There will be more information available to patients and health professionals about ongoing clinical trials and the results of those studies under new disclosure policies established by Congress and medical journal publishers.  

Provisions to expand registration of active clinical trials have been included in legislation to renew prescription drug user fees (PDUFA) and to promote drug safety. The policymakers also seek to link trial registration to stronger requirements for posting study results. At the same time, leading medical journals are expanding their trial registration requirements for sponsors and investigators that hope to publish articles on their research findings. 

Under these new policies, sponsors of studies involving a broader range of drugs and medical products will have to submit more detailed information on trial design and enrollment. Clearer links may be established between registries and sources of information on trial results and outcomes. This data aims to help patients and health professionals make appropriate prescribing decisions, as well as inform clinical trial participants of the outcomes of their voluntary efforts. 

Many of these initiatives build on registration requirements authorized by Congress a decade ago, followed by the policy set in 2005 by the International Committee of Medical Journal Editors (ICMJE). The editors of 12 leading journals said they would not publish articles on the results of research studies unless sponsors and investigators register these trials in any of five recommended registries. In addition to better informing patients of clinical research opportunities, the policy establishes a system for tracking safety and efficacy issues related to clinical research. 

In 1997, Congress called for registration of trials involving drugs to treat critical diseases, but the program was very slow getting started and many pharmaceutical companies failed to comply. Sponsors were reluctant to make public what they considered competitive information, such as study design, controls, inclusion and exclusion criteria, and primary and secondary outcomes. Many pharmaceutical companies also withheld the company name, product name, and other important information. 

The journal editors appear to have been more successful. In June, the 

Journal of the American Medical Association

 (JAMA) published a two-year evaluation of the program, reporting that "the research community has embraced trial registration." Listings on 

, the largest registry operated by the National Library of Medicine (NLM) at the National Institutes of Health (NIH), has jumped from about 13,000 prior to the ICMJE policy to more than 40,000 trials today. This surge reflects similar registration policies adopted by many medical journals. At the same time, more local and regional trial registries have been established, many linked to the World Health Organization's International Clinical Trial Registry Platform. 

To facilitate registration, the ICMJE now aims to make compliance easier for sponsors by accepting registration in a larger number of primary registries that meet WHO-specific criteria. These primary registries usually are managed by not-for-profit entities and accept information from partner registries that tend to cover a specific disease, company or geographic region. All combined, these registries provide a coordinated network and "one-stop search portal" for patients and researchers to list and locate trials all over the world. 

The ICMJE also is expanding registration requirements to apply to more early clinical trials, a change that fits WHO policy more closely. The ICMJE initially did not seek registration of preliminary studies designed to test pharmacokinetics or toxicities. Now the group has decided that Phase I studies can provide useful information for patients, prescribers, and researchers on a drug's safety and efficacy. 

Therefore, ICMJE will require as of July 1, 2008, the registration of all trials that meet the WHO definition: a research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Covered interventions include drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes. Purely observational studies still do not require registration. 

An important clarification from the ICMJE is that posting limited trial results to meet disclosure requirements will not preclude later journal publication of articles on that study—an issue that had raised concern among sponsors and investigators. The editors specify that summaries of results posted in a standard abstract format in the same trial registry will not prevent publication in a peer-reviewed journal. However, editors may consider more detailed information on trial results in publicly available registries as prior publication. 

While sponsors and investigators do not have to comply with the ICMJE recommendations, they will have to submit more information about ongoing clinical trials under registration requirements included in the PDUFA/drug safety legislation. The legislators agree that sponsors are doing a better job of listing more complete information on the 

 Web site, and they aim to support this trend. 

The legislation expands the information included in registration listings to include the WHO 20 minimal data points, plus the address of each trial site, a toll-free number for obtaining additional information, time frame for study completion, and information on expanded access to not-yet-approved test treatments. The measure also wants to know if the sponsor has placed any restrictions on the ability of an investigator to discuss or publish information on a study. 

Congress emphasizes that the registration system should make it easy for patients to search for trials based on disease or condition, intervention, trial location, age group, study phase, recruitment status, and study identifier. Sponsors will need to update enrollment status every 30 days and report when the trial is completed. 

In addition to requiring registration for all studies submitted to the Food and Drug Administration, Congress extends the policy to clinical trials supported by grants from NIH. Sponsors of some studies for generic drugs, biotech therapies, and medical devices also will have to register. 

A key goal of the new policy is to link the clinical trials registry to results information. Many sponsors do that now voluntarily, but the legislators want a more comprehensive approach. They specify that such listings should include information posted about the drug at FDA advisory committee meetings, any FDA health advisories or notifications related to the product, and the action package used by FDA to approve the application. The results also would include Medline citations to publications reporting study results, along with information in the NLM structured product labels database of FDA-approved medicines. Policymakers want sponsors to provide summaries of study results that are written for a lay audience, as well as more technical summaries for scientists and health professionals. 

One issue to be determined is whether this expanded results database builds on or replaces the 

 Web site and just how to link a trials registry to a results database. NLM staffers have long expressed concerns that a results-posting system requires much more vetting and oversight than straight registration. To address the complexities of establishing an NLM drug results database, policymakers first may conduct a feasibility study on how best to make the results of clinical trials publicly available. If the experts conclude that a public results data bank makes sense, officials at NIH, NLM, and FDA then would develop regulations for submitting trial information based on an appropriate format, time frame, and procedures. 

A thorny issue is how sponsors can comply with registration and results disclosure policies without drawing charges of illegal promotion. Posting information about the indication and study design of a test product could bring up unapproved uses. And requiring sponsors to provide a non-technical summary of a study in lay language could expose a company to liability for off-label promotion and false claims. Pharmaceutical companies believe that such summaries are of limited value and that clinical trial results should be written primarily for a medical and scientific audience. 

The trial registration and results disclosure provision fit the broader legislative goals of ensuring drug safety. The PDUFA bill provides FDA with authority to require more extensive clinical trials following product approval and to impose new labeling requirements within a set time frame. Applications for new drugs will have to spell out a range of pharmacovigilance activities for sponsors to undertake in order to manage the risks associated with the use of a new drug by patients and prescribers. While there was considerable debate on these and many topics covered in the broad bill, proposals for making public more information on clinical research activities and results were relatively uncontroversial, reflecting the rise in public acceptance of these programs. 

Articles

View from Washington

Journal editors and legislators expand the scope of clinical trial registration and results disclosure.

New Policies to Increase Information on Trials

A significant part of clinical development activity is outsourced by pharmaceutical companies, which must still maintain responsibility for the oversight of the service providers to whom they outsource. Pharma companies fulfill this responsibility through quality management, which includes precontract and in-process audits of these service providers. Conducting such audits not only requires significant pharma resources but also significant additional time and resources from the service providers to facilitate these regular and routine audits from different sponsor companies. 

As these audits from different sponsors often seek the same information, it should be possible to use our limited resources more efficiently. This duplication of effort could be avoided and efficiencies maximized for both sponsor companies and service providers if sponsor companies entered into a Cooperation Agreement solely for, and limited to, the sharing of objective and nonproprietary information gained from auditing activities. 

The principles of such a Cooperation Agreement would relate to audit scope, what information may/may not be shared, protection of sponsor's proprietary information, the rights to use audit reports, and respect for existing confidentiality agreements. 

Other safeguards built in would ensure that there would be no sharing of information on commercial matters between the collaborating sponsor companies and no cooperation to achieve commercial leverage. The scope of the Agreement would include only the sharing of objective information from audits conducted under strict controls and with the prior agreement of the auditee. None of the collaborating sponsor companies would have the right to access other sponsors' proprietary information during the conduct and reporting of audits. 

Once the audit is completed, the objective findings and any related follow-up actions (excluding any reference to proprietary information) is shared between the collaborating sponsor companies who have the right to cross reference the audit activities in applications and submissions to regulatory authorities on a global basis. 

This initiative has been tested by six big pharmaceutical companies. Benefits for both sponsor companies and about 30 service providers taking part in the program have been demonstrated. 

A continually increasing and significant part of a sponsor's clinical development activities is outsourced to a variety of service providers, including: 					

full or single service contract research organizations (CROs)

laboratories (clinical, bio-analytical laboratories, specialty laboratories)

central reading laboratories (ECG, imaging)

clinical trial supplies, storage, and distribution companies

Even with such outsourcing, the ultimate responsibility for the quality and integrity of the work performed always resides with the sponsor.

  Sponsors fulfill such responsibility through quality management oversight of their service providers, including qualification and in-process audits. Therefore, the increasing use of service providers by pharma, with concomitant increases in auditing, still poses a significant requirement for resources from the sponsoring companies and specifically from the auditing functions of these companies. 

Many of the service providers used routinely by pharma are audited by companies often seeking the same information related to the same generic systems used for activities performed. Moreover, the time required of service providers to facilitate routine audits from different sponsor companies performing similar audits should not be underestimated. It should be possible, however, to more efficiently use the limited time and resources of both pharma and service providers and avoid duplication of effort in quality management oversight. 

To avoid this duplication of effort and to maximize efficiencies, F-Hoffmann-La Roche and five other peer companies have entered into a Cooperation Agreement. This agreement is solely for, and limited to, the sharing of objective and nonproprietary information gained from auditing activities. 

Typical resource requirements for pharma to conduct a service provider audit and the resources required of the latter to host one are provided in Tables 1 and 2. 

Table 1. Time and personnel are two key resources required when a sponsor company conducts an audit.			

These resource requirements are based on a standard auditing methodology that involves the assessment of the service providers compliance to international and local regulations and guidance, standard operating procedures (SOPs), and contracts; reviewing/verifying data and evaluating control documentation; interviewing key personnel; presenting observations according to a root cause approach; and following up after receipt of a corrective action plan and audit closure. 

It may also be the case that the service provider personnel taken away from their normal activity to host audits as per Table 2 may be the same personnel used for activities relating to more than one pharma company, thus compounding the inefficiency and effects of duplicative efforts. 

Table 2. The type of time commitment service providers can expect to make when they host an audit. 			

It is the intent of the inter company audit collaboration initiative described here to avoid such duplication of efforts and achieve greater efficiencies for both pharma and service providers in the quality management oversight of routinely used and cyclically audited service providers. 

The basic concept of this initiative is the pre-agreed (with service provider) sharing of objective and nonproprietary data in audit reports between clearly identified sponsor companies. These reports are used as one component of each sponsor company's risk management strategy related to their service providers. Each company draws its own conclusions from the report in the context of the scope of the audit performed and their specific needs at the time. The auditing company does not make recommendations to the other sponsor companies receiving the report—an important facet of the program with regard to anti-trust legislation. The initiative is not: 					

one of performing audits on behalf of another company or partnership.

Nor is it for any collusive discussion to exert commercial leverage. Rather, it is an initiative for the simple sharing of objective information in audit reports. The detailed concept is made clear in the Cooperation Agreement signed between the sponsor companies taking part and in the agreement letter signed by service providers prior to the sharing of the audit reports. Principles embedded in the Cooperation Agreement include mutual recognition of auditor capability, audit conduct, and audit reporting of the different parties; protection of proprietary information; controlling the use and distribution of information obtained during pre-agreed and approved processes; respect for existing confidentiality agreements,  especially no sharing of information on commercial matters. 

Tools developed for the management of the collaboration process and the standardization of audit report presentations and interpretations are presented in Table 3. 

Table 3. Standardization plays an important role in successfully managing the collaboration process.			

Participating sponsor companies meet at regular quarterly face-to-face meetings and hold monthly teleconferences to share and align selected QA programs related to service providers of mutual interest. Minutes are kept and archived. No participating sponsor company will perform an audit that was not already on their own audit plan. Agreeing upon which company will conduct a particular audit will depend on when each company had intended to conduct it, the particular audit scope, and the priority of the audit for the individual members. 

The overriding principle is to maximize the efficient use of the participating sponsor companies' resources in performing quality audits of service providers normally audited in a routine cyclical fashion by group members. The aim is to avoid the duplication of time and effort required by these service providers in facilitating multiple audits of similar scope. 

The principles of the Cooperation Agreement that effect the service provider relate to audit scope, what information may/may not be shared with whom and when, protection of the sponsor's proprietary information, the rights to use audit reports, and respect for existing confidentiality agreements. This is detailed in the standard service provider letter of consent, which also provides the identity of the sponsor companies with whom the report will be shared and which must be signed before any audit report is shared. 

Audits are conducted in accordance with the normal SOPs of the auditing company who will have access only to its own information and will not have right of access to proprietary information of the other sponsor companies during the conduct and reporting of these audits. All conditions of confidentiality agreements between the service provider and any of the named collaborating companies remain fully in force and nothing in this process shall be in conflict to this. 

All proprietary information related to the auditing company gathered through the review of documents and relevant interviews is used to test the generic systems (people, processes, and equipment) of the service provider that are also used routinely during the provision of similar services to the group members who have signed the Cooperation Agreement. 

The detailed scope of the audit will be described, as usual, in the audit confirmation letter sent by the auditing company. Upon completion of the audit, the objective findings and related follow-up actions (excluding any reference to proprietary information) will be discussed with the service provider, and only then will be shared between the named collaborating sponsor companies in a standardized process. In this way, the nonauditing group members will only see the audit report when it is completed in the context of the auditee comments and provision of follow-up action plans. 

These shared audit reports and follow-up action plans may be transferred within the individual group sponsor companies in a controlled manner and to the extent that this is already allowed in the individual agreements between the service provider and individual sponsor companies. 

A key element of the collaboration process, and of benefit to both the group of sponsor companies and service providers alike, is the focus on standardization of audit conduct and, in particular, standardization of interpretation of audit reports. 

Six big pharma companies have joined forces to share the generic results of some of the cyclical routine audits each conduct, thereby obviating the need for the other five to conduct the same audit. All have significantly benefited from significant cost and time savings. These audits have been conducted in Europe, the United States, and Australasia by group sponsor companies. About 30 service providers have signed up for the program and have also begun to see the benefits of time and cost savings comparable to those seen by big pharma. 

It is clear from the initial proof of concept phase for this initiative that by increasing (in a controlled way and with the consent of all present parties) the number of collaborating companies in the group, we can even more efficiently share limited resources involved in the strategic risk management of independent third-party service providers of common interest. 

It is envisaged that a controlled expansion phase of the project to allow, at least initially, for up to 10 collaborating QA groups will enable all parties participating to derive even significantly more benefit. The number and size of participating service providers are not limiting factors, but the type of service provider is. Specifically, investigator sites and clinical pharmacology units are not suited to such a program since such audits may be of a more project orientated and proprietary nature. 

In addition to maximizing efficiencies and avoiding duplication of effort, it is also envisaged that this initiative will encourage the development of auditing criteria and standards so that audits become more standardized in the ways they are conducted and the kind of issues they are trying to assess. Challenges still remain both within pharma and within the service provider sector. These challenges include the conservatism of especially those pharma companies that could contribute to and benefit from maximizing the initiative, as well as an unfounded fear by the service provider of collusive discussion to exert commercial leverage. However, progress to date is showing that these barriers are being broken down. 

PhD, is global head of CQA external alliances at F-Hoffman-La Roche Ltd., Bldg. 670/515, CH-4070 Basel, Switzerland, email: 

1. ICH GCP Part 5.2 Contract Research Organization, http://

Feature Article

Big pharma collaborates on routine audits and quality management of third-party service providers.

Laying with the Lions

All experimental compounds tested in humans during clinical development are under stringent control to ensure that these drugs are administered only to eligible patients participating in approved study protocols. To that end, regulatory agencies worldwide mandate that all investigational products manufactured for clinical trials must have cradle-to-grave tracking for accountability, reconciliation, and destruction.

The life cycle of an investigational product (IP) is complex, transitioning from a manufacturing environment during production to a clinical environment during experimentation. Each of these situations has a unique body of governing regulations, Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP), respectively. The IP also reverts back to GMP when accounted, reconciled, stored, and packed for destruction as waste, creating an additional transfer between environments.

Sponsors must be able to document and demonstrate to regulatory authorities that they are in complete control of the drug supply chain at all times and can account for the whereabouts of all manufactured investigational products, whether consumed or destroyed. Currently, the administrative burden of accounting for and reconciling clinical supplies rests largely on the investigative sites, monitors, and depots, who generally perform these tasks manually and without the benefit of a central tool that tracks clinical material from manufacture to dispensation and return.

Sponsors can reduce this burden and streamline the process start-to-finish by planning up front for the consideration of closeout activities and budget requirements. A plan that also includes the collection of data through a centralized, interactive database can help sponsors minimize errors, stay within budget, and more efficiently reconcile all IPs at study closeout per regulatory requirements. 

The need for rigorous control over IP progress through the manufacturing and clinical trial processes is apparent for controlled substances—those drugs with high potential for abuse, including narcotics, stimulants, and hallucinogens. However, in reality, every investigational product requires a clear and documented plan for accountability and reconciliation, not just those that can create physical or psychological dependencies. 

In many instances, the timeline to launch the study and dose the first patient is very tight. Typically there are delays each step of the way, such as when batches fail analytical testing, protocols need to be finalized, and the labeling and packaging vendors impose their own requirements for lead time. The study start date is almost never extended to compensate for these delays. The narrow focus on study startup activities often does not include consideration of endgame activities, which can result in significant unexpected costs if a procedure for an IP has not already been addressed and incorporated into the study budget. 

Early planning can help studies close out more quickly and efficiently and also bring hidden costs to light for inclusion in the overall study budget. Failure to account for closeout activities up front can result in the need to subcontract out the reconciliation tasks with potential budget overrun. 

Figure 1 illustrates the potential paths of an IP through its life cycle and the types of information captured at each step during transit. This information is typically recorded by different users in different formats (supply logs, dispensation logs, and spreadsheet files) as the IP travels through the supply chain. The manufacturer, packager, warehouse, depot, and site may all account for and reconcile the IP as the study drug flows through their respective locations but typically do not reconcile their data with each other. The study sponsor, however, must ultimately be able to trace and document the drug's path through each functional area and resolve any discrepancies in the accounting process. 

 Figure 1. Potential paths of progress for an investigational product through its life cycle, from manufacturing to destruction.			

Sponsors need to be aware of their own unique business practices regarding how to handle the remaining IP at the end of a trial and be mindful of the demands created on resources and budget in order to comply with regulatory requirements. While it is possible to backtrack and collect existing IP data after the fact, proactive planning can minimize the time and effort required to gather and clean the information for accurate accounting and reconciliation. 

There are important questions that ideally should be answered prior to study startup. These include the following: 

Who will manage the accountability/reconciliation of IPs?

 Defined roles and responsibilities for these tasks help make the process more efficient at the time of reconciliation. Assigning a resource proactively during the planning phase rather than reactively when the need arises ensures the task will be completed and according to regulatory requirements. 

What levels/details should be documented?

 Regulatory agencies globally require documentation of and accounting for all IPs produced, but the requirements can vary depending on the country in which regulatory approval is being sought. Sites must abide by local authorities and sponsors must abide by the local regulations where the drug application is being filed. 

 Typically, IPs must be destroyed by a licensed incineration facility that can issue a certificate verifying destruction. For noncontrolled substances, sponsors also have the option of having the sites destroy unused drugs themselves. However, many sponsors elect not to go this route due to the risk of the drug being diverted and ending up on the street, creating legal and liability issues. Processes must be defined for returned IPs to travel from the warehouse to the destruction facility and these agreements established prior to the accumulation of IPs. 

 Again, it is important for sponsors to engage their shipping and destruction vendors early on to understand the lead times required and the costs associated with freight and transport. Often, transport runs to the destruction facilities must be scheduled a month in advance to ensure that a full load is being delivered. 

Determining how to approach the accountability and reconciliation process will depend on local regulatory requirements, each sponsor's unique business practice, and preferences of the study manager. Nearly all of the aspects described below are best discussed early in the planning process rather than dealing with the situation as it arises toward the end of the study. Neglecting to address these issues at the time of planning and prior to final budget approval can result in inefficient closeout, delays in destruction, and additional storage and transportation fees incurred for unreconciled IP. 

Site reconciliation vs warehouse reconciliation. Having both the site and the warehouse perform reconciliation on the same IP invariably leads to discrepancies. Site reconciliation is usually more accurate, more efficient, and less costly. That's because sites, for the most part, deal with smaller quantities at any given time and can reconcile the IP as it is returned. GCP guidelines require that sites account for both used and unused drugs at the time of study closeout, and sponsors can leverage this requirement for site-level accountability as part of the overall accountability process. Since site reconciliation is done before the IP is shipped back to the warehouse, the site knows exactly how much study drug was consumed during the study. 

Contract warehouses can also perform accountability and reconciliation, but will often charge an additional hourly fee or per-receipt fee to receive, count, report, and prepare IPs for destruction. Many also charge a per-pallet, per-month fee for storage, starting with the first receipt of a clinical return. Warehouses also may not have resources immediately available to perform ongoing reconciliation as the returns arrive. Shipments may begin to accumulate before reconciliation is performed, and the accumulation can then translate into additional storage fees passed on to the sponsor. 

Warehouses do not operate under GCP; consequently, their reconciliation activities are often performed with unregulated documentation procedures (often using simple spreadsheet programs) that also require reconciliation. The tracking spreadsheets are neither validated nor controlled, and must be printed and signed to be used as data for the audit trail in compliance with 21 CFR Part 11 (the FDA's requirement for electronic record keeping and maintaining an audit trail around investigational products). Further, warehouses can often only track kit numbers because they do not have access to study data from the sites, and thus cannot map kit numbers to patient numbers. This gap becomes the responsibility of the sponsor to fill, reconciling warehouse spreadsheets with the site accountability records to track assignments and returns at the level of the medication kit. 

 It is common that not all IPs allocated to a site are consumed due to poor recruitment or low enrollment. To maximize the use of available study drugs, sponsors often redeploy supplies to other sites with true demand. This practice can help prolong the supply of study drugs, but can also introduce uncertainty and complexity in accountability due to the difficulty of tracking all the locations where the IP has been and the route taken. While redistribution is a fairly common practice, regulatory agencies typically discourage site-to-site and site-to-warehouse-to-site shipments because storage cannot be confirmed once the initial shipment leaves the warehouse, and these subsequent shipments may not have QA inspection and release processes. 

 In the event that the sites are authorized to destroy returned IPs, what documentation is required? What is the disposal procedure? 

Many sponsors elect not to have sites destroy IPs directly due to the risk of the drug being diverted from a controlled environment. Having the sites return drugs to the warehouse serves as an internal check to ensure that all drugs stay within the sponsor's control. Once the IP concludes its life cycle in the realm of the site, it transitions out of GCP and back to GMP. When returned goods are approved for destruction, they are then packed and treated as waste. 

Shipping the remaining IP from the site to the warehouse or depot. 

Again, return activities are often not considered when the study budget is being developed and can lead to cost overruns during close out. There are additional charges for hazardous material, regulated waste, medical waste, and any other materials that require special handling and transport, which the sponsor should be aware of early on in the process to avoid surprises. Sponsors should also engage in proactive consultation with the waste management vendor, as not all materials can be destroyed locally and the vendor can advise as to transport requirements and freight charges. Insufficient planning can lead to delays due to the need for monthly scheduling of transport runs, which can in turn translate into additional storage time and costs at the warehouse. 

As described previously, packagers, warehouses, and sites all touch IP as it flows through each location and all use different tools to account for and reconcile materials that they handle. However, because these processes are piecemeal and largely manual, there is no easy way for the sponsor to follow the progress from one environment to the next. 

One way to streamline the data collection of the accountability and reconciliation process is to incorporate the IP return function into a centralized database such as an interactive voice response (IVR) system, which is already being used to track IP release through clinical distribution and dispensation to patients. An IVR system can significantly minimize the administrative burden on the site when used for randomizations and drug assignments, and with proactive planning the system can also be leveraged to facilitate site accountability of returned IPs. In addition to investigative sites, warehouses and depots that are already familiar with the IVR system can also use the tool to enter what IP a patient has returned and even capture the date the IP was destroyed. 

The IVR system houses all the data that would otherwise be captured separately by the sites and warehouses in a single database, which the sponsor can access easily. Most commercially available IVR systems are fully validated and developed in compliance with 21 CFR 11, eliminating the sponsor's need to piece together disparate data sources in a way that is acceptable to regulatory authorities. As some data is still captured through handwritten documentation, using an IVR system also eliminates the need for data entry and verification required for transcription into an electronic tracking file. 

Importantly, an IVR system does not eliminate the need to count unconsumed medication, but it can consolidate all information from release to destruction in one system. The entire reconciliation can be easily accessed at any time through IVR-generated reports either by request or on a scheduled basis. An IVR system can also help consolidate cost and reduce or eliminate the per-hour fees associated with warehouse reconciliation and per-receipt return fees. This approach can reduce many hours of reconciling various reports and documents manually, which also reduces costs. 

Investing in proactive study planning with early consideration of endgame activities can save time and reduce the risk of cost overruns. Although it is often difficult to establish concrete plans while a protocol is still being developed, thoughtful planning and consideration in conjunction with the clinical study manager and clinical supply manager can prevent the surprises of unforeseen tasks and hidden costs. 

Leveraging readily available tools such as IVR systems not only during the study but also after the last patient out can streamline many labor intensive activities and minimize errors. By addressing these processes during the planning phase, a study is more likely to stay within budget and close out activities will include the all-important final disposition of IPs. 

 is a manager with Covance IVRS, 210 Carnegie Center, Princeton, NJ 08540, (609) 452-8550, email: 

*To whom all correspondence should be addressed.

1. European Commission, Enterprise Directorate General. Volume 4, Good Manufacturing Practices, Annex 13: Manufacture of Investigational Medicinal Products (EC, Brussels, July 2003). 

2. Code of Federal Regulations, Title 21, Volume 5, Part 312, Investigational New Drug Application, Part 59, Disposition of Unused Supply of Investigational Drug (2006). 

3. Code of Federal Regulations, Title 21, Part 210, Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs (2006). 

4. Code of Federal Regulations, Title 21, Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, Section 150, Distribution Procedures; Section 196, Distribution Records; Section 204, Returned Drug Products (2006). 

5. The Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscellaneous Amendments) Regulations 2005 (2005). 

6. N. Dowlman, M. Kwak, R. Wood, G. Nicholls, "Managing the Drug Supply Chain with eProcesses," 

Tracking the life cycle of a drug is a complex process that early planning and IVR technology can help ease.

From Cradle to Grave

Hosted Service Offering Validates Data Prior to FDA Submission to Improve Review Process

announces a new submission checking service based on its Web Submission Data Manager (WebSDM) application. The hosted service offering produces a comprehensive report detailing all errors identified by WebSDM. Following the report, Phase Forward's CDISC specialists conduct an interactive review session using the customer's data and the same review capabilities that FDA uses.  

WebSDM gives organizations a way to test FDA submissions for compliance with the CDISC Study Data Tabulation Model (SDTM) standard for human clinical trials. The Submission Checking System makes WebSDM data validation services broadly available as a hosted service, which enables organizations to quickly confirm if the data from trials conforms to SDTM standards to reduce possible delays from FDA data-related queries. 

The service is available now, and current customers can convert to a license for ongoing studies. 

eShowcase

eShowcase: WebSDM

As usual, the DIA annual meeting this year was a great success. The thing I enjoy the most is a walk down ALL the aisles of the increasingly dramatic trade show floor, where vendors, consultants, and service providers of all shapes and sizes get to display their wares and offerings. "Reading" the show floor can create a very vivid snapshot of the issues facing the industry in any given year.  

There seem to be dozens of different vendors offering any particular technology, many with an expensive and well-designed booth with carefully worded descriptions of their systems. If somebody is interested in piloting a particular technology and goes around to all the vendors at the show for screen demos, it will become increasingly difficult to distinguish one from another. They all seem to have a great Web demo, full of functionality, and all the necessary 24/7/365 services that one could want. 

I wonder how any nontechnical, nonexpert can possibly distinguish between the different technologies and vendors. I can imagine that many decide that there isn't really a difference between the offerings. "Why not," they might conclude, "just pick one and try it on an unimportant project. Even if it doesn't work so well, what have you lost?" they might say. 

To anyone who has taken economics, the answer is obvious: opportunity cost. From the Wikipedia (today, at least): Opportunity cost is...the cost of something in terms of an opportunity forgone (and the benefits which could be received from that opportunity), or the most valuable forgone alternative. 

With opportunity cost firmly in mind, let me relate to you a brief personal story of the last few days. As the title to this section suggests, consider the parallels between this story and a clinical trial pilot of some technology. 

The story starts, innocently enough, with a little pet project I have been putting off. I was asked to design a timeline of the history of my company with photos, links, and descriptions of key milestones. It is, in my mind, an ideal task for everyone to participate in. But somehow, I knew that sending an email out to the company was unlikely to unleash an onslaught of descriptions in my inbox. In addition, I figured, few would be formatted properly, thereby increasing my work. 

As I thought about it, I came upon what seemed to be the perfect solution. I would use an open-source timeline program (http://

) that takes XML and/or JSON files (typical export files from a database application) and automatically creates a very functional timeline. To get the data into the database, I would create a Web page with a single form that would allow people to enter the properly formatted information onto a Web page. Now the task would be easy—send people a request to help with the history along with a link to the form on a Web page. If I did it right, they would see the data appear on the timeline as they entered the Web page. 

The best rule about technology that I know is: Use the software that best fits the task at hand. For a simple Web page form, I wouldn't need to build a relational database with a sophisticated application on top simply to collect five or six fields. In fact, I realized that this would be a great opportunity to try out one of the really cool new Web-based programming tools that don't require any programming experience. 

These programs are part of a new breed of Web 2.0 Software as a Service (SaaS) offering. SaaS applications are provided entirely through a Web browser and many use technology that gives them the feel and functionality of a client application. Many of these are so functional they are being discussed as threats to the hegemony of Microsoft Office, including Google Spreadsheets and Google Docs. 

In fact, Google isn't completely dominating this concept. One company that has an impressive array of SaaS programs is Zoho (

). Zoho offers free or very inexpensive applications, including a word processor, spreadsheet, presentation software, Web meetings, email programs and more. These programs are highly functional and offer more than many people would ever need in these areas. 

Zoho's newest offering was exactly what I (thought I) needed for my project. Called Zoho Creator, it is an application that allows nonprogrammers to create database applications for simple business use involving the entry and viewing of data. Without worrying about database design, the Zoho user simply drags the particular type of data entry fields onto a form (dropdown boxes, text boxes, checkboxes, etc.) and voila: Automatic database entry screens and reports are created. 

With similar drag and drop validation elements, it is very easy to do range checks and logic checks on and between fields. In literally minutes it is possible to have a working data entry form with underlying database. These forms can be very easily inserted into Web pages, creating the look and feel of a professional Web form. In fact, some companies and organizations are using Zoho forms for simple surveys, course signups, and other simple tasks. 

I toyed with using Zoho's newest competitor, Coghead (http://

), but decided to stick with Zoho because I found it to be simpler to use and faster to implement. 

Within the first 30 minutes of using Zoho, I had built the form I wanted and tested it on a Web page. I was actually amazed at how easily and quickly the application came together. Despite this, I knew I had a few hours of tweaking and developing range checks to make sure the application would collect clean data. I began to enter some scripts, and the minutes turned to hours as they always do when programming. I added, tested, and modified in iterative cycles. Some of the features that made the Zoho application easy to use became annoying, as they took more steps and longer than a real Web development tool. Despite these minor annoyances, the tool was fast and easy to use. 

At some point during the evening I entered a snippet of script that prevented my application from working and issued an error message. Not knowing which validation script item it was that caused this, I spent an hour or two taking pieces of script out of the application, each time restarting and entering data. Over time, the application became really slow and funny things began happening. I couldn't enter data. I couldn't delete data. I couldn't even delete the application itself. Finally, in exasperation, I tried to delete my entire account and start over. After going through this same cycle three times, the entire Zoho Creator "execution engine" choked on two lines of my script. Apparently, nobody, including me, could log in for a period of hours. Through the whole process, I had several calls to the help desk with friendly responses and rapid problem solving. 

Before I knew it I had spent about 12 hours over two separate days developing a simple Web page that I could have done in about three hours with a variety of well-tested Web development tools. 

Of course, going in I understood that all Web 2.0 applications are in "beta" for months to years (take a look at the Gmail logo!) and Zoho Creator 2.0 was only one month old. I reasoned that all software had bugs and recently launched beta software would have a bunch, but somehow I thought I would be the one to avoid all the obstacles. 

The next morning the entire development team from Zoho Creator called me from India. It seems that a bug in their code caused my little program to bring their application server to a grinding halt, preventing me and anyone from logging in. They were incredibly helpful and very responsive, fixing the problem on the spot. Zoho Creator, they explained, was a work in progress, still young and prone to these sorts of problems. Although it looks great and does exactly what I want it to, it isn't the robust timesaver I hoped it would be today. By my next project, I am sure it will be robust and reliable. 

When I related this story to our CTO, he told me that this was the very reason that he spends a great deal of time researching technologies and tools—to make sure that the ones our developers use are stable and don't create these same sort of problems, which can cause delays and endless frustration. 

When I decided on a new, flashy Web 2.0 development tool for this simple project, I thought I was matching functionality with task. However, I wasn't taking into account the opportunity cost, which was significant. I had spent all of my free time for two days in frustration and wasted a time window when I could have completed my project and several others. Although I learned a lot about a new tool, I did little else during these two days. 

In choosing Zoho Creator, I had the same problem that the DIA attendee has at the booth demos—I was considering the superficial features and not the quality, robustness, and scalability of the tool. While an evening or two of frustration isn't a large problem for a one Web page project, it can be greatly magnified when implementing clinical trial technology, even for a single pilot. 

The moral of the story is: When choosing clinical trial software of any sort for your important projects, respect your opportunity costs and do your due diligence. Seek out and interview those with experience (preferably recent experience) in using the application. Find out how many companies are using it, on how many clinical trials, and how quickly they were able to scale up. Don't get fooled by the allure of feature-rich, "easy-to-use" software that has great promise but has had only limited use. It may turn out to be a major source of frustration, or much worse. Go with the features you need and the tools that work, and work reliably. 

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

Technology Viewpoint

Fresh and flashy may appeal to the senses, but when it comes to trial software, it's experience that counts.

Software Decisions and Opportunity Costs

There has been a buzz from clinical trial sponsors that they feel more and more sites are requesting separate payments for startup fees in their budget agreements. Sponsors are feeling pressure to answer why more investigators are requesting these fees and what activities investigators typically consider part of a startup fee. 

Information on numerous clinical costs, including startup fees, have been collected from over 26,000 protocols and over 237,000 investigator contracts worldwide and compiled by Fast Track Systems for use in the proprietary database supporting Grants Manager.

				  An analysis of that database showed that sponsors are indeed contracting more investigator budgets that include startup fees, as seen in U.S. and Canadian clinical trials.

  Presently, more than half of investigator contracts in the United States include a startup fee, supporting the sponsors' perceived dramatic increase in startup fee requests from investigators.

Further analysis indicates that this trend does not appear to be significantly influenced by clinical phase, therapeutic area, sponsor type (pharmaceutical vs biotechnology), investigator site type (those affiliated with universities or hospitals vs independent physicians), subject status as inpatient or outpatient or even total number of completed subjects the budget is based upon. Figure 1 does, however, show an interesting subtrend in the increasing quantity of contracts including startup fees; the increasing occurrence of startup fees in oncology investigator contracts are outpacing the average increase observed in all other therapeutic areas.

Figure 1. Oncology is outpacing all other therapeutic areas when it comes to study grants requiring startup fees.1			

So if the expected clinical drivers are not behind this trend, what is? Sponsors are obviously aware that academic medical centers as a whole have been paying closer attention to their financial expenditures and reimbursements with regard to conducting clinical trials. Certainly, many research universities have even created dedicated Clinical Trial Offices, which typically serve to approve and oversee all clinical trials conducted by their academic medical centers.

  A former State University of New York (SUNY) Clinical Trial Offices Director specified that negotiation of "proper institutional indirect cost rates" meant inclusion of startup fees.

Many Clinical Trial Offices have SOPs in place that require payment of a startup fee. However, academic medical centers are not the only site types analyzing their clinical study participation costs. Experts in the industry have encouraged even independent physicians to dedicate staff and resources to reviewing their expenditures and reimbursements for clinical studies to ensure the viability of continued clinical research participation.

 This industry viewpoint shift may well be a driving force behind this sweeping change. 

Figure 2. It appears grants contracted without startup fees have become a thing of the past in the United States.			

So what activities does a startup fee cover? The startup fee has only recently become a widely contracted reimbursement (see Figures 2 and 3).

  This has caused a fair amount of variation in what is considered part of the fee. 

Figure 3. The number of grants charging startup costs is starting to catch up with the number of startup fee-free grants in Canada.			

The aforementioned former SUNY Clinical Trial Offices Director itemized pharmacy setup, agreement processing, file archiving, IRB review, and principal investigator and coordinator study initiation as the activities included in a startup fee.

  Analysis of Fast Track's data from across the industry and globe revealed some similar components. Contracts that specified what the startup fee covered often cited study preparation costs, including preparation for submission to the ethics committee, protocol review, and general administrative setup. Pharmacy setup fees were usually singled out as a separate reimbursement.

Some sponsors argue that these activities are reimbursed as part of the overhead fees factored into the cost per patient. However, sponsors are increasingly contracting competitive enrollment agreements with investigators.

  For investigative sites that initiate these competitive enrollment studies but fail to enroll subjects before enrollment is terminated, setup activities will go unpaid unless the site negotiated these costs as separate fees. The University of Michigan Medical School states, "A contract that garners $1800 for an IRB Fee and $1562 for advertising ($1250 + 25%) regardless of patient enrollment is much more viable if it enrolls no patients in competitive enrollment than one that has the costs built into the per patient amount."

  While the University of Michigan Medical School used typical pass through costs in their example, this is a financial principle driving many sites to request or require startup fees as a separately reimbursable item. 

It is important to make the distinction that startup fees are not bonuses. In their June 2000 report, "Recruiting Human Subjects: Pressures in Industry Sponsored Clinical Research," the Office of Inspector General (OIG) defined bonuses for recruitment as "payments given to investigators purely to encourage speedy enrollment."

  The startup fees defined herein are remuneration for legitimate costs incurred during the initiation of a clinical trial by an investigator (see sidebar: Typical Startup Fee Itemization). In fact, the OIG has posited that the practice of paying investigators on a per-subject basis in a competitive enrollment schema "penalizes those sites with a slow startup period and encourages aggressive recruiting."

It is therefore reasonable to view proper startup fee reimbursement as a way of relieving sites of this potential financial conflict and thereby ensuring human research protections. 

In summary, startup fees are increasingly being negotiated into contracts by all types of sites in all areas of clinical research.

In light of the coinciding increase in competitive enrollment schemas and their potential for creating ethical conflicts for investigators,

  proper reimbursement of startup fees should continue to be encouraged. Sponsors must evaluate their current budgeting practices and determine a compliance strategy for these fees. A starting point might allow for reasonable startup fees to be paid out upon study initiation in the case of studies employing a competitive enrollment design. 

In these cases, sponsors may be able to negotiate further which line items they will base overhead calculations on or otherwise adjust overhead in order to compensate down slightly for the upfront payment. Likewise, if the site contract is guaranteeing the investigator a minimum allotment of subjects, then perhaps these fees should be considered already included in the overhead specifications just as they were in the past. In this way, sponsors ensure that sites are appropriately reimbursed for startup fees and overhead expenses, and the fees could not be misconstrued as bonus payments. 

As mentioned, some sites are considering startup fees a standard part of doing business with them; sponsors will need to evaluate these sites on a different basis, taking into account nonfinancial considerations such as thought leaders, available subject populations, etc. In any case, sponsors must think about and develop strategies for their own best practices for startup fees—it is clear that most investigators have already done so. 

 is vice president of operations at Fast Track Systems, Inc., 20 Ash Street, Millennium I, Suite 330, Conshohocken, PA 19428, email: 

 CCRP, is client relations manager at Fast Track Systems, Inc., and 

1. PICAS Database, 1991–2007. Proprietary Database of over 25,000 finalized Clinical Trial Protocols and over 250,000 Negotiated Investigator Contracts Worldwide. Fast Track Systems, Inc. 

2. Multiple Academic Medical Centers including but not limited to: The University of North Carolina at Chapel Hill, Office of Clinical Trials: http://

; The University of Iowa, Clinical Trials Office: http://

; Emory University School of Medicine, Clinical Trials Office: http://

 (all Web sites accessed January 24, 2007). 

3. K. Durdon, "What Can a Clinical Trials Office (CTO) Do For You?" 

4. C. Pierre, "Participating in Clinical Trials: A Guide for Practices," 

5. M.R. Yessian, "Recruiting Human Subjects, Pressures in Industry-Sponsored Clinical Research," OEI-01-97-00195, Office of Inspector General (June 2000). 

6. University of Michigan Medical School. Corporate Budgeting Issues. Available at: http://

www.med.umich.edu/medschool/grants/budgeting_issues.htm

Data confirms more sites are asking for separate startup fees and that oncology trials are leading the way.

Sponsors: PAY HEED

Every parent knows the feeling. You've been dealing with the kids for so long that when they finally grow up you think: "That's good. It was great fun, but now at last they've left home." But they haven't. They come back—to borrow the car, to store some furniture, to bring some washing, to hang out with friends or just to get a good meal.  

The clinical trials community in Europe is getting the same sensation with the pediatric medicines regulation [Regulation (EC) No 1901/2006 on medicinal products for pediatric use, http://

.] which came into force at the start of this year. Everyone thought the real work—including its new requirements on clinical trials for children—was years ago, as the regulation wound its slow way through consultation, legislation, implementation. But it wasn't. It's still here. And it's still calling for attention. So here's the latest snapshot. 

The new pediatric committee at the European Medicines Agency held its first meeting in early July, and reviewed the scientific and procedural aspects of assessing the pediatric investigation plans that the new rules make obligatory. It also looked at the strategy for setting up an EU-wide pediatric-research network, and at how to conduct a survey of existing uses of medicinal products in the pediatric population in the EU. 

The committee is assembling some of the best scientific expertise available in the EU in areas relating to pediatric medicinal products—pharmaceutical development, pediatric medicine, general practice, pediatric pharmacy, pediatric pharmacology, pediatric research, pharmacovigilance, ethics, and public health. And its main responsibility will be to provide opinions on the development of medicines for use in children. 

The pediatric committee is not responsible for marketing authorization applications for medicinal products for pediatric use. This remains the responsibility of the European Medicines Agency, although the Agency's Committee for Medicinal Products for Human Use may request an opinion on the quality, safety, and efficacy of a medicinal product for use in the pediatric population if the relevant data have been generated in accordance with an agreed pediatric investigation plan. 

For the moment, the committee is chaired by Daniel Brasseur, pending the election of a chair at its September 2007 meeting. He was chair of the committee's predecessor, the Agency's pediatric working party, which met for the last time at the end of May after six years of operations as a temporary expert group. During this time, the working party laid much of the groundwork for the pediatric regulation and contributed to the development of pediatric medicines. It identified and regularly published pediatric needs across many therapeutic areas and provided guidance on development and supervision of pediatric medicines, including on formulations of choice, pharmacovigilance for medicines, pharmacokinetics in the development of medicinal products, and investigating medicines in the neonatal population. It also established the priority list of off-patent medicines for studies in children, which will be funded through the EU's new research program. 

The membership of the committee is not yet complete. The Agency has just asked for expressions of interest from people who wish to be appointed to it to represent health professionals and patient associations. The regulation requires six such members—and six alternates—to be appointed by the European Commission, in consultation with the European Parliament. They will be expected to attend the monthly committee meetings in London. 

The rest of the committee consists of five members and five alternates drawn from the Agency's Committee for Medicinal Products for Human Use, and one member and one alternate appointed by each member state not represented by the members appointed from the Committee for Medicinal Products for Human Use. 

As from July 1, the Agency has to be formally notified two months in advance of the intention to submit an application for a pediatric investigation plan (or a request for waiver or deferral), and it has just published guidance on the practical aspects [available at http://

www.emea.europa.eu/pdfs/human/paediatrics/practical_aspects.pdf

]. The application for the pediatric investigation plan itself should be submitted in line with the meeting timetable of the committee. The Agency will issue a letter validating the application and indicate the name of the rapporteur allocated to the file. The company should immediately send identical sets of the final application to the appointed rapporteur and to each of the pediatric committee members. 

The Agency has also just published an overview of comments it received on its draft guideline on conduct of pharmacovigilance for medicines used by the pediatric population. The main reservations expressed were that "much of the guideline refers to new or evolving concepts with which there is limited experience" and "the document is limited in its provision of details that pharmaceutical firms can use in routine pharmacovigilance planning." The specific difficulties of monitoring pharmacovigilance in off-label use were highlighted and clarifications about the roles and responsibilities of pharmaceutical companies regarding the implementation of the guideline were considered important. 

After a long and winding journey, now the real work begins on the EU Regulation for all those involved.

Applied Clinical Trials-08-01-2007