place. 

For approximately 85% of the companies, the audit report contains an executive summary, which is normally distributed as part of the full audit report. 

All companies, with the exception of one, apply QC measures to the audit report generation process—most after peer reviews, conducted by either an auditor colleague or line manager within QA. 

Around 90% of the companies make the draft and/or the final audit report available to the auditees. Two companies neither provide the draft nor the final report to the auditees. About 30% of the companies do not provide management with the draft report, but 97% do provide them with the final report. Only one company doesn't make the draft or the final audit report available to management. 

Approximately 50% of the companies send the audit report to other affected functions (e.g., regulatory affairs, regional organization members, training, purchasing, etc.), but from the available information, no pattern could be identified. 

The defined time frame between the conduct of the audit and the release of the report varies between 5 and 40 working days (median of 15 working days, mean of 16.6 working days). Thirty-four percent need to issue the report within two weeks, 59% within three weeks, and 76% within four weeks. Ten percent of the companies need to issue the audit report after more than five weeks. Two companies have no defined timeline for the availability of the audit report (see Figure 3). 

Two-thirds of the companies report critical findings in an expedited manner. Some companies stated that critical findings have to be reported to QA senior management and/or appropriate clinical management either immediately (i.e., during the audit conduct) or within up to 5 working days by phone, email, or meeting. 

About 60% of the companies report critical audit findings and/or corresponding corrective actions in their final clinical study report. 

Only 17% of the companies report critical audit findings and/or corresponding corrective actions directly to IRBs/IECs and agencies. 

Recommendations/requests for corrective actions. 

Two-thirds of the audit reports contain recommendations or requests for corrective actions for either critical findings or major findings. About half of the audit reports contain recommendations or requests for corrective actions for minor findings. Fourteen percent of the companies do not give recommendations or requests of this kind at all in their audit reports. 

All companies, except one, request responses to each of their audit reports. This company, though, expects responses in the case of critical or major findings as well. In terms of addressing individual findings, all companies expect critical and major findings to be individually addressed. Still, 83% of the companies expect a response to minor findings. 

In about 60% of the companies the study manager and the monitor are both responsible for replying to audit findings; in six of the companies, this responsibility lies with either one. Thus, in 80% of the companies at least one of these two individuals is responsible for replying. 

In half of the companies, line management is involved in providing responses: For eight companies, in addition to the monitor or the study manager, line management is responsible for replying. In six companies, only line management is responsible for addressing audit findings. 

Articles

Feature Article

CQA benchmark survey finds companies use a similar method to conduct and report audits.

Investigator Site Audit Performance

You've heard it before. We all have. Pharmaceutical industry productivity is down, while costs are up.  

We hear it from our mothers, grandmothers, and friends at social occasions: "Why can't drugs be cheaper," or "Why can't we cure diseases faster?" We all know the issues. The only key question is, what are you going to do about it? Yes, you. 

Whatever your role in clinical development, step back for a moment and ask yourself if it can be done better. The pressures that we face in the pharmaceutical industry are not that different than the pressures faced by the chemical, aerospace, and automotive industries over the last two decades. What can we learn from their experiences? And what can you do to make a difference? 

If you read the first chapter of Thomas L. Friedman's 

, you will recognize that anything that can be digitized or routinized can be outsourced. So, we need to rethink what the core competencies of pharmaceutical development are and how to radically improve them. 

That is what we are about at Wyeth, and why we have re-engineered Clinical R&D through our clinical breakthrough and Springboard initiatives, formed a joint venture with Accenture called the Alliance for Clinical Data Excellence (ACE), and launched an alliance with ReSearch Pharmaceutical Services (RPS) called MMAX (Maximizing Monitoring Availability and excellence). These changes are just the starting point. 

But Wyeth is not alone. Pfizer has launched an alliance with KForce for field monitoring. Quintiles has teamed up with Solvay and a number of biotech firms for joint development and risk-sharing in bringing new compounds to market. 

Nowadays, existing models are undergoing major scrutiny. For example, "Because that's the way we've always done it" is no longer an acceptable answer to process questions. And regulatory agencies have been embracing new ideas for conducting studies. In an industry that has largely focused on conformance to standards, we need new ways of thinking. 

Good Clinical Practice (GCP) does not mean that there is only one way to conduct a clinical study or enroll patients. GCP is a set of guidelines aimed at ensuring a level of quality consistent with existing regulatory guidelines. 

But are there better ways to perform our basic tasks? Are there new approaches to processes that we take for granted as the accepted way of doing things? 

What about at your firm? What about your role? Begin to ask yourself how you can make a difference, and embrace change. We all need to contribute to the future success of our industry and the time to begin is now. 

 vice president, clinical development operations, Wyeth Research, Collegeville, PA			

A Closing Thought

Rethinking the current pharmaceutical model

Improvement Through Change

Effective subject recruitment is the cornerstone of clinical research. Delays in patient recruitment cost pharmaceutical companies time and money. According to a recent report in Cutting Edge Information, clinical trials last 42% longer than expected in Phase I, 31% longer in Phase II, and 30% beyond planned deadlines in Phase III—all because of recruitment delays.

  Each day a drug is delayed from market, sponsors lose up to $8 million.

While it can be challenging to reach a general audience for clinical trials, it is much more difficult to target "special populations" and motivate them to participate. Special populations are defined as specific ethnic and demographic groups, such as women, seniors, children, African Americans, Native Americans, and Hispanics. 

As clinical trials become more complex and specific, protocols increasingly require recruitment of special populations. While these groups have been historically underrepresented in clinical research, their participation is critical to the success of many medical research studies and to the evaluation of marketed pharmaceutical and medical products. 

 Percentage of special populations without insurance			

Furthermore, it has been mandated that minorities be adequately represented in clinical research.

  The National Institutes of Health (NIH) Revitalization Act went into effect in 1993, requiring that NIH-sponsored clinical research include women and members of minorities and their subpopulations to determine whether the investigational product will affect them differently.

  Although this mandate does not apply to all clinical research, it does emphasize the importance of ensuring diversity in clinical research. 

Despite this mandate, special populations are still not being recruited into studies efficiently and effectively. According to Michael Kritschgau, director of late-phase feasibility and development at Radiant Research, a recent Medstat survey entitled "What Patient Recruitment Methods Work Best for Women and Minorities" found that: "Industry efforts to enroll minority volunteers in trials remain unsystematic and unsophisticated."

This article outlines specific strategies and important issues to consider when recruiting special populations. It will discuss the importance of recruiting special populations, the barriers to recruiting them, and some solutions for effectively recruiting these groups into research studies. 

There is a view that the industry has historically taken a "one-size-fits-all" approach to clinical research and drug development. For instance, children have traditionally been given smaller doses of medications that were approved for use by adults but never tested in children. Women have been treated with medications tested mainly, and sometimes exclusively, on men. There is now a realization that children might not be treated most effectively with an adult medication and that medication that works on a man may not work on a woman in the same way. As a result, "the current research climate encourages the active recruitment of groups that have often been neglected in research. Examples include the inclusion of women and ethnic minorities."

There are many factors that make patient recruitment of special populations particularly difficult, including distrust, ethics, cultural issues, the population pool, health insurance issues, and the role of caregivers. 

 Trust—or rather, a lack of it—is among the many issues that sites, sponsors, and patient recruitment partners must consider when undertaking recruitment campaigns for targeted populations. First, they must address the basic distrust for research expressed by these groups. 

Each ethnic and racial community brings a distinctly different history to clinical research. Researchers must be familiar with each group's experience with unethical research and find solutions that address distrust and fear to ensure optimal conditions that foster participation.

Among American Indian and Alaskan native peoples, there is a longstanding distrust of government rooted in a history of disease, coercion, broken contracts, and denial of basic rights. In the African-American population, there is the case of the Tuskegee syphilis study. Among Hispanics, women have often been the target of the most blatant unethical research and medical practices. These practices indicate a climate of unethical medical practices and the violation of the reproductive rights of poor women and women of diverse ethnic groups. As for Asians and Pacific Islanders, there is a history of U.S.-funded research conducted in the countries of origin, as well as the overall oppressive political conditions to which this population has been exposed.

  Given this history, it is no surprise that these groups may view clinical research somewhat skeptically. 

Recent research indicates that this cycle of distrust may be changing, but researchers are far from the point of declaring it a nonissue in the recruitment of special populations. The NIH recently released research findings indicating that minorities participate in health research studies at the same rate as Nonhispanic whites when they are made aware of the study and they meet medical requirements. This brings to the forefront the issue of making information accessible to all special populations. 

There is a natural conflict between the researcher's desire to recruit patients to fill a study and the right of subjects to not be coerced into participating in a study. Ethical practices must be in place to ensure that special populations, who have historically been at risk for abusive and exploitive practices, are protected.

  The issue of placebos must also be addressed and is especially important if a subject is required to discontinue his or her current medication to participate in a study. If the study is testing an investigational drug against a placebo and the patient is receiving a placebo, that person is not being treated for his or her condition. During the informed consent process, there must be full disclosure made to all subjects that they may be receiving a placebo. 

 Sites, sponsors, and patient recruitment partners must also consider cultural issues, often exacerbated by socio-economic disparities. Culturally sensitive communication vehicles in the subjects' language and vernacular must be used to foster a rapport. Also, it is critical to determine which communication vehicles and which communications media will reach a particular target audience most effectively. 

Researchers need to be aware that recruitment materials that are effective with one ethnic group might not be successful for recruiting subjects from another culture or demographic. Translation is an issue. It is important to preserve the original meaning of the study materials, so the translator must have a clear understanding of the study. 

 Another important factor to address is population breakdown. Because special populations represent a smaller population pool nationwide than the general population, there are fewer individuals from these groups available for studies. The total population of the United States is 281,421,906 according to U.S. Census statistics.

  African Americans comprise 13% of the U.S. population, senior citizens comprise 12% of the U.S. population, and women ages 25 to 44 comprise 14%. Sponsors must consider the availability of any special population when formulating patient recruitment goals for a protocol. 

 Special populations tend to be more medically vulnerable than the general population. The percentage of individuals in all special populations that have health insurance is lower than in the general population. For instance, in 2000 only 19% of African Americans had health insurance. Since many protocols require patients to have used certain medications or at least be diagnosed with a particular indication, many individuals will not participate because they may be unaware of their condition or may not have had the opportunity to use a certain medication. In addition, if due to lack of insurance a potential participant does not see a physician regularly, the opportunity to learn about a study from a medical professional is considerably limited. 

On the positive side for sites and sponsors, the inexpensive and sometimes free medical care that patients receive during clinical research may draw these special populations to the study as an option for affordable, accessible health care. Subjects that are seen by an Investigator have the potential to be treated for their condition. Subjects may also receive medical exams that can diagnose and detect other medical issues. They can then be referred to other physicians and specialists for follow up. This is one way for the underinsured to possibly obtain medical care for a condition that would otherwise have gone undetected. 

It is important to keep in mind that with many special populations, the target audience for the recruitment message might not be the actual patient. In fact, the likely target is the patient's caregiver. 

An adult caregiver for a senior citizen, usually a relative, is most likely to make the decision to place the senior in a medical research study. Families can be very hesitant to have their elderly relatives participate in clinical research because they do not want to put their loved ones through procedures or experimental treatments that may not work. Another key factor to consider is that many seniors are dependent on others for assistance, since more than 50% report having at least one disability that limits their daily activities. This may make it too difficult to participate without the assistance of others. They are also often hesitant to report their illnesses and frequently under-report their symptoms. 

Parents may be reluctant to allow their young children to participate in clinical trials, especially if the condition is not life-threatening or if other viable treatment options are available. Recruitment is even more challenging if it is for a double-blind study where some subjects will receive a placebo, or if the research involves a painful procedure. Parents want to make sure that their children are receiving effective treatment. Furthermore, they don't want to expose them to the pain of something like a blood draw if the procedure does not clearly benefit their child's health. 

On the other hand, parents are very willing to have their children participate in clinical trials for life-threatening conditions like cancer, when nonstudy treatment options are limited. A study conducted at the Walter Reed Army Institute of Research in conjunction with the National Cancer Institute (NCI) found that pediatric patients were recruited into clinical trials at high levels; whereas after adolescence, only a small percentage of cancer patients were enrolled in clinical trials. This suggests an aggressive stance by parents to find lifesaving treatments for their children. In fact, more than half of all children attracted to NCI-sponsored trials are between the ages of 5 and 9, compared with less than 1% of adults ages 75 to 79. The highest percentage of adult patients accrued are between the ages of 40 and 55.

And, in some populations, while the patient ultimately makes the medical decisions, family members may be quite influential and should be considered when targeting these groups. Within the African-American population, for instance, 47% of families are headed by a female, who is likely to be making medical decisions for the entire family. 

Given these challenges, there are certain steps that sites, sponsors, and patient recruitment partners can take to effectively recruit these groups for clinical research. Assessing population and demographic information is critical. 

 It is important to note that study sponsors, including major pharmaceutical and biotechnology companies, are providing the funding for the majority of clinical research studies. These sponsors are deciding who the patient population is and what the inclusion/exclusion criteria will be. Thus, it is essential for sites, sponsors, and patient recruitment partners to know the audience they are recruiting. It is critical to understand their motivations, influences, and media habits to reach them in the most efficient and effective manner. 

Informed consent can be particularly difficult with special populations. For one thing, language barriers must be overcome. Although informed consent requirements vary across the country—and in some cases consent may not even be required—potential subjects should be given an official form written in their own language. 

Another issue is that immigrants may not understand the basic human rights afforded to them in the United States. They may feel coerced into participating because they fear retaliation if they do not. Social status is another factor. Some members of special populations, such as Asians and Pacific Islanders, sign a consent form simply because the person who asked them to sign it is influential. As a result, they may not understand the risks of the study.

Informed consent is the primary mechanism of protecting subjects against unethical treatment. The NIH, IRBs, and investigators must work together to tailor the consent process so that it will be effective for all special populations. This means avoiding any appearance of inducement to participate in clinical research, monetary or otherwise.

Sponsors can integrate tools into the recruitment process to increase the autonomy of subjects. Recruitment materials should include effective educational components that explain clinical trials and the medical research process in a simple, easy to understand manner. Informational Web sites that share valuable information about a particular condition and effectively outline study specifics can play an important role in informing subjects about the trial. 

In addition, the purpose of IRBs is to protect medical research participants and to look out for the patient's best interests. IRB contact information is distributed to all subjects at the outset of the study so participants have an outlet to go to if there are concerns or questions. 

Implementing these measures ensures that all subjects are fully informed about their participation in the trial process. 

Market research and media consumption patterns.

 The proper medium must be selected to reach the target audience, whether it is the patient, family, caregiver, or parent. It is imperative to know which medium influences the target audience (see sidebar). 

 Market research and media consumption patterns are then used to develop the right message, visuals, and tools to reach the target audience. For example, for an African-American audience, the message and visuals need to connect with a strong image of family and community. Also, because research shows that in general, African Americans are not heavy newspaper readers, a television or radio advertisement or news segment may be more effective than a newspaper advertisement in informing them about the clinical research study. 

 The recruitment industry must also take geography into account when focusing on special populations. If there is the opportunity to choose markets, it is crucial to select markets where individuals in the target population largely reside (see sidebar). While it may seem as if the differences in population size are insignificant, remember that the overall size of these groups is smaller compared to the size sought in a general recruitment campaign. Choosing geographic regions with more potential participants is therefore in the best interest of the study. 

The following case study illustrates how population and demographic information can be effectively used to recruit special populations. 

A clinical research study to test the safety and effectiveness of a dual cardio drug in African Americans was implemented by a major pharmaceutical company. The purpose of this dual cardio drug was to treat high blood pressure and high cholesterol with one pill. The six-month study took place in 100 sites across the United States. The goal was to randomize 500 African-American subjects aged 18 to 80 years. The purpose of the study was to test the investigational medication in African Americans for effectiveness. 

The American Heart Association reports that African Americans are at greater risk for cardiovascular disease and stroke-related death than Caucasians. For African Americans age 20 and older, 36.7% of men and 36.6% of women have high blood pressure. Among African Americans, 45% of men and 46% of women have total blood cholesterol levels over 200 mg/dl.

  Research has confirmed that, although the prevalence of the conditions is high in this population compared to other groups, the use of prescription drugs to treat the indications has traditionally been below average.  

Through syndicated research, individuals taking high blood pressure medication, cholesterol medication, or a combination of both were targeted for the study and an age profile was analyzed. It was determined that individuals taking separate medications for both conditions would be most likely to take a dual cardio drug for convenience sake. Since many individuals in the target do not take medication, the media consumption patterns of the target age range of 30 to 64 years was also researched in an effort to reach potential study participants that were not captured through the research on medication. Although African Americans in general are light readers of newspapers, these particular audiences are heavy readers of African-American publications. 

The strategy was to develop messages that would communicate the high incidence of the disease in African Americans by appealing to the family as well as the patient. The text was written to provide a sense of comfort, familiarity, and trust in the research and the FDA-approved study medication. Also developed were materials that explained what clinical research studies are and answered frequently asked questions. Astute planning also ensured that the sites were located in communities with high African-American populations. 

Common barriers to enrollment can be overcome by using targeted recruitment strategies.

Recruiting Special Patient Populations

There are three key clinical development regions in Asia, namely India, China, and South East Asia. Each of these regions offers similar attractions and poses similar questions with respect to the placement of global clinical trials.  

The similarities between the regions are the attractions of rapid patient recruitment driven by large patient populations with diseases of both the developed and developing world and fewer competitor trials as compared to North America and Europe. In addition, there could be a substantial potential for cost savings as well as the opportunity to penetrate some of the fastest growing pharmaceutical markets in the world.  

Photography: Comstock Illustration: Paul A. Belci			

Although regulatory approval timelines are longer in Asia as compared to North America, they are the most prolonged and uncertain in China. In Singapore and Korea, regulatory processes are the most streamlined, quick, and predictable.  

Regulatory approval in China for clinical trial initiation may take up to nine months as the approvals dossier navigates its path through six regulatory approval bodies, as shown in Table 1. The potential for delay at any one of these bodies contributes to the unpredictability of the process. Factoring in this lengthy regulatory approval process is essential while planning clinical trials in China. A thorough understanding of the local regulatory requirements is necessary to ensure that the dossiers are correctly assembled to keep delays to a minimum.  			

Korea is positioned at the other end of the spectrum, with its regulatory processes streamlined such that the Korea Food and Drug Administration (KFDA) is able to deliver approval for a clinical trial application within 30 working days. Furthermore, the Institutional Review Board (IRB) approval process occurs in parallel.  

In Singapore, the average regulatory approval period is four weeks followed by an additional four to six weeks for site-level IRB/ethics committee (EC) approval. In Hong Kong and Taiwan, parallel processing of regulatory and IRB/EC approval is possible and takes on an average eight and ten weeks, respectively, to obtain both approvals. This is followed by a further two week wait to obtain the license to import clinical trial supplies. 

Table 1. Six regulatory bodies in China must examine a clinical trial prior to granting approval. 

Over the past two years, the regulatory approvals process in India has become progressively more streamlined, with median approval times reduced  from 16 to 10 weeks. Approval from local ECs at the site level is processed in parallel. If biological clinical trial samples need to be exported, then additional approval from the Directorate General of Foreign Trade is required, a process that takes four to ten weeks. Because the Drugs Controller General of India (DCGI), driven by the increased volume of international clinical trial applications, has become more experienced and better resourced, the uncertainty regarding regulatory approval times has substantially diminished. This phenomenon will be notable in numerous emerging countries as their nascent clinical development environments become more mature with time.  

Evolving intellectual property protection legislation 

The local pharmaceutical industry in Asia has historically been dominated by generic pharmaceutical companies. Not surprisingly, therefore, innovative pharmaceutical sponsors have concerns about the protection of their intellectual property (IP) in these countries. However, IP protection legislation in Asia is evolving as a result of international pressure as well as domestic economic development.  

India represents a good example of an Asian country that is embracing international IP protection legislation, with important consequences to both its local industry as well as its positioning in the global pharmaceutical industry. Historically, the Indian Patents Act (1970) that replaced British colonial laws related to intellectual property rights did not recognize pharmaceutical product patents. Instead, the manufacturing process patents were recognized for a seven-year period. Not surprisingly, this legislation enabled the growth of a domestic generic pharmaceutical industry. Winds of change were heralded when India agreed to uphold the WTO Trade-Related Intellectual Property Rights (TRIPS) agreement finalized during the Uruguay round of multilateral trade negotiations in 1995. As a signatory to the TRIPS Agreement, India is committed to recognize and enforce product patents in all fields of technology including pharmaceuticals. The Indian Government, DCGI, and the Indian pharmaceutical industry appear committed to fostering a life science innovation-based industry with the realization that robust IP protection is a prerequisite. Furthermore, India's growing software and entertainment companies continue to lobby for robust IP protection legislation capable of protecting the IP that they are generating. Legislation for the enforcement of IP protection was passed by the Indian Parliament in January 2005 in spite of protests from patient consumer groups—evidence that India's legal system has responded to both the external and internal drivers of change. 

China has also declared a commitment to comply with TRIPS and has amended several IP related laws including the 1993 Patent Law in 2001, Implementing Rules in 2002, and more recently the copyright law. In addition, the enforcement of IP Rights has been strengthened such that there are stiff penalties for patent, trademark or copyright infringement; options to utilize preliminary injunctions; and criminal liability for trademark infringement. The drivers for these legislative changes are the recognition that strong intellectual property protection is necessary to attract foreign investment, protect indigenous IP, and facilitate alliances with international technology leaders.  

Singapore has been ranked as the top Asian country for strong IP protection and legal enforcement by the World Economic Forum (WEF), the Institute for Management Development (IMD), and the Political Economic Risk Consultancy (PERC) three years in a row, from 2002 to 2004. This has contributed to the fact that in addition to clinical development, Western companies have established successful drug discovery alliances with both academic and commercial organizations in Singapore. 

Looking ahead, the expectation for Asia is that both India and China will ultimately evolve their IP protection legislation and enforcement systems to the same standard as South East Asian countries. Meanwhile, however, sponsors remain wary about the protection of their IP in these countries and exercise cautions with respect to the nature of research activities they outsource or offshore.  

China represents one of the fastest growing pharmaceutical markets in the world and is the most lucrative market in Asia. Today, China is the 7th largest pharmaceutical market in the world in revenue terms, valued at approximately 14 billion USD in 2005. In the next five years, this market is expected to grow by another 10 billion USD. The driver for this rapid growth is a population of 1.33 billion that is expected to substantially increase its consumption of Western pharmaceutical products. China has 160 million people over the age of 60, which is expected to increase to 280 million by 2025. The per capita drug expenditure in China is 12 USD, which equals only 2% of that in the United States. Urbanization and increasing affluence is expected to result in an exponential growth from this modest baseline. Furthermore, large-scale conversion from the exclusive use of Traditional Chinese Medicine would augment the sale of pharmaceuticals based on Western medicine. Hence, not surprisingly, most large pharmaceutical companies have a major presence in China and are seeking to continually augment their sales efforts.  

It is worth noting that the widespread concomitant use of Traditional Chinese Medicines with Western pharmaceutical  products represents a challenge with respect to clinical trial design and interpretation of trial data, as the effect, if any, of drug interaction remains to be delineated.  

The commercial value of the Indian market is presently miniscule in value, but is large in volume and growth potential. In volume terms, it is the world's fourth largest market in unit sales, but ranks 13th in value terms with an annual revenue of approximately 5 billion USD. It remains a highly fragmented market, with Indian companies enjoying 70% of the total market share and the leading player having only a 7% market share. The biotechnology market is worth about 1 billion USD and is enjoying high growth driven by exports and domestic vaccine sales. The present per capita pharmaceutical expenditure is only 4.50 USD, providing a modest base for future growth. India's middle income group is comprised of 300 million, which is increasing both in number and affluence, and represents an attractive market. This is especially true with the relaxation of price controls that is expected to result from changes in the domestic generic industry.  

Korea represents another high growth Asian market—the Korean pharmaceutical market is estimated to be worth 5.6 billion USD and has grown on average 8% annually for the past five years, outpacing the growth in the global market. The Korean pharma market has continued to experience restructuring since 1999, when the Korean Government implemented initiatives to improve the cost effectiveness of health care. The implemented initiatives that have had a significant impact on the pharmaceutical market are: Separation of Prescribing and Dispensing (SPD), Actual Transaction Pricing (ATP), and the A-7 policy of pricing innovative drugs at international prices. These initiatives have improved transparency in the reimbursement system and have facilitated the positioning of multinational pharmaceutical companies' innovative drugs in the domestic marketplace. There have also been positive changes in the regulatory climate that have allowed smoother and earlier market access for new, innovative drugs. This, however, is counter balanced by the drive to fix lower drug prices and promote the use of generics by the financially constrained Korean health care and insurance system.  

Clinical trial data from all Asian countries has now been accepted by international regulatory authorities for pivotal studies. An FDA audit of clinical sites within a country is triggered by the presentation of a certain amount of data to the authority from that country and clinical site. Thus, the occurrence of the first FDA audit serves as an indicator of the extent of global clinical trial activity in a country. The FDA has audited the National Cheng Kung University Hospital and Tri-Service General Hospital in Taipei and the Queen Mary Hospital in Hong Kong with no significant finding. The first FDA audit did not take place in India until mid-2005 when two sites in Southern India participating in a global infectious disease trial were audited by FDA inspectors with no findings. China is yet to receive its first U.S. FDA audit. 

Generally, sponsors have been satisfied with the quality of clinical data provided by clinical trial sites in Asia in spite of the relatively nascent clinical development environments. An important reason for this is the availability of numerous hospitals well suited to serve as investigative sites. The vast majority of specialty care in Asia is provided by state-funded general hospitals. The university teaching hospitals have state-of-the-art facilities and technologies with thousands of inpatient beds to provide diagnostic, therapeutic, and support services in all major therapeutic areas. It is at sites like these that the majority of clinical research in Asia is conducted. There are over 17, 10, and 6 such hospitals in Taiwan, Malaysia, and Singapore, respectively.  

Veteran's General Hospital in Taipei, Taiwan, is a multidisciplinary specialist center with 440 attending specialists, over 500 resident doctors, and 300 beds. In 2005, 2.5 million patients attended the outpatient clinics and 1 million received inpatient care. Various specialists at this hospital have served as clinical trial investigators, and in order to facilitate this activity the hospital has its own ethics committee. The National Taiwan University Hospital is Taiwan's premier teaching hospital and leading medical center. Since its establishment in 1897, the institution has trained more than 10,000 physicians. Presently, 840 students are enrolled in medical and other related programs. The 4000 staff serve approximately 2000 inpatients and 7000 outpatients daily.  

Queen Mary Hospital (QMH) is the teaching hospital of the medical school of The University of Hong Kong, with about 1400 beds. This center provides acute and specialist services to a population of about 1.5 million on Hong Kong Island. Not dissimilar is Singapore's National University Hospital—a 930-bed acute and specialist hospital. 

Tata Memorial Hospital in Mumbai, India, is an example of a specialty oncology center that is very well suited to participate in global clinical development. Each year, 25,000 cancer patients visit this hospital, not only from India but also from neighboring countries. Each day, 1000 patients attend out-patient clinics and there are 441 inpatient beds. Over 10,000 major operations are performed at Tata Memorial Hospital, and about 5000 radiotherapy and chemotherapy treatments are delivered each year. The center is equipped with state-of-the-art facilities, including spiral CT scanner, gamma cameras, linear accelerator, and bone marrow transplant facilities. In order to coordinate the ever increasing interest from international and domestic sponsors, a Clinical Research Secretariat, Scientific Review Committee, and Ethics Committee have been established.  

China, too, has numerous hospitals with the potential to participate in global clinical trials. Renji Hospital and its extension in Pudong Shanghai is a teaching hospital with a campus space of over 56,067 square meters, 1000 patient beds, and 2300 staff—among them 221 senior doctors. Ruijin Hospital is another general teaching hospital in Shanghai with 1385 patient beds and 3242 staff, including 367 senior doctors. Numerous clinical trials are being presently conducted at Peking Union Medical College Hospital, which is upgrading some of its facilities to be better able to serve the needs of international sponsors seeking to execute their clinical trials in China. This institution was founded by the Rockefeller Foundation and is one of the six hospitals included within the prestigious Chinese Academy of Medical Sciences, China's premier nation-wide medical science research institution. 

Availability of these types of world-class investigational sites in Asia enables rapid patient recruitment. Furthermore, there are numerous well-trained and motivated investigators supported by their clinical research teams comprised of resident physicians and nurses. It is these factors that enable the provision of high-quality and timely clinical data from Asia. 

Clinical trial execution is a labor-intensive and process-driven activity, hence access to suitable resources remains an important prerequisite. English-speaking, motivated work forces are well suited to meet the needs of the clinical development sector. Most of the region's leading specialists have received postgraduate medical training in the United States or United Kingdom. Although the level of experience is variable in the labor market (see Table 2 for a comparison of experience level and other key  factors), there are numerous training initiatives arranged by state and private organizations that attempt to teach candidates with a biomedical background the principles of GCP-compliant clinical research.  

Table 2. Key regions in Asia and the differentiating factors to consider when running a clinical trial. 			

Retaining trained resources, however, is becoming a serious challenge in India—a reflection of the growing clinical development sector that is providing many opportunities for trained clinical research personnel. 

Cost savings from including Asia in global clinical trials could be substantial, resulting from a combination of the following factors. Investigator and site fees are approximately one-half of those in the United States. Further costs to the sponsor for providing trial-related medication, investigations, and hospitalization could be as low as 30% of those in America. Domestic travel costs for monitoring sites are lower because of the concentration of sites in the major cities and comparatively less costly fares and tariffs. Support services such as printing, translation, and local courier fees are also less expensive. Although the cost of labor is less, it is mandatory to make investments in training and support systems to ensure data quality.   

It would be remiss not to highlight the compelling case for conducting data management in India for global studies, i.e., not only studies conducted in India. Access to a large resource pool with IT and business process skills in a low-cost labor environment provide the basis for cost-effective data management services. Furthermore, excellent English language skills, large numbers of IT-literate biomedical graduates, and a motivated and flexible work ethic contribute to the attractiveness of this proposition. Prevalent high-speed Internet connectivity and absence of the biases stemming from the use of legacy systems make countries like India ideally positioned for the widespread adoption of EDC technologies.  

In order to leverage the opportunities in Asia for timely, quality, and cost-effective clinical development in a risk-controlled fashion, sponsors must have access to the following capabilities: knowledge of local regulatory processes, relationships with local physicians and medical centers, understanding of the requirements of international regulatory authorities, and application of international standards to the local clinical research environments. Then, sponsors would be able to select countries in Asia best suited to meet their clinical development objectives with minimal risks. Sponsors who lack the above capabilities can access them with the assistance of contract research organizations (CROs). Many of the world's leading global CROs have developed operations in Asia to meet this need. 

, MD, PhD, MBA, is vice president business development international with PRA International, Pacific House, Imperial Way, Worton Grange, Reading, Berkshire RG2 OTD, United Kingdom, +44 118 918 1025, fax +44 118 918 1001, email: 

Rapid recruitment, potential cost savings, and investigative sites are just a few of the factors attracting sponsors to the region.

Conducting Clinical Trials in Asia

Conducting clinical research rapidly and cost effectively is the dream of every biopharmaceutical company. But there's more to it than just ensuring activities are completed in a timely manner and without additional expense, or even that a drug spends the maximum time on the market once it is approved. Biopharmaceutical companies want to make sure that their treatments are safe and efficacious, and that risks to the intended patient population are kept to a minimum. An essential ingredient for improving the clinical trials process is an information management approach based on industry standards. 

Standards support industry best practices 

Currently, many clinical development programs are plagued by data quality problems, duplicate data entry, and excessive transformations from one format to another that steal time and introduce errors. Interest in using industry standards for the collection, organization, and submission of clinical trials data is certainly growing, but is not yet ubiquitous. Based upon work in other industries, Gartner reported that automating processes and using data interchange standards can produce significant benefits in process efficiencies and could save the biopharma industry between $5.8 and $6.6 billion dollars per annum (this number was calculated using the industry's 2004 spending on R&D and Gartner's average of the percent of R&D costs attributable to clinical trials).

Nonetheless, a robust and defendable business case is required so that biopharmas can make decisions on the optimal process stage and implement data interchange standards in the context of clinical development.   

With that goal in mind, CDISC, working with the support of Pharmaceutical Research and Manufacturers of America (PhRMA) and Gartner, undertook a research project to: 					

collect information on current environments and processes that influence standards implementation and adoption

identify benefits that may not immediately translate into cost savings

assess the impact of implementation on the development process.

Through a series of interviews with biopharmaceutical company representatives and service providers, a baseline of information for current processes, personnel, time, and cost required to conduct clinical trials and other processes within the clinical development continuum was collected. Following the interviews, an online survey was conducted to capture additional metrics. In this article, we present an initial high-level summary of the findings thus far. The complete results will be reported in future communications.    

The interviewees were familiar with the CDISC standards and how they enhance the end-to-end data flow across the clinical research process (Figure 1). By utilizing the CDISC Operational Data Model (ODM) as a transport standard, data about the protocol and study data collected on subjects can flow seamlessly through the entire clinical trial process—from source to analysis/reporting to regulatory submission and electronic data archive. The data content and metadata are structured using the Study Data Tabulation Model (SDTM), which can be transported via the ODM.  

 Figure 1. End-to-end data flow across the entire clinical research process.			

Common issues expressed as problems in a process without standards relate to the disruption in the data flow shown in Figure 1. Many sponsors expressed the belief that standards could provide a significant improvement in their clinical development process. They pointed to a reduction in the time required to: 					

create case report forms and the database

lock the database after last subject visit

program a table or develop an SAS program 

Many sponsors indicated that standards also offer some difficult to quantify benefits, such as the ability to: 					

devote more time to the science behind the trial, not just the data

enable better communication among the various teams involved in the clinical trials process, including as data management, clinical operations, and statistics 

reconcile and report on adverse events across a series of clinical trials

eliminate data transformations and rework

cull out unnecessary work and improve trial design

ensure consistency from one step in the process to another

minimize redundant data sets and data flows 

reduce the chances of errors and inconsistencies

permit the population of a data warehouse across trials/programs.

Contract research organizations (CROs) spoke of similar issues, as well as the problem of dealing with multiple sponsors who all have their own ways of doing things. They cited problems such as: 					

multiple formats for case report forms and databases

multiple vocabularies that must be reconciled

CROs thought that standards would help them alleviate many of these problems. They cite significant decreases in set-up time for trials if they can use standards from case report form design through the reporting stage of the trials. 

What's next for business case development?

The next steps in the business case project are to review in depth the information gleaned during the interviews and combine it with the information gathered through the online survey. Typical scenarios can then be developed so biopharmas can select a standards implementation path that will best meet their situation. The best practices will also be detailed. 

One of the challenges mentioned by many of the biopharmas during the interviews was the concern that the standards were not stable or that they would change frequently, thus requiring constant upgrades. 

To address this concern, CDISC is committed to maintaining the production standards and to making any enhanced versions backwardly compatible. They are also documenting how the standards work together. The technical roadmap for CDISC includes the development of one common, harmonized standard that will ensure ease and consistency across the full life-cycle of a clinical trial. Hence, efforts are underway to align the various CDISC models throughout the data flow process. This year, CDISC reorganized from seven standards-development teams into three focus areas:  

				   1) maintaining the production standards; 			

				2) providing implementation support and services; and 			

A single, industry-wide standard could streamline the clinical trial information management process.

CDISC Standards: Enabling Reuse Without Rework

In 10 years, our view of software may be very different than what it is today. Much of the software we use now, whether desktop tools or enterprise applications, will probably not reside on our desktop computers. It will no longer be delivered in shrink-wrapped boxes or on CD-ROMs. Rather, the functions that software provides today will be delivered tomorrow as a service over the Internet that will take away the expense and frustration of configuring, installing, maintaining, and decommissioning. The user will log on to the software through a Web browser and use it as needed with "zero footprint" on the desktop. This concept is known in business circles as SaaS (Software as a Service). The change is well underway with some consumer and enterprise applications, but will soon be a major force in a wide variety of software deployments. An illustrative example will help to clarify, and I will fall back on an old favorite: the spam filter. 

For more than five years, spam email has been the scourge of every corporation. Many companies have repeatedly installed spam programs to deal with the ever increasing onslaught. These software packages were identified, installed, maintained, and replaced by the corporate IT department at considerable cost, with varying degrees of success. With many conflicting business priorities, the spam filter life cycle isn't always on the top of the list in IT departments. Recently, the emergence of a SaaS application, Postini (http://

), has brought a new model to spam filtering. Postini provides the service of spam filtering to thousands of companies through a simple method. 

Before Postini, email intended for "Company A" would be routed to a corporate mail server, where it would pass through whatever spam-filtering software was being used and then be released to individual users. After Postini services are deployed, all of Company A's email is first routed to Postini, where it is processed through a variety of state-of-the-art spam-filtering software—both standard and proprietary—that is carefully tuned for optimal performance and run on single purpose servers. Once filtered for spam, the email is forwarded to the company email server, where it can be routed, unimpeded, to the individual employee. 

The company's IT department can configure the software through a Web browser interface, and each employee can fine tune the filtering rules. Nobody in the company, however, ever has to worry about supporting the infrastructure needed to run a spam filter—from the redundant power supply and backups, to the server and software. For a very reasonable monthly cost per user, the company can get best-of-breed spam filtering with none of the hassles. 

Postini is a very successful example of a Saas company, but it is far from unique. In fact, one version of SaaS has been around for seven or eight years under the descriptive name: Application Service Providers (ASPs). Many of the older ASPs were offering conventional client-server software that were made available through the use of Citrix or "bolted on" Web front ends. More recently, SaaS software is predominately modern software, designed to be specifically used through a browser. 

SaaS is a broad term that encompasses many types of software and service models. At one end of the spectrum are SaaS vendors that will host any standard, off-the-shelf software for a customer. This type of SaaS typically involves the outsourcing of hosting and support functions for software that has been licensed by the customer. In contrast, "Web-native" applications are typically built by software vendors specifically for deployment on the Web. These companies will often host and support the software themselves, acting as both software developers and service providers. A good example of this type of company is 

, which offers sales force automation to small and large companies alike. 

SaaS has the potential to bring value in the three key areas of interest to most businesses: cost, quality, and time savings. In a larger company that deploys licensed software under a traditional model, the significant fixed costs for acquiring and managing IT infrastructure and routine technical tasks can be amortized over many different software applications. With a SaaS model, many customers effectively share these costs, which can provide substantial savings—especially for small companies. Similarly, the cost of licensing expensive software applications can be shared over many users in enterprise deployments for large companies. Small companies and divisions of larger companies may not be able to justify the cost of purchasing expensive software for a small number of users, but could benefit from limited use through SaaS provided in an "on-demand" fashion. 

The quality of software installation, maintenance, and support is important in most critical business processes, and it can fall short in companies whose primary focus isn't software deployment. SaaS vendors have the benefit of developing best practices from many different sources and can incorporate them into their businesses. They can focus on fine tuning the installation and configuration of the software, and take the responsibility for maintenance and upgrades out of the hands of the customer. Finally, in theory, the SaaS vendor is fully aligned with their customer. They aren't making a perpetual software sale; rather, they are continuing to demonstrate their value to the customer over time with services. If they don't, it is at their peril—in a Saas model, the cost of switching applications and vendors is much lower than with traditional licensing. 

In addition to the low cost of switching, the time required between selecting an application and implementing it can be dramatically shortened. For example, Postini can be up and running for an entire corporation within days. This flexibility is ideal for growing businesses whose needs may change from year to year. Additionally, no customer is "stuck" with a buying decision forever. They can monitor the vendor landscape and change, when required, to a SaaS vendor who offers significantly better software and/or service for their needs. 

When considering SaaS for a business need, there are several key questions to consider. The first consideration is the suitability of the software being offered by the SaaS vendor for the task at hand. This is especially a consideration for some Web-native applications. For example, Google and others are taking a run at Microsoft Office with gmail as a substitute for Outlook initially, and soon a Web-based word processor as a substitute for Word known as Writely. While these applications may function perfectly well for individuals, they don't yet have the robust functionality that major corporations and other institutions require. Furthermore, they are designed as one size fits all, rather than the flexible and customizable Office applications we have become accustomed to. Of course, the functionality gap between desktop applications and Web-based applications may shrink as technology options and Internet bandwidth continue to improve. 

Another issue to consider is the security of external data. With SaaS applications, mission-critical data may be collected and housed on a server in a facility that can't be seen or inspected. Enterprise customers are very unlikely to trust their data to a company without a complete understanding of their facilities, operating procedures, disaster recovery plans, and financial stability. However, individuals who purchase SaaS applications are more susceptible, as they can place their important data onto servers from companies that could go out of business, aren't committed to timely backups or don't adequately protect themselves from the newest virus attack. 

SaaS applications can be deployed as "single-tenant" applications or "multitenant." In a typical single-tenant application, each customer would have their own server(s), where their application and data would reside. While more expensive, this configuration reduces the risk of exposing data to others and eliminates the possibility that a configuration or data issue from another user would interfere with their own use of the software. In a multitenant deployment, many or all users of the application would be working on the same server(s) and using the same application. This would reduce the costs of hardware and support in deploying the application, but it does require attention to security and application availability issues. In enterprise deployments, SaaS vendors typically have designed the applications and have the motivation to ensure that each customer's data is secure and available only to the intended users. 

The decision of an individual user to choose a SaaS application is often related to convenience and availability. The cost is usually low, and the risk is similarly minimal. A company, whether large or small, needs to do a very different assessment of SaaS. They should consider their needs in relation to the total cost of ownership (TCO) of the software. In many instances, the TCO may be very high for licensing, installing, maintaining, and supporting software when all costs are carefully considered. The use of SaaS applications is often a cost-effective alternative. However, as a company's needs grow over time, some companies may find that it becomes cost effective to bring the software in-house and manage the application internally. With many SaaS applications, especially multitenant applications, this option may not be available from the vendor. Therefore, companies should carefully consider whether in-house deployment of software is a consideration in the future. If it is, they should choose software and software vendors that can support both options. 

While SaaS is only a small portion of the software market today, it will undoubtedly grow rapidly over time. In fact, the SaaS model is particularly prevalent in clinical trials electronic data capture applications, where some major vendors and third-party suppliers offer a SaaS-like model. As with many things in life, what seems unique today may well be the standard tomorrow.  

 MD, PhD, is the founder and chairman of Phase Forward, 880 Winter Street,Waltham, MA 02451, (888) 703-1122, 

Technology Viewpoint

Software as a service might be the future of computing, but it won't reside on desktops.

Solutions Delivered, Not Installed

Legislation was recently enacted to ensure that new medications and biological products contain adequate pediatric information in the package insert. This resulted in the need for increased pediatric subject enrollment in medication and biological clinical studies. However, concerns were raised about the ability to enroll pediatric patients in sufficient numbers and the willingness of parents to enroll their children in research studies for agents that were available off-label. This specific concern was raised during a retrospective review of 15 months of screening data from U.S. investigative sites in the RESOLVE trial (Randomized Placebo Controlled Study of the Efficacy and Safety of Drotrecogin Alfa [activated] in Pediatric Severe Sepsis]. 

As a result of these findings, the RESOLVE study team identified the need for discussion on the informed consent process. The trial's sponsor approached an investigative team that was meeting study enrollment expectations without experiencing parental refusal, and asked them to share their process and discuss with investigators their informed consent practices. As a result of their presentation and discussion, this article will suggest a positive approach to the informed consent process for pediatric trials. 

In the last decade, Congress issued legislation that resulted in the need for increased pediatric subject enrollment in medication and biological clinical studies

 ). The intent of these legislative acts was to ensure that new medications and biological products contain adequate pediatric dosing information and labeling. 

 Table 1. Recent legislation resulting in the need for increased pediatric patients in clinical trials.			

The Pediatric Rule and subsequent legislation were implemented after an industry incentive approach—the FDA Modernization Act of 1997 (Pub. L. 105-115)—failed to provide a significant increase in pediatric label data. Limited resources to conduct pediatric studies, difficulties with studying the youngest of the pediatric population, and the need for developing expensive pediatric formulations contributed to the failure of the incentive. 

A specific concern raised about the Pediatric Rule was the ability to enroll pediatric patients in sufficient numbers and the willingness of parents to enroll their children in research studies.

  In the FDA's estimated costs to industry for the required new pediatric studies, it was noted that an additional 10,860 pediatric patients would be required.

Enrolling pediatric patients is a challenging responsibility for the investigator. An investigator contracts with a sponsor to provide a specified number of patients for the trial. Time and effort is spent on screening and identifying patients based on the protocol's inclusion and exclusion criteria. 

The process of obtaining informed consent may have a significant impact on the ability of an investigator to meet sponsor enrollment expectations and, in the long term, may contribute to sufficient patient enrollment to meet the pediatric labeling requirements of the FDA. 

Informed consent has been defined as a process by which  a subject voluntarily confirms his or her willingness to participate in a trial after having been informed of all aspects of the trial that are relevant to their decision to participate. Informed consent is documented by means of a written, signed, and dated form and an entry in the patient's medical record.

The responsibility of the investigator with regard to informed consent is outlined in the International Code of Harmonization Good Clinical Practice (GCP) Guidelines and in the Code of Federal Regulations.

A successful investigative team shares their ideas on improving enrollment in children's research.

Applied Clinical Trials-06-01-2006

Investigator Site Audit Performance

Improvement Through Change

Recruiting Special Patient Populations

Conducting Clinical Trials in Asia

CDISC Standards: Enabling Reuse Without Rework

Solutions Delivered, Not Installed

Positive Approach to Pediatric Informed Consent

Integrating Recruitment into eHealth Patient Records

Innovative ePRO: Tapping into the Potential

Audit Preparation Class: Does It Really Help CRAs?

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