One reason DIA chose Barcelona to host its 20th Annual European meeting—in addition to the city's beauty and mild March temps—is because it represents a gateway to Eastern and Southern Europe, where the association hopes to expand moving forward. The pharmaceutical industry has gained global stature, and DIA wants to continue its mission "to enhance health and well-being around the world," said Linda McGoldrick, DIA's new executive director, at the start of the plenary session, which this year took on a new and shorter format. Instead of speeches, the session took the form of a debate/panel discussion. 

The EMEA's Executive Director Thomas LÃ¶nngren and Jacques Demotes-Mainard, ECRIN program coordinator, INSERM, France, meet up after the plenary. 

Eight distinguished professionals representing different industry segments, including regulatory, pharma, public health research, and patient groups, took the stage along with two moderators. The plenary panel shed some light on the research scene in the EU today. Topics explored included the private/public Innovative Medicines Initiative to reestablish Europe as a hub for research; the idea of a single European price and reimbursement system for prescriptions, which most agreed would prove difficult and one session chair later said would benefit wealthier countries and hurt poorer ones; the need to increase capacity and expertise across the network of national agencies, thereby strengthening the agency as a whole; and the cons of centralizing clinical research, such as depriving the national agencies a close relationship with its citizens/patients. Also discussed was the EU and U.S. transatlantic partnership and how future collaborations could include fighting counterfeiting and eliminating duplicate inspections of non-EU and -U.S. manufacturing sites. Said panelist Martin Terberger of the European Commission Enterprise and DG Pharmaceuticals: "Transatlantic partnership is a huge benefit for patients, even if they don't know it."

The sessions, which almost all took place on Level 2 inside the Centre Convencions Internacional—making getting around easy—packed in plenty for the 3000+ attendees. This year, the subject of patient groups and the unique role they can play in drug development proved popular (check out 

 "A Pandora's Box for Clinical Trials?" for a patient group that's making history). One interesting remark made during the meeting: Apparently in the UK, after the 2006 TGN1412 tragedy, trial volunteerism increased. 

India and China, two emerging markets explored in Theme 11—themes replaced the traditional session tracks—will for the first time host DIA meetings. The 1st India Annual Meeting, taking place in Mumbai April 28–29, is expected to draw 200–300 attendees. McGoldrick fondly compared the event, "Building Bridges Between the Regulators and the Pharmaceutical Industry," to the first Euromeeting and, just like Barcelona, considers it a gateway to nearby regions like Pakistan. As for China, DIA is planning to host its first meeting there in 2009.—

Articles

News

The Drug Information Association hosted its 20th Annual European meeting in Barcelona, Spain, where industry experts discussed topics at the forefront of European pharma.

Buenos DIAs from Barcelona

Drug pooling's potential to reduce waste and minimize supply outage is of keen interest to biopharmaceutical companies. Yet confusion persists about what pooling can and cannot do—and about how pooling can and cannot be done.

Pooling, which is employed in conjunction with IVRS/IWRS, is possible when more than one protocol operating at the same depot and/or clinical site uses the same drug. By treating identical supplies as commutable among pooled protocols, pooling allows supply and safety stock to be shared. With pooling, dispensing units are interchangeable (indistinguishable in content, count, and container/closure system) and while in their pooled state, they are protocol independent, with a single, shared IVRS definition. 

There are three basic levels of pooling that might be of interest to clinical trial designers and managers. First, a fairly obvious one: pooling a set of packaged kits or kit components that are not yet labeled. We might call this "Pooling Prior to Labeling." This method is uncontroversial and is out of the scope of this article. 

A second method is to deliver packaged and labeled goods to depots without a protocol number on the label. This is useful for a variety of different simultaneous clinical trials in the same program (or at least using the same kit types). We might call this method "Pooling at Depots." 

Pooling at Depots is somewhat more controversial because it requires that the protocol number be written or affixed to the label of all kits prior to shipping, but after being requested by clinical sites (usually via IVRS) for particular trials. Both the process around this activity and the regulations in various countries—especially in Europe—are rather unclear. However, Pooling at Depots represents a significant clinical supply advantage over Pooling Prior to Labeling, and is thus worth consideration. 

The third method of pooling encompasses Pooling at Depots but also makes the assumption that some clinical sites may be running multiple "pooled" protocols at more or less the same time. In this type of pooling, kits may actually be shipped from the depot without a single protocol number, although sometimes they do show a set of protocols, or a program code. In any case, the kits remain protocol independent, even at the clinical site, until they are dispensed. At dispensing time, the IVRS marries the protocol to the kit number and any required label modifications may be made at the site. We might call this method "Pooling at Sites." 

Pooling at Sites, done when there is more than one protocol operating at the same investigative site, is actually far more commonly applicable than may be apparent at first blush. Although in earlier phase studies it is uncommon to have multiple studies sharing the same formulation, in later Phase III and IV studies it is not uncommon at all. However, many clinical supply managers interpret various European or other regulations as prohibiting the shipment of drug to sites without a protocol number on the label. Others note that exceptions are made in cases where centralized randomization systems are used. Others still note that regardless of the letter of the law, certain regulatory agencies will never allow pooling at sites. A common reaction to the notion of pooling at sites is "good luck." 

Nevertheless, Pooling at Sites does indeed occur in the biopharmaceutical world, and has indeed been shown to save significant supply when used. We will assume that the reader accepts on some level the regulatory viability of Pooling at Sites, even if the concept is neither universally endorsed nor applicable to all geographies. The remainder of this article will address specific pitfalls and requirements of Pooling at Sites both in terms of electronic records and of actual labeling. 

As noted above, in Pooling at Sites, the IVRS does not marry any particular kit to a protocol or subject ID until the kit is disbursed. This allows the IVRS/IWRS to tally stock against the future needs of all the protocols at a particular location: All projected shortfalls can be covered with a single, nonprotocol-specific shipment. That shipment will equal the location's projected need for a specified period (minus at location and en route unexpired/ing stock). Each patient in a pooled protocol may be dispensed the appropriate kit type from the common supply. 

Traditionally, clinical supply managers package lot for a particular protocol. In a pooling scenario, they may naturally assume that they can and should package or electronically earmark the drug for the set of protocols for which it is to be used. However, marking drug for use electronically or on the label for a specific protocol—or even for a subset or specific group of protocols—can compromise pooling. Only if kits are protocol independent until dispensed can an IVRS resupply algorithm consider the needs of all protocols using a particular kit at a single location as a whole. 

Consider, as an illustration, the predicament of Murphy, a clinical supply specialist. His protocols, A, B, and C all use a dispensing unit type called "10mg Samplovir." In this example, we will focus on only one physical location, "Fenway," where all three protocols are being conducted. 

Doing what he's always done, Murphy packages "Lot 1" of 10mg Samplovir, labels, electronically marks it in the database for protocols A, B, and C, and distributes it to his supply chain. 

In marking for specific protocols, Murphy has broken pooling's fundamental principle that dispensing units must be protocol independent. But the protocols for which he has labeled happen to be the only protocols that use 10mg Samplovir, so all drug need calculations—for plotted subject consumption, safety stock, floor/ceiling—are successfully totaled. 

Now, however, Murphy packages a "Lot 2" of 10mg Samplovir. He feels that protocol C is just about wrapped up and does not want to dedicate any new supply to it. So this time he only marks it for protocols A and B. Murphy distributes Lot 2, and some ends up at Fenway alongside Lot 1.

Murphy's supply at Fenway is now comprised of 17 total dispensing units of 10mg Samplovir: two units of 10mg Samplovir from Lot 1 and 15 units of 10mg Samplovir from Lot 2. Lot 1 is usable for protocols A, B, and C, but Lot 2 is only usable for protocols A and B. In this example, he still has subjects enrolled and active at this location for all three protocols. 

That night, Murphy's resupply algorithm now begins counting his supply at Fenway. When it counts drugs at location, it can no longer count all 17 units of 10mg Samplovir together in a single bucket. At a minimum, it needs to count once for protocols A, B, and C (two units) and again for protocols A and B together (15 units). There is no way for the algorithm to represent the stock with a single number for the location. At the moment, however, this is little more than an inconvenience. 

The following week, Murphy needs to supply drugs for projected subject need. Protocols A, B, and C have two subjects each scheduled to arrive in the next week; each subject is scheduled to receive one 10mg Samplovir. Ordinarily, a pooled supply algorithm would compare this summed need (six units) against stock at the site (17 units), but since Murphy broke the absolute nature of the pool, the algorithm must count the needs against the stock at site separately. 

If the algorithm does this for each protocol separately, it may predict that the needs of protocols A and B for two each will be easily supplied by their total available stock of 17 and 17, respectively, and that protocol C's need for two will also be covered by the remaining Lot 1 supply of two. But the algorithm's prediction may not necessarily be correct. 

Consider the drug consumption for randomized subjects scheduled to have dispensing visits at Fenway during the following week. If both subjects from protocol C arrive earlier than subjects from protocols A and B, one should see something like what appears in Table 1. 

The order of the last four subjects, in this case, does not really matter; it matters only that the subjects from protocols A and B all arrive after the subjects from protocol C. But what happens if a subject from protocols A or B arrives prior to a subject from protocol C? The dispensing algorithm should be dispensing the oldest usable medication first so Lot 1 will be consumed by subjects in protocols A and/or B (see Table 2). 

The more subjects are intermingled at a location and the more stock is labeled for different subsets of protocols, the worse the problem gets. Even in this example, if subjects from A or B arrive in the first two dispensing positions, both subjects from protocol C will encounter stock-outs and be lost. Losing subjects in this manner is clearly unacceptable. Why can't an algorithm figure out on the fly which lots are for which sets of protocols and do the math accordingly?

While it may seem intuitive that the algorithm should be able to do modified calculations to rescue Murphy, or at least to set aside the Lot 1 stock for the protocol C subjects, in fact the algorithm is ill suited to the task. To preserve certain drugs for the projected need of specific incoming subjects, the dispensing algorithm would need to be linked to the predictive resupply algorithm, and the two functions are mismatched. 

Dispensing in IVRS studies is an uncomplicated operation: The algorithm looks at the dispensing unit type(s) required by the subject, chooses the earliest expiring usable unit(s) from stock at the site, and dispenses. This simple process is carried out in real time many times a day to provide drugs to subjects. A resupply algorithm, by contrast, is a very complex process that usually runs once a day and considers numerous factors and projections in its decision making. 

All in all, drug pooling has the potential to increase supply efficiency in an unexpectedly wide range of scenarios, although its limits may be unexpected. As the inherent flexibilities and inflexibilities of the technique—and the breadth of situations in which it can help contain costs—become more commonly understood, the use of drug pooling will undoubtedly continue to expand. 

 is associate research fellow in supply chain management at Pfizer. 

* is the founder and chief executive officer of Tourtellotte Solutions, 321 Commonwealth Road, Suite 303, Wayland, MA 01778, email: 

*To whom all correspondence should be addressed.

1. L. George, "Investigational Medicinal Products—Optimizing the Supply Chain," Applied Clinical Trials, April 2005, 42–48. 

Feature Article

When done right, pooling clinical supplies can increase efficiency and contain costs, but limitations exist.

Drug Pooling: Power and Pitfalls

In August 2006 I wrote a column about the exciting potential of Web 2.0, the latest and greatest "philosophy" of Web sites that involves collaboration, shared knowledge, and very flashy design. Two well-known examples are Wikipedia and Facebook, which most people have encountered nowadays. In writing that column, I didn't discuss or consider the potential dark side of this technology. 

Recently, I have been exposed to some of the most interesting examples of Web 2.0 in medicine, and I have begun to see an even greater potential for Web 2.0 in our industry, but also a substantial risk for the future of clinical trials and pharmacovigilance, especially in serious disease indications with small numbers of patients. 

It occurs to me that the Pandora myth may be a telling metaphor for some aspects of Web 2.0 for the biopharmaceutical industry. In the Pandora myth, after Prometheus steals fire from the gods and gives it to mortal men, Zeus creates the beautiful and seductive first woman, Pandora, to punish men. Pandora is given a jar (erroneously described as a "box") and told not to open it, but curiosity overcomes her and she does—releasing all the evils of mankind. She closes the jar quickly enough to keep Hope inside. 

Web sites and communities designed with a Web 2.0 philosophy are powerful tools for the participants in these communities. Virtually unregulated interaction and collaboration can generate information and knowledge far greater than the sum of the individual's knowledge. This is one of the key messages in the book, 

, by Don Tapscott and Anthony Williams. A story from this book that dramatically illustrates this point is that of Rob McEwen, chief executive officer of Goldcorp, a gold mining company.  

In 1999, Goldcorp owned 55,000 acres in Canada that had been seemingly mined to exhaustion, although there were some hints of data suggesting that gold might still be found in the mines. However, company geologists couldn't agree on whether these leads were significant or worth pursuing. Inspired by a conference at MIT on open source software, McEwen made a bold and astounding move: He created a contest on the Web with cash prizes totaling $575,000 to be awarded to the best suggestions as to where to mine the gold. His company posted all the proprietary geologic data they had on the region on their Web site. 

The response to this challenge was beyond McEwen's imagination. Submissions from 52 geologists reaped 110 potential deposits, of which half were previously unknown by the company. Many contestants won prizes from $10,000 to $100,000, and 10 were actually hired by the company. An astounding 80% of the identified deposits yielded a useful amount of gold, and the company has since mined over 8 million ounces of gold (currently in futures markets near $1000 per ounce, retail!). If ever there was a demonstration of the collective power of the Web, this is it. Unleashing power of this magnitude is surely akin to Prometheus bringing fire to earth. 

The usefulness of this model for collaboration is being tested in the pharmaceutical industry by Innocentive (

). In this collaboration marketplace, major pharmaceutical and food companies are posting challenges anonymously for some of their most difficult problems in discovery, medicinal chemistry, manufacturing, assay development, and even clinical trials statistics.

Potential solvers of these problems can register and submit solutions to the challenges, with hopes of winning prizes from $5000 to $1 million for accepted solutions. Participating companies have awarded over $3 million so far for 215 solutions, with solvers coming from India, China, Eastern Europe, and even the United States. Many of the successful solvers aren't even trained in the same field as the problem. Despite the risks of competitive disclosure, companies post challenges because the power of the Web exceeds, by order of magnitudes, the resources they could make available within their own companies.

The power of Web 2.0 collaboration may extend into the clinical development and marketing phases of the drug lifecycle, where its demonstrable benefits may potentially be overshadowed by some major risks. The risks to which I am referring are related to the open, collaborative discussion of drug efficacy and safety in communities of physicians and patients. As I will show, this might even extend to a quasi-analytical analysis of data that may be highly influential. A Web 2.0 community with huge potential benefits and risks is PatientsLikeMe, and will be the focus of our discussion. 

) is a beautifully constructed social networking Web site that allows patient communities to form around the diseases they jointly suffer from. Unlike many bulletin board attempts at this concept, PatientsLikeMe provides patients with diseases such as ALS, MS, Parkinson's, and HIV/AIDS to create a publicly viewable (in most cases), structured Web site with their photo, a narrative, and a longitudinal collection of the most important objective and subjective variables in following the course of the particular disease. 

For example, a typical MS patient's site may show a longitudinal graphic of their disability score with relapses indicated, and a patient profile-like graphic of their symptoms (with severity) and treatments over time. The visual display is nothing short of stunning, and the data are highly organized and accessible.

In addition to individual data, the site aggregates data so that an MS patient with anxiety can discover, with one click, a pie chart of its severity in thousands of patients with anxiety and a list of dozens of medications prescribed for anxiety. In addition, they can link to the profile of other patients with anxiety and search for discussions on anxiety on the forum.

PatientsLikeMe is not alone. Similar sites exist for diabetes, depression, alcoholism, and other health issues. If one of my relatives or I had MS or any other serious disease, the information on such sites would be powerful and compelling. These sites are, in their construction and attractiveness, quite beautiful and seductive—just like Pandora.

The nature of openly available, patient-reported data found on these sites is disconcerting in some aspects. The first, and most immediate concern, is that such patient-reported information contains a potentially enormous number of reported adverse events. Will regulatory agencies hold companies responsible for identifying and reporting such data as they must for published reports? If that is the case, will they have to pay each Web site for the aggregated data and manually sift through narratives to identify issues? These are not new ideas and are being actively considered on both sides of the regulatory divide. 

Another concern relates more to the synergistic power of collaboration in this setting. The power of suggestion and confirmation bias will surely lead patients to cluster in their reporting of symptoms. The aggregated statistics on symptoms and medications are presented with scientific graphing techniques, suggesting an accuracy and quality that may not be inherent in the source of the data. A patient reading these graphics who discovers that most other patients have a particular subjective symptom or side effect from a medication may over report such a symptom. If an influential member or two from the community start on a new medication and report a particular adverse effect, the occurrence of that adverse effect may be magnified within the community. With diseases like ALS, where a substantial percentage of the patient community may be participants in such a Web site, the effect of this could be unfairly damaging to a new, potentially effective medication. 

Finally, there has recently been a very interesting development at PatientsLikeMe that holds amazing opportunity but increases potential risks. On a public blog at the site (

), one of the founders discusses a recent paper suggesting a benefit for lithium in slowing the progression of ALS. Rather than wait for the slow process of a follow-up clinical trial, PatientsLikeMe started "the first real-time, real-world, open and nonblinded, patient-driven trial" now with 117 patients involved. These patients have started lithium with their physician and are tracking their progress on the Web site. 

PatientsLikeMe believes that through their data modeling techniques, they can "determine the significance of each reported change in each patient as he/she deviates from his/her predicted course." The results will likely be reported on the Web site with the same quality of graphics and display found elsewhere on the site and will appear to be a critical look at this question with eight times as many patients as were enrolled in the originally reported clinical trial. 

Aside from data quality and placebo effect issues (which they do take seriously), the bias from openly available data is enormous, and the potential for incorrectly concluding that a possibly ineffective and toxic drug is effective is very high. In addition, these activities could potentially starve active clinical trials from recruiting the needed patients to complete their blinded analysis of the same problem. 

Another concern will emerge as participants in PatientsLikeMe begin to enter conventional clinical trials. There open reporting of their experiences with study medications, along with any adverse experiences they encounter, would likely be available individually and possibly in aggregate on the site. Again, in tightly affiliated patient communities, this could lead to bias and even unblinding of conventional clinical trials. 

While these concerns aren't anywhere near the evils of Pandora's jar, they certainly have the potential to create some major headaches in the halls of biopharmaceutical companies in the foreseeable future. 

To their credit, the company has been proactive in engaging pharmaceutical companies about some of these concerns. 

As in the Pandora story, there is certainly reason to be hopeful about the value of communities like PatientsLikeMe. As they are compelling for patients, they may become a major center of gravity for some disease communities, especially if they align with officially recognized patient advocacy groups. 

In the Web 1.0 world, we might have thought of these as sources for improving patient recruitment in clinical trials—in the past, a model that has been less than stellar in accomplishing this goal. Instead, we should think of them as potential registries of patients, which are possibly available for improving our understanding of the biopsychosocial aspects of disease, and disease therapies. They might be used to generate hypotheses, follow patients in naturalistic settings, and even test some ideas in a more structured fashion. 

Technology is here to stay, and it will bring changes in communication and interactivity that we can't even anticipate, along with many opportunities and some risk. Much as we would like to, we can't stop Pandora from opening that jar; we can only try to maximize our benefit from the hope that remains. 

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

Technology Viewpoint

How one patient community on the Web is single-handedly forging new ground in the clinical trials world.

A Pandora's Box for Clinical Trials?

Publicity about abuses involving people who participated knowingly or unwittingly in medical experiments and research studies usually have been followed by the tightening of existing rules and calls for new laws. So it was again at the close of the 20th century.

  Such a response occurred after the highly publicized death of 18-year-old Jesse Gelsinger, who took part in a gene transfer trial.

Reviews by two government watchdog agencies of the existing system of research oversight concluded that the system was overburdened, under-resourced, and paper driven and paid little attention to determining whether research institutions were actually fulfilling their responsibilities to protect human subjects.

  At the request of the Secretary of Health and Human Services (HHS), the Institute of Medicine (IOM) of the National Academy of Sciences examined how to improve human research protection programs.

The Health Improvement Institute, a tax-exempt research and educational organization that conducts forums on emerging treatments, gives national awards to organizations and individuals who demonstrate excellence in improving the quality and productivity of America's health care. The Institute believes that incentives to do the right thing (carrots) are needed as much as increased compliance oversight and tighter regulations (sticks). 

As a counterpoint to these regulations, the Institute designed the Award for Excellence in Human Research Protection. It launched the Award in 2001 to encourage, recognize, and reward excellence and innovation in human research protection on the part of individual investigators, institutions, and research sponsors. The Award is also intended to facilitate improvements and openness in human research. 

"I think that there are lots of institutions doing innovative things in human research protection, and it is important that we share and recognize these efforts," said Susan Kornetsky, director of clinical research at Children's Hospital Boston—a 2006 award winner. The Hospital designed an educational program to increase parental knowledge about the nature of medical research, winning the 2006 Annual Award for Best Practice. This award is given to a research institution, unit or individual with the best way, one of the best ways, or a proven way to achieve or contribute toward achieving the human research protection specified by the practice (see Table 1). 

Past Annual Award Winners for Best Practice 

Then there is the Award in Innovation (see Table 2), which is given to an individual or team who has introduced an innovation or a novel approach to the protection of human research subjects. The final category is Lifetime Achievement (see Table 3), and this is awarded to an individual who has made significant contributions to the protection of human research subjects over a continuous period of at least 20 years. 

Past Annual Award Winners for Excellence in Innovation 

Acceptance of applications for an Award begins in February and continues until the last Monday of September. Winners are announced in December on the Web site of the Institute (http://

), which also broadcasts the announcement to program participants and health-related associations and issues a media release through a national newswire service. 

Winners of the Award for Excellence for Lifetime Achievement 

Recipients of the Award of Excellence are given a certificate and invited to use the Award logo on their Web site and in print media. Annual Award recipients also receive an engraved brass plaque to proclaim their award. "It's something that's nice internally and externally," said Sarah Fowler-Dixon, education specialist at Washington University's School of Medicine. The merger of the University's multiple IRBs earned a 2006 Award for Excellence, which, according to Fowler-Dixon, validates her work and earns it publicity. 

At the end of 2005 and again at the end of 2006, the Institute surveyed former Award of Excellence winners to determine the value of the award. In summary, winners indicated that the Award had brought personal recognition within the institution and community; created personal satisfaction regarding the awardees' contribution to protecting people who participated in clinical research; and imparted recognition to the best practice/innovation within the community. "Not only does it help people know what different IRBs are doing, but it helps publicize what different institutions are doing, and helps validate what they are doing," assessed Fowler-Dixon, "[and] it gives people incentive to continue to do good things." 

But you don't need to win an award to provide insight. Regardless of the final outcome, the Institute encourages all former participants to provide feedback, and periodically conducts various surveys of all or selected participants to seek suggestions for improving the Awards program. 

The federal Office for Research Protections (OHRP) was the founding sponsor of the Award program. The OHRP is responsible for the oversight of the protection of human research subjects. It established the Division of Assurances and Quality Improvement to assure and improve the performance, quality, and effectiveness of research institutions' human research protection programs, including their IRBs. 

The OHRP provided initial financial support to the Institute to launch the award program (because of its regulatory roles and responsibilities, it is not in a position to issue commendations nor to run a program to recognize excellence). And since the beginning, the Institute has received intermittent financial support from the American Diabetes Association, Pfizer, and from a number of other private organizations. 

During the first five years of the Award program (2002–2006), 40 individuals and institutions submitted applications. Of the applicants, four won the Annual Award, 17 were granted the Award for Excellence, and 14 received the Certificate of Merit. Of note, Washington University, School of Medicine and Human Studies, has walked away with awards four times, with three awards for best practice. 

The program's success to date has depended on the Institute's willingness to continue the Award program, and the volunteers who serve on committees and judge applications. Knowledge about the awards program is spreading slowly by word of mouth. The main incentives for applying for an Award are self satisfaction and peer recognition, as previous winners can attest. Said Kortensky, "We applied for it because I thought we had developed something that was innovative and deserved some type of recognition, and we were very proud of it." She added, "It's nice to be able to attach an award to it [so people] can see that there is recognition behind it." 

In the years ahead, one can expect such factors as internal and external satisfaction to reinforce one another and result in an increase in the number of applications and in the prestige of the Award for Excellence. Inevitably, the process of building awareness and recognition of the value of an award takes time. Further, although the community of researchers is growing in both number and professionalism, the pool of potential applicants for an Award remains relatively small. 

Going forward, the Institute expects the Award to both make a lasting contribution to increasing awareness of the importance of subject protection and improving the quality of protection for people who participate in clinical research. 

For those interested, the Institute welcomes participation as a sponsor, judge or applicant for an Award. By doing so, you can contribute to the promotion of and receive recognition for excellence in human research protection. For more information about the Award for Excellence in Human Research Protection, visit the institute's Web site or call 301-320-0971. 

This article was peer-reviewed and accepted with additional editing and content provided by Samantha Etkin, associate editor for 

,* MD, DrPH, DMS, is the founder and president of the Health Improvement Institute, 5800 Madaket Road, Suite 200, Bethesda, MD 20816-3201, email: 

 MBA, is the the Awards coordinator at the Institute.

1. P.G. Goldschmidt and J.M. Cohen, "Accreditation and Certification: Can They Work in Clinical Research?" The Monitor,  20 (2), 35–40 (2006.) 

2. S.G. Stolberg, "The Biotech Death of Jesse Gelsinger," New York Times Magazine, November 1999. 

3. In 2000, bills were introduced in Congress to further regulate human research subjects and Donna Shalala, Secretary of DDHS, announced several initiatives designed to heighten government oversight of biomedical research and to reemphasize to research institutions their responsibility to oversee their clinical researchers and IRBs. The Office for Protection from Research Risks (OPRR) of the National Institutes of Health became the Office for Human Research Protections (OHRP) in the Office of the Secretary of DHHS. 

4. U.S. General Accounting Office, Scientific Research: Continued Vigilance Critical to Protecting Human Subjects, GAO/HEHS-96-72 (Washington, DC, March 1996). 

5. Inspector General of the DHHS, Institutional Review Boards: A Time for Reform, OEI-01-97-00193 (DHHS/OIG, Washington, DC, June 1998). 

6. Institute of Medicine, Preserving Public Trust: Accreditation and Human Research Participant Protection Programs (National Academy Press, Washington, DC, 2001).

Award for excellence in human research protection is the incentive for better oversight and regulations.

A Carrot and Sticks Approach

Congressional leaders are calling for stronger rules and more effective enforcement of clinical research, putting pressure on the Food and Drug Administration to stiffen its enforcement policy. "It may be time to seriously rethink the regulatory framework for the clinical trial industry and Institutional Review Boards and Contract Research Organizations," stated Rep. Bart Stupak (D-MI), chairman of the Subcommittee on Oversight and Investigations of the House Energy and Commerce, at a February 2008 hearing. 

At issue is why FDA officials failed to take action against the sponsor and other parties involved in clinical trials supporting approval of the antibiotic Ketek (telithromycin). Evidence of investigator fraud has generated questions about the adequacy of oversight by the CRO and IRB involved, whether the sponsor Aventis (now Sanofi-Aventis) withheld damaging information from FDA, and whether agency officials knew about these problems when they evaluated the drug. 

Stupak and Energy and Commerce chairman John Dingell (D-MI) are urging FDA and the Justice Department to further investigate possible fraud by Aventis and other parties. The Congressmen have suggested, moreover, that FDA Commissioner Andrew von Eschenbach misled them in testimony last March (2007) about what FDA knew regarding "data irregularities" when it approved Ketek in 2004. House and Senate leaders have been furious at FDA for refusing to hand over all the documents on the case and for preventing agency investigators from testifying before Congress. 

The Ketek case points out the importance of effective research monitoring and oversight by sponsors to ensure the integrity of research data submitted to FDA. Due to limited resources supporting its Bioresearch Monitoring (BIMO) program, the agency usually inspects only a few key sites to check whether investigators followed the rules in conducting an important clinical trial. FDA relies largely on sponsors to monitor that investigators follow good clinical practices (GCPs) and other rules while trials are going on, which is important in protecting the rights and safety of research subjects as well as for ensuring data validity. 

Continued Congressional focus on research lapses related to Ketek, though, is encouraging a more activist FDA role in clinical trial oversight. At a February conference on FDA enforcement sponsored by the Food and Drug Law Institute (FDLI), Deborah Autor, director of the Office of Compliance in the Center for Drug Evaluation and Research (CDER), noted that Congress' concerns about clinical research has made this "an area of emphasis for us as well." Autor cited more warning letters to pharmaceutical companies that call for systematic changes in clinical trial monitoring and oversight. FDA is investigating data integrity concerns related to Theravance's antibiotic telavancin and cancelled an advisory committee meeting pending further site inspection. 

With more funding, FDA's BIMO program could be more active, Autor observed. CDER's Division of Scientific Investigations (DSI) moved back into her compliance office two years ago, where it is poised to become more involved in compliance. FDA also hopes to revise many clinical research regulations, which Autor considers "very outdated." The agency issued draft guidance last year clarifying how principal investigators should ensure that research site staff follow GCPs and other rules. Another draft guidance aims to clarify responsibilities of sponsors, IRBs, and investigators in reporting adverse events. FDA's BIMO council is working to streamline and coordinate these and other research policies across all Centers.

One area of focus is FDA's cumbersome process for disqualifying clinical investigators who violate GCPs repeatedly or commit fraud. Rep. Joe Barton (R-TX), top Republican on the E&C Committee, released a report in February criticizing FDA for not using its authority to exclude convicted individuals or firms from involvement in the drug regulatory process. Under current law, FDA can debar law breaking entities from participating in generic drug development and production, and it can disqualify investigators from conducting trials.

Unfortunately, "it takes absolutely forever" to disqualify an investigator, commented attorney Phil Katz of Hogan & Hartson at the FDLI conference. The agency's Byzantine rules require formal notification and a lengthy hearing, review, and appeals process. FDA issued a guidance several years ago to clarify that it can impose a clinical hold on a study where an investigator fails to meet GCPs or submits fraudulent data—which reflects how clinical holds can more effectively halt unethical behavior and better protect patients than can the disqualification process.

As a result, FDA has not implemented disqualification procedures that often, but, Katz said, "that may be changing." Autor reported that FDA wants to streamline the process for disqualifying violative investigators and is working to "clean up those procedures."

The Ketek case may spur such action. Most evidence of fraud and misconduct for this drug involves a huge multisite safety study launched by Aventis in 2001 to address FDA concerns about liver toxicity and other safety signals from clinical trials. This "usual care" trial (study 3014) enrolled 24,000 patients at 1800 sites in three months, but was rife with problems ranging from "deviations" and sloppy record keeping to data fabrication and fraud. Congressional critics say FDA and Aventis ignored or covered up the trouble signs and want the Justice Department to pursue an investigation. 

A rural Alabama site under Dr. Anne Kirkman-Campbell stood out for its high enrollment and poor records. Ann Marie Cisneros, a former staffer with PPD Inc., the CRO hired by Aventis to oversee the study, told the E&C committee in February that there were a host of "red flags" signaling trouble when she visited the site in 2002. The investigator/physician had enrolled 400 subjects (at $400 a head), compared to a dozen at another local site. There were discrepancies in informed consent forms, under-reporting of adverse events, no patient withdrawals, and no patients lost to follow-up. A lack of variability in blood samples suggested sample "splitting" among study subjects. 

Cisneros says she reported these findings to PPD and to the Copernicus Independent Review Board, the IRB of record for the study, but nothing happened. Copernicus Chairman Sharon Price claimed she never received Cisneros' message. Aventis acknowledges troubling reports from PPD, but claims that the violations did not constitute fraud—an important distinction because knowingly filing false data with FDA can be a criminal offense. 

FDA field investigators uncovered enough problems for its Office of Criminal Investigations (OCI) to investigate. Kirkman-Campbell went to jail for fraud in late 2003, but OCI special agent Robert West told the House committee that he was unable to expand the fraud investigation to other sites or to Aventis. 

When FDA finally approved Ketek in April 2004, it decided not to rely on the tarnished data from study 3014, partly because there was ample clinical trial evidence plus safety data from some 3.7 million patients in other countries where the drug already was approved. Over the next two years, though, reports of serious liver toxicity prompted FDA to reconsider Ketek's labeling, resulting in stronger warnings and narrower indications for the product. 

Was FDA justified in approving Ketek for market based on noninferiority studies documenting efficacy (which FDA accepted at that time) in the face of serious safety signals and questionable data from a major study? Although some critics say the drug has harmed thousands, FDA and public health officials point to the desperate need for more new antibiotics as drug-resistant infections multiply. 

But the evaluation of even a potentially important medication should be based on accurate information. At the February hearing, FDA agent Douglas Loveland challenged Aventis' claims that study 3014's problems reflected sloppy record keeping and not research fraud. Either way, "we want reliable data at FDA," he said. "Whether it's fraudulent or sloppy, it's not reliable." 

Sanofi has made changes in its research program to prevent such abuses from occurring in future trials, Paul Chew, Sanofi-Aventis R&D president, told the E&C panel. The company now has stronger training for research personnel, stricter site enrollment limits, and more oversight. There also is a plan to validate investigator qualifications prior to study enrollment. While these policies are fine, they might have saved the company a lot of trouble if they had been established five years ago. And they may not be enough to head off further investigation by Congress and law enforcement agencies.

The Ketek case also increases the pressure on FDA to demonstrate that it can police the research community and that it is not trying to protect pharmaceutical companies that bend the rules. This investigation, stated Chairman Dingell, "raises questions about the very integrity of the drug approval process." In the current climate, questionable research activities may keep even a potentially beneficial drug off the market. 

View from Washington

Ketek probe raises questions about research oversight by FDA, sponsors, and investigators.

Research, Investigator Conduct Under Scrutiny

 identifies Coartem, an artemisinin-based combination therapy, as the country's first-line treatment for uncomplicated malaria. Previously, chloroquine was the country's first-line treatment, but a rise in chloroquine resistance prompted the country to make the switch.

(EC) history, European drug company offices are now subject to surprise inspections, as the EC recently initiated an inquiry into the state of competition in the pharmaceutical sector. The EC hopes to uncover the reasons as to why there has been a decrease in novel medicines that make it to the market and why there is a holdup in generic market entry. The Commission will also attempt to determine whether certain agreements between pharma companies infringe upon restrictive business practice laws. Inquiry results are expected in the spring of 2009.

International health research and bioethics experts and policy makers took part in a roundtable on the establishment of 

 Conference, Science with Africa, held in 

 March 3–7. The discussion aimed to encourage the development of a foundation for legal and regulatory best practices in science and ethics in Africa, which could boost research and development in the country and help find cures for major diseases that affect a disproportionately high number of Africans as compared to the rest of the world.

Global News

Clinical operations productivity has declined by a median of 15% since 2005, according to a recent survey from KMR Group. That decline directly represents that industry is putting in more money for what it is generating—specifically, for every $1 million spent in resources, it is getting back 902 patient visits. This is an industry-level view; some companies fare better than others. Indeed, a few have had significant recent gains in productivity. The study explored the variance, examining why some outperform. 

Clinical Operations Productivity Industry Distribution 

Measuring productivity for a large pharmaceutical company can be a daunting task. KMR Group, a Chicago-based consultancy exclusively focused on biopharmaceutical R&D, uses the expenditure divided by the number of patient visits to determine the clin ops investment numbers.

According to Scott Martin, principal of KMR, the company has undertaken this Herculean task every two years since 2000 and has released some other findings in regard to pharmaceutical clinical operations for 2007. 

"We looked at outsourcing rates, and there is not a major change in the levels of outsourcing over the years," Martin told 

 Outsourcing consumes about half of the total resources spending in clinical operations, and that two-thirds of this outsourcing spending is for site monitoring. However, Martin noted that the companies with the higher rates of outsourcing also tend to be less productive. "Basically, the more you outsource, the less productive you are," explained Martin. The reason? Sponsors may be finding it difficult to manage the CRO and outsourcing process effectively, and sponsors are spending a lot of time fixing things and/or managing the CRO directly.  

On a better note, it appears that companies that conduct more studies have a higher productivity level. "While it is a more modest correlation, it maybe be an advantage of throughput," said Martin.

Factors that don't affect productivity? Apparently, speed does not affect productivity. Even if you're faster at conducting a trial, you are not necessarily more productive. And therapeutic area complexity? Complex clinical trials may be more costly, but they offer no positive or negative impact to productivity.

Another interesting tidbit surfaced in the area of where the trials are being conducted. Forty percent of the patients are still being enrolled in North America. As noted, KMR monitors the total number of patient visits and does this at a protocol level, site by site by month. "We get the number of patient visits per month, even if the trial is in Poland or Bulgaria," said Martin. "It was surprising that there hasn't been a substantial decline in the North American trials. What I believe is that companies are looking to other regions, but they are not yet there and they are not finding it easy," explained Martin. "Three or four years ago, sponsors would have expected more globalization at this point in time, but it hasn't happened." 

This could be a factor of the types of patients needed for the current top therapeutic areas—CNS and oncology, which aren't typically found in the emerging regions. Or it could be based on the fact that although it may cost less per patient in a global trial, the issue of finding the patient wrapped with other issues such as data collection and administrative challenges may be throwing a barrier to the predicted global warming trend.

The KMR report also found a 15% increase in productivity in clinical pharmacology. While clinical pharmacology overlaps Phase I and exploratory trials, Martin noticed a strong push in these first-in-man and exploratory trials as a way to make earlier decisions to further the compounds onto larger and more expensive trials. "Major pharmaceutical companies have developed creative ways to get more sufficient information to make decisions earlier in the process. And this increase shows that this creativity may be having a positive effect." 

KMR and the sponsor companies measure productivity in the following areas: biostatistics, data management, medical writing, clinical pharmacology, statistics, clinical sciences, and clinical operations. 

To measure productivity, KMR first works with the sponsor company to identify the dynamic or current issues, and the importance of issues have changed over time in the past eight years. After the issues are identified, the definitions are agreed upon so that true data benchmarks can be developed. At that point, data is collected from the sponsor company via a stringent querying process. 

This cycle, data was collected from Abbott, Amgen, AstraZeneca, Bristol Myers-Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck Research Laboratories, Novartis, Schering-Plough, and Wyeth. The companies themselves, representing over two-thirds of the world's top 15 companies in terms of research and development, also change over the measurement cycle depending on company circumstances. The ensuing report is shared among the responding companies for internal benchmarking purposes.—

A recent survey from KMR Group shows a 15% decline in clinical operations productivity since 2005.

Marked Decline in Clinical Operations Productivity

Overall, sponsor companies and CROs have a fairly consistent view of the criteria used to select CROs, although there are some notable differences. The pharmaceutical industry makes widespread use of CROs and, most likely, this trend will increase in the coming years. But little empirical research exists on why and how pharmaceutical companies select CROs. 

The University of the Sciences in Philadelphia (USP) and TTC, a drug development data company, are conducting a multiyear research program on the factors associated with improved speed and cost effectiveness in clinical studies. Since outsourcing to CROs represents an integral part in developing drugs, USP and TTC will also analyze how CROs are selected and used in clinical trials. Part of this CRO analysis involved a Web-based survey of sponsor pharmaceutical companies and CROs to understand the following:  

Specific outsourcing processes and techniques, such as project budgeting, CRO selection, managing studies, bid grids, and managing cost overruns

Perceptions of how CROs and sponsor companies interact in the areas of business development, CRO selection, and project management

Training needs for professionals to improve CRO selection and CRO project oversight.

Previous studies have reported that industry professionals involved in outsourced clinical studies expect the overall level of outsourcing to continue to grow. In addition, quality and timelines of a CRO's work dominate as the basic selection criteria.

 This article accepts that previous work quality is a central criterion for selection and focuses on other issues that might be involved in the CRO selection. Set within the anticipated continued growth of CRO usage, the article examines these additional key criteria that individuals working in drug development use to select CROs, highlighting the differences between the selection criteria that sponsor companies emphasize and how CROs think sponsor companies decide. 

Using factor analysis, we also determined that the individual elements used to select CROs can be summarized within a set of five broader dimensions: Processes for Issue Identification and Resolution; the Specifics of Project Execution; Team Chemistry; CRO Experience; and CRO Capabilities. 

Pharmaceutical company participants indicate that approximately two thirds (64%) of all post Phase I studies involve the use of CROs for one or more parts of the study. However, when measured by pharmaceutical company size, there are very large differences in current outsourcing practices. For example, within the largest 20 pharmaceutical companies, half (52%) of all post Phase I studies use CROs, a number that jumps to 88% for smaller companies. These smaller pharmaceutical companies often do not have the permanent in-house staff to conduct all aspects of a clinical trial, especially where the trial involves many sites and multiple countries. The smaller companies may, for any number of reasons, also lack the employee headcount or expertise to carry out clinical trials. 

While many industry professionals expect the use of outsourcing to increase [see Table 1], only one quarter of people from pharmaceutical companies think that their company is better than competing companies in selecting CROs, with no significant differences based on the size of the companies involved. That is, large companies are no more likely to think they are especially good at CRO selection than are small companies. Similarly, there are no appreciable differences based on a participant's geographic location, whether it be North America, Europe or other locations worldwide. There is a slight but statistically insignificant difference in the age of individuals who think their company is better than others in selecting CROs—they are a year older, but have the same number of years of industry experience. 

There is a general agreement between the reasons pharmaceutical companies cite for selecting an outsourcing organization and how CROs think pharmaceutical companies select them. There are also some striking differences in the individual decision criteria. Survey participants evaluated 17 individual considerations often used in selecting a CRO and rated each item on a scale ranging from very important to not important at all [the 17 criteria arose from our literature review and preliminary interviews with industry professionals]. Five of these 17 items were deemed to be especially crucial in the selection of CROs—that is, specified by at least half of all the study participants. 

Team chemistry. The most important overall quality in selection is a sense of positive sponsor–CRO project team relationship. Both sponsor company and CRO respondents think that the sponsor wants to know above all else that they could work with the CRO. More than any other single selection criterion, sponsor companies stressed the importance of a good relationship between the two company teams. These teams must work closely with each other for an extended period of time, often on projects involving multiple countries and large sums of money. The sponsor company needs to know that both its team and the CRO's team share the same values, work ethics, and general approaches. CROs also clearly understand the need sponsors have for teams that work well together. 

The CRO's project management team contributes significantly to the overall positive sponsor–CRO project team relationship. Yet sponsors were far more likely than CROs to stress the importance of the project management team as a CRO selection criterion. While more than two thirds (68%) of the pharmaceutical company participants stressed this criterion in their selection process, only half (51%) of the CRO respondents thought sponsor companies valued this as very important.

CRO experience. Sponsor companies and CROs placed great weight on a CRO's relevant experience, both in the same indication as the study and in the CRO's overall experience in the appropriate therapeutic area. Sponsor companies and CROs differed somewhat on the importance of a project member's background. While only 45% of the pharmaceutical company participants considered this very important, 62% of the CRO respondents considered it very important to sponsor company decision makers. Sponsor companies seem more interested in the overall cohesiveness of the CRO team members than their vitae. A vitae may be a constructive starting point, but positive sponsor–CRO project team relationship is vital to the project's success. As one pharmaceutical company project manager put it: "CVs can only take you so far. You want to know that the CRO's team fits with the way you want things done and the way you want to work." 

Project execution plan. Another essential criterion (i.e., raised by more than a third of the study's R&D professionals), was the project execution plan. On no other single criterion, though, was there a greater difference between sponsor company and CRO responses. Fifty-nine percent of pharmaceutical company professionals considered the execution plan as fundamental in hiring a CRO; only 28% of respondents from CROs placed the same importance on the execution plan.

In their responses to this criterion, the pharmaceutical company decision makers appear to be emphasizing a level of project specificity that many of the CROs may not appreciate. Far more than the CRO project team's background, pharmaceutical companies want to see a convincing project execution plan, including such concrete items as resources, countries, and site selection. According to one pharmaceutical company outsourcing professional: "Every CRO claims to be customer oriented, responsive, and so forth. Exactly how a CRO proposes to carry out a project...now that can be convincing—or not." 

Problem solving processes. Sponsor companies are also more likely to value the internal processes CROs use to make appropriate senior CRO managers aware of project problems. Forty-seven percent of the pharmaceutical company participants considered this capability to be essential in selecting a CRO. In contrast, only a third (34%) of the CRO respondents thought it was essential for sponsor companies. 

Other criteria. A smaller number of respondents, from both sponsor companies and CROs, considered the CRO's role as a preferred provider and the CRO's geographic scope to be very important. CRO staff turnover was somewhat more critical to the sponsor companies than many CROs thought was the case. 

Of the remaining criteria, one in particular merits its own discussion: the role of the lowest price bidder. Sponsor companies and CROs differ in how they view the role of the lowest price. According to an experienced business development manager from a major CRO, "Pharmaceutical companies rarely say price is important. But we know that it really is." But in this study, fewer than one in 10 (7%) of the sponsor company respondents considered the lowest price as decisive in selecting a CRO. In contrast, more than a third of the CROs (38%) felt price was a fundamental selection measure for sponsor companies. 

There were major differences in the importance the survey participants placed on the 17 individual items. People rarely make decisions using one consideration at a time. Rather, they relate one consideration to another and decide what's best. Companies follow the same process in selecting CROs. In fact, as mentioned earlier, sponsor companies use five general dimensions in evaluating and selecting a CRO:   

Processes for Issue Identification and Resolution

The study used factor analysis to distill these five dimensions from the 17 individual survey items. 

Factor analysis only provides a mathematical solution to how the various items relate to each other and how they relate to any underlying dimensions. Factor analysis does not label the individual factors. Items heavily associated with a factor are said to "load on" that factor. Items that load more heavily than others have a bigger explanatory role in understanding the communality of the items associated with that factor. Only a review of the items associated with a given factor can provide a rationale for what the individual items may have in common. 

The individual factors appear in the order of the variance they explain, which is often a function of the number of individual items "loading on" that factor. That order does not necessarily mean that a given factor's explanatory importance is more or less than the factors before or after it. [Table 2 summarizes which of the individual selection criteria load on each factor.]

In this survey, five items load heavily on the first factor, Processes for Issue Identification and Resolution. The individual items all concern the same general issue area: processes used to identify and resolve project and financial issues. Three items are associated with the second factor, the Specifics of Project Execution. Critically, price is inversely related to the other criterion in this factor. The more participants stress the other two items of the factor—quality of the project team and the project execution plan—the less likely they are to emphasize price. Conversely, those who stress price put less weight on the quality of the other items in the factor. The third factor covers the Project Team's Chemistry, including the individuals, their backgrounds, staff turnover rates, and the sponsor company's sense that they can work with the CRO's personnel. Two items, both related to relevant CRO experience, load on the fourth factor: CRO Experience. The fifth factor addresses items associated with a CRO's Capabilities, including the CRO's relationship to the sponsor company. 

The factor analysis provides a score for each individual for each factor. The higher the score for an individual participant on a factor, the more prominent that dimension is to the individual. The relative importance of these five decision-making dimensions differs within key groups involved in selecting and using CROs. For example, sponsor companies and CROs view the importance of one dimension, the Specifics of Project Execution, quite differently. 

As we have seen, sponsor companies value the quality of the execution plan far more in selecting an outsourcing partner than many people in CROs realize. CRO personnel tend to think that price plays a larger role in the selection process than sponsor companies do. There is also one important difference that relates to an organization's size. Participants from the 20 largest organizations, whether they are sponsor companies or CROs, differ from individuals in smaller organizations on one decision-making dimension: CRO Capabilities. 

Larger pharmaceutical companies and CROs give more weight to a CRO's size, geographic reach, and relationship with the sponsor companies. Large organizations, both sponsor companies and CROs, may be more comfortable working with one another as large organizations, especially for bigger studies requiring extensive geographical coverage. 

The greatest differences across the dimensions are associated with a respondent's geographic location. The components of the CRO selection criteria are important to both Europeans and Americans. However, Europeans and Americans do differ on three of the dimensions. 

For example, Europeans are far less interested than others in the details and mechanics of identifying and resolving issues and, ultimately, in a CRO's willingness to accept accountability. Americans are more likely to consider Execution Specifics and CRO Capabilities important. They want to see the details of the project plan and project management team devoted to the study. They are more interested in a preferred provider relationship with a larger CRO having geographic reach. 

While Americans stress the mechanics of the CRO/sponsor company relationship, Europeans tend to emphasize more intangibles. These differences by a respondent's geographic location remain significant even when we use ANOVA (analysis of variance) to control for the possible influence of other variables, such as company size and whether a person works for a CRO or sponsor company.

Most of the pharmaceutical companies surveyed believe that they are on the same skill level as their competitors in selecting CROs, although a few believe that they are more adept at the process. Interestingly, there is no difference in the selection criteria between those companies who believe they are better at CRO selection and those who do not. No matter how well a survey participant's company believes they handle CRO selection, there is no difference when it comes to the five dimensions of selecting a CRO. 

In later research we will examine in more detail the impact of geography in how people approach CRO selection. In addition, we will also present the profiles of companies who do consider themselves better at selecting and managing CROs.

 PhD, is a professor of health policy at the University of the Sciences in Philadelphia and the president of TTC, llc, 4548 Market St., Suite M-20, Philadelphia, PA, 19139, email: 

 MBA, is an associate director at TTC, llc.

A recent survey uncovers key criteria that influence a sponsor's decision when selecting a CRO.

Key Factors in CRO Selection

It is imperative that subjects participating in a clinical trial understand exactly what they are engaging in. Thus, informed consent is a crucial aspect in any trial, and clinical research professionals would be remiss if they allowed trial subjects to agree to take part in a study that they did not fully understand. 

Screen shot of 3D animation showing how the RNAi drug inside the cells produces the active molecule (siRNA) to destroy RNA molecules produced by the virus. 

With this in mind, Horsham, PA-based Nucleonics began to think outside the box when deciding how to best inform subjects about the scientific rationale and technology used in the company's recent trail of its RNA interference (RNAi), NUC B1000, a treatment for chronic Hepatitis B. 

The Phase I study dealt with an experimental gene silencing therapy and utilized a technology known as expressed interfering RNA, which is a method not easily understood by your average study participant. 

Therefore, Nucleonics turned to Arkitek Studios, a company in Seattle, WA, that specializes in creating visual materials for science, technology, and education. The partnership gave way to the first ever use of 3D animation for informed consent in a Phase I trial. 

"This is complex information, and it's always hard to winnow down what the key concepts are within living systems in order to really understand a particular concept," explained Beth Anderson, chief executive officer of Arkitek, to 

. "None of these processes are simple, so the art is to figure out what is really needed to tell the story in the most compelling, understandable way to that particular audience." 

To accomplish this, Anderson worked with Dr. C. Satishchandran, Nucleonics' chief operating officer and executive vice president, to understand the experimental therapy's technology and drew up storyboards explaining the process. Arkitek then developed 3D models and scenes, as well as a voice over script to compliment the animations. The company combined the animation, voice over, stills, and text to establish the finished product, which can be viewed on the Nucleonics Web site 

www.nucleonicsinc.com/clinical/video/video.html

In the end, the animation succeeded in illustrating how Nuceleonics' therapy targeted four different sequences of the Hepatitis B virus genome to significantly disable the manufacture of specific Hepatitis-related proteins.

"It explained to the patients in laymen-friendly terms what RNAi therapy is, and why it works," said Anderson. "Also, equally importantly, it explained what it was not." 

Since subjects entering a trial expect clear, accurate information about the treatment they will receive, the use of animation to map out complicated processes is an invaluable approach to informed consent.

"It allows greater standardization of information to the patient," observed Anderson. "Informed consent is absolutely critical, and is, quite rightly, essential to running successful trials. Hardly anyone participating in clinical trials has the depth of knowledge necessary to understand molecular biology—it's too involved, and why would they? But given the fact that they are participating in these trials, they really need to understand what they are being given, and I think that animation is one of the best ways to do that."—

For the first time n a Phase 1 trial, 3D animation is used for informed consent.

Applied Clinical Trials-04-01-2008

Buenos DIAs from Barcelona

Drug Pooling: Power and Pitfalls

A Pandora's Box for Clinical Trials?

A Carrot and Sticks Approach

Research, Investigator Conduct Under Scrutiny

Global News

Marked Decline in Clinical Operations Productivity

Key Factors in CRO Selection

Animating Informed Consent

EU Seeks Hematology Guidance

The Local Central Lab Model

Genotyping: Under the Microscope

Russia Grows its CRO Market

Business and People Update April 2008

CDER Gains Permanent Chief

Europe's Thirst for Trial Information