The number of new clinical trials worldwide has increased significantly, forcing the biopharmaceutical industry to look for new markets to conduct studies. Double-digit growth in the number of clinical trials conducted over the past five years in regions like Central Eastern Europe, Asia, and Latin America is a clear indication of this trend. 

The globalization of clinical trials has resulted in changes to clinical research regulations around the globe. Regulatory authorities, particularly in emerging regions, have continued to introduce changes to existing clinical trial legislation and requirements to ensure patient safety. This situation has created a more complex scenario for project managers who now need to deal with several parties, fully understand updates to regulations, address increasing logistic and operational issues (as well as import/export requirements of products and supplies), and grasp cultural differences. 

This article will address how global clinical trials can be successfully planned and managed within this increasingly complex environment.  

First, it is important to clarify what successful management means. This can be defined as meeting clinical trial objectives in terms of timelines, quality, and budget. The key driver to successfully carrying out a clinical trial is to develop a comprehensive project plan, which needs to be in place before starting any trial activity. The project plan has several components to manage the quality and budget of the study, and to achieve the expected timelines with clear communication channels and defined roles and responsibilities. This document should be the source for risk management and decision making. 

 Figure 1. Chart includes a description of tasks and their predecessors, countries involved, and duration of activities.   

The main purpose of planning is to anticipate all possible actions that will take place throughout the project. Therefore, a diagnosis should be done for each aspect of the study to anticipate those actions and set realistic project objectives. Previous experience in the areas subject to planning is required to determine realistic objectives. 

One of the main areas to address when developing a project plan is creating a system for the project team in a type of template format, which can be used for each new study, therefore avoiding rework. It is recommended to structure the knowledge of the organization in a tool that can be utilized by any project team for any new clinical trial. 

This concept changes the traditional way of planning because the responsibility remains to a great extent with the organization and not just the project team. The organization is responsible for creating the framework that facilitates the planning for any project team. The planning should come down from the highest level of the organization to the lowest level and across functions; otherwise, each new clinical trial is like doing the first study again. 

There are several tools available that can be used for the planning of a clinical trial, but those are useless if the organization cannot capture and structure the knowledge and expertise of its people in a way that can be utilized by the entire organization. Project planning tools available on the market allow the project manager to have under control all tasks to be performed throughout the clinical trial, including the duration of each activity, the resources needed, and the milestones. 

Apart from the technologies that are used by the project team, the main obstacle the project team faces is defining the critical path for a global clinical trial. This includes all the tasks that need to be carried out in parallel and sequentially, when those tasks should be completed in order to achieve clinical trial milestones, and how those activities should be performed to successfully complete them. In order to determine the critical path for a study, it is important to understand what the end goal is as well as to use the strategic thinking of the experienced people in the organization. As a result, the best possible strategy will be structured in a way that can be utilized by any project team that needs to conduct a trial. 

The knowledge previously described should be in any organization that conducts global clinical trials. For organizations beginning to implement such concepts, the process of structuring knowledge can be done step-by-step as the organization gains experience in conducting clinical trials. In either case, the project team must involve experts experienced in global clinical development programs. It is critical to capture this knowledge and implement it into the projects so that the knowledge remains in the organization. 

The planning of a global clinical trial should be done on a study, country, and site basis to increase the accuracy of planning. The project plan template should be developed by senior staff with input from the different departments, as a successful plan requires a high level of detail that can only be completed by people who know the best possible strategies to achieve study goals in the shortest period of time. Using this template, the project team does not need to go through the planning process each time there is a new clinical trial. 

One of the main challenges project managers face in managing global trials is achieving the "last patient in" milestone on time. Delays in site activation have a significant impact on all study milestones. The complexity of the start-up phase is driven by several procedures, regulatory activities, and contracting processes with sites, as well as the availability of study drug, supplies, and site training. This results in countries and sites being initiated at different stages and times; however, the plan is usually simplified by defining key general study milestones. 

The process described can be understood through an example. If a company wants to organize the planning of the clinical trial start-up process, we may assume that the project starts with country selection and identification of clinical trial sites at the same time the company starts the translation of all essential documents. However, the local Ethics Committee (EC) submissions will not start until the applicable essential study documents are translated for those countries that require document submission in the local languages. 

The duration of each activity should be defined based on previous experience doing these activities, internal metrics, and information provided by study sites. At the same time, those tasks linked by dependency (in this case, essential document translation is the predecessor for EC submission) and those to be done in parallel should both be identified (e.g., site identification and essential document translation) in order to get the critical path for any trial. In other words, a planning structure and framework that increases the level of predictability in the conduct of any trial should be provided to the project team. 

Based on the above considerations, the process that leads to successful planning is as follows. 

Introduce the concept of planning into the organization.

 Senior management should involve people from all levels of the organization to structure the knowledge so that the project teams can use this approach as a framework for planning the tasks to be performed throughout the duration of the study. 

Define the limits of the planning by identifying the main goals.

 For example, if a company is defining the planning for a trial start-up phase, the main goal is to get all sites up and running. 

Define the critical path including the duration of each task. 

The most important part of this step is to consider the best possible strategy when deciding which tasks will be done in parallel and which ones will be performed sequentially. 

Describe how each activity should be performed.

 It is important not only to list the activities, but also to describe how they should be done by the project team. For example, if translating all essential documents into the local language is one of the activities of the clinical trial start-up, the plan must describe how this task should be carried out. 

Test the planning tool before final implementation.

 During this process, it is important to check whether the duration of each activity is realistic and if the critical path reflects the best possible strategy to be followed by the project team. 

Once the project plan template is developed and implemented, the project manager should customize the tool according to study specific requirements. The next step is to lock the planning by saving the baseline—a screenshot of the activities and timelines expected to be accomplished. The baseline should be saved as early as possible after initiating trial activities to evaluate (throughout the project) any deviations from initial expectations. It is very important that the tool is updated on a regular basis with the actual data in real time and that it is shared with the project team accountable for the deliverables, as well as with the senior management to show study progress or for the purpose of escalating trial issues. A Web-based tool is the most suitable option for data entry and verification. 

Project control means evaluating the system put in place using standardized metrics to measure progress and quality. Project managers can easily lose control of the project and its scope when they do not manage based on the project plan. Deviations from the study baseline should be measured and tracked in a timely manner to identify issues, assess the impact of the changes in the plan, and apply corrective actions. The risk management plan should be followed in parallel with clear mitigation strategies and contingency plans, such as the activation of backup countries or the selection of additional sites. In this way, the delays are predicted with sufficient time, reduced, and resolved efficiently. 

Lessons learned and metrics from current and past clinical trials are helpful to improve the project planning tools, re-design the processes, better estimate the timelines, and implement adequate strategies to conduct studies. A big issue in a majority of organizations is that the best strategies are not organized in a way that people can use—usually, SOPs are not enough to guarantee employee performance. 

The development of a planning system where the knowledge strengthens the companies and remains in the organization allows teams to learn from past projects. Even if a project team does not have the knowledge to conduct a global clinical trial, the study can be performed with a good chance of success. 

* is director, Clinical Operations, Latin America, at PAREXEL International, email: 

 is senior director, Clinical Operations and Peri-Approval Clinical Excellence (PACE), Latin America, at PAREXEL International.

*To whom all correspondence should be addressed.

Articles

Feature Article

Structuring the knowledge and expertise within the organization is key to a project plan that works.

Create a Successful Project Plan for Global Trials

India and China offer attractive environments for clinical studies, with India emerging as a major market for clinical trials and China not far behind. Both countries provide huge and accessible treatment-naïve patient populations and cost-effective research opportunities with low procedure and professional fees. While these countries presently account for less than 1% of the total FDA-regulated clinical research,

  forecasters estimate an expanding market for new clinical trials in both countries.  

In this article, we describe why this rapidly developing market for clinical trials will create an industry wide challenge for researchers who have less than a complete understanding and experience with cultural issues and nuances of clinical trials in India and China. We focus on the key components of investigator grant budgeting and negotiating in these countries, detailing how clinical investigators can maximize their resources and enhance their trials in these rapidly expanding economies. 

To construct budgets that reflect market conditions in both India and China, the industry must have access to current actual cost per visit and cost per patient numbers. These data ensure successful budget negotiation and create a positive relationship between pharmaceutical companies and the clinical sites in these countries. 

 Procedure and Professional Fees: India vs. the United States 

We contacted more than 30 sponsor companies to determine if they anticipated new clinical trials in China or India in 2007. The companies indicated that for 2007, nearly 4% of new clinical trial sites would be in India and 5% in China; by 2010, they expect this number to jump to 10% of new sites in India, and another 10% in Asia, especially China. These forecasts match A.T. Kearney's Overall Country Attractiveness Index,

  which ranks India and China as the most attractive countries for clinical research after the United States. This index was constructed using five variables: Patient Pool, Cost Efficiency, Regulatory Conditions, Relevant Expertise, and Infrastructure and Environment. 

Procedure and Professional Fees: China vs. the United States 

India provides an attractive setting for clinical research. Some of the benefits include:  

More than 500,000 English-speaking doctors, many trained in the United States or UK

The highest number of FDA-approved laboratories outside of the United States.

The larger cities of Mumbai, New Delhi, and Chennai offer both large patient populations and better equipped research institutions, which have the capability of handling greater patient populations as well as more complex trials. Some examples include the Adyar Cancer Centre in Chennai and the Tata Memorial Hospital in Mumbai. The major ongoing clinical trials in India are for cardiovascular diseases and diabetes. 

In 2000, there were 60 unique 1572s filed; this number increased to 174 in 2004 (0.5% of the global 1572 filings). By 2010, the clinical research market is expected to surpass $2 billion.

Of course, low cost budgeting for clinical trials and the potential for significant cost savings in India's emerging market provide incentives for companies as they look for ways to contain expenses in the expanding clinical services industry. 

In India, local offices build investigator grant budgets, which traditionally have been based on intangibles such as experience and gut feelings. Most contracts are two-party arrangements between the investigator and the hospital. Most clinical grants in India have four main components: procedures, professional fees, site costs, and overhead. 

 Procedures are activities done to or on a patient. Common procedures in most clinical grants are electrocardiograms (ECG), informed consent, and chest x-rays. Procedure costs are 21% of the U.S. costs. Some specific cost differences can be seen in Table 1.  

 Wages, salaries, drug preparation, and facility fees are examples of professional fees. Contracts do not include pharmacy fees, and the cost for dispensing the investigational product is already included in the principal investigator's salary. India does not include subject reimbursement in the initial budget, but this cost may be added to ensure that the study retains subjects. 

On average, India's professional fees are half the cost of U.S. fees. Some examples are illustrated in Table 1. Physician fees are budgeted on a per visit basis and study coordinator fees are budgeted as monthly salaries. Principal investigators decide how many full-time salaried support staff (i.e. study coordinator, nurse, and dietician) are needed and what their compensation should be. 

One of the cultural differences when negotiating site budgets in India is subject reimbursement. Oftentimes, a family member will have to accompany the patient to each visit; therefore, additional reimbursements may be included. This is not typically included in the initial budget presented to the site, but may be added in order to accommodate the sensitive needs of this population and their families. 

 Site costs tend to be one-time fees, such as advertising, Institutional Review Board or Ethics Committee fees. India's enormous patient pool and the country's 13 official languages make an advertising campaign impractical. Rather, hospitals recruit patients directly, with each site determining its fees for this service. Health Authority & Ethics committee fees are also predetermined. 

 Overhead in India runs between 10% and 20%, which is applied for both procedures and professional fees. Some have questioned whether the overheads varied between public and private hospitals. Based on our analysis and survey results, the cost difference is not significant enough to warrant a comparison. 

Once sponsors create a budget they believe represents market conditions, they submit it to the site for approval. At this point, a site may choose to negotiate certain aspects of the budget to reflect its own requirements. 

Negotiating contracts in India always takes place directly with the principal investigator. Contracts are usually in English and the negotiating currency is in dollars; at times, the currency may be in euros or pounds. 

A smaller amount is paid at the initial visit to encourage investigators to retain patients. Typically, payments are made on a per visit schedule (i.e., cost per visit times total number  of patients). Monthly site payments are used to provide wages and salaries for support staff. 

When we consider all of the aforementioned costs, the total investigator grant on average ranges from 30% to 40% of the cost in the United States. The information in Table 1 is provided from the GrantPlan®  Database,

  which is a large database of current international clinical grant costs in the world. Most major pharmaceutical companies contribute data to, and access, GrantPlan®  for clinical grant data. 

As with India, China represents a vast new marketplace for the clinical research community. The country offers:  

The largest urban, treatment-naïve patient population in the world

More than 1.5 million physicians, almost 2 million physician's assistants, and more than 1.6 million well-trained registered nurses and technicians, all working at significantly lower salaries.

Some key clinical trials underway in China are primarily for lung cancer and infectious diseases. Beijing, Shanghai, and Guangzhou are three of the major clinical research cities. The Beijing Tong Ren Hospital and Peking Union Medical College Hospital are two examples. 

In 2000, there were 26 unique 1572s filed; this number increased to 76 in 2004 (0.2% of the global 1572 filings). Experts predict that by 2010 China will become the fifth largest pharmaceutical market and the world's third largest market by 2020.

  Simply put, China is the next frontier for pharmaceutical clinical trials and offers both opportunities and challenges for the pharmaceutical industry. 

Similar to India, investigator grant budgeting in China follows key practices that create a cost-friendly environment for clinical trials. For example:  

Only public hospitals are allowed to participate in clinical research.

Most contracts are solely between the investigator and the hospital.

Budgets are built according to a local office's experience or sometimes according to headquarters' "gut feelings."

Most budgets are built on a cost-per-visit basis, although the costs for some expensive procedures, such as biopsies, are disclosed to the investigator as individual line items.

On average, procedure costs in China are 39% of the cost in the United States (examples can be seen in Table 2). Procedure fees are hospital specific and almost all public hospitals provide the procedure costs to the public either in the hospital or online. However, these publicly available prices do not represent clinical costs and can only be used as one of the sources of information to begin budgeting. 

 Physician fees are usually budgeted per visit. The principal investigator decides if additional staff should be hired and whether study coordinator fees are paid on a per visit basis or on a monthly salary. Subject reimbursement is provided for patients who travel from a long distance and for invasive procedures. Pharmacy fees are often included in the contract with the hospital and include specific milestones. Infused medications are usually double or triple the cost for an oral or topical medication. On average, professional fees are 50% of the costs in the United States. Table 2 displays some specific examples. 

 Administration fees are typical in hospital contracts. Hospital bed fees are used for surgical procedures. A "leading fee," in the form of a certain percentage, is applied for hospitals that are overseeing the study. Site costs are commonly included in the hospital contract. 

 The investigator contract and the hospital contract may have two different overhead percentages. Overhead is applied to both the procedures and the professional fees (including both subject reimbursement and pharmacy fees) and can be presented as both overhead and administrative fees on budgets. Most contracts have an overhead of 10%. 

In China, budgets are almost always negotiated directly with the principal investigator and signed by the principal investigator and the hospital official, and sealed or stamped by the hospital. Study managers or CROs negotiate the contracts locally; the common negotiating currency is the yuan, although occasionally contracts are in dollars or euros. 

Communication is key in successful negotiation in China. Compared to India, English is not as widely spoken in China; therefore, consistency and transparency are essential in presenting and negotiating the budgets. 

Industry must grasp the cultural nuances of these two burgeoning countries to find success there.

Grant Budgeting and Negotiating in India and China

To read more about how sponsor and vendor relationships are changing in a world where outsourcing is the norm, check out the following articles:

Vendor Quality Assurance Audits: A Formula for Success by Carl Anderson, Cathy Tashiro, and Laurie Taddonio

Successful Outsourcing: Tracking the Evolving Use of Full-Service andNiche-Service CROs by John R. Vogel and Kenneth A. Getz

A Clinical Development Solution Tailored for Biopharmaceutical Companies by Vincent Charlon

Master Service Agreements (MSAs) and Preferred Vendor Agreements have been used for years to provide pricing predictability and consistency in contracting to outsourcing departments. While generally successful, the extent to which they ensure companies are extracting maximum value from them is difficult to measure. 

Increasingly, these Agreements include provisions that extend well beyond volume-based discounts and rate cards with negotiated fees. Most organizations have created standard MSA templates that include performance requirements, metrics to track performance of their providers, and penalties for noncompliance. In addition, provisions are frequently included that require both parties to meet regularly to discuss the status of the relationship and address specific issues or concerns. This is one of the most common methods of measuring the quality and consistency of service being provided by the preferred provider. 

These Agreements also serve to streamline the contracting process associated with specific projects by eliminating the need to renegotiate key terms for each study. In most cases, this provision is effective for both parties and expedites the execution of contracts. 

While some companies formerly allowed exceptions when a business case seemingly warranted the use of a nonpreferred provider, these requests are rejected more frequently in the context of these Agreements. The ad hoc selection of a provider has become the exception to most standard processes, and compliance with these Agreements is generally very good, ensuring business is going to the preferred providers as intended. 

 Figure 1. Consolidation Creeps In: Subject Recruitment 

As a result, the process by which vendors are selected has become more rigorous, and in many cases has the cache of a formal audit. 

In the current environment, there are no assumptions made regarding a provider's competence or capabilities in any area, even if the sponsor has availed itself of these services in the past. While classic audits are conducted by the QA function of both organizations, more and more purchasing decisions are preceded by site visits and live demonstrations of core processes. 

PowerPoint presentations and marketing materials are still helpful in supporting these on-site evaluations; however, they do not generally provide sufficient details regarding Standard Operating Procedures (SOPs) and other information required by the sponsor. Final presentations are common during the process of identifying preferred vendors, and the costs associated with bringing all the appropriate support personnel together for these meetings can be tens of thousands of dollars for companies operating on a global scale. It is a significant investment for a provider to participate in this process; therefore, the expenses associated with doing so should be contemplated in any Business Development or Sales and Marketing budget. The ultimate cost of not winning is exclusion from the preferred vendor list for the term of the Agreements, which can extend for two to three years and include automatic renewal provisions for the incumbent providers. 

Another significant challenge for outsourcing professionals is the cost of switching providers for a particular service. If the benefits of changing vendors are deemed to be only incremental, the time and cost associated with the transition may not be justifiable in the current climate. It is critical for newer providers or those that have expanded or enhanced their services to clearly differentiate themselves from incumbents to secure these key relationships. The current pace of mergers, acquisitions, and licensing agreements poses a particular challenge in this area. As companies combine their pipelines and try to realize other synergies expected from these transactions, the outsourcing function is often charged with selecting the best of breed suppliers on behalf of all the merged entities. 

While the value of existing contracts are contemplated during the due diligence process surrounding an integration, long-term contract commitments of one party may prohibit near-term transitions to alternate, preferred providers of the other. Incumbent providers should not take their preferred status for granted even in these circumstances, since most contracts allow for termination for nonperformance or include changes in control provisions that provide the customer the option to terminate the Agreement prior to its expiration. The most effective way to avoid difficult and protracted negotiations in these circumstances is for all parties to communicate early and frequently during the transition process and to pursue legal remedies when disputes arise only as a last resort. 

An additional external factor effecting outsourcing groups is currency exchange rates. Choosing the currency in which payments are made to suppliers has become increasingly complex for companies conducting studies on a global basis. In cases where both the sponsor and provider incur costs to support their infrastructure in various countries, establishing fair and equitable payment terms is challenging. Further, given the significant fluctuation in the value of the U.S. dollar vs. the euro and pound, it is difficult to establish precise payment terms that do not impose unnecessary risk associated with currency exchange rates for either party. Many companies establish exchange rate corridors on the effective date of the Agreement that can be adjusted prospectively based on a mutually agreeable formula. 

However, despite the inclusion of such provisions in contracts, the risk associated with currency fluctuations is an ongoing concern for both sponsors and providers. As both sponsors and providers expand into emerging markets such as Asia and India, this issue will become increasingly complex. Beyond the currency challenge, companies must learn the unique business cultures of the markets they serve. In some organizations, subsidiaries are allowed to contract with providers outside the Agreements that govern the relationship with the provider in other parts of the world. It is important for providers to fully understand and track the various Agreements they have with all the entities related to a particular customer. It is equally important for the sponsor to share this information with all affected providers to avoid confusion and lack of alignment. 

The scope of MSAs has also been broadened in many companies to include service providers that have historically not been subjected to this heightened level of scrutiny. Most CROs, central labs, and central ECG providers have been party to these agreements for many years. One of the most noteworthy is the long-standing Agreement between GlaxoSmithKline and Quest Diagnostics for central laboratory services. While this relatively exclusive agreement is somewhat exceptional for the industry, it has been watched closely and served as a benchmark for outsourcing executives for the past nine years. 

One service area that is facing increased visibility is central imaging. Historically, imaging necessary for a clinical trial was provided by the investigator physicians in clinics and hospitals—particularly in the university setting. The need for better coordination of this service across multiple sites has prompted many companies to engage a core imaging lab to manage this aspect of a study. 

Over the last 10 years, several commercial organizations have developed the scale to support global trials with consistent methods of analyzing imaging endpoints. The increased focus on diseases such as cancer, osteoporosis, and Alzheimer's, where imaging is an important marker of efficacy, is driving growth in this industry. This subjects imaging providers to the same selection and contracting processes that have traditionally applied to others. 

One of the potential risks in the current environment is that new entrants into the market will use price as their primary differentiator, thereby creating a quality vs. cost dilemma for existing providers with a proven track record of strong performance. While no one in the industry would knowingly compromise quality for low prices, the potential does exist for the decision-making process to become overly focused on the latter. It is important that these and other vital services remain available and that the companies that perform them remain viable by not succumbing to the pressure to commoditize their services by offering unsustainable pricing. 

Similar to MSAs, Requests for Proposal (RFPs) and Requests for Information (RFIs) are more comprehensive and address a broader array of issues. A recent RFI issued by a large global pharmaceutical company included a series of questions about potential providers' policies regarding the use of minority owned subcontractors, employment nondiscrimination, and environmental responsibility. 

Increasingly, companies require their suppliers to provide detailed, nonconfidential information regarding their experience with other sponsors. This attempt to establish a providers' credibility extends beyond traditional reference checks that invariably provide little objective information. While responses to these requests do not typically constitute a formal, binding offer, the sponsor's expectation is that any final agreement for the services described will be consistent with the proposal and not require material changes, amendments or change orders once the contract is executed. 

In an effort to avoid as many unexpected issues as possible, some sponsors' RFPs can span several hundred pages and include inquiries about issues as diverse as whether or not a provider intends to initiate an acquisition or use off-shore resources to provide any of its services. There is no tolerance for ambiguity in providers' responses, as evidenced by the use of scoring systems to compare multiple bids. 

These systems are used to rate each proposal on a standard set of measures to ensure an objective analysis is performed. In this context, if a response is not provided or an answer is deemed to be inadequate or unclear, the overall assessment is negatively impacted. Providers should ensure that they have adequate oversight of their bids and contracts function and that a final quality check is performed on all proposals before they are presented to the customer. 

One method that is being used to address the financial pressures faced by some manufacturers is a bidder's auction. In some situations, each provider that has issued a proposal for a specific project or trial must participate in an online auction to win the business. During these auctions, representatives from each party that has provided a proposal are able to see the anonymous bids of the other parties and must decide whether or not to alter their bid during the time allotted. Based on the fact that the lowest bidder wins, these are frequently referred to as reverse auctions. While the outcome of this process could be considered a success for the sponsor, it represents a virtualization of the negotiation process and the potential of rendering face-to-face value discussions obsolete. 

In another effort to ensure key purchasing decisions are made in an unbiased manner, many companies have implemented a team approach that includes representatives from many different functions in the organization. The intended outcome of this approach is alignment across the company and a seamless implementation of the decisions reached by this group. This internal collaboration can be supported by aligned incentives for the participants on a team. 

Another important dynamic is the involvement of members of senior management in purchasing decisions, up to and including the CEOs of multibillion-dollar drug development companies. In some cases this is prompted by corporate governance policies that require executive oversight of key financial decisions. The Sarbanes Oxley regulations are invoked with increased frequency to justify the position that start-up payments or deposits to suppliers are unacceptable because they allegedly represent payments for services that have not yet been rendered. This position places the burden on the supplier to provide evidence of the effort expended on behalf of the company at a very granular level. 

The seemingly straightforward process of obtaining approval from key decision makers in both organizations and physically executing contracts has become more complex. As a result, both parties should agree on specific timelines and milestones and monitor them carefully to ensure they are achieved. 

In the current environment of doing more with less, many companies have consolidated their purchasing organizations. They have done this primarily in three ways. First, some companies have aligned their outsourcing group with specific therapeutic areas. As cost pressures mount, several companies have eliminated this redundant structure and consolidated the outsourcing function into one organization that is responsible for all therapeutic areas. 

Second, several companies are assessing the disparate processes employed between the United States and Europe. Given the mergers and integrations of many U.S.- and EU-based companies, a fair amount of redundancy still exists across the purchasing function. In some cases, contract templates from one side of the Atlantic can be completely different from the other. The need for translations and compliance with applicable country specific laws aside, a provider cannot only become confused, but miss an opportunity to provide services for a particular project altogether. 

Finally, cost constraints in some companies have prompted a consolidation of purchasing for a broad range of services. While one department may have focused on ancillary providers and another on strategic CRO relationships, the staffs have had to expand their knowledge base to include many more services with which they may not be familiar. In some cases, the outsourcing groups have been faced with workforce reductions at the same time, making it very difficult to take on the extra burden of these increased responsibilities. 

 is senior vice president, sales & marketing, Synarc Inc., 575 Market Street, 17th Floor, San Francisco, CA 94105, email: 

Performance and noncompliance clauses change the partnership between sponsor and vendor.

Preferred Providers Face Outsourcing Challenges

For years now, clinical research professionals across a variety of disciplines—from government- and industry-funded research sponsor professionals to investigative site staff, bio-ethicists, and IRB members—have spoken passionately about the need for improvements in the informed consent process. Numerous initiatives have been implemented, including those utilizing multimedia technologies, those simplifying and streamlining consent form language, and those modifying approaches to communicating and educating study volunteers. Despite all of these well-intentioned initiatives, however, little has been done to fundamentally and sustainably improve the informed consent process. 

"Most initiatives are ineffective and in some cases ignore the spirit if not the letter of federal regulations on the matter," explained Mark Hochhauser, a Minnesota based readability consultant, IRB member, and informed consent expert. "Repeated attempts to shorten consent forms have really accomplished nothing," he said. Factoring in the eight elements mandated by the FDA, six "when appropriate" elements, and another five to 11 pieces of information required by the Health Insurance Portability and Accountability Act (HIPAA), the average consent document still averages more than 12 pages, according to Hochhauser. 

The informed consent process should begin with general education about clinical trials before participants walk in the door. Next, during informed consent form review and discussion, the study volunteer has the opportunity to read, talk about, and question the protocol and the risks and benefits of participation with the investigator and study staff. The informed consent process continues during the clinical trial with the sharing of any new information investigators learn about the molecule being studied. The process ends with poststudy communication about how participants' involvement mattered. 

Conceptually, this process seems not only reasonable but also essential to engaging study volunteers and establishing their partnership with clinical research professionals. In practice, the informed consent process leaves much to be desired. 

Problems abound widely and at every level. Informed consent form review is generally not viewed as an educational experience but rather as "information overload" for most study volunteers. It may be irrelevant, for instance, to tell would-be participants about side effects seen solely in animals, although some would argue it is Good Clinical Practice to do so. Lengthy lists of side effects—some containing hundreds of them—likely leave a number of prospective subjects ruminating more about the many dangers of a given clinical trial before they properly understand and can weigh the benefits. Decision-making is further hindered by vague statements about medical benefits rather than what sponsors hope the study might accomplish. 

Investigative sites, for their part, may be reticent to share any new information learned about an undesirable side effect midway through a study. Yet, according to Hochhauser, there is no evidence of subjects dropping out of trials because a site is forthcoming with such information. "If they have cancer, especially, it may well be a risk they're willing to take," he said. 

There is little to no evidence demonstrating that various initiatives and interventions are actually improving volunteer comprehension. Based on research in this area, all that appears to help is for study participants to spend more time reviewing and discussing the protocol and clinical trial expectations with the investigator and study staff. Hochhauser suggests that these studies are themselves scientifically flawed, in part because there are no baseline or follow-up testing phases. "For all we know, the consent process makes comprehension scores go down," he added. 

Hochhauser is an advocate of federally funded research on the consent process using forms written at the recommended 6th to 8th grade reading level, which no one has ever been able to produce. "If that is to change," he said, "federal regulators need to provide sponsors with examples of simplified narratives pulled from real consent forms used in real clinical trials." He would also like to see federal agencies offer plain English examples of a complete HIPAA privacy notice. "Without these examples, health care organizations and their law firms develop compliant HIPAA notices that are then used by the organizations' members, even though such notices cannot easily be understood by patients. The goal is compliance, not communication," Hochhauser said. 

"The FDA, the Belmont Report, and Nuremberg Code all speak of the feasibility of comprehension testing," said Hochhauser. "But what's a passing grade? If it's 70 and the grade gets posted in patients' medical records, can that score later be used to support an injury claim based on inadequate understanding of the protocol? Should retesting be done on would-be participants whose score falls below a certain threshold?" he said. 

Improving the informed consent process once a trial concludes may be the most difficult task of all. Even study results published in mass media reports aren't particularly useful to participants. Due to highly technical—often incomprehensible—titles on consent forms, participants often have no way of knowing if the results referred to in a published report came from the same study that they participated in. 

Clinical research professionals can help by directly sharing study results with participants. But simply sending them a difficult-to-read article from the 

Journal of the American Medical Association

 is unlikely to clear up the confusion. At a minimum, care and time must be taken in communicating study results with the volunteers who gave the gift of their participation. There's no question that this step will add costs to the study budget. The return on such an investment, however, is likely invaluable, as it builds stronger relationships with people who are familiar with the clinical research enterprise and who can serve as ambassadors for public outreach and education. 

Some investigative sites are independently doing what they can to improve the situation. At Clinical Research Atlanta, for example, Clinical Operations Director Michelle Sowell tries to get consent forms in the hands of prospective enrollees days before they step foot in the clinic. Some sponsors worry that sending out consent documents in advance will scare people and discourage participation, but she believes it gives people an opportunity to highlight sections that concern or confound them and write questions in the margins so they can make a truly informed decision. "Subject comprehension of study protocols has noticeably improved since the site started mailing out consent documents three years ago," Sowell said. "It has also cut down on screen failures." 

"It helps that the clinic requires study coordinators to read, initial, and date the portion of the investigator's brochure dealing with adverse and serious adverse events," added Medical Director Nathan Segall, MD. "If they're asked a question, they either know the answer or know where to look it up." 

At the initial screening visit, coordinators carefully review with subjects the purpose of the study and what to expect at each visit as well as clear up any misunderstandings they have about compensation, says Sowell. "Questions are heavily encouraged and if comprehension is still a problem, those people simply don't get enrolled. For pediatric trials, children who express worries about blood draws or injections also don't get enrolled—no matter how enthusiastic their parents might be. At every study visit, coordinators go over what to expect moving forward and remind participants of their volunteer status," she said. 

"Whether it is months or years between the final study visit and when the trial is unblinded, participants are always told if they were on an active compound or a placebo," said Segall. "That can be medically important information to someone with a ragweed allergy who received an active immunotherapy injection. When actual study results would be of value to participants, the site passes on whatever it learns from sponsors despite the cost and logistical difficulties of doing so." 

At Pivotal Research Centers in Peoria, AZ, "Coordinators will sometimes spend an hour with prospective study subjects completely reading through consent forms out loud to ensure the information gets properly digested," explained Clinical Research Coordinator Laura Vigliotti. "Coordinators might also highlight certain sections, such as duration of the trial and possible side effects, which tend to be decisive enrollment factors." 

On high-enrolling obesity trials, the site will do a "group consent" of 20 to 25 people simultaneously if the sponsoring company approves. "When one person in the room asks a question, everyone benefits," said Vigliotti. "By the time we're done, they all have excellent comprehension of the purpose of the trial and what's expected of them." Patients also have the opportunity to ask questions privately regarding any personal matters. Those who are still interested in participating get sent home with the consent forms to read again and come back with a new round of questions at their screening visit. "Enrollees who have been group consented seem to have a somewhat better retention rate and reliably show up for study visits," Vigliotti added. 

Before any trial begins, participants are reassured that they will be kept up to date regarding any amendments to the protocol, including ones that don't directly impact them. "During a trial, Pivotal supplies participants with all available sponsor-produced, IRB-approved press releases about the experimental compound—good or bad," said Vigliotti. "With increasing frequency, sponsors have also been producing newsletters specifically for participants in their trials to improve communication." 

Pivotal always requests that sponsors provide treatment allocation information after a trial ends, says Vigliotti, and not just to satisfy participants' curiosity: "It gives them the sense that they've come full circle with us...and gives us a great way to continue building and establishing rapport with them." This type of follow-up gives former volunteers a sense of connection to the clinical research enterprise. 

Vigliotti says she doesn't believe subject comprehension of consent documents is a significant problem because informed consent is taken very seriously at Pivotal Research. But educating people about clinical trials can be tough, she said, when dealing with first-timers who have never heard of an "adverse event" and don't understand the importance of reporting minor complaints they perceive as unrelated to the study medication. 

This isn't the case everywhere. "I know of other coordinators at other sites who simply hand people a consent form, give them 15 minutes to read it, and have them sign it without prompting them for questions," said Vigliotti. "Those are also the cases where patients are not as compliant." 

There are numerous opportunities to improve the informed consent process. It is time, however, for clinical research professionals to collectively act upon them. Recruitment and retention rates in North America and in Western Europe have been worsening, as public distrust in the clinical research enterprise has increased. Fundamental and sustainable changes to the informed consent process may hold an important key to building longer-term relationships with patients and, ultimately, with the public as a whole. 

MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Clinical Trial Insights

Creating sustainable change is the key to fixing this broken process and advancing clinical research.

In Search of Informed Consent Improvement

Europe remains as challenging as ever for clinical trials, but also for everyone trying to make sense of Europe as a political entity. The jumbo meeting on clinical trials at the European Medicines Agency in early October—on which a report appears at 

—provided further evidence of just how complex life can become in the European Union. This unique organization binds 27 member states together tightly, voluntarily, legally—but not completely. And the conduct of clinical trials is one of the activities that keeps slipping between the gaps in the curious configuration of EU rules, which resemble wickerwork more than cast-iron. 

This is not the place for a lengthy disquisition on the constitution of the EU. Suffice it to say that the 27 member states not only disagree with one another on clinical trials regulation, but that even where they do agree in principle, they frequently disregard at national level the rules they have created at the European level. 

At the end of the meeting at the Agency, Georgette Lalis, the senior official from the European Commission, openly acknowledged that the majority of member states just do not comply with the guidelines they have signed up to on clinical trials. Worse, under the system in force, there is no way that either the European Commission—supposedly the watchdog of compliance —or the Agency can do anything to oblige member states to comply. 

Thomas Lönngren, the executive director of the European Medicines Agency, told 

 that it was outside his powers. The Agency handles only some of the technical work on clinical trials, such as site inspections and databases, he insisted. "It is not involved in clinical trials legislation. That is in the hands of the member states and it is their responsibility," he underlined. And, he made clear, it will require "a political decision" to change the system. 

EU Documents Set for Release in Early 2008  

Nonetheless, the key clinical trials experts at the Agency have, meanwhile, been looking ahead with undiminished energy. The Agency's efficacy working party has just agreed on its workplan for the next two years under its chairperson Dr. Barbara van Zwieten-Boot of the Netherlands. In terms of direct contact with individual sponsors, it expects to provide support in terms of scientific advice on 15 occasions each year, protocol assistance five times a year, product assessment six times a year, and postauthorization pharmacovigilance issues related to a product or a class of products just twice a year. 

But the bulk of the work will, as usual, consist of the generation or revision of guidelines for efficacy testing. The ones to watch out for particularly are those still in the consultation process because there, everyone in the clinical trials community has a chance to influence the outcome. The first quarter of 2008 looks like it will see a volley of consultation documents released. A revised draft on clinical development of medicinal products for treatment of HIV infection is expected to be released for consultation in early 2008, following the adoption of a concept paper last February. So too are drafts of new guidelines on the clinical development of medicinal products for tuberculosis and Hepatitis C, now that there has been time to digest comments on the concept papers adopted in April 2007 (see Table on page 38 for a list of other consultation documents expected to see the light of day next year). 

A cynic might be tempted to discourage the clinical trials community from getting involved in a discussion of these guidelines if the member states are not going to take them seriously. But cynicism has no place in Europe—or in this column. In general, the guidelines from the efficacy working party have tended to harmonize thinking—among regulators as well as sponsors—on new medicines development. The conspicuous member state noncompliance at present relates to the detailed guidance on methodology for the conduct of clinical trials in line with good clinical practice. 

Cynics might also interpret the delays in another EU policy as evidence that it is going adrift. The Innovative Medicines Initiative (IMI) is taking on the appearance of a mythical beast—frequently referred to, but never seen. This is the partnership-in-the-making between industry and the public sector to boost pharmaceutical research and speed valuable medicines through to market. It is invoked at every pharmaceutical-related meeting in Europe as a panacea for all ills—but it still hasn't happened. 

The IMI is one of six so called "Joint Technology Initiatives" introduced in the EU's new research support program, aimed at bringing together universities, hospitals, public authorities, patient organizations, clinical centers, and pharmaceutical companies to boost biomedical research and the development of new therapies. The idea is that it will create partnerships through open calls for tender, with the main focus on precompetitive pharmaceutical research—tools to make early and reliable predictions on safety and efficacy of candidate products. Priorities will be treatments for diseases like cancer or Alzheimer's, and the total budget will be o2 billion ($2.8 billion) for 2007 to 2013—half from the EU budget and half from research-based pharmaceutical companies, in the form of staff, laboratory equipment, and clinical research. The EU funding will go exclusively to smaller firms, nonprofit organizations, academia, authorities, clinical centers or patient organizations, but not to big companies. 

Recently, EU ministers gave another blessing to the concept. But the European Parliament, which has to give its opinion on the exercise, is taking an uncommonly long time to get around to even a preliminary discussion of the proposal. The French MEP appointed by the Parliament to prepare its opinion, Françoise Grossetête, has still not managed to produce an initial working paper—and requests to her office for information about the drafting are stonewalled. 

Things are moving faster (though no less bizarrely) in another Parliament committee that is merely offering a secondary view. Dagmar Roth-Behrendt's draft welcomes the concept of support to the development of high tech medicines, but it also insists that research into herbal and nonprescription medicines should be included too. 

Meanwhile, so nervous are some pharma industry organizations becoming about the entire project that they too are clamming up, refusing to divulge not only how far they have gone toward joining the project, but also ducking questions about where they find difficulties with the proposal. "We don't like to say anything about it to outsiders," darkly muttered the spokesperson for one high tech research organization, "because every time we raise any criticism we get into trouble with the EU authorities." 

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

Expect a raft of new or revised EU guidelines for efficacy testing of pharmaceuticals in '08.

Getting Efficacy into European Trials

Country study managers (CSMs) are pivotal players in patient recruitment for multinational clinical trials. They are the gatekeepers who can make decisions that affect which recruitment tactics and materials are submitted to ethics committees and ultimately implemented. These individuals hold a world of invaluable knowledge about their countries and cultures that can positively inform a recruitment strategy. Ironically, it is this body of knowledge that can make a small number of CSMs impediments to successful patient recruitment. Their reliance on cultural precedent or tradition can limit success. 

During collaborations with CSMs in recent years, my colleagues and I began to notice certain resistance among them to consider or condone patient recruitment approaches that they had not personally seen used. "That won't work here," was a familiar refrain. In the absence of laws or cultural taboos against practices we might suggest (should they be necessary or appropriate), such as radio, television or the Web, CSMs might still point to convention and veto submission of these viable and necessary tactics to ethics committees. 

The larger problem is a tendency to simply equate patient recruitment with advertising. Patient recruitment is a discipline—a considered set of practices in response to a problem or set of risks—and direct-to-patient (DTP) outreach is just one of those practices. However, this belief may also cause CSMs to mistakenly equate DTP outreach to pharmaceutical advertising (direct-to-consumer advertising of approved drugs), a practice that is illegal in most countries and widely considered unethical. The mere mention of advertising, even if it is the logical strategy for patient recruitment, may be immediately rejected. What many CSMs may not realize is that DTP outreach for clinical studies is most often legal and conducted using strict ethical guidelines. Its purpose is to educate and inform patients about trials, a particular condition, and a particular study—not to coerce or misinform. 

The CSM conundrum led BBK to conduct research on this group. The company used a methodology in which CSMs from 16 different companies and 10 different countries completed a behavioral assessment survey to uncover their core work styles. Among other findings, data revealed that about 80% of CSMs surveyed have a work style or trait that causes them to "seek to minimize risk" [BBK Worldwide, Maximizing Clinical Research Talent for Successful Multinational Trials: A Case for a New Approach to the Work of the Country Study Manager (2006)]. 

This representative sample may explain their resistance to trying new methods of patient recruitment—especially those that they believe may be unethical or questioned and rejected by site staff, ethics committees or patients. 

This tension may also be explained by another human trait: the tension and resistance that is created when an outside party makes suggestions about how to do your job. This may be compounded when the methods and materials suggested to CSMs are new and not well understood. 

The challenge for patient recruitment experts is to build good relationships with CSMs and to educate them on effective new ways of reaching out to patients using ethical guidelines in this changing clinical trial climate. At the same time, there is an opportunity for CSMs to become true pioneers of patient recruitment and to gain more success in their roles by using innovative recruitment tactics and materials. Their challenge is to continue to share their country and cultural knowledge with colleagues in the field who rely on it, while also understanding the changing environment and then allowing themselves to step outside of their comfort zones. 

A Closing Thought

Matt Kibby, leader of global operations for BBK Worldwide, discusses why country study managers hold the key to global enrollment success but are afraid to use it.

The Gatekeepers to Recruitment

Just when Food and Drug Administration officials thought they could relax a little after months debating legislation to ensure safe drug use, federal investigators leveled charges that agency oversight of clinical research is weak, disorganized, and thus unable to ensure the safety of clinical research participants. This criticism came from the Office of the Inspector General (OIG) in the Department of Health and Human Services (HHS), which has called repeatedly over the past decade for stronger efforts to monitor clinical research and to take action against rule violators. Sen. Charles Grassley (R-Iowa), who requested the OIG investigation as part of his campaign to uncover FDA malfeasance, promised to keep a close watch over how FDA implements the OIG recommendations. 

The OIG complains that FDA cannot identify all ongoing clinical trials, their associated trial sites or Institutional Review Boards (IRBs) overseeing the research. The main reason is that the agency lacks an efficient information system for tracking clinical research activity, site inspections, and resulting corrective actions. 

Due to these inefficiencies as well as limited resources, FDA inspects less than 1% of relevant clinical trials. The OIG estimates that from 2000 to 2005, FDA was charged with overseeing some 350,000 trial sites involved in more than 15,000 clinical research programs for drugs and medical devices registered with FDA. However, the agency inspected only 2855 sites during this period, ranging from 633 BIMO inspections in 2001 to 854 inspections in 2003. 

Similarly, FDA inspected less than 300 Institutional Review Boards (IRBs) each year, partly because the agency has no complete IRB database and thus cannot identify all review boards evaluating clinical trials for regulated products. FDA is working with the HHS' Office of Human Research Protections (OHRP) to establish a mandatory system for registering all IRBs. The OHRP database already lists more than 3500 review boards, primarily those at research organizations that receive National Institutes of Health (NIH) grants or other federal funding and have to register their IRBs as part of the federal "assurance process." FDA backs IRB registration as a way to improve agency communication with these organizations. 

The OIG report [OEI-01-06-00160 available at 

] is the latest in a series of investigations into FDA's bioresearch monitoring (BIMO) program. Back in 1998, the OIG issued  reports criticizing FDA's ability to ensure that IRBs appropriately monitor research under their jurisdiction. Another investigation in 2000 documented weaknesses in FDA's clinical trial oversight program. The OIG is currently assessing how efficiently FDA disciplines clinical investigators charged with research misconduct plus how well the agency and sponsors can monitor financial conflicts of interest of clinical investigators. 

FDA established a Human Subject Protection/Bioresearch Monitoring Council in 2006 to better coordinate and streamline the agency's diverse BIMO program, partly in response to such criticism. The agency also has been clarifying research policies through the publication of several new guidances on timely research activities. 

But the main problem, according to OIG, is that FDA needs a centralized database of all clinical trials involving drugs, biologics, and medical devices to better coordinate research oversight. FDA currently has six different databases collecting information on BIMO inspections for different Centers, as well as one in the Office of Regional Affairs, which manages the inspection field force. These systems collect different kinds of information, using different formats and definitions, which makes it difficult to coordinate inspections and track responses to citations. 

In addition, the OIG criticizes FDA Centers for frequently reclassifying field recommendations for corrective action. The result is that the Centers often decide that an inspection subject may make promised corrective actions instead of receiving a warning letter. And when FDA Centers do send out warning letters, they often cannot determine whether a site takes corrective action. 

Another factor undermining FDA BIMO enforcement is the agency's limited oversight authority. FDA rules governing clinical trials apply to sponsors and investigators, but not to clinical trial support staff that now play a large role in implementing studies and dealing with participants. And FDA policies do not extend to foreign study sites, which now produce more than 20% of clinical trial data submitted to the agency. FDA investigators do visit some foreign sites to ensure data integrity, but have little authority over patient protection issues. 

In responding to the OIG report, FDA deputy commissioner and chief medical officer Janet Woodcock pointed out that BIMO inspections are just one narrow component of the agency's broader efforts to protect human participants in clinical research. More important is FDA's careful scrutiny of proposed research protocols, a process that usually leads to protocol revisions to ensure human subject safety before the trial begins. And even though FDA visits only a small fraction of sites, "the possibility of an inspection helps keep all parties aware of their responsibilities," Woodcock noted. 

Because its resources for site inspections are limited, FDA is looking to apply risk-based approaches to all its field inspection programs, including BIMO activities. The aim is to target FDA oversight to those sites and operations involved in more vital or difficult research activities. This approach also involves establishing quality systems for BIMO activities that provide incentives for sponsors to ensure adherence to good clinical practices. 

In addition, the FDA Amendments Act (FDAAA) may address some OIG concerns about better protecting human research participants by expanding information on clinical research activities. The legislation, which was finalized by Congress in late September to reauthorize the prescription drug user fee program (PDUFA), also strengthens FDA authority to require clinical trial registration and disclosure of research results [

]. And increased user fees should provide additional funding to improve clinical research data banks as part of broader agency efforts to create an electronic platform for managing all regulated product information. FDA envisions the database recommended by OIG as an internal, nonpublic listing of all trials, as opposed to expanded registration of clinical trials on a public Web site required by FDAAA. 

The details for expanding the existing clinical trial registration program [

] were uncertain until FDAAA was finalized and still require considerable explanation to be fully implemented. Registration now extends to all trials for drugs, biologics, and medical devices beyond Phase I intended to support a market application to the agency—and not just those for products that treat serious and life-threatening conditions. Trial listings have to fully describe each study, including name of intervention, start and completion dates, eligibility criteria, target number of subjects, and expected outcome measures. Listings also must provide information on site location, contacts, and updates on recruitment status. 

Each listing will have a protocol identification number to facilitate tracking and eventual links to a results database. NIH will begin to establish this data bank in 90 days with information from FDA's application review process. This may include clinical trial data considered by advisory committees or posted in review packages. NIH will link to drug labels posted on its product label database, plus to publications found in its Medline Plus database. 

Within a year, the results data bank will expand to include a listing of basic data elements for approved drugs: study participant demographics, trial outcomes, and any agreements between sponsors and investigators limiting results disclosure. During this period, FDA also will work with NIH to post additional information on serious and frequent adverse events of registered test drugs. 

The legislation gives FDA, NIH, and sponsors three years to explore ways to provide more complete trial results information to the public. Issues to be decided are whether trial results should be posted for medical products never approved by the FDA; whether there should be nontechnical lay summaries of trials, as well as technical summaries; how much detailed protocol information would be required; time frames for submitting results information (e.g., if results of early trials have to be submitted before filing a market application); and how to register studies supporting new product uses. 

FDA will hold a public meeting to discuss these issues and will conduct a pilot project on how best to verify that sponsor information is accurate and not false or promotional. Sponsors want clear rules and an effective information system because they will face fines and legal action for failure to comply with registration requirements.  

View from Washington

Information systems and lax enforcement criticized as Congress expands trial disclosure requirements.

FDA Hit for Poor Clinical Trial Oversight

October 3, London-A major meeting hosted in London by the European Medicines Agency provided plenty of examples from industry and academia of what doesn't work in this 2001 legislation (Directive 2001/20/EC). Even Thomas Lnngren, the Agency's executive director, acknowledged that there are problems in the implementation of the directive, and that there was "a need to find a way forward." But the contributions that European Union officials made to the debate fell a long way short of offering any dramatic improvements in the foreseeable future.

The catalogue of problems was extensive. For Alan Morrison, vice president international regulatory and safety at Amgen, the legislation needed changing, at the European and national level. There was "an urgent need to address fundamental issues" on loose definitions (particularly of what constituted "substantial" and "nonsubstantial" amendments to a trial), divergent information requirements for trial authorization applications, divergent national rules on manufacturing and labelling of investigational products, and inconsistencies in review processes both at the regulatory and ethics committee level. He pointed out that some member states impose "unreasonable" requirements going beyond the directive-such as refusal by some of them to accept the qualified person's declaration as an assurance of GMP compliance for third-country manufacturers.

Mats Ericson of Wyeth Research insisted that improvements to clinical trial authorizations had to be achieved. This would require renewed commitment from all national authorities to implementing the directive so that it resulted in harmonization. National exceptions from EU guidelines would have to be removed, agreed EU guidelines would have to be respected, and no further national guidelines should be issued. It would also need a clearer focus on public health issues-notably safety reporting.

The current duplicative assessments are not the best use of EU resources, said Ericson. Above all, what is needed is a new, additional and optional alternative procedure. This should provide one assessment and a single approval per study-particularly valuable for multinational studies. He recognized that this would require some tough decisions about which body would become responsible for the scientific review (and how it was resourced and funded), and how its "approvals" would be transposed across all member states involved in a trial. Eventually, it might even require a tough decision to switch to a single EC review, he suggested. But it was necessary to consider radical change, because there was "a fundamental flaw in the Directive which cannot be addressed within the current framework," he insisted.

For Gaby Danan of Sanofi-Aventis, safety reporting was bedevilled by divergent behaviour from country to country. He listed variations between national rules on reporting SUSARs (in relation to whether they originated locally, within the EU or beyond), on investigational products, on trials, on indications, and on unblinding rules. He said national practice varied on annual safety reports, with some countries demanding serious adverse reaction reports periodically, others cumulatively, some local and some global, some by trial and some inclusive, some blinded and some unblinded.

Europe took a step toward improving the operation of its much-criticised clinical trials directive on October 3-but only a step.

Applied Clinical Trials-11-01-2007