The new European Union directive on pharmacovigilance is likely to be fully implemented by late 2010 or early 2011, and expectations that it will help to contribute to a much improved climate for drug safety appear to be growing. 

Several serious public health disasters—from thalidomide in the 1960s to the recall of rofecoxib (Vioxx) in 2004—have provided reminders that effective pharmacovigilance is vital for protecting the public. These events have led to a protracted discussion of how best to revise the regulations, and the process is now approaching completion. 

Pharmacists and patient groups seem happy with the likely outcome. They welcomed the new directive at an event held on September 15, 2010 at the European Parliament. In a statement, they said that it is an opportunity for pharmacists and patients to work more effectively together to improve medication safety. 

The meeting was organized jointly by the Pharmaceutical Group of the EU (PGEU) and the European Patients' Forum (EPF) and sponsored by the pharmacovigilance rapporteur, Linda McAvan, a member of the European Parliament. 

The new directive proposes a stronger reporting framework for pharmacists and health professionals, and introduces direct reporting by patients. The data gathered from such reports will be used to monitor risks posed by medicines once they have been approved and become available to patients. 

Three-quarters of medicines are prescribed and dispensed in primary care, and pharmacists often come into contact with groups who do not take part extensively in clinical trials (e.g., children, the elderly, and those taking a number of medicines simultaneously), according to PGEU President Filip Babylon. Therefore, pharmacists have a key role in reporting adverse drug reactions (ADRs) and helping patients to understand their importance. 

"We welcome the proposals regarding direct patient reporting and giving patients wider access to safety data, as this contributes to patients' empowerment and greater patient safety," said EPF President Anders Olauson. "These efforts should be seen as integral to the wider EU debate on patient empowerment and health literacy, with the aim of enhancing the safety and quality of care for all patients."  

The PGEU represents community pharmacists, while the EPF is the umbrella group of European patient organizations active in the field of European public health and health advocacy. 

McAvan estimated that 5 percent of hospital admissions are due to ADRs. She supported an EU-wide system that allows creation of a wider pool of knowledge on ADRs that can detect patterns earlier and avoid duplication. Nevertheless, she emphasized that ADRs must be reported more quickly, particularly by member states (about half of member states report late compared to 5 percent of pharmaceutical companies). She noted that transparency is the key, and welcomed the idea of a European Medicines Agency web portal and public hearings on ADRs that are open to the public. However, according to McCavan, the database should not be open to the public because it is too technical. 

Under the directive, member states must facilitate direct patient reporting through the provision of alternative reporting formats, in addition to web-based formats. They must ensure the public receives important information in good time on pharmacovigilance concerns relating to the use of a medicinal products through publication on the web portal and through other means. They should also ensure any biological medicinal product prescribed, dispensed, or sold in their territory that is the subject of a report on a suspected adverse reaction is identifiable by, where available, the name of the Market Authorization Holder, the International Nonproprietary Name, and the name of the medicinal product and the batch number. Standard forms and procedures complying with Regulation (EC) No 726/2004 should be used and account must be taken of the EudraVigilance system.  

The European Parliament voted in favor of the directive on September 22, 2010. For the latest information about the status of the directive visit: 

http://www.europarl.europa.eu/oeil/file.jsp?id=5729272

It is also important to be aware of EudraVigilance, a data processing network and management system for reporting and evaluating suspected ADRs during the development, and following the marketing authorization, of medicinal products in the European Economic Area. The EudraVigilance helpline can be reached by phone at +44 (0)20 7523 7523 or by e-mail at 

Articles

Global News

Pharmacists and patient groups welcome the new European Union directive on pharmacovigilance.

Hope Rises for Safety Law

Transdel Pharmaceuticals announced positive Phase III data for Ketotransdel® (TDLP-110), a transdermal non-steroidal anti-inflammatory drug. The Phase III study of the cream showed statistically greater reductions in pain for acute soft tissue injuries.  

Interim analysis for MoxDuo IR in a pivotal Phase III shows the sample size of 140 patients is statistically powerful and does not require further enrollments. This comparative study is being conducted in 10 US-based centers, evaluating analgesic efficacy and tolerability of a flexible dose regimen (12 mg/8 mg) versus a fixed low dose (3 mg/2 mg) of MoxDuo IR in patients with moderate to severe pain following total knee replacement surgery. 

Cumberland Pharmaceuticals published new data supporting the safety and efficacy of Caldolor® (ibuprofen) Injection in pre- and post-operative orthopedic surgery patients. The study concluded that IV ibuprofen significantly decreased pain and morphine use when compared with placebo. This multi-center, randomized, double-blind placebo-controlled trial evaluated 185 adults undergoing orthopedic surgery at eight hospitals. Subjects were randomized to receive either 800 mg IV ibuprofen or placebo every six hours, and pain was measured through patient self-assessment in the immediate post-operative period through hour 28 of the study. All patients had access to intravenous morphine. The study met its primary endpoint; patients who received IV ibuprofen reported a 26 percent reduction in pain with movement. The study met its secondary endpoints, pain assessed during rest was reduced by 32 percent in patients receiving IV ibuprofen. These patients used nearly 31 percent  less morphine than those who received placebo. 

The FDA's Anesthetic and Life Support Drugs Advisory Committee voted in favor of expanding the pain indications for Eli Lilly's Cymbalta® (duloxetine HCl) to a broader pain population. The committee reviewed efficacy and safety data from three new Cymbalta studies in chronic low back pain and two new studies in chronic pain due to osteoarthritis of the knee, along with overall safety data for the medication. Cymbalta is approved for management of diabetic peripheral neuropathic pain and fibromyalgia in the areas of pain, and is also approved for other indications. In split votes, the advisory committee was supportive of the adequacy of evidence for efficacy in chronic low back pain based on two positive studies, but not chronic pain due to osteoarthritis based on a single positive study. The committee also voted that there was insufficient evidence of significant additional efficacy of 120 mg compared with 60 mg in these conditions. The committee voted positively regarding the overall safety profile of Cymbalta. 

In July, the advisory committees for Anesthetic and Life Support Drugs and Drug Safety and Risk Management voted against the FDA's proposed classwide REMS for extended-release and long-acting opioid analgesics. According to Jill Wechsler's 

). "the practitioners and academics on the panels said that FDA's plan was too weak and unlikely to do much to stop unsafe use of potentially dangerous products..."

Editor's Note: Applied Clinical Trials will next report on pain in the August 2011 issue. The new section entitled Therapeutic Corner, will focus on specific clinical trial needs for pain trials. Please send your information, news, or ideas to 

Phase News

Pain Drugs: A Diverse Field

In the pharmaceutical industry, costs are becoming an increasingly scrutinized component of the clinical development process. In addition, companies are looking to increase profits by getting drugs to market faster and to bolster margins by conducting trials with fewer and fewer resources. Along these lines, many clinical operations groups are collecting metrics as fast as they can in order to get their bearings and improve performance. However, most groups do not have a true understanding of the "why" behind the metrics, and as a result end up collecting far too much data and subsequently misapplying or misinterpreting the resulting information—when they aren't too busy drowning in their own data. Stepping back, it becomes apparent that on the whole an R&D organization's approach to metrics shouldn't differ much from that of any other department, or that of any other industry. In fact, many valuable lessons can be learned by reviewing cases where the use of metrics went horribly wrong in other industries. By analyzing from the top down why metrics are important and how they should be utilized in order to maximize the impact on a company's—not a department's—bottom line, clinical operations and other groups within the industry can save much time and effort while making a difference where it counts: their company's bank account. 

In his book "Pharmaceutical Metrics: Measuring and Improving R&D Performance," David Zuckerman discusses his three principles of measurement: (1) Metrics measure progress toward our goals; (2) Metrics help us prevent failure; and (3) Metrics get us out of ruts. These principles handily describe on a strategic level why metrics exist in an R&D environment. Before we get to this tactical level, an understanding of the more strategic needs behind the use of metrics needs to be in place. The first question that needs to be asked is, "Why do we need to collect metrics to begin with?" The answer to that question will be rooted not at the departmental level, or even the divisional level—it will ultimately be embedded at the corporate level. Since the overwhelming majority of pharmaceutical and biotech companies are publicly traded (or wish to be), it follows that like any company they share the goal of serving shareholders first and foremost. One issue that clouds this seemingly straightforward proposition is the nature of the industry itself. Many people whose work in the industry—and particularly those whose jobs are closely tied to clinical research—view the idea of having monetary profit as the primary goal of their company as distasteful and contrary to the more idealistic notion of helping their fellow man. As a result, many process improvement efforts (and related metrics) are justified not by the support of solid business cases but by qualifications such as "this will make our lives easier." The problem with this approach is that even if everyone can agree that their lives will be made easier, no one seems to know if the company will actually benefit financially from such an endeavor. Helping people and benefitting monetarily are not mutually exclusive ideas; just because money is being made, doesn't mean that benevolent intentions are any less. 

The financial benefits of an improvement project are not necessarily easy to figure out. For example, many such projects, and the metrics surrounding them, revolve around cycle-time reduction. This leads to a few issues. Example: if you do in fact reduce cycle times in one process, does that gain propagate all the way through to releasing the drug to market? According to business management guru Eli Goldratt, "Throughput is the rate at which the system generates money through sales."

  In other words, will the improvement really allow the company to increase throughput and start earning revenue sooner? Even if it does, is it possible to truly estimate the financial impact of that improvement given all of the variables that exist in attempting to get a drug approved years down the road? The financial impact of an improvement project centered on operational efficiencies is simpler to estimate—it usually isn't connected to future revenues from drug sales, but rather reduced operating expenditures and/or increased throughput in the here and now. Even so, it can be difficult to agree on what the net impact of a change might be, or even how to measure it accurately.   

In order then to maintain alignment with the "ultimate" metric—shareholder value—senior management of pharmaceutical and biotech companies must ensure that all projects, whether improvement related or otherwise, will ultimately benefit the bottom line over the long run. Considering that the cost of bringing a single drug to market can easily reach $800 million or more over 10 plus years, it is imperative that a sponsor organization has all the metrics it needs to maximize its return on this enormous investment. Any metrics collected for the sake of improvement efforts must satisfy the criteria of adding shareholder value, with the possible exception of projects that are part of a larger strategic initiative and do not have shorter-term payoffs which can be directly measured. Similarly, even operational metrics should align to the corporate—not departmental—bottom line as much as possible. Only cycle times that have a direct impact on last subject out, for example, should be monitored and managed. Many sponsor companies focus on the date of first subject screened or first site initiated as "key" milestones, but really, isn't it the 

 site initiated that really drive the timelines for the rest of the study? And even then, how important (or more specifically, how 

 important) is it to worry about these things for a non-critical path study? We all want our trials to run smoothly and quickly, but the return on investment for making this happen for each and every study needs to be considered if companies are to maximize value for their shareholders. 

Many companies still do not seem to derive the benefit from metrics that they should. As mentioned above, a large part of the problem is that they just don't "get" why metrics should be collected in the first place. Looking more closely, there are certain pitfalls that are common throughout the industry, which companies and departments continually tumble into. By being aware of what they are, operations groups will be better able to navigate around them.  

The biggest mistake companies make is that they tend to make things way more complicated than they need to be. Specific examples abound, but the facts can be boiled down into three general categories.  

 Over collection makes it hard to focus and act on the metrics that matter. Albert Einstein once said, "Everything should be made as simple as possible, but not simpler." Following this bit of advice, the first requirement of metrics, as mentioned above, is that all measures should be "actionable." If you're not taking an action (or refraining from doing so) based on a metric, you don't need it. Moreover, those actions should serve to drive positive changes on some level of the organization. Having too many metrics causes confusion and obscures any clarity of purpose. Employees are charged not only with carrying out practices aimed at improving metrics, but must also report back progress so executives can see if those programs are working. If metrics are too complex, the handoffs from goal to implementation to feedback can be easily mishandled. Keep it simple: if an objective can't be expressed in three to five key thoughts, it's probably too complicated. Simplifying drives performance by enabling comprehension. 

Companies must be fully aware of the Data Rich but Information Poor (DRIP) principle. In the 1990s, GM followed several hundred metrics on a monthly basis according to Jay Wilber, director of Quality Programs at GM, "We were measuring everything." GM executives went through an extensive analysis of the metrics, keeping only those that offered meaningful and actionable information. The manufacturing division later narrowed its scorecard down to 30-50 metrics. 

In another example, the firm Bain & Co. at one time had a large client, with revenues on the order of $20 billion. The client's CEO received 6,000 metrics and was somehow expected to create a mental picture of the health of the company. Much time was wasted in debating what all the numbers meant. The metrics were later condensed to a single-page dashboard of 25 key performance indicators for the CEO to focus on. In addition, each executive team member received a personal one-page dashboard tailored to their area of oversight. 

Do any of these examples ring a bell? While these may be extreme cases, it's not unusual for a clinical operations group to utilize dozens (and dozens) of charts, graphs, and tables to manage its business where a fraction of that amount would do. 

 Each company is different (products, market position, vision, etc.), and must decide for itself which metrics, based on which data, will provide a road map to success. For example, Continental Airlines was so focused on cost cutting in the mid 1990s after emerging from bankruptcy, that it rewarded pilots for saving fuel. Many pilots flew slower and behind schedule and skimped on air conditioning, driving valuable business customers into the arms of competitors. Clearly, Continental's business performance doesn't center on saving fuel; it centers on filling up as many planes with passengers as it possibly can. This was a costly lesson for the airline and one that seems to be repeated on different scales across pharmaceutical R&D organizations. How many clinical operations groups focus on "small picture" metrics such as first subject screened and departmental budget targets? The moral of the Continental story is clear: when it comes to metrics, focus on using the right data by keeping the big picture in mind.  

Ideal metrics should provide leading indicators, pair financial and non-financial indicators, and display central tendencies with a companion measure of variability. Leading indicators help personnel understand where the business is going (in the same way a fuel gauge gives you an idea of when you'll run out of gas well before you actually do), not just where it's been. In clinical operations, for example, too many reports focus on delivering cycle-time reports, but during a study what is the point of knowing what has already happened? Ideally the reports would center on what would 

 to happen in order to hit agreed upon targets. So instead of (or in addition to) cycle times for completed milestones, the reports should provide cycle times in the form of "X days and counting" for open items, and add alarms for when days in progress passes a certain point. This will focus the users on what needs to be done rather than what has already happened.  

Pairing financial (bottom line information) and non-financial indicators is important in order ensure a company's action, based on a particular metric, is (literally) paying off. It is clear from the earlier example that Continental Airlines failed to do this, and unintentionally sacrificed significant revenue and market share of business travelers in an effort to cut down on costs. Certainly it wouldn't hurt if clinical operations groups started to use this approach when implementing process improvement initiatives. How else will they (or management) know if it was really worth it?  

If proper sources of data are not used, then having "ideal" metrics in place will not help very much. Completeness and accuracy of data are obviously crucial; equally crucial is the place you are getting your data from. As an example to highlight this last point, a company by the name of InterFirst Mortgage was getting an inaccurate read on "turn time" (the time its staff took to close a loan) because it asked its sales force, not its customers (mortgage brokers who ultimately created value for the company), for information. The company later discovered through an online feedback tool that its turn time was as good as, if not better than, its competition. By adjusting sources of data and getting a more accurate read from its valued customers, the company avoided focusing on what was really a non-issue and instead focused on improving efficiencies elsewhere. In another example, a company called eePulse once consulted with a software company that had measured the impact of a merger on employee morale and concluded that it was a smooth transition, and a major success in the eyes of employees. Upon closer examination however, it turned out the post-merger data came from workers who joined the company after the merger; most of the employees present during the merger had left the company. Regardless of what is being measured, it is apparent that without authoritative data sources and appropriate information sources (especially given the increased use of outsourcing these days), the interpretation of results can easily be compromised. 

 This practice can produce satisfactory results near term but ultimately guide the company to severe problems later on. Metrics should in some way address the big picture. Many companies focus on short-term metrics to please someone else (such as Wall Street, or a parent company) much to the detriment of the future health of the company. Instead of just saying "our hands are tied, that's what the Street wants," companies should instead sit down with analysts and get them on the right track. Similarly, clinical operations people should sit down with upper management to discuss why blowing past this year's budget will yield benefits for years to come. A different twist on this tale is the struggle between corporate and departmental performance goals. Maximizing performance of a department or division is often done at the expense of corporate financial goals. A department from a mid-size pharmaceutical company, this author was once told, utilized a large amount of contractors despite the fact that they were generally about 50 percent more expensive than fully-loaded full-time employees (for which there was more than enough work for years to come). Why? The simple reason: hiring of permanent employees came out of the departmental budget, whereas contractors were paid out of the corporate budget. In short, for the department to keep under budget they needed to cost the company more money.  

In another example of short-sighted metrics, a major North American cell phone company tracked a key performance indicator (KPI) called "customer churn," which was an undesirably high 3 percent. The company spent huge amounts of money through a combination of promotional pricing and marketing activities on customer retention. However, when the company took a closer look, it found that 75 percent of its customers were unprofitable or only marginally profitable. Once it discovered this, it refocused its marketing resources on the 25 percent of customers it really wanted to keep, and on attracting more like them (but only after wasting large sums of money on pointless efforts). This brings to mind the old marketing axiom, "there are some customers you just don't want." In the world of clinical operations, one can argue that a parallel (of sorts) exists when dealing with investigator sites…but that is another article unto itself. 

In another example from the cell phone industry, many companies were going out of their way to improve on the primary Wall Street metric of new subscribers (which turned into net new subscribers, then cost of acquiring customers, then net additions of profitable customers, etc.). As a result, early on many companies fell into the trap of pumping up new subscribers (through promotions, discounts, etc.) to the disadvantage of their own profitability and cash reserves. Many of these companies, not surprisingly, are now out of business. 

It is obvious from these numerous examples that companies need to keep their "eyes on the prize" when defining metrics and setting goals. If it is not clear that what has been set in place will help to incent and guide employees to corporate (not departmental) success over the coming years (not months), then the company should head back to the drawing board. 

Now that we know what the common mistakes are (too much data, using poor or misaligned data, and being short sighted), we can work on how to avoid them through streamlining, proper alignment, and use of leading indicators, and focusing on the big picture. How can we apply this knowledge to the clinical operations framework? By looking at four broad categories of clinical operations metrics—quality (Table 1), delivery (Table 2), cycle time (Table 3), and cost (Table 4)—we can translate the lessons learned from GM and the cell phone companies into some specific and relevant clinical development examples. 

 Table 1. The financial benefits of an improvement project are not necessarily easy to figure out. 

Quality is always a challenge to define in the context of the conduct of clinical trials; ask ten different people, get ten different answers. Regardless, by applying the three avoidance techniques, we can see that there are ways to at least approach the topic in a thoughtful way.  

Table 2. When it comes to metrics, focus on using the right data. 

Delivery refers to producing the correct output, which in the case of clinical trials can be taken to mean that sites are attracting a sufficient amount of subjects and producing good, clean data as directed by the protocol.  

Table 3. Pairing financial (bottom line information) and non-financial indicators is important in order to ensure that a companys action, based on a particular metric, is (literally) paying off. 

Cycle-time metrics are often the most simple to measure, and as a result many organizations track down to the most detailed milestone level without really getting much out of it. Many reports are generated that don't get used and obscure the few that are of value. 

Table 4. Metrics should in some way address the big picture. 

Cost metrics can be the most difficult to collect, but at the same time are often the best and most direct method of measuring value. By looking at cost metrics relative to the other categories—quality, delivery, and cycle time—the organization can get a comprehensive and crystal-clear picture of the effectiveness and efficiency of its operations. 

The fundamental purpose of performance measurement is to encourage behavior that achieves the goals of the organization. Especially in a people-driven area like clinical operations, one can never ignore the power of incentives or the damage that can be wrought by fear. The Continental Airlines example of the fuel-savings incentive was a good display of what not to do. The company later decided that on-time departures were a priority, so scheduling and operating department employees were given a $65 bonus every month that the airline finished in the top five in on-time performance. Employees therefore had an incentive to make the corporate goal a reality. The key of course is to avoid "window dressing," where employees can circumvent the system by putting up impressive incentive-related numbers at the expense of other areas (such as in the fuel example), which is why a scorecard approach is valuable since it's extremely difficult to "fool" every dimension of a scorecard. At GM, there is a rewards program for employees who make suggestions that result in cost savings. GM employees receive 20 percent of savings after implementation, for a maximum bonus of $20,000. Results were remarkable (though not remarkable enough, given the company's declaration of bankruptcy)—in 2002, the company saved $397 million and paid $60 million to employees. This shows what a dramatic impact motivated, experienced employees can have on profitability. The point here is that incentives are powerful and, when used properly, are win-win. The key of course is that these incentives should affect the metrics that align with the corporation's market and financial goals. 

Albert Einstein said, "Not everything that can be counted counts, and not everything that counts can be counted." As previously discussed, clinical operations groups need to start cutting down on the quantity of metrics collected and start concentrating on the quality and relevance to corporate objectives. The life sciences industry is a nice one to be in as it can have a truly significant impact on people's lives, but still it's a "for profit" industry. Any project—be it a drug program or a process improvement initiative—should be justified with a favorable business case. This is not always easy in an R&D environment as the consequences of actions are often not directly observable due to the long lag time between investment and return.   

In the end, it's not just about choosing the right individual metrics, but doing so in a way that provides a complete view of the organization's performance relative to its goals, without overwhelming people or giving them incentive to act in a manner counter to the company's best interest. By following the basic principles outlined above and keeping the bottom line in mind, a company's metrics can be both simpler and ultimately more rewarding.  

2. C.H. Loch, U.A. Tapper, "Implementing a Strategy-Driven Performance Measurement System for an Applied Research Group,"  

The Journal of Product Innovation Management,

Feature Article

Collecting too many metrics can lead to misappropriation and misinterpretation.

Improve the Business of Science

 has been appointed Chief Financial Officer of 

, MD, has been named Vice President and Global Head, Medical Affairs, at 

(Cincinnati, OH) where he will provide global leadership for the company's medical affairs organization. 

has been appointed as Senior Director and Global Head, Patient Recruitment.  

to fill its newly-created position of Director of Patient Recruitment.   

(Raleigh, NC)  has made four additions to its team including 

as Vice President and Chief Business Development Officer, 

 as Regional Directors of Business Development, and

 as Manager of Quality Assurance and Regulatory Compliance.   

, MD, as Senior Vice President of Global Regulatory Affairs. 

 will strengthen the company's proprietary HD360° technology platform. 

• Previously the Senior Therapeutic Director for Oncology at i3, 

 (Research Triangle Park, NC) as Vice President, Clinical Operations. 

, PhD, as Patient Reported Outcomes Scientific Advisor where she will lead CRF Health's PRO consulting initiative providing scientific insight and guidance to clients and internal staff, as well as to the global clinical trial sector.   

(Princeton, NJ) oncology team in his new role as Vice President, Clinical Research.  

Concord, OH) Analytical Chemistry department. 

• Leading sales, marketing, and business development strategies for late stage business, 

 will use her previous drug development experience as  

(King of Prussia, PA)  Executive Vice President, Global Business Development.  

 to the position of Director of Contracts and Budgets where she will supervise a team of contract specialists in the St. Louis and Brussels offices, and 

has been hired to the position of Business Development Director, Europe. 

(Manchester, UK) has made several changes to its executive management team with the appointment of 

• Bringing with her more than 20 years experience, 

, PhD, has been appointed Global Regulatory and Clinical Affairs Manager by 

CTI Clinical Trial and Consulting Services

has joined as Director, Business Development Operations. 

 (Redmond, WA) have entered into an agreement to jointly implement a technology solution designed to improve efficiency in managing Risk Evaluation and Mitigation Strategy programs by using Microsoft Amalga Unified Intelligence System and Microsoft HealthVault.

 (Newtown, PA) has created strategic partnerships with 

(Flemington, NJ) to strengthen the BioClinica Certified Partner Program and provide customers with additional support in therapeutic areas of study and data monitoring and management.

(Califon, NJ) has signed a master services agreement with 

 (Dresden, Germany) to begin clinical studies and regulatory filings for ANAVEX 2-73, its lead compound for the treatment of Alzheimer's Disease.  

(Toronto, Canada) has created a global collaboration with LabCorp through its 

(Cranford, NJ) division, providing clients with access to CAP-accredited laboratories across both. Under the agreement, clients of each company will be able to access LabCorp's  assay portfolio and Clearstone's central laboratory protocol management system: APOLLO CLPM.

 (Surrey, UK) have entered into a strategic partnership giving Argint exclusive distribution rights for the Academy's training courses throughout Central and South Eastern Europe.

(Buckinghamshire, UK) has entered into a collaboration with the 

 (PACRA) (Singapore), which allows ICR to expand its global presence in the Asia Pacific region by letting the company provide research and training to PACRA members research professionals across the region. As part of the agreement, the ICR's members' journal CRfocus will be produced quarterly and rebranded as "Silk Route" for the Asia Pacific members via the PACRA website.

(San Ramon, CA) have been named to the Inc. 5000 list, a listing compiled annually by Inc. Magazine, recognizing America's fastest-growing private companies, for the fourth year in a row. 

(Chapel Hill, NC) has been designated as one of the 50 most family-friendly places to work in North Carolina for 2010 by Carolina Parent Magazine.

 (Wilminton,  NC) has established preferred provider relationships with a network of sites including Commonwealth Biomedical Research (Madisonville, KY), 

 (Albuquerque, NM), in order to conduct Phase I trials to meet growing client demand for these services.

(Chicago, IL), has formed to provide study visits in the home or other alternate site settings through a network of clinicians.

 (Plymouth Meeting, PA) has launched an Inventory Management Program that offers device buyback options, third-party brokerage services to transfer devices between clients, new equipment for long-term investment, reconditioned equipment to reduce the upfront costs, refurbishing services on both client owned devices and newly acquired devices, and leasing options. The company has also recently completed the ePRO vendor certification program for use with the EXAcerbations of Chronic Pulmonary Disease Tool, a patient-reported outcome measure designed to standardize the method for evaluating the frequency, severity, and duration of acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitis in the United States, as well as international based studies and clinical trials.  

(Derby,  UK) has been appointed by a Japanese pharmaceutical company to handle the clinical trial drug manufacture of two NCEs for UK trials, which marks the first time the Japenese company has outsourced clinical trials manufacture to a European company.  

(Woodlands, TX) has played a role in the development of 42 novel cancer therapies approved by the US Food and Drug Administration, assisting most recently with Tasigna capsules, a medicine developed by Novartis.

To expand its biopharmaceutical development services globally, the 

(Boston, MA) have made a series of acquisitions including 

(Bethesda, MD) for approximately $730 million. 

(Redwood Shores, CA) has completed its acquisition of 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update October 2010

Act cover

Every now and then it's good to step back and take a broader view. The natural focus of Brussels tends to be introverted—as was so tellingly demonstrated, for instance, by the September spats about French treatment of Roma. French President Nicolas Sarkozy was struggling to win popular support in the run-up to national elections by forcibly repatriating immigrants from Eastern Europe under the slender pretext of criminality. When the European Commissioner for Justice publicly criticized these actions, Sarkozy's response was "Are you ready to take them in your country?" And the chattering classes in Brussels became obsessed with discussions of the legal details of whether citizens of Romania, Bulgaria, and Slovakia—all of them EU member states—could legitimately be "repatriated," and on what grounds.  

All very spirited, of course, but none of it really contributing towards any type of solution to the long-standing challenge of integrating—or at least not discriminating against—millions of marginalized European Union citizens.  

A similar introversion is evident in European discussions of clinical trials. The need for reform of the EU clinical trials directive, the fine-tuning of the new pharmacovigilance rules, the limits on what adverse drug reaction information the European Medicines Agency (EMA) could, or should, disclose. These are topics that have absorbed political attention in Brussels, almost to the exclusion of any other consideration. 

Consequently, it is a breath of fresh air to look for a moment beyond the shores of Europe, and beyond the confines of one of the richest corners of the world, and to consider the relation between clinical trials and those who live in far less comfortable conditions.  

In early September, the EMA held a three-day international workshop to discuss a global framework of clinical trials. The heart of the discussions was how to protect the rights, safety, and well-being of patients participating in clinical trials anywhere in the world. Some 170 participants from around 50 countries from the Americas, Asia, Africa, and Europe came to London, representing patient organizations, health-related non-governmental organizations, clinical trial sponsors, the pharmaceutical industry, ethics committees, regulatory authorities from all continents, and intergovernmental organizations. 

The workshop was part of the consultation process on a reflection paper from the agency on ethical and Good Clinical Practice aspects of clinical trials conducted in third world countries and used in support of marketing authorization applications to the agency. The motivation is administrative as much as humanitarian, but is nonetheless to be welcomed. As the agency points out, with the increasing globalization of clinical research, less than 40 percent of patients enrolled in pivotal clinical trials for marketing authorization applications to the agency received their treatments at clinical trial sites in western Europe. These trials involved more than 44,000 clinical trial sites in 89 countries. As Fergus Sweeney, head of inspections at the agency, put it: "Wherever in the world we stand, the majority of clinical trials are being conducted somewhere else in the world, under a different regulatory framework and in different cultural settings." 

The practical problem from this is, he went on, that "we all rely on the same trials to make decisions: as regulators, to allow or disallow marketing authorizations, and as patients and healthcare providers, to use or not to use a medicine." But the quality of the trials may not always be the same. 

And from a broader humanitarian or ethical perspective, there are challenges too. As the meeting took its course, some consensus emerged around the conviction that EU regulators should never accept (or require) studies conducted beyond the EU that would be ethically unacceptable in the EU. There should not, became the refrain, be a different standard applied to trials conducted in the EU compared to those conducted elsewhere. 

Achieving this refined state will depend, participants underlined, on cooperation and networking between regulatory authorities and ethics committees involved in the supervision of clinical trials. It will also require greater transparency of clinical trials, including clinical trial registries and the provision of information about ethical and GCP aspects in the European Public Assessment Report that the agency produces on each application it processes. In addition, patients will have to be involved early on in the design of protocols, to ensure the adequate protection of clinical trials subjects, participants suggested. 

The EMA's principal role is obviously to reach opinions on medicine matters that affect Europe. But it is also empowered to give a scientific opinion, in cooperation with the World Health Organization, on the evaluation of medicines intended exclusively for markets outside the EU, based on the same standards that apply to assessments of medicines intended for use in Europe. 

The latest rewrite of EU pharmaceutical legislation also spells out a duty to provide for the ethical requirements laid down in the clinical trials directive when clinical trials are conducted outside the EU on products destined to be authorized within the community. When evaluating authorization applications for such medicines, the agency must verify that the way the trials were conducted met EU good clinical practice standards and ethical requirements. 

The agency's reflection paper points out that most countries now have a regulatory authority to which application should be made before a clinical trial can commence—and insists that these requirements must be met in each country in which a clinical trial is conducted. Regulators must support compliance with local requirements in each country as well as reinforcing international ethical and good clinical practice standards, it emphasizes. In addition, every trial must receive a positive opinion or approval from an ethics committee with appropriate jurisdiction for the investigator sites and trial concerned.  

In countries with what the reflection paper politely terms "limited frameworks for ethical review or regulatory oversight," sponsors should seek an additional review of the study protocol with an ethics committee in a country with EU-level standards. EU regulators should refuse to consider data from any trial where an independent ethics committee has not assessed the protocol. Informed consent must be assured, and appropriately renewed as necessitated by significant changes in the conditions or procedures of the research or if relevant new information becomes available. In developing countries, the research project should ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings.  

Similar constraints should be imposed on information to trial subjects, on the protection of personal data, on the observation of special considerations for trials conducted with pediatric populations, on archiving of trial documentation, and on insurance. 

And in respect to groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized, protection should be provided against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.  

Similarly, economic or logistical reasons for the unavailability of an established effective intervention cannot justify a placebo-controlled study in a country of limited resources when it would be unethical to conduct a study with the same design in a population with general access to the effective intervention outside the study. Regardless of the location of the trial, all patients participating in these trials should receive the same or a similar standard of care and comparable treatment options as trial participants within the European Economic Area.  

When considering whether it is appropriate to conduct a specific research study within a low- or middle-income country, one issue that should be considered by the sponsor, ethics committee, and national authorities, is whether the intervention being studied is likely to be available in that country if it is shown to be effective. If a product developed or knowledge generated by research is unlikely to be reasonably available to, or applied to the benefit of, the population of a proposed host country or community after the conclusion of the research, and if the sponsor does not foresee arrangements to make it available, the ethics of conducting the research in that country or community need to be carefully considered, reflecting on the need for access to treatment and on the risks and benefits that would apply to those participating in the trial and to their community including the medical care environment of that country/community.  

There are often great attractions in conducting trials beyond Europe, the reflection paper acknowledges. These may range from the obvious availability of patients willing to participate in clinical trials and with the relevant disease profile, to availability of qualified investigators willing and available to conduct the trials, and include lower costs or more rapid approval of trials. But sponsors should provide appropriate justification for the location of a clinical trial and detail its plan for addressing ethical and operational issues related to its proposed development plan. 

The agency recognizes that there is no one-stop-shop solution for these complex issues. It is minded to establish a pool of experts to provide advice in assessing the ethical aspects of such clinical trials submitted in support of applications in Europe. A program of routine inspections is likely to be set up, with facilities for responding to specific triggers of concern too. Priority will be given to the countries that have recently featured most frequently among sites where non-EU trials are conducted in support of EU marketing authorization applications including South Africa, India, the Philippines, China, Thailand, Brazil, Costa Rica, Peru, Russia, and Ukraine. 

The intention—and it is a laudable one—is to ensure that patients in the richer parts of the world are not benefiting unduly from the exposure of patients in the poorer parts of the world in the assessment of new treatments. This is a nobler pursuit than an internal slanging match between EU leaders on how to redistribute unwanted immigrants. 

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

View from Brussels

Routine inspections and regulations can help maintain GCP standards in global trials.

Conducting Clinical Trials Beyond Europe

As part of the campaign to promote transparency in pharmaceutical industry relationships with health professionals, recently enacted health reform legislation requires drug and medical product companies to report to the federal government fees paid to physicians for conducting clinical trials. The Physician Payments Sunshine Act, which was included in the Affordable Care Act (ACA) enacted in March 2010, establishes a process for publicly disclosing industry payments to physicians and teaching hospitals for research activities, as well as marketing. Sunshine advocates believe that pharma companies may influence prescriber behavior by engaging physicians as clinical investigators, consultants, and advisors—in addition to commercial encounters.  

The Sunshine Act specifically requires "applicable manufacturers" to report "a payment or other transfer of value" to a "covered recipient." Data submission includes recipient's name, address, medical specialty, amount received, date of payment, type of payment (cash, stock, items, or services), and if the payment is related to a specific drug or medical product. Anything worth more than $10, or outlays that total $100 a year, have to be reported, and that includes consulting fees, honoraria, payment for research, gifts, entertainment, travel, education, charitable contributions, royalties, licenses, grants, stipends to speakers in medical education programs, or anything else that the feds add to the list. Because small amounts can add up quickly, pharma companies are establishing aggregate spend information systems able to capture every dollar provided to doctors and to track those amounts over time.  

The Department of Health and Human Services (HHS) is charged with writing implementation regulations by October 2011 to clarify which companies have to report what information about who. Everyone is looking for clearer definitions of "consulting fee," "honorarium," "teaching hospital," and how reporting applies to affiliated companies, product co-development partners, and third party service firms.  

There's considerable uncertainty related to research expenditures:  Does reporting apply to the clinical spend for both interventional and observational studies? Or to fees paid to physicians presenting to Institutional Review Boards or serving on data safety monitoring committees?  

Another gray area is equipment supplied by a sponsor to a clinical site on a temporary basis. This is "unchartered territory," commented Wanda Toro, President of Bull's Eye Innovations, at the August Aggregate Spend Forum sponsored by the Center for Business Intelligence (CBI), an Advanstar Company.  

The process for submitting data to HHS, for recipients to review reports, and for the feds to make this information public also remains murky, making it hard for pharma companies to set up the computer systems needed to collect transaction data beginning January 2012, in order to file their first reports the following year (March 2013). That may seem like plenty of time to launch new programs, but the standard-setting process can take months, and no one at HHS seems to be in charge. 

Manufacturers will have to report amounts paid to physicians every year, but fees related to clinical research can be withheld from the public until after product approval by the FDA, or four years after the payments are made, whichever comes first. Pharma companies lobbied for this delay as a way to retain some secrecy for investigational programs. However, it calls for sponsors to identify what items fall into the clinical spend "bucket" so they can benefit from delayed publication. Investigator fees related to post-marketing clinical studies, though, are not delayed, further complicating the data tracking process. 

Pharma companies have been tracking and reporting fees and entertainment expenses to health care professionals (HCPs) for several years to comply with a range of state laws and other standards. Eight states, including Massachusetts, Vermont, Maine, Minnesota, and Washington, DC, have enacted transparency policies, and about 10 states were moving in that direction when health reform was enacted. In fact, the Pharmaceutical Research and Manufacturers of America (PhRMA) backed federal Sunshine legislation as a way to replace diverse state laws with a uniform national policy. Unfortunately, the ACA provision pre-empts state laws only partially, permitting states to enforce policies that are more stringent than the federal requirements. Minnesota and Vermont request disclosure of payments related to clinical trials, but several other states exempt such payments. Even so, specific exclusions raise questions about what qualifies as a "bona fide clinical trial" in Washington, DC or Maine, and what's "genuine research" in Massachusetts.  

The aim of these state initiatives is to reduce health care spending, pointed out Vermont Assistant Attorney General Wendy Morgan at the CBI forum. She and others believe that disclosure of payments will reduce marketing outlays and rationalize drug use. Drug companies spend millions marketing to doctors, and this "affects the way doctors prescribe," explained Illinois state representative Jack Franks. But he added that he won't continue to pursue an Illinois disclosure law because a federal policy is "better than a hodgepodge of legislation across the country." Morgan noted that Vermont will adopt federal definitions and standards as much as possible to avoid redundancies.  

Although the federal Sunshine Act does not ban doctor payments or other practices, Vermont and several other states have moved from disclosure to outright curbs on gifts to HCPs, which more clearly aims to cut marketing expenditures. If you limit gifts, said Morgan, you eliminate "a huge chunk of money added to the cost of pharmaceuticals."   

The state policies reflect the steadily rising demand for transparency in industry relationships with HCPs. A revised PhRMA marketing code in 2008 banned gifts to physicians and pricey restaurant meals. In addition, last year PhRMA updated its principles on conducting clinical trials to encourage "reasonable" payment to investigators; this aimed to curb the use of lucrative consulting and research contracts to camouflage promotional payments to docs. Several pharma companies, moreover, including Eli Lilly, Merck, GlaxoSmithKline, and Pfizer, have begun to post physician payments on their websites to comply with corporate integrity agreements negotiated to settle charges of illegal drug marketing. Most disclosure involves fees related to marketing activities, but Pfizer includes payments to research entities conducting clinical trials, an amount that totaled $15.3 million in 2009.  

Unlike most state laws, the federal policy clearly brings clinical research under the "aggregate spend" umbrella. That makes collection of data on payments to HCPs all the more complex, extending to almost every facet of pharma company operations, as well as to such activities at biotech and medical device manufacturers.  

Public disclosure of physician payment data is expected to have a noticeable impact on sponsor relationships with health professionals. Many doctors have become reluctant to make speeches on behalf of pharma companies or to consult on research projects. It may become more difficult to engage investigators in the United States in face of public disclosure of research fees and the implication that such work compromises a physician's independence.  

While all-inclusive aggregate spend programs may improve company information systems and help sponsors detect potentially damaging conflicts of interest, these initiatives are likely to create tension within companies. Pharma R&D and medical affairs staffs don't see themselves as part of marketing, and they are not accustomed to pulling out fees to investigators from large research budgets. Corporate caps on annual compensation to an HCP for marketing activities, as recommended by the PhRMA code,  may generate conflicts between the marketing department that wants to use a prominent clinician as a spokesman, and the research department planning to engage the same individual as an investigator.  

Just what HHS and states do with all the aggregate spend information remains to be seen. Beginning in September 2013, the government will start posting all payment reports on a public database in a format that is searchable and easily aggregated and downloaded. This wealth of information on corporate marketing and research may be surprising even to the reporting company, and certainly will attract industry critics and enforcement officials. HHS will provide Congress with an annual report aggregated by manufacturer, and each state will receive a summary of payments to its practitioners.  

Failure to comply with all the requirements "in a timely manner" carries fines that start at $1,000 for each reporting failure and jump to $1 million a year for firms that knowingly and deliberately disregard the rules. To avoid problems, sponsors need to update research agreements with investigators to ensure they obtain all required information, and to revise co-promotion and co-development agreements to clarify responsibilities for collecting and reporting required information. It will be important to get data right, as a host of attorneys, whistle-blowers, and prosecutors will have a sharp eye out for inadequate drug company disclosure and for situations that warrant charges of submitting false claims to the government. 

View from Washington

Reform law requires tracking and disclosure of fees to investigators and research consultants.

Sponsors Cope with New Sunshine Act Rules

Recently, I've been privileged to participate in a workshop led by the Institute of Medicine as part of a roundtable sponsored by the Office of the National Coordinator to discuss the "Electronic Infrastructure for the Learning Healthcare System" (LHS). The project has a long-range horizon—the "system after next" that would be in place by 2020. This was the second in a series, exploring three priority focus areas highlighted at an earlier meeting, namely: engaging patients and the public, promoting technical advances and innovation, and fostering stewardship and governance.  

Having the opportunity to engage in a forum comprised of so many experts and thought leaders in health informatics, technology, patient advocacy, and health policy reminded me of John F. Kennedy's characterization of his circle of advisors later remembered as the best and the brightest: "the most extraordinary collection of talent, of human knowledge, that has ever been gathered together at the White House with the possible exception of when Thomas Jefferson dined alone."  

Indeed, Jefferson himself also later made a spiritual appearance in one participant's summary comments, as having set a noteworthy precedent by successfully marrying his philosophy to architecture in the establishment of the University of Virginia. 

This engrossing and thought provoking event began with the premise of defining a health environment that can ensure that we fully capture and capitalize on all of the information resources relevant to our health and healthcare wherever and whenever we need them—quite a stretch from today's predominately paper-based world, but one that we hope will ride the wave of transition to electronic healthcare records in the near future.  

When first exposed to this extraordinary mission, I imagined the combined sense of thrill and terror probably felt by the first group of NASA scientists in 1961 after hearing JFK challenge the nation with "the goal before this decade is out of landing a man on the moon and returning him safely to the earth."  The magnitude of a goal to create this learning healthcare system involves no less of a technical challenge, but with a much steeper sociopolitical context. Like those anxiously energized scientists, many at the workshop must have been wondering "how do we get there" and "where do we start?" 

The focus of this most recent workshop meeting was to define the technical, governance, and social infrastructure of the year 2020 that would support the LHS, which immediately brings to mind the futility of predicting what technology will be like in a decade. Consider, for example, the likelihood of accurately anticipating the impact of the following technology game-changers at various points of time:  

So, thinking ahead to 2020, let's begin with the notion that technology will probably be unlike anything we can imagine. Yet given the recent historical pace of technology advancement, it's hard to imagine that it will be the ultimate obstacle. But we can certainly predict that the need to manage the cost and effectiveness of our health care system will still be a critical concern in 2020, and we can expect that considerable human, political, and economic barriers will still be in the way. 

Among the technology planners, there was a rapid convergence toward an infrastructure for the LHS based on ultra-large scale (ULS) systems, a concept defined by a team at the Carnegie-Mellon University Software Engineering Institute, as part of a federally funded study to describe how to approach future massive, decentralized systems based on a set of core principles. ULS systems are described by the study lead, Linda Northrop, Director of the Research, Technology, and System Solutions Program at the Software Engineering Institute, as "interdependent webs of software-intensive systems, people, policies, cultures, and economics ... systems at Internet scale."  

Applying ULS principles implies a tectonic cultural as well as technical shift in how we design software; when applied to the LHS it might involve building a permissive, loosely-coupled, all-inclusive enabling architecture based upon what Chris Chute described as a "parsimonious core" of standard data elements and design characteristics.  

This will be a leviathan of a system—a complex, distributed, adaptive ecosystem beyond anything most of us can imagine, which will affect the quality and extent of lives for the entire population of our nation, and perhaps much of the rest of the globe as well. But the key insight to many of the workshop participants (who may not have been previously exposed to ULS and admittedly may have had widely divergent concepts of what it means) seemed to invoke a "less is more" architectural approach. Design a system that is inclusive enough to easily accommodate the multitude of legacy systems that will still exist, and that encourages widespread adoption with the least burdensome approach.  

Of course, the ULS model today consists only of a set of principles intended to guide a research agenda rather than a defined blueprint, and its 

 entry cautions that ULS systems have been defined informally as "systems that are currently impossible to build due to limitations in the fields of software design and systems engineering." Here, again, we must depend on that 10-year window for technology to catch up, but in the meantime we need to start describing a road map immediately, and look for opportunities to move along the path step by step. 

Interestingly, a less prescriptive ULS architecture could be somewhat at odds with the tightly defined architectural approach employed by a benchmark example such as the National Cancer Institute's CaBIG project, one of the most ambitious and far-reaching system initiatives which has already proven to deliver many innovative system capabilities. Since the ULS strategy—and the way it would apply to a proposed LHS—has not yet been sufficiently fleshed out, it's not yet clear which approach would better achieve semantic interoperability —a tightly defined set of architectural, data, and content standards that would require strict conformance (though potentially at the cost of more widespread adoption) or a much broader approach with fewer restrictions that encourages broader participation, but requires a lot of things to sort themselves out much farther downstream.  

It's important to remember that it's not just a matter of getting data—though what a mountain of data this would be—we also need to ensure sufficient quality and trust so we can understand and use the data consistently and make critical life-altering decisions based upon that knowledge.  

Which brings us back to the original question we share with the NASA founders: "Where and how exactly do we start?" Well, one way to start is by simply imagining stories—to visualize the world as we'd like it to be in 2020.  

For example, one such story that resonated with me from the first workshop was described as a large-scale, real-time rolling clinical trial, where, when a patient is diagnosed, they are presented with a range of options and associated probabilities of cure versus risk presented by their physician. Once the patient and their doctor choose what looks like the best option, they are enrolled in a virtual clinical trial which tracks the progress of their treatment versus others with the same condition right through to outcome. This information in turn would feed back into the learning system to adjust the probabilities for the next patient treatment scenario and so on. 

In such a world, there are no precise boundaries between patient care and clinical research. Patient data is collected once in a common format that can be used equally for patient care, administration, and research. Health information is easily available to research, and research information is readily available to healthcare providers and patients, eager to share their information in the hope that it helps improve the health of others. The learning system is always conducting research, readily adapting to new knowledge, and the entire population can benefit from the cumulative and accumulating wealth of information that is generated from healthcare. In such a world, there's also a blurring between primary and secondary uses of data—since all uses are primary in the mind of the user.   

Of course, such a future world must be based on a great deal of trust, and we have quite a ways to go in that area before we can hope to let the technology take us the rest of the way home. But we can start by envisioning more of the stories. Try to visualize what it would be like to have such a system available in 2020, and how it could improve the lives for so many. Then think about what we can begin to do now to help make it happen. 

is Senior Vice President and Chief Quality Officer at Lincoln Technologies, Inc., a Phase Forward company based in Waltham, MA. He can be reached at 

1. Software Engineering Institute, "Ultra-Large-Scale Systems: The Software Challenge of the Future," June 2006, 

http://www.sei.cmu.edu/library/abstracts/books/0978695607.cfm

http://www.sei.cmu.edu/library/assets/northropkeynote.pdf

http://en.wikipedia.org/wiki/Ultra-Large-Scale_Systems

Technology Viewpoint

Access to all available medical evidence can profoundly improve treatment effectiveness.

A Learning Health Care System: One Giant Leap

Clinical grant expenditures represent a major portion of the budget for later phase clinical trials. Although not the ultimate reason for picking a site or region to conduct clinical trials, the relative cost of conducting a clinical trial can play an important role in the decision.  

TTC provides annual current global data on the relative costs of clinical grants around the world using data pulled from the GrantPlan® database. The sponsor company and CRO subscribers to this database conduct over 76 percent of all commercial clinical trials.  

Mean Costs per Subject in Phase II-III Trials			

This year, the data shows that the United States remains the most expensive country for clinical grants, often by a large margin, followed by the United Kingdom. Newer geographies such as Eastern Europe, Latin America, and Asia are distinctly less expensive for clinical research.  

While less expensive, these areas show more rapid increases in clinical research spending than in North America or Europe. The United States and Western Europe (excluding the United Kingdom) have been averaging 3 percent to 4 percent annual increases. In contrast, clinical grants in the new geographies are increasing at rates over 14 percent.—TTC (for more information, please contact 

Clinical grant expenditures represent a major portion of the budget for later phase clinical trials.

Clinical Grants Expenditures are on the Rise Throughout the World

In every clinical trial there are study subjects who are very close to meeting one or more inclusion or exclusion criteria, but for one reason or another don't. 

A screening creatinine of <2 mg/dL is required, and the subject has a creatinine value of 2.2 mg/dL. 

Subjects must be >18 years old, but the volunteer is 17 years and 10 months old.

A screening hemoglobin of >10 mg/dL is requited, but the subject has a hemoglobin value of 9.8 mg/dL.

Dosing is to occur within 14 days of the screening visit, but the subject is dosed on day 15.

Oftentimes, the scenario goes like this: The principal investigator identifies a subject who does not meet one or more of the inclusion/exclusion criteria and contacts the sponsor to request a waiver. The sponsor provides the waiver. The subject is enrolled into the clinical trial. The principal investigator notifies the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that the sponsor has provided a waiver, and a subject who did not meet inclusion/exclusion criteria was enrolled into the trial.  

To many readers, this scenario makes sense, is appropriate, and it is what they do. The purpose of this paper is to remind these readers that this scenario is not GCP-compliant. GCPs require the IRB/IEC to approve the enrollment of a subject, not meeting inclusion/exclusion criteria, prior to that subject's enrollment into the trial. This article will review the regulations and guidelines when a sponsor provides a protocol waiver to enroll a subject who does not meet one or more inclusion/exclusion criteria; the FDA's apparent position on sponsor-provided waivers (based on warning letter references); the IRB/IEC's responsibility regarding these waivers; and the risks to the subject, investigator, sponsor, and clinical trial when protocol-ineligible subjects are enrolled into a clinical without the prior approval of the IRB/IEC. 

 Before the trial begins, the principal investigator signs the FDA 1572 and, typically, signs the sponsor's protocol signature page. By signing, the principal investigator has documented his/her intention, commitment, and obligation to conduct the trial in compliance with GCPs, the applicable regulations and guidelines, and the protocol. In the absence of a life-threatening situation, US regulations and ICH guidelines stipulate that changes to the protocol are only permitted if the sponsor has alerted the IRB/IEC, and the IRB/IEC has granted prior approval.  

Waiving inclusion/exclusion criteria affects investigators, subjects, sponsors, and the trial itself.

Applied Clinical Trials-10-01-2010