In the life sciences, there has always been a need to store biological materials such as blood samples and active pharmaceutical ingredients generated during research and drug development. Stored biomaterials can be used for a range of purposes, from medical education to examination of disease processes over time. In the biopharmaceutical industry specifically, there are many compelling reasons to store samples derived from clinical research, all of which have potential commercial, scientific, and medico-legal importance in drug development.  

However, despite sophisticated protocols that delineate all aspects of drug development, companies often overlook the critical step of developing a strategy for the specialized, long-term storage of biological samples. This represents a significant missed opportunity for many businesses because of the intrinsic value these samples can represent. Biotech and pharmaceutical companies, large and small, must take seriously the need to develop such strategies, which can help them: 					

react quickly to unexpected adverse reactions

identify new assay techniques or biomarkers.

A carefully planned sample management strategy will include considerations such as cold chain logistics and storage, a centralized sample inventory, and information management systems to track and manage data. These elements should be backed by a comprehensive audit trail showing exactly how samples were managed from collection to destruction, and they should be compliant with all applicable regulations. 

				This article outlines the commercial, scientific, and legal implications for storing biological samples from clinical research and suggests steps companies can take to develop "good storage practice."			

Stored samples can have a critical impact on the commercial viability of a drug in several ways. 

 Time is of the essence in drug development. A day lost in development is a day lost in the marketplace. Because one day during the product's peak sales may be worth millions of dollars, biopharm companies must investigate all options for working more efficiently and effectively. It may be necessary to start clinical work on a drug before the assay has been developed to an ideal level of precision or before metabolite assays have been fully developed. Stored clinical trial samples may then be used later for retrospective analyses once the assay has been fully developed and its accuracy and precision validated. 

Additionally, it is not uncommon for existing assay techniques to be improved upon further and made more sensitive during the course of a drug's development. For example, there may be a need for an assay with enhanced sensitivity if the drug has a long half-life or is widely distributed through the body so that it is only present in very low concentrations in plasma. Furthermore, active metabolites of the drug may be discovered after it has already been administered to many subjects, which would allow the metabolite to be developed instead of the original parent molecule. Again, in these situations, retrospective analyses of stored samples may eliminate the need to repeat a large number of studies and can reduce the resulting delays in development. 

All clinical studies must be conducted with the informed consent of the subjects, and the consent form associated with the protocol needs to make clear that samples may be stored and analyzed at some point in the future. The subject should also be able to withdraw their samples from future testing at any time. The use of stored samples to uncover genetic markers of predisposition to a disease has engendered much debate on how to handle patient consent under these circumstances. Clearly the ethical implications of discovering that a seemingly healthy person (and their healthy descendants) may develop a serious condition are very significant.

 One trend in the pharmaceutical industry has been that larger companies are in-licensing more and more compounds that are developed by much smaller biopharmaceutical companies or research centers. To ensure quality and perform due diligence, these larger companies may use the samples to re-examine analytical methods and re-assay specimens collected during early development of the drug. Confirmation of the findings from stored samples adds important financial value to the acquisition of the product. Hence, even small companies should have a clearly defined sample storage policy and process. 

 Because drug development is a long and protracted process, new biomarkers that further delineate disease processes may be discovered during the development phase. The impact of the drug on those biomarkers may be very important to understanding its efficacy and safety. However, these biomarkers may not have been discovered when the original development plans were written and the trials started. In this case, stored samples can be reanalyzed to look retrospectively at these effects and, at the very least, can help developers save time by designing better prospective trials of the drug. 

It is important that samples are maintained in the best possible condition and a history of the samples' storage kept in the greatest possible detail. For example, plasma samples should be stored at –70°C to –80°C without any freeze–thaw cycles, which could damage the integrity of the samples. Research has shown there is a minimal effect on protein in plasma stored at –70°C for four years, compared to samples that were thawed and refrozen.

In order to validate such results fully, it is also necessary to prove long-term stability of the biomarker under consideration. These tests can be run in parallel with the further clinical development of the drug. 

Proper sample storage can also have a significant impact on scientific research in several areas. 

 Over the years, stored samples have proved invaluable in establishing the natural history of diseases and their transmission. For example, analysis of stored samples from a variety of sources (including a plasma sample from an immune system study in the Congo in 1959,

  tissue samples from an American teenager who died in 1969,

  and samples from the NIH archives) have helped researchers learn more about the progression of HIV/AIDS. Scientists have been able to discover when the disease first appeared in humans, when it might have been introduced to various populations, and how it evolved. 

 There is a continuing discussion of the need for long-term storage of samples from blood transfusions to test for diseases that were not tested for, or were unknown or undetectable when the blood was collected. For example, infectious diseases like Bovine Spongiform Encephalopathy ("mad cow disease") can take years or even decades to incubate in humans. If an infected person donated blood several times, their blood could potentially infect many people. However, if transfusion samples were kept longer than the usual several weeks, it might be possible to test them in the future to determine if an individual contracted the disease through the blood transfusion and to determine who else might have been infected. 

Addressing the needs of unique populations.

 Different patients respond differently to drugs, may not respond at all, or may develop adverse effects. Because these groups will not be discovered until trials have been completed and unblinded, stored samples can be used for later analysis to see if there are biological reasons for the differences in patient response. For instance, a lack of response may be caused by genetic differences in the way the drug is metabolized. As the "genomic revolution" progresses, allowing scientists to use their understanding of the human genome to develop drugs targeted at populations with a specific genetic makeup, there has never been a more pressing reason to store samples. 

 Stored genomic material from patients with particular diseases may yield genetic clues as to how the disease may be treated and allow biopharmaceuticals to be designed and "targeted" specifically for the disease. For example, it is now possible to quantify the likelihood of breast cancer recurrence in women with newly diagnosed, early-stage breast cancer. In addition to predicting distant disease recurrence, the test on the disease tissue can assess the benefit from certain types of chemotherapy.

 DNA analysis is becoming increasingly important as a source of medical information. In the future, DNA banking will be a critical element in the design of therapies for many diseases. It is often said that "your genetic profile loads the gun but environmental factors fire it." DNA banking will allow the identification of these genetic factors and potentially provide targets for therapeutic products that could "disarm the gun" or protect from environmental triggers. 

Such ventures may well take up national resources. In fact, the UK Government has largely funded the UK Biobank, which is a long-term national project to build the world's largest information resource for medical researchers. It will follow the health of 500,000 volunteers aged 40–69 in the United Kingdom for up to 30 years.

The project will help approved researchers develop new and better ways of preventing, diagnosing, and treating common illnesses such as cancer, heart disease, diabetes, and Alzheimer's disease, with much of these advances being based on DNA analysis. In line with the discussion earlier on informed consent, the project has an established governance procedure to ensure that appropriate consents are obtained for future analysis of samples.

Recently, certain high-profile drugs have been withdrawn from the market due to unpredicted life-threatening adverse effects. These events have highlighted the need to retain samples from patients who received the drug during clinical trials. 

Clinical trial samples can be used to identify particular groups at high risk, especially if the medication was continued in responding patients at the end of the trial. The identification of such subgroups increases the safety of the drug and may prevent it from being removed from the market, which could cause billions of dollars in losses for the pharmaceutical company and deprive patients of its life-saving effects.

Recent damages awarded by courts to plaintiffs and potential litigation due to adverse effects are strong motivators for the industry to store samples, if only to help prove that adverse effects were truly unpredictable. 

There are several key components to an organization's good storage practice. 

 Because it may be years before samples are needed for future research, testing, or audits, specimens must be maintained in highly specialized and consistent conditions, often for decades. For example, scientists recently deciphered the genetic sequence of the devastating 1918 influenza virus using samples that had been preserved since that epidemic. To maintain sample integrity for such long periods of time, standardized, secure, and compliant storage is critical. Some factors that must be considered in defining sound storage practices include: 					

a facility capable of storing specimens at a wide range of temperatures, from ambient to vapor phase liquid nitrogen (–190°C)

reliable, state-of-the-art storage equipment

business continuity plans and redundant systems to protect sample integrity during emergencies.

 Biopharmaceutical manufacturers often store samples at multiple investigator centers and laboratories. In this situation, it can often take up to several weeks to locate specific samples when there is a regulatory request for more information or when further testing is required due to an unexpected effect of the drug. Because rapid response in this situation is in the best interest of all concerned, centralized specimen storage is an important consideration. 

 Cold chain logistics refers to the supply and distribution chain for products that must be kept within a specific low-temperature range. Maintaining the integrity of the cold chain requires logistics and management expertise to ensure that temperature-sensitive samples are constantly monitored and properly packaged so they do not degrade during packing, shipping, processing, and storage. Effective cold chain practices incorporate continuous monitoring and tracking systems to ensure that sample integrity is not compromised at any stage. 

Additionally, well-documented, centralized systems and processes as well as comprehensive inventory management and knowledge management strategies are critical to ensuring sample integrity. Without them, staff turnover can jeopardize sample integrity because of the loss of "knowledge" that occurs when employees leave an organization. Processes and procedures ensure uniform application of best practices and successful knowledge transfer. 

 Implicit in good storage practice is the associated documentation that verifies that samples have been stored in optimal conditions from collection to final retrieval. Complete electronic audit trails help prove the samples have not been compromised. For a comprehensive audit trail, continuous freezer temperature recording is required. 

As the volume of sample collections increases, there is a need for a well-designed sample or inventory management system capable of recording each specimen's: 									

exact location, from specific freezer to shelf and package position

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Feature Article

Effective strategies for ensuring the long-term integrity of specialized biological samples

Precedents for Good Storage Practice

The cardiac safety market has expanded rapidly over the past few years. This expansion has been due to the regulatory concerns about drugs that cause QT interval prolongation. The recommendation for adoption by the ICH steering committee of the S7B and the E14 guidelines in May 2005 is further evidence that cardiac safety is now a major regulatory issue. As a result, there will be a substantial increase in the number of cardiac safety studies that need to be outsourced by biotechnology and pharmaceutical companies. In fact, the total number of ECG analyzed in 2005 by core ECG vendors was an estimated 2.5 million.  

The increase in the number of ECG vendors together with the increase in the number of critical cardiac safety studies such as Phase I Thorough QT (TQT) studies means that the pharmaceutical and biotechnology companies' outsourcing decisions will be increasingly significant. The question of what criteria they use when selecting from a range of ECG vendors is pivotal to ensuring a successful study outcome.  

Fourteen ECG Vendors were identified as commercial centralized ECG companies and were approached to provide information for the ECG Vendors Report 2005

 : BioMedical Systems, CardiaBase, Cardio Analytics, Cardiocore, Covance Cardiac Safety Services, eResearchTechnology, Gentiae Clinical Research, Medifacts International, MDS Pharma Services, Nabios GmbH, Quantum Research Europe (now known as Hertford Cardiology), Quintiles ECG Services, Spacelabs Medical Data, and VIASYS Clinical Services. All of the ECG vendors were sent the same questionnaire. 

The response rate from the CROs was an exceptionally high 93%, with only Quantum Research Europe declining to provide information. The report did not consider the Academic Research Organizations (AROs), which also provide core ECG services. The detailed questionnaire required the ECG Vendors to provide both qualitative and quantitative information. The qualitative information was collated based on the following criteria:  					

countries worked in/type of services provided

services and technology solutions provided

training processes for the central readers

To quote from one of the ECG vendors within the report, "When sponsors are evaluating companies with similar capabilities, the decision can sometimes be based on intangibles." "Intangibles" in this context refers to the subjective nature of sponsors' decision-making process and could mean that a final decision is based on criteria outside the ECG vendors control (i.e., a bias toward a particular country or quality of office facilities). However, after assessing the qualitative information given by the vendors in the ECG Vendors Report 2005, much of the information presented will give the outsourcing sponsors a better understanding of the companies they are evaluating. However, care still needs to be taken when interpreting the data as the following example illustrates. 

Figure 1 shows the direct clinical ECG experience in years for each ECG vendor within the sector. The graph shows that nearly 75% of the vendors claim more than 10 years experience. Furthermore, information not shown here but captured by the questionnaire revealed that nearly 60% of vendors claimed greater than 10 years of cardiology experience within the academic or university environment prior to becoming a commercial core ECG laboratory. All the companies claim to have acquired similar cardiology expertise either within the commercial or the academic environment prior to becoming a commercial business. This makes it difficult for the sponsors to use this criterion to differentiate between vendors, and it is therefore necessary to consider other data presented in the report, some of which are outlined below.  

Figure 1. Company experience in years for each ECG vendor.			

Understanding the senior management team is a key criterion and allows sponsors to truly assess and differentiate the vendors. The vendors with confidence in their senior management team or who had senior management support gave detailed information of their senior managers' careers, experience, and business vision, and emphasized the stability of the management team and their implications to the sponsor. To truly assess a vendor, it is essential that sponsors have a thorough understanding of the senior management team. 

This criterion allows the sponsors to look at how each vendor manages and deploys their limited resources to help meet the expectations of the sector. In addition, it also provides the sponsor with an understanding of how vendors see their roles and those of their competitors. For example, one vendor took a strategic approach that involved developing their ECG services to specifically target Phase I cardiac safety studies. 

It is essential to understand how the vendor companies manage their deployment of limited resources to meet strategic objectives, as this will be a good indication of whether the sponsors' own needs and concerns can be met. 

Assessing the partnering solutions allows sponsors to understand how vendor companies work with external parties to improve their service offering. Successful partnering will have required the vendors to take a strategic decision on what benefits the partnership will bring (e.g., a technology partnership to ensure ECG equipment supply or a partnering to outsource ECG analysis to overcome projected capacity issues), how long they are entered into it, and what due diligence is required. Vendor companies that have implemented comprehensive strategic partnering solutions are more likely to have a greater understanding of sponsors' particular concerns and, more importantly, a flexible approach to delivering solutions using both their internal and external resources. 

Outsourcing and clinical departments need to take a flexible approach when trying to differentiate between the core ECG laboratories. Although information from vendors regarding their ECG analysis methods, quality assurance, and how they can ensure on-time delivery of quality data is still an essential part of the outsourcing decision-making process, our preliminary observations suggest that by understanding their senior management team, business strategy, and partnering solutions, sponsors will make a soundly based, strategic selection decision rather than one based on "intangibles." 

 are directors with Macto Consulting Limited, The Lodge, The Long Road, Rowledge, Famham, Surrey GU10 4DL, United Kingdom, +44 (0) 207 731 8478, fax +44 (0) 1252 795325, email: 

*To whom all correspondence should be addressed.

1. J. Sulola and D. Harvey, ECG Vendors Report 2005, Macto Consulting Limited. 

What to look for when outsourcing cardiac safety studies, including a compatible business mindset.

Finding the Right Core ECG Laboratory

During the past two years, we have been enamored with the disclosure of trial information online. All stakeholders—among them the pharmaceutical industry, medical journal editors, the American Medical Association, the Association of American Medical Colleges, patient advocacy groups, the U.S. Congress, and the World Health Organization—actively and openly support improving information transparency and disclosure. What specifically is disclosed, how it is disclosed, and how to ensure compliance are the issues now stoking the flames of debate.  

Under the 1997 FDA Modernization Act, disclosure of clinical trial information for serious or life-threatening conditions on 

 has been required of all research sponsors. Yet compliance and enforcement of this nearly decades-old mandate has been lax. Heightened attention and urgent debate around clinical trial and trial results registries has been prompted most recently by serious allegations that the lack of transparency and accountability, and the appearance of concealment, has compromised patient safety and public health. Recently, in an effort to stimulate higher levels of compliance, the International Committee of Medical Journal Editors began requiring that sponsors register their clinical trials, before enrollment of the first patient, as a condition of consideration for publication in major peer-reviewed journals. Legislators want to go even further by forcing sponsors to publicly post the details of their clinical trials, including results, on the National Library of Medicine's Web site (

). Some have suggested that the failure to do so should carry substantial monetary penalties. 

At the center of the "trial transparency" debate is whether or not disclosure is best accomplished via either one central registry—with 

 the seemingly obvious choice—or at many different online locations. More than 1500 organizations —including private sector research sponsors, investigative sites, general and health information publishers, and disease-specific groups—are now listing clinical trials on the Internet, and the rate of proliferation of these autonomous Web sites is accelerating.  

Although disclosure and transparency of clinical research information via online registries is primarily intended for use by the public, to date the debate has not had input from the public and patient communities. Shamefully, no one has bothered to inquire what registry users think about all of this. Had they asked, they would learn that the public isn't concerned about the volume and sophistication of clinical trials data they can find online. What the public wants is easy access to summary information and some sense of what to do once they find it.   

In the absence of information on the attitudes and behaviors of registry users, The Center for Information and Study on Clinical Research Participation (CISCRP)—a nonprofit organization—conducted an online survey in late 2005 among nearly 5000 registry users. This initial CISCRP study begins to amplify a voice that is too often unheard and forgotten. It is critically important that 

 and other well-established publishers of registries also make efforts to share what they have learned about their users to better inform the debate.  

According to the CISCRP survey, at this time the public does not want a single registry. They don't trust one source for information—regardless of whether a government or private-sector organization is sponsoring the site. Users would prefer to browse multiple locations to support their desire to self-advocate their health care decisions. Eventually, registry users want the convenience offered by a single source—but their trust in that source needs to be better established. 

Approximately 40% of users access clinical trial and trial results registries through links from other Web sites such as those listing general or disease-specific health information. Another 40% of respondents access registry information through major search engines such as Google and Yahoo. Very few users report book-marking (i.e., capturing a favorite Web page for future reference) a given clinical trial or trial listing registry. Users are visiting an average of four registries per search, and it does not appear that they discriminate between general, disease-specific, and company-specific content. Each visit averages less than five minutes since registry users are looking for very specific information. This harried and brief browsing behavior is not conducive to dense, highly technical and detailed clinical research and medical information.  Indeed, users don't want that much information. 

Registry users most want easy-to-process, summary trial information; details on whether the trials are being conducted in conveniently accessible locations; and investigative site contact information. Investigator and staff credentials, highly detailed study requirements, glossaries of terms, and compensation amounts are of far less interest to users at this stage of their search. Individuals want summary descriptions of trial outcomes and short listings of relevant citations from peer-review journals.   

The typical registry user is a middle-aged female with some college education. They are not university-trained scientists who subsist on footnoted, highly technical peer-reviewed literature. Many intelligent, would-be research participants don't understand exactly what a clinical trial is all about. The majority of registry users positively rate the amount and quality of information that is provided on a registry, but such ratings may be largely explained by users having no context or basis with which to compare information quality and quantity. One-out-of-five users report that finding information is very difficult, and one-out-of-six users report that registry information is very hard to understand.   

Users appear somewhat lost and confused. Clinical trial registries do not elicit strong calls to action. Among those who succeeded in finding a clinical trial, most never bothered to contact the research center. Approximately 10% of users initially emailed registry information to a family member or friend. Only 1% of registry users report initially emailing the information to their health care provider. Eventually, half of all registry users report showing the information to a family member or friend, and one-in-four showed the information to their physician or nurse.  

Most telling, 87% of respondents said that they want suggestions on what to do with information once they find what they're looking for. And more than eight-out-of-ten (84%) users said that they would like registries to teach them how to evaluate the information in order to determine the appropriateness and risk/benefit of a given clinical trial. This feedback captures the high importance of providing more than just clinical trial and results information on registries. Users are asking for hand-holding and guidance. 

And all this is to say nothing of the limitations of the medium itself. Forty-two percent of Americans don't use the Internet, and about a quarter of them don't have access to the Web. This includes a disproportionate share of English-speaking Hispanics and African-Americans, the lesser educated, and the disabled. Of those who use the Internet regularly, a recent Harris Interactive poll finds that one-fifth would prefer not to use the Web to access registry information anyway. If the intent of disclosure and transparency is to be fully embraced, then research sponsors and registry information publishers must entertain using coordinated offline and online communication and dissemination vehicles. 

In the real world of clinical trials, the gap between knowledge and personal action remains huge. Americans by and large believe in the importance of clinical research, yet lack a fundamental understanding of why and how it is conducted and feel severely ill-equipped to find and evaluate trial information on their own. They consider their physician the most trusted source for health-related information, yet few of them learn about trials this way. And while they are receiving promotional messages about clinical trials, they rarely consider a clinical trial when faced with a serious, life-threatening or debilitating illness for which limited or no viable treatments exist. 

Loading up the Internet with increasing numbers of independent Web sites containing mind-dizzying amounts of clinical trial and results data will not raise awareness, aid decision-making or build trust among those who currently enjoy Internet access. Less than 20% of registry users believe that the listing of clinical trials and trial results on a public Web site would greatly increase their trust in information received from clinical research professionals. Public distrust of clinical research is the result of lapses in integrity on the part of stakeholders on all sides of the debate—academia, medical journals, regulatory organizations, government agencies, industry, and other members of the research community. None of these stakeholders are licensed to drive the debate alone. They must collectively address the rising level of public distrust with the benefit of input and insight from the public.   

Clinical trial registries, in and of themselves, are not the answer. Grassroots and national awareness building, education, and outreach must be essential ingredients of any and all attempts to disclose information. In the interim, the trial transparency debate would be enriched by amplifying the largely forgotten voices browsing the Internet in search of information and hope for treatment options.  

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

Clinical Trial Insights

Online trial registries alone will not succeed at rebuilding public confidence.

Forgotten Voices in the Transparency Debate

Enterprise Resource Planning (ERP) systems—every manufacturing organization has one and each of them has invested a good deal of time and money implementing them. Introduced in the 1990s as an evolution of materials requirements planning (MRP) and manufacturing resources planning (MRP II) software, ERP systems were designed to integrate the material and resource management, distribution, and accounting activities; human resources; and financial management activities of the manufacturing enterprise.  

PHOTOGRAPHY: EYEWIRE ILLUSTRATION: STEPHEN DUDASH

ERP systems are the latest in an evolution of information systems designed to maximize the productivity of manufacturing organizations by providing controls on costs and the tools to enable companies to better meet the needs and expectations of their customers. For the most part, ERP systems have been very successful in delivering on their promise: improving the commercial operations of small, medium, and large manufacturing companies. In fact, it is unlikely that any such business could exist today without an ERP system. 			

However, are some companies who own expensive ERP licenses trying to stretch their usability too far? Are these systems being asked to manage business processes that they just don't fit? 

This article will outline the real gains that are being made in clinical supply chain management by using information technology tools from many sources and will explain why ERP software may not be the best tool to use to capture those gains. 

 What is the primary business problem pharmaceutical companies are trying to solve today?  

 Increasing the speed of development while reducing the cost of bringing drugs to market.   

This problem becomes more complicated when external factors are considered, factors that seem to work against each other. For example, the pressure from consumer groups and advocates to reduce prices is often out of sync with government policies, the rising cost of the labor pool, and changes in compliance procedures, which add time and cost to the drug approval cycle—contrary to the original intent.   

Despite these factors, the business imperatives for pharmaceutical companies to reduce drug development costs and get drugs to market more quickly have been the same for several years. Meeting these imperatives becomes a primary focus and challenge for those faced with managing the clinical supply chain. Specifically, their challenges can be summed up as follows: 					

accurately forecasting the demand of the study and managing supply to that demand

controlling the expenditures on expensive materials or comparator drugs

getting the right drug to the right patient at the right time

responding to changes in the study parameters

ensuring full backward and forward traceability at the blister well/patient level

enforcing compliance (e.g., 21 CFR Part 11) at every step necessary.  

These are specific issues particular to the pharmacist, the quality managers, and the materials managers involved in managing supplies for the trial. As such, they need tools designed specifically to address these issues. Clinical trials supplies management and associated systems are built along a business process flow that addresses these and other specific needs, starting with the study design step and progressing through the multitude of functions through final drug accountability. ERP systems are not built to address these process needs, and for good reason. 

ERP systems are designed to meet the needs of manufacturing/distribution companies across many industries, from semiconductors to industrial machinery, sneakers, beer, and snack foods. They are built to meet broad requirements for a set of independent commercial functions from industry to industry, and consequently provide mixed results in meeting the needs of any specific industry. ERP systems are designed primarily to ensure that the right amount of inventory is available for the timely fulfillment of changing customer demands—demands typically influenced by seasonality, promotions, and competitive activity.  

As such, ERP demand management systems are driven by sophisticated forecasting algorithms that assist the production planners in arranging the manufacture of commercial products. A quick survey of several ERP vendor Web sites shows the business problems they address: 					

new product introduction to meet evolving customer needs

profit optimization by distributing products through the most attractive channels

reduction in the amount and cost of carrying inventory

the need to better understand internal capacity and that of suppliers

creation of new streams of revenue through services that extend the customer relationship after the sale.

When considering life sciences companies specifically, these systems are designed to: 									

recognize pipeline gaps and identify the products with the best market opportunities

decrease the time from launch to peak sales by increasing sales and marketing performance.

Although important and practical, these functions are general and for the most part not specific to any industry, let alone to a specialized function within an industry. Further, ERP has little to offer the product development function, as its primary focus is management of activities after the enterprise determines what products it is going to produce (i.e., it manages commercial production). For pharmaceutical companies, this means at the point after the drug is approved. It is at that stage—the commercial activity stage—that ERP systems can be extremely useful indeed. 

Rob Pizzie, senior director, Schering-Plough Corporation, articulated it this way: "The difference between commercial drug supply management and clinical trials supplies management is that in commercial you design once and manufacture repeatedly. In clinical trials supplies, you design once and manufacture once, repeatedly."

Pizzie's observation points to the underlying design of ERP systems. Generally, but not always, ERP systems are designed for repetitive manufacturing operations, where the same products are made over and over. Examples include automotive parts, consumer packaged foods, chemicals, and commercial pharmaceutical products. Clinical supplies management better fits a job-shop scenario, where each job is different from the previous one. ERP systems are not well-suited for this type of an environment. 

On a more technical level, a close look at the data model of any of the leading ERP systems will reveal the sophistication of their design that appeals to multiple industries, but it will also highlight their shortcomings in terms of the specific data attributes required for the planning and production of patient drug kits for clinical trials. It is this issue that directly or indirectly translates into most of the challenges experienced by companies attempting to utilize their ERP system as the cornerstone of their clinical trials management function.  

This will be discussed in detail later in the article. Let's first consider why companies are looking to their ERP systems to serve a broader purpose than their original design intended. 

"We've licensed an ERP system. We should try to fully utilize it." Good point. Most big pharma companies have spent millions of dollars licensing their ERP system and many more implementing it. In most cases, their license allows them to extend the system with no additional license fees or for a modest upgrade fee. In addition, considerable money has been spent ($1.2 million on average

 ) in training users and IT teams on the use of their ERP system. Considering this, it makes good financial sense to use the software already licensed. 

Secondly, the leading ERP systems have a successful history of implementation in the commercial pharmaceutical industry; so at the outset, the risk appears low. Furthermore, chief information officers (CIOs) will point to "IT standardization" as another reason—also a valid point. 

Finally, and more recently, the powerful integration platforms offered by the leading ERP companies have become compelling reasons to look to the ERP system as the foundation for all the enterprise's business systems. 

Financial investment, risk mitigation, standardization, and effective integration—when taken together (and excellent reasons on their own) make a formidable case for proceeding down the ERP path. However, it is worth looking at each of these reasons more closely and analyzing how they have played out with companies that have gone down that path. 

At a recent conference for clinical trials supplies professionals, one group of speakers outlined their company's success in customizing their ERP system to suit their clinical supplies and electronic batch record (EBR) functions. Although the project sounded quite successful, it came at a high price.  

The cost of modifying the system and implementing the functionality—primarily secondary packaging and EBR—without any licensing costs was quoted at close to $15 million.    This is at least twice the cost of buying, implementing, and validating a comprehensive and automated clinical supplies management system, and it took much, much longer to achieve a workable result than a purpose built system would have taken. The difference is so great that it brings into question the fiscal benefits of staying with a legacy ERP system for supplies functions.  

This is not to say that this company made a mistake. Given what was available in the way of fully integrated, off-the-shelf clinical supplies management systems at the time, they probably made the best choice they could. However, even in light of the expensive, protracted clinical supplies management projects based on ERP software, there are more recent examples of companies starting similar projects with their ERP system, only to see modest results, lengthy implementation times, significant expenses, and in the end nonvalidated systems. There is a cost for trying to push a square peg into a round hole that some companies do not recognize. 

Staying with your ERP system for financial reasons may be valid in some cases, but a survey of the available purpose-built systems, their costs, and implementation track record is necessary in order to conduct a true financial comparison. 

To pharmaceutical companies that fit the early pragmatic majority market described in Geoffrey Moore's 

  risk mitigation is important when assessing new project decisions. Your ERP vendor is likely to be a large established company with revenues of several billion dollars and a large installed base of clients. Those are comforting characteristics. However, that is only part of the story.   

Several hundred or even thousands of successful ERP implementations do not mean that these vendors have met with success in mission-critical, niche business activities such as managing the clinical supply chain. Working to mitigate this argument are the marketing divisions of large ERP vendors intent on increasing revenues from specific market segments. To help achieve their objectives, these groups engage in the creative marketing and repackaging of standard modules to appeal to specific segments—in this case, life sciences. 

In many cases, the repackaging results in valid, useful solutions for specific business functions; in other cases, it does not. The reason for this is the potential impact that the changes required to deliver specific functionality would have on the standard ERP product. The example here is the building, shipping, and tracking of patient kits, randomized and blinded for specific trials. Building that logic into an ERP system has massive rewrite implications on the data model and software design. The obstacles and costs of such a rewrite are usually prohibitive for what is a tiny, niche market to the ERP vendor. 

To properly assess the risk of going down either the ERP or purpose-built solutions path, one should obtain a thorough understanding of the requirements of the business process owner, examine the track record of the prospective vendors in that specific application niche, and ask probing questions about timing, cost, results obtained, and lessons learned. 

Some companies may be stretching their ERP systems and squandering opportunities for productivity gains.

Is ERP the Key to Supply Chain Success?

For drug manufacturers intending to conduct clinical trials on a global scale, ascertaining the complex and at times ambiguous ethical and regulatory requirements of various countries can be a rather daunting experience. In Serbia, fortunately, this is not the case, as this country has consistently identified ways to further improve its already streamlined procedures for initiating clinical studies. There has never been a better time to conduct clinical research in Serbia, as the country has undeniably become one of the most popular destinations in this ever competitive field.  

Good Clinical Practice (GCP)-compliant, multicenter clinical trials were common practice in the former Yugoslavia until the 1990s, when the nation descended into a bloody and futile civil war with the gradual formation of five separate republics. As these individual countries get ready for eventual EU membership, Serbia, more than any other ex-Yugoslav state, has radically reinvented and positioned itself as a leading center in Europe for high-quality, cost-efficient clinical studies. 

The pharmaceutical industry has been recognized for some time as a key factor in the Serbian economy, and the Belgrade government has been actively involved in stimulating growth in this valuable sector. At the same time, the department of trade and industry is at the forefront in promoting foreign investment and encouraging international companies to establish their businesses in Serbia. 

This goal is steadily being achieved through the government's recent introduction of low-tax incentives, which together with the availability of an already well-established, educated, skilled, and cost-effective labor force at all levels, makes Serbia a most interesting investment opportunity. Indeed, the tax regime in Serbia is such that it has arguably become the envy of Europe,

  with corporate profit tax (fixed at 10%) cited as one of the lowest in the continent to the point where it is now even more competitive than in Ireland (see Table 1).  

Table 1. Corporate profit tax rates for 2004			

The Serbian authorities have also implemented tax credits for investments in fixed assets, with an upper limit of 80% of the invested amount. In addition, venture capitalists can also benefit from a 10-year tax breather for investments over $7.5 million. 

These steadfast efforts are already bearing fruit, as global giants such as GSK have made substantial gains in one of Serbia's leading pharma companies, Hemofarm Concern. Over the years, this Vrsac-based company along with its main market share competitor Galenika in Belgrade have made substantial investments in R&D, and as a result have expanded their product portfolio. Their pragmatic steps have ultimately paid dividends, making them even more attractive for further foreign financial input. 

Another leading Serbian company that has recently benefited from these positive developments is Zdravlje in Leskovac. This manufacturer of generic products for gastroenterology and cardiology was acquired by the Icelandic company Actavis in 2002. In 2004, Actavis invested some $8.3 million and plans for a further investment of $24 million by 2008; it is also continuing to develop its sales presence in a number of neighboring countries and beyond. Zdravlje Actavis has close to 200 registered pharmaceutical preparations, and last year alone introduced 14 new products. 

Serbia prides itself on having an impressive number of prestigious universities and medical schools along with well-established hospitals located in major cities and towns such as Belgrade, Novi Sad, Nis, Kragujevac, Kraljevo, Leskovac, Vrsac, Subotica, Zrenjanin, Sremska Mitrovica, and Pristina.   

These institutions are adequately equipped with the latest scientific and medical instruments and have highly qualified, experienced staff. Furthermore, the vast majority of investigators from these institutes have extensive experience in leading clinical research strategies both at home and abroad, or at the very least, they have conducted trials as part of a global research program and are naturally fluent in English. Incidentally, Serbia has the highest percentage of English language speakers in southeastern and central Europe

Figure 1. Familiarity with the English language.			

Moreover, the country has gained an auspicious reputation for high rates of evaluable subject recruitment, with high patient compliance stemming in part from the confidence the Serbian general public has in the medical profession. This is especially evident in oncology, rare disease, and pediatric clinical trials, which have become increasingly difficult to conduct in Western countries because of considerable patient reluctance. This is not to say that high recruitment rates in Serbia are attributed to some degree of indifference or naivety on the part of the subject, but rather on their immense eagerness to learn and try novel treatments for their ailments. 

Furthermore, the general public have always had a high interest in health matters, with health care issues occupying a dominant position in the media and in most cases gaining more public interest than general current affairs. One also should take into account the fact that Serbia & Montenegro is one of the largest populated countries in the surrounding region, with a populace approaching 11 million (see Figure 2).  

Figure 2. Population of Serbia-Montenegro & surrounding countries.			

Not surprisingly, in response to the high interest in conducting clinical trials in Serbia, more and more CROs have established offices in Belgrade. They have done so not only to meet the increasing demands for clinical studies in the country, but also to act as an ideal strategic center of operations for the Balkan region and neighboring territories. In fact, satisfaction within the pharmaceutical world with clinical research conducted in Serbia has resulted in the number of studies more than doubling over the past few years (see Table 2).  

Table 2. Number of ongoing CTs in Serbia			

The current ethics committee (EC) procedure in Serbia is very straightforward. All key clinical research institutions across the country have their own local ethics committees (LECs) that meet on a monthly basis and comply with the ICH guidelines for GCP. Their operations and decisions are closely monitored and have a well-established reputation over the years for professionalism and efficiency. One major plus point for sponsors wishing to conduct a multicenter study is that only one LEC approval is necessary for all relevant sites. 

The review process is quick, with protocols being approved within 30 days (although the approval process has been known to be as short as three weeks). A list of the key documents required for submission is outlined in Table 3. In keeping with the existing streamlined procedure, ethics submissions can be done in parallel with the regulatory application. However, it should be noted that the Serbian Regulatory Agency has to receive a copy of the EC approval before issuing their formal authorization.  

Table 3. Some key documents required by SerbiaÃÂ´s Ethics Committees			

In order to ensure the continued effective and efficient running of ECs, the establishment of a central ethics committee (CEC) at the Serbian Medical Association is being finalized this year.

  The working group will consist of a set number of members who will meet on a regular basis to oversee the review of Phase I clinical trial applications.

  The CEC will ultimately be responsible for monitoring the performance of LECs and will have the overall authority to ascertain whether a clinical trial is deemed suitable to proceed. 

It is also anticipated that the CEC will play a pivotal educational role by making physicians aware of ethical dilemmas and by contributing to the training of research teams. Board members will be men and women from nursing, legal, and religious backgrounds as well as physicians and scientists. 

Clinical trial applications are assessed and approved by the Medicines and Medical Devices Agency of Serbia (a division of the Ministry of Health), commonly referred to as ALIMS (Agencija za lekove i medicinska sredstva Srbije). The agency is responsible for instigating legislation and guidelines pertaining to medicinal products, medical devices, biologicals, food supplements, and cosmetics. ALIMS is also responsible for ensuring the safety and effectiveness of medicinal products, regulating controlled substances, and approving manufactured and imported medical devices. 

With the government's implementation of revised clinical research legislation in 2004 (Official Gazette of the Republic of Serbia No. 84/2004), the aim of bridging the gap between the current system and procedures stipulated by the EU Clinical Trials Directive is now accomplished. Above all, the regulatory procedure for clinical trial application (CTA) approvals is wholly transparent, quicker, and even more efficient, with most studies approved well within the 60-day review period. 

Additionally, members of staff at the agency have been known to be particularly helpful, with written queries regarding document requirements and other pertinent issues being promptly dealt with. The application form can be obtained from the agency's Web site (

) and the information to be filled in is very similar to that required in the EudraCT form. Table 4 gives a list of the key regulatory requirements stipulated in the CTA form.  

Table 4. Essential documents required for regulatory submission as stipulated in the ALIMS application form			

Once received and validated, the CTA dossier is subsequently reviewed by a panel of scientific experts who currently meet on the first Tuesday of every month to discuss and ultimately give their verdict on the application. Final regulatory approval is issued as soon as the agency receives a copy of the positive opinion from the EC. 

Furthermore, the study drug import procedure is very clear cut—only three documents are requested by customs. Required is a copy of the regulatory approval letter, a declaration from the coordinating investigator regarding the purpose of the study medication, and the proforma invoice. 

Once the clinical trial has ended, ALIMS requests a copy of the final report to be forwarded to them for the completion of the regulatory procedure. 

Serbia has for some time now witnessed a continual increase in the number of commercial and noncommercial clinical studies conducted within its borders. The country's popularity among foreign sponsors has been attributed in part to government and health ministerial initiatives, where legislation pertaining to clinical trials is very much on par with that in the European Union. Other key contributing factors are the availability of highly qualified medical staff and the long-standing readiness of the local population to try new and improved medicines for the treatment of their conditions.  

These practical approaches have ultimately placed Serbia in a highly competitive position in comparison to a number of EU member states that have yet to implement the Clinical Trials Directive and, notably, accession countries that are gradually losing their competitive edge in terms of subject availability and increasing study-related overheads. This upward trend is set to continue as the country prepares itself for imminent EU membership. 

After struggling to find sufficient patient numbers for a rare disease study in the European Union, the decision was made to recruit patients in Serbia. Here, the potential for high-quality clinical research had only recently been tapped by global pharmaceutical companies despite the relatively large population within this particular region of Europe. 

Within three weeks, we had identified and conducted preselection visits at three possible sites in Belgrade, Novi Sad, and Nis. The hospitals at these centers were highly reputable, and the investigators were of high international standing within their therapeutic areas of research. 

Serbian translations were naturally required for the patient information sheet, informed consent form, and study drug labels and regulatory authorization was obtained within 30 days. In a similar manner, the EC reviewed and approved the application within three weeks. Both applications were submitted in parallel, allowing us to begin work at the Serbian sites approximately six weeks after the feasibility study was completed. 

The Investigators screened 18 patients within four weeks (an impressive number given the rarity of the condition), all of whom were successfully randomized. The overall level of enrollment at the Serbian sites ultimately contributed to the entire global recruitment process to such an extent that the total patient number target for the program was achieved well before the deadline date. Consequently, the sponsor did not need to proceed with a number of other countries that were on the reserve list.

, PhD, is a senior member of the regulatory affairs department, Chiltern International, 171 Bath Road, Slough, UK, SL1 4AA, +44 1753 216695, fax +44 1753 511116, email: 

1. Pharmaceutical Industry in Serbia—Serbia Investment and Export Promotion Agency (SIEPA). 

, 2nd Edition, May 2005, Bank Austria Creditanstalt. 

3. Development of Research Ethics in Serbia—Vladislav Stefanovic.  

4. "Changing Clinical Trial Regulations for a Transforming Yugoslavia," 

Out of the remnants of Yugoslavia, Serbia has reasserted itself on the European pharmaceutical stage.

Clinical Trials in Serbia: From Strong to Stronger

Bloggers, Barroso, and biomarkers have more in common than their initial letter. They are all terms that have started to gain currency only very recently. And while Brussels has had no difficulty in digesting the latest fad in public diary-keeping on the Internet, and only a little more difficulty in getting used to the obscure Portuguese politician who was thrust into the limelight when he became European Commission President a year or so ago, it is taking rather longer to come to terms with biomarkers.  

But it is not for want of trying. In a bid to move the debate along, the European Medicines Agency has been assiduously promoting exchanges of information on the subject. It held its first wide-ranging meeting on the subject in December, bringing together investigators and researchers, learned societies, health professionals, and regulators. It published a report on the subject in February. And it is promising a further major meeting, to include industry participants too, during the course of 2006. 

According to the agency, the prospects overall for biomarkers are "very positive," although it admits that generally the development is still "at a very early stage," as scientists continue searching for relevant biomarkers and as efforts continue to define and validate them. But the agency's view is clear: "Intellectual pressure should be put on the implementation of translational research early in clinical trials." 

As a sign of the importance attributed to the subject by the agency, the workshop was co-chaired by Dr. Daniel Brasseur, chair of the agency's Committee for Human Medicinal Products, and by Professor Bruno Flamion, chair of the Scientific Advice Working Party. It paid particular attention to current views on validation of biomarkers. Presenting experience with the validation of surrogate endpoints in HIV, Professor Michael Hughes of the Harvard School of Public Health stressed the importance of having a reasonable biological model, sensitive assays, potent treatments, large databases (in particular when treatments are not so potent), and developing methodologies for linking information from shorter-term studies when endpoints are distant in time. 

It also discussed the influence of pharmacogenomics on new drug therapies, and examples of successful biomarker programs. Much of the discussion focused on cancer. Dr. Francesco Pignatti presented the agency's own experience with biomarkers in oncology drug approvals and the revision of the CHMP oncology guideline to include considerations on the use of biomarkers throughout the development of noncytotoxic compounds. In his remarks on statistical validation of surrogate endpoints in oncology, Professor Thomasz Burzykowski of Hasselt University in Belgium underlined the importance of meta-analysis techniques to look at data from several randomized trials and study the association between the surrogate and the true endpoint at the trial level. Professor Helgi Helgason of the Netherlands Cancer Institute noted the clinical utility of proteomics in oncology drug development, including potential applications in malignant disease for screening, monitoring progression or relapse of disease, treatment monitoring, and possible new leads for drug targeting. 

The role of biomarkers in translational research—including successful and so far unsuccessful developments—was discussed by Professor Heinz Zwierzina of the European Society for Medical Oncology, who underlined the importance of identifying subgroups of patients with a high chance to respond to targeted therapy in order to speed up drug development and avoid turning down potentially active drugs, and to define optimal combinations. Single biomarker approaches have not been shown to have a strong potential in lung cancer so far, observed Dr. Alexandre Passioukov of the European Organisation for Research into Treatment of Cancer in his presentation of developments in biomarker identification and validation for lung cancer, including detection/diagnostic biomarkers and prognostic biomarkers. He suggested that the future might rather depend on the successful use of a set of biomarkers. 

Dr. Pieter de Graeff of the Medicines Evaluation Board in the Netherlands discussed regulatory implications for the use of biomarkers in cardiovascular research. His cautious view was that biomarkers are useful for drug development and risk estimation, but currently not as endpoints for pivotal studies in the cardiovascular field. But Professor Carlo di Mario of the Royal Brompton Hospital in London claimed that biomarkers could become very useful in coronary vascular imaging interventions in atherosclerosis, because this condition is clinically silent until it reaches advanced stages. 

The complexity of the issue was demonstrated by the remarks of Dr. Francois Alhenc-Gelas of INSERM in Paris, whose discussion of genetic variations and genomic biomarkers in cardiovascular imaging ranged across monogenic forms of complex arterial diseases as well as genomic wise scans versus candidate gene approach for cardiovascular diseases such as the ACE gene polymorphism and disease outcome. 

Participants at the workshop took the view that one bottleneck to development is the pre-analytical phase, and that prospective sampling of fresh frozen material required for most techniques should be promoted, with a focus on methods that improve reproducibility. The importance of sharing data among companies as required for validation of surrogate endpoints, in particular from the statistical point of view, was also underlined.  

In many areas the trend is to use a combination of several biomarkers, but this raises issues of multiplicity that need addressing from a statistical point of view. At the same time, it will be essential to establish the role and weight of the different biomarkers within a composite score, and to establish the link to the true endpoint. 

And while application of biomarkers may, in the best of cases, result in an overall decrease in the size of the trials, or the increased use of prespecified subgroups, this will entail study design with what the agency politely refers to as "increased plausibility." As a clear indication of the agenda still to be covered in this rapidly developing field, the role of biomarkers for safety was mentioned only briefly at the workshop, "and will require more discussions," according to the agency. 

Development of biomarkers also plays a prominent role in the plans being pushed by the European pharmaceutical industry for a new European initiative to support innovative medicines. The draft strategic research agenda

  being developed for this project suggests that "thoughtful and proactive use of biomarkers can improve the mechanistic information generated in drug development, allowing a better understanding of the sources of variation and the correlation between discovery, preclinical, and clinical information." The result should, it says, be better early decision-making, thus reducing late-stage—and more costly—attrition of projects.  

The Innovative Medicines Initiative defines biomarkers as "quantitative measures of biological effects that provide informative links between mechanism of action and clinical effectiveness," and claims they can provide "new insights into a drug's mechanism of action, metabolism, efficacy and/or safety and into disease mechanisms and disease course." They can be used as tools to understand the biology of a disease, to understand the effects of a new drug, and to provide information on patient subpopulations that might respond to a new drug or be susceptible to side effects. "The value of biomarkers is that they hold enormous potential to point us in the direction of critical information for developing better diagnostics and drugs, and for helping the industry to manage the innovation process in a more cost-effective manner." 

In fact, such is the enthusiasm of this manifesto that biomarkers are depicted almost as the Holy Grail of future drug design. "The application of biomarkers in the drug development process will translate into such benefits as: increasing the probability of program success and reduced cycle times; matching patients with therapy; faster optimization of therapy; improved compliance with therapy; reduced complications of therapy and disease; more efficient drug development; more efficient health care delivery; and  ultimately reduced societal health care burden," it says. 

But—and there are still plenty of "buts"—"the vision will only be achieved if there is the right approach to optimization of biomarker investment, performance, and application," admits the IMI research strategy. Validation of biomarkers is a lengthy and expensive exercise involving many patients and years, and "there is no real consensus among all partners." The strategy paper recognizes the need for further refinement to the technologies such as improvements in resolution, sensitivity, and comparability, and a pressing need for greater access of patients to centers of excellence in imaging methods. "For this to happen, standards and registries of biomarker and clinical data will need to be agreed upon, and existing European-wide national networks will need to be coordinated."  

Biomarkers also reared their heads at the European Forum for Good Clinical Practice meeting in Brussels in late January. Fritz Buhler from the European Center of Pharmaceutical Medicine in Switzerland insisted on the need to construct mechanistic validity of biomarkers and model-based linkage with disease and pharmacological mechanisms and/or clinical endpoints. Ole Bjerrum of the European Federation of Pharmaceutical Sciences called for research into new biomarkers for characterizing chronic disease. Ian Ragan, in charge of European scientific affairs at Eli Lilly, urged greater acceptance of efficacy biomarkers in regulatory approvals and the establishment of a framework for biomarker development. And summing up a workshop session on reducing the bottleneck between preclinical and clinical development, Denis Lacombe of EORTC reported that one of the key topics to emerge was the use of biomarkers to allow more individualized treatment. However, as he pointed out, "biomarker" still has multiple meanings.  

There's growing awareness that wider and sharper use of biomarkers may be crucial in constructing shorter and smaller, but more precise, clinical trials. Unfortunately, there's still not enough agreement about how to use them. And that may have to wait until Barroso is writing about biomarkers in his blog. 

"Biomarkers play an increasingly important role in the development of new drugs. It is expected that they will contribute to increase the rate of success of new developments and to expedite the development of drugs. Also, biomarkers are key in the shift away from the 'one size fits all' to 'the right drug at the right dose in the right patient' approach. Hence, biomarkers play an important role for scientists and industry in drug development and for regulators in the approval process."

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

1. Report on the 16 December 2005 EMEA/CHMP Biomarkers Workshop, 16 February 2006, European Medicines Agency, 

2. The Innovative Medicines Initiative Strategic Research Agenda, European Commission, http://

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