 Clinical trials are increasingly global. They commonly span the United States and the European Union, and—due to increasing trial activity in Japan—sometimes include all three ICH regions under a single protocol. Companies have both an operational and an ethical need to harmonize the provision of Suspected Unexpected Serious Adverse Reactions (SUSARs) to all investigators participating in a trial. International pharmaceutical developers also desire to implement consistent processes among all affiliates for alerting investigators of SUSARs in company-sponsored good clinical practice (GCP) studies. 

However, there are still substantial international differences in regulations on SUSARs. The rules on reporting to regulatory agencies are not fully harmonized, and different regions have different expectations on the timing and amount of information provided to investigators and regulators. This paper will cite the major regulations and guidance related to expedited reporting of SUSARs in the EU, the United States, and Japan, and point out fundamental differences in requirements between the three ICH regions. 

The regulations and guidance describing investigator notification under the European Commission, the U.S. Code of Federal Regulations, and the Japanese Pharmaceutical Affairs Law were reviewed and compared to the relevant ICH documents (Table 1). 

ICH guidance related to SUSAR reporting to investigators are found in the E6 Guidance on GCP and the E2A Guidance on Clinical Safety Management. E6 sections 5.16 and 5.17 read as follows

5.16.2: The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favorable opinion to continue the trial. 

5.17.1: The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.  

 is more specific regarding the definitions of "serious" and "unexpected," and indicates reports that are both serious and unexpected should be expedited to regulators. However, E2A does not suggest the timelines for reporting information to investigators—the well-known seven- and 15-day timelines described in section III.B of that document apply only to reporting to regulatory agencies. Also, E2A does not clarify the format of such reports, or specify if the requirement applies just to SUSARs arising from clinical trials or if it includes spontaneous reports. As described below, these omissions reflect a lack of harmonization in international regulations. 

 instructs on regulations for the implementation of GCP in the EU with definitions given in Article 2 and sponsor obligations for reporting SUSARs given in Article 17. The actual implementation of the directive in member states varies. These national variations are beyond the scope of this review, but further complicate unified reporting to investigators. Guidance on clinical trial SUSAR reporting was issued in April 2004 as "Detailed guidance on the collection, verification, and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use."

 Section 6.4 provides the general guidance that the sponsor must inform all investigators on "findings that could adversely affect the safety of study subjects" but the only timeline given for investigator reporting is "as soon as possible." 			

 The FDA regulation is the only one of those reviewed here that gives a specific timeline for reporting to investigators: 15 days for any reactions that are both serious and unexpected. It is important to note that a Proposed Rule was published in the Federal Register on 14 March 2003 that would modify these reporting requirements; however, the proposal has not been finalized, so it will not be discussed further here. Although there are several guidance documents for reporting postmarketing events in the United States, there is no guidance specific to reporting reactions from clinical trials or to investigators participating in those trials. 							

Reporting of adverse reactions occurring during clinical trials is covered in sections 80-2-6 and 66-7 of the Pharmaceutical Affairs Law. This portion of the law as written describes reporting to the Minister of Health, Labour and Welfare. In practice, though, reports are submitted to the Pharmaceuticals and Medical Devices Agency (PMDA). Section 20-2 of the Japanese regulation on GCP requires sponsors to report "immediately" to investigators and the heads of institutions involved in the clinical trial. Guidance on reporting is issued in Notifications, which are frequently modified and superseded by subsequent Notifications. The most recent Notifications relevant to this discussion were issued on 30 March 2004

 but their content is the same as earlier Notifications regarding the issues below. 			

Differences—Nonserious hospitalizations

In the definition of "serious," all hospitalizations are considered "serious" in the ICH E2A document and in U.S. and EU regulations. However, in Japan only hospitalizations or extension of hospitalization "for treatment" qualify as serious. When the E2A ICH document was translated into Japanese, the words "for treatment" were added to the portion of the definition of "serious" covering hospitalizations. Section 66-7 of the Pharmaceutical Affairs Law also specifies that hospitalizations are only considered serious if they are for treatment. In practice, it can be difficult to determine when a hospitalization is "for treatment" and counts as serious under Japanese regulations. Further, having a different standard for what qualifies as a "serious" adverse event in Japan as compared with other ICH territories can complicate compliance with internal standard operating procedures for multinational companies and safety data exchange agreements for licensing partners outside Japan.  			

An additional difference in the definition of "serious" is that where the ICH, EU, and U.S. documents use the phrase "persistent or significant disability/incapacity," the Japanese PAL uses an unqualified term equivalent to "disability." However, in later notifications,

 sponsors are instructed to map this definition of disability to the ICH definition when creating an electronic (E2B) report. Therefore, in practice these different expressions are treated as equivalent. 

In both the United States and Europe, an event is considered unexpected if its degree or nature are inconsistent with what is written in the Investigators Brochure, and all subsequent reports of a previously reported event continue to be unexpected until the Investigators Brochure has been amended to include it. In contrast, once an event has been distributed to investigators as a SUSAR in Japan it is considered "expected."

 Whether the Japanese practice will mean that subsequent reports of that event are subject to expedited reporting depends on whether the event is one of "death" or "life-threatening," or only meets the other criteria for seriousness. 			

Expected life-threatening and death SUSARs

The United States, EU, and Japan all require seven-day reporting to regulators of unexpected life-threatening and death SUSARs, although none of these territories specifies a seven-day timeline for reporting to investigators. In all three regions, unexpected serious reactions, which are serious by any of the other criteria, are to be reported to regulators within a 15-day timeline. In Japan, unlike the United States and EU, expected life-threatening and death SUSARs qualify as 15-day reports to the PMDA and must also be reported to investigators. 			

When a drug being studied in clinical trials is already marketed either in the country where the trial is being performed or overseas, spontaneous reports of adverse reactions will be available for possible reporting to investigators. In the United States, spontaneous reports do not need to be reported to investigators if the study drug already has U.S. marketing approval for any indication. Similarly in the EU, if a drug has marketing approval in any EU member state, then spontaneous SUSARs do not need to be submitted to investigators.  			

In contrast, in Japan spontaneous reports from within Japan and from outside must be distributed to investigators if they meet the other criteria for expedited reporting. The result is that there is usually a much higher reporting burden to Japanese investigators in clinical trials than to their U.S. or EU counterparts, especially if the study drug is already marketed. 

Reports from non-health care professionals

Spontaneous adverse reactions may reach companies from a number of sources besides health care professionals, including patients, their families, and lawyers. Indeed, there is still no definition of a "healthcare professional" that is accepted in all ICH regions. To simplify the discussion, the term "consumer reports" will be used to indicate any adverse reaction that is initiated by someone other than a health care professional.  			

Because a sponsor may receive spontaneous reports while clinical trials are ongoing, there is a need to consider whether or not consumer-reported SUSARs should be provided to trial investigators. United States regulations do not distinguish between health care professional and other reports. In fact, most consumer reports internationally are received in the United States. However, because consumer reports can only be received after a product is marketed, and FDA regulations specify that once a product is marketed in the United States spontaneous SUSARs do not need to be distributed to clinical trial investigators, there is never a need to triage U.S. consumer reports for reporting to U.S. investigators.  

In the EU, only adverse reactions that have been reported or verified by a health care professional are currently considered reportable. So again, consumer reports would not be sent to investigators.  

The situation is more complicated in Japan. The Pharmaceutical Affairs Law does not distinguish between health care professionals and other reporters, although very few consumer reports are received in Japan. Because development of a given compound in Japan frequently lags its development in the United States and Europe, there are often a large number of foreign consumer reports that must be considered for reporting to investigators in Japan. For consumer reports, unlike those from health care professionals, it is acceptable in Japan for the company to decide unilaterally whether or not the report is a reaction. Nonetheless, any consumer reports that the sponsor determines are SUSARs will be reportable to investigators in Japan. 

Only U.S. regulations give a clear, 15-day timeline for reporting SUSARs to clinical trial investigators. The EU Clinical Trials Directive states that "The Sponsor shall also inform all investigators" but gives no timeline on reporting to investigators. The EU guidance4 only states that notification to investigators should be "prompt." Similarly, the phrase used in Japanese regulations indicates that reporting should not be delayed but gives no indication of whether a week, 15 days, or a month is appropriate. 			

Both the U.S. and Japanese regulations indicate that individual reports of SUSARs are to be provided to investigators in the same format they are provided to the agencies. Section 6.4 of the EU Guidance4 suggests that line-listings accompanied by a concise summary may be an appropriate format for informing investigators. 			

EU regulations give the same timelines for reporting to regulators as to ethics committees (ECs) and clearly state the sponsor is responsible for reporting to ECs. Although the EU regulations do not give timelines for reporting to investigators, they specify the same seven- and 15-day timelines for reporting to ECs as apply to reporting to regulators. Japanese regulations also place responsibility for reporting to the institutional review board (IRB) on the sponsor. In contrast, U.S. regulations give investigators the responsibility for reporting to the IRB. Although this does not change the sponsor's responsibility for distributing reports to investigators, similar logistic and timing issues are faced in reporting to the EC/IRB and study investigators. 			

Although great strides have been made in harmonizing reporting requirements for adverse reactions, substantial differences continue between the three ICH regions in what reports must be expedited to clinical trial investigators and when (Table 2). The effect of many of these differences is to increase the reporting burden for investigators who are based in Japan, even if they are working with the same protocol and Investigator's Brochure as investigators in the United States or Europe participating in the same clinical trial.

 Table 2. Differences in reportability to investigators 			

1.  ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice. 			

2.  ICH Harmonised Tripartite Guideline, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 

3.  European Commission Directive 2001/20/EC. 

4.  European Commission, "Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use" April, 2004. 

5.  Code of Federal Regulations, Title 21, Part 312 Section 32 (U.S. Government Printing Office, Washington, D.C.). 

6.  Notification #0330020 of the Evaluation and Licensing Division and Notification #0330003 of the Safety Division, Japanese Ministry of Health, Labour and Welfare, March 30, 2004. (Japanese) 

7.  Notification #0330014 of the Evaluation and Licensing Division, Japanese Ministry of Health, Labour and Welfare, March 30, 2004. (Japanese) 

 MD, is with Eisai Co., Ltd., Koishikawa 4-6-10, Bunkyo-ku, Tokyo, 112-8088 Japan, +81 (0)3 3817-5288, fax +81 (0)3 3811 2980, 

Articles

Feature Article

It can be difficult to determine when a hospitalization is "for treatment" and counts as serious under Japanese regulations.

Reporting Adverse Reactions to Clinical Trial Investigators in the ICH Regions: Key Differences

The head of your company's clinical development department requests you to draft a project plan for a multinational Phase III trial of 800 asthma subjects within three weeks. This plan should be quite specific regarding the number of countries and study sites involved, the subject recruitment period, and the expected total cost of monitoring visits. 

You are in a considerable dilemma. You have been opposed to implementing a proper performance metrics system. What tools should you now use? Memory? Intuition? Best guesses? Will the development head be impressed with you at the conclusion of your project, should this ever happen, if time and money spent exceeds your plan by as much as 100%? 

Table 1B.   Micro benchmarks: Choice of clinical project cycle times and quality project metrics			

The terms "development cycle times," "performance metrics," and "benchmarking" are terms you remember well. Admittedly, you have only superficially read some topical articles. However, being so extremely busy and not really convinced that those publications were strictly applicable to your work situation, you did not further pursue the idea of implementing a performance metrics system in your environment. 

Figure 1. Variance in planned versus actual recruitment. Analysis based on N=9 studies initiated in 2002. The difference (days) between the plan as specified in the initial protocol outline and the actual recruitment period (first patient in to last patient out) was compared. The overall median was three days ahead of plan.			

Despite or because of all the pressure on you, you are a solution-oriented manager. You identify quickly that the only way to address the challenge imposed on you is to send urgent requests for proposals (RFPs) to five contract research organizations (CROs). Your interpretation of the proposals' operational plans will allow you to deliver the project plan on time. Your best guess of country numbers, site numbers, time needs, and resource needs depends on how many CROs respond in time, and how robust their metrics databases and current feasibility surveys are. 

Table 2.  Operational capacity and productivity metrics			

Suddenly, you awake. This was only a bad dream. Your team and all other operational departments did their homework a few years ago. You introduced a performance metrics system in all operational departments, at project level, and across all countries in which your company maintains development operations. You use metrics to track the efficiency of the cooperation with study sites and CROs. As a result, you can easily write a study plan in line with the above specifications. 

Figure 2. Monitoring performance over a four-year period. The median number of enrolled patients for 10 countries is shown per clinical research associate (CRA) FTE and per FTE for all staff within the entire clinical operations group.			

Reasons for a performance metrics system 

Pharma industry associations and cooperating institutions like the Tufts Center for the Study of Drug Development and the Centre for Medicines Research International Ltd. (CMR) maintain sophisticated systems for R&D timeline, cost, and productivity tracking based on the input from research-based pharma companies. They generate benchmarks for development of new medicines, as well as their relationship to output in terms of new active substances (NAS) that obtain marketing authorization. 

Table 3.  Site-specific performance metrics						

Disproportion of development time/cost and number of new product launches. 

Total development time from preclinical testing to marketing authorization increased from 8.8 to 13.9 years between the 1960s and the 1990s.

 Of 5000 screened compounds, only five reach Phase I of clinical development. Ultimately, one NAS obtains a marketing license.

 The latest estimate puts the average R&D cost for one NAS reaching the market at $802 million. This translates into an almost six-fold increase between 1975 and 2000.

 This is also reflected in the dramatic increase in the annual global pharmaceutical R&D expenditure, which more than doubled between 1990 and 2000, from about $20 to 43 billion. Disappointingly, the output in terms of annual NAS marketing authorizations reached an all-time low of 26 in 2003.

Clinical development is the major cost driver.

 The duration of the clinical phases rose from 2.8 to 6.3 years between the 1960s and the 1990s.

 In 1997 and 1998, the mean duration of clinical development of a new chemical entity (NCE) ranked at 5.4 years, down from a maximum of 6.9 years between 1990 and 1993. For biopharmaceuticals, the mean duration was 5.2 years, the highest-ever average. Depending on the therapeutic class, an average of 3.4 (AIDS antivirals) to 7.5 years (gastrointestinal) was spent in the period between 1995 and 1999. Despite the high attrition rate from discovery to first use in man, clinical development absorbed 37.8% of the total 1999 R&D expenditure.

Figure 3A. Expected differences in total enrollment duration for three scenarios based on the companys actual metrics data. Anticipated enrollment duration was calculated based on median enrollment rates (in patients/center/month) from previous trials for the respective therapeutic area. The country selection and site numbers are shown in Table 5. Left bar: scenarios with 128, 51, and 45 sites. Right bar: All scenarios with 128 sites, showing the effect on enrollment duration. Taken from Ref. 10.			

Clinical trial performance tracking by all involved players is mandatory.

 The workload in clinical trials is ever-increasing. Global and more stringent clinical trial regulations, maximum demands on subject protection, documentation of processes, data quality and validity, system validation, and pharmaceutical quality of the investigational medicinal product have been large contributors to the workload. Trial sponsors, their increasing number of contractors, and investigational sites are all bearing equal shares in this joint endeavor. In view of this mounting complexity, it became mandatory to track where the resources in terms of people, money, and time are spent, and which impact various measures have on productivity and efficiency metrics over time. 

Figure 3B. Estimated total monitoring visit costs for scenarios 1-3. The monitoring costs for the number of site visits were estimated for each scenario based on the country and site numbers given in Table 5, assuming a six-week monitoring visit interval, a six-month patient treatment period, and an average cost of 800 f per monitoring visit. Taken from Ref. 10.			

Performance metrics used in clinical development

The large stages of research and development, known as R&D macro benchmarks, are illustrated in Table 1A. 

Table 4.  Outsourcing performance metrics						

The causes for below-industry-standard performance and areas for improvement can only be identified and addressed if all contributors to a new drug application (NDA) track those key performance metrics that they impact. 

such as clinical monitoring, data management, and clinical quality assurance (CQA) track capacity and productivity by selected use of metrics (Table 2). Clinical project management or clinical operations collects project metrics from every clinical trial conducted. A variety of so-called "micro benchmarks" are available for scrutiny as outlined in Table 1B. 

Certain clinical project metrics are heavily influenced by country-specific regulations or conditions, e.g., regulatory authority or independent ethics committee (IEC) review times. In consequence, tracking such metrics at the country level is advisable. They may be displayed as multidimensional project metrics, underlining the interdependencies between project timeliness, cycle time, quality, and efficiency.

Table 5. Construction of three proposed trial scenarios based on actual past performance metrics			

keep track of critical steps and/or elements at the source of clinical data generation. Both sites and study sponsor benefit from the information that can be obtained from the metrics shown in Table 3. 

 graphically demonstrate the correlations between single metrics, such as number of subjects per site, time spent for site selection per site, number of queries per subject, and the monitoring time per enrolled subject. Using such approaches in multinational projects can be of enormous value for forecasting purposes in comparable future studies. 

, as highly important contributors to today's development output, use operational metrics that match those of their customers. Certain pharma companies make cycle times track records a prerequisite for contracting with a CRO

—both quality and productivity performance are of utmost relevance to the prospective customer. In addition, CROs use utilization (refer to Table 2) more consistently as departmental metric than pharma does. The metric realization compares the achieved to the contracted revenue. Other, more sophisticated calculations are used as well. High productivity and quality must translate into profitability of their endeavors, should their development business remain viable. 

 such as indicators of the efficiency and productivity of the cooperation between sponsors and CROs, seems to be the logical missing link in the clinical development production chain these days. Selected time periods and other indicative metrics of potential value

How to launch and maintain a metrics system

Senior management must demand and drive improvement of clinical development productivity, and its transparency to all hierarchy levels. Current processes, tools, resource utilization, and clinical trial tracking systems have to be evaluated for effectiveness. Gross performance deviations from industry standards should be addressed as first priority.  			

Operational task forces develop the principles of the new system via either an independent in-house manager or an external consultant. The information technology (IT) department has to be represented in the task force.  

Once the direction is identified and agreed to, IT should receive the funds to set up a new performance metrics database. The data for this database usually derive from sources originally set up and maintained for other purposes—clinical trial management system, human resource database, project finance tracking system. This avoids duplication of data entry efforts. Headcount is allocated to oversee the generation of management reports, and to analyze, interpret, and summarize the findings across the organization. This staff also assumes responsibility for the benchmarking of the internal progress in the light of best industry practices. 

The various department heads receive reports and share the key conclusions with their staff. Achievements are the basis for periodic assessments for further improvement at the departmental level. Department heads and their staff work toward and agree on new performance targets. Functional departments assume ownership of "their" performance metrics and continually strive towards optimization without fear of unreasonable pressure and personal punishment. The development staff obtains this information in the context of the "big picture" of the company's R&D efforts. This includes time spent for go/no-go decisions at the management level between cycle times, and of the fundamentals of the entire business performance in a "digestible" format. 

Collected project metrics are used as required by new development programs on the horizon. As a principle, only experience in the same indication and of similar country distribution is used for reference purpose. And that has to be substantiated by newly set-up feasibility surveys. 

Internal achievements and external benchmarks

The macro-cycle times of the past decade might look discouraging, if not analyzed for confounding factors. From 1994 to 1999 there appeared to be a decrease in drug development from more than 12 to a little less than 10 years,

 driven by decreases from first submission to first launch and first patient dose to first pivotal dose.

 This trend was, however, of a temporary nature. The latest analyses

 refer to a 12-year development time again. 			

These data do not account for the time spent for go/no-go decision-making, which is outside of any operational productivity impact. Neither do these evaluations account for the extent of regulatory requirements and related documentation workload, which have dramatically increased from the early nineties. The shortening of the authority review cycle time is probably a product of both strengthened productivity at the regulators level and also a reflection of higher dossier standards based on studies conforming fully to ICH GCP and other applicable regulations. 

From 1996 to 1999, the cycle times from protocol approved to first patient first visit (FPFV) increased by 15%.

 This may be a result of inefficient start-up processes, a slow take-off at the study sites, or a more thorough and hence longer review process of clinical trial applications at the authority and/or IEC level. The cycle times of last patient last visit (LPLV) to database lock (DB lock) and from DB lock to key statistical analysis decreased to 110 and 50 days, respectively. They can probably be improved further. The entire subject enrollment period (300 days) and the time from key statistical analysis to final study report (150 days) remained essentially unchanged. 

Implementation of a performance metrics system applying prospective metric targets at an individual company level can lead to major improvements.

 In our experience, time targets of protocol approved to Essential Document package approved and from package approval to FPFV could be reduced by 10% and 30% respectively, one year after launch of the performance metrics system, independent of the clinical trial indication.

 Subject enrollment was ahead or within plan in six out of nine studies analyzed (Figure 1), compared to 86% of studies being behind plan for the industry.

There were further achievements due to an internal performance metrics system applied via a three-year goal-setting program.

 They included cutting enrollment time into half, greatly increasing planning accuracy with respect to time to FPFV and enrollment time, and increasing the proportion of active sites from 65% to 88% of all initiated sites. Patient enrollment rates (patients/site/month) also matched or exceeded industry standards in the majority of countries.  

Reaching specific metrics targets may be at the cost of other related aspects, and will require corrective action. For example,  a monitoring team has managed to carry out an average of 10 site visits per month. But the median time to complete a monitoring visit report now exceeds 10 days and the internal audits provide evidence of decreasing quality. Given these circumstances, this should be the time to think of more training or system improvements and also the creation of more feasible metrics targets. There seems to be a maximum number of CRF pages and, hence, number of subjects that can be monitored by one CRA per year, as illustrated in Figure 2. For obvious reasons, this metric depends on the clinical trial indication and its pertinent treatment duration.

The value of metrics for creating new study plans

The collection of metrics in the same indication and in a comparable geography over three years allows construction of three proposed scenarios. The hypothetical multinational trial was for 800 asthma patients (Table 5) with a significant variance in enrollment duration and total monitoring visit costs (Figures 3A and 3B). Note how the key drivers, enrollment rate per site and total number of subjects per site, allow for lower total site number with comparable enrollment times, but considerably lower monitoring visit needs or greatly decreased enrollment time at an equal site basis. If only economics is superimposed and no strategic regulatory reasons, the likely choices are evident. 			

This example demonstrates one of the key values of such data. A huge amount of money and time could be saved if we utilize the corporate wisdom derived from properly maintained performance metrics systems for the sake of more effective future developments. 

The data available from decades of benchmarking in clinical development provide clear evidence of the excessive absorption of time and cost before marketing authorization. The goal-setting of strengthened productivity while balancing capacity is not only legitimate but a must in view of three factors. These are the natural resource limitations, the economic pressures on the health care market at large vis-á-vis the unmet therapeutic needs requiring innovation that remains affordable. All players, operational departments, investigational sites, and clinical project leaders have a role in streamlining the processes and making drug development more cost-effective. 			

Out of the numerous performance metrics, it is advisable to select and track five to six key performance indicators at the department or project level that will change behavior and drive performance. The right time-points for collection—whether monthly, quarterly, annually or at the completion of tasks—are crucial. Past performance should set the stage for the new performance metrics targets. These targets must be demanding but achievable. Outperforming on one metric target might have a negative impact on others. Consequently, interdependencies have to be observed and acted on. Metrics should not be changed before sufficient data supporting sensible conclusions are available. Appropriate comparisons across therapeutic areas, projects, and countries are a prerequisite for meaningful decisions on future targets or trial programs. Joining large benchmarking studies is advisable despite the associated cost and efforts needed to maintain them. 

Performance metrics systems can be valued as a change management trigger. Their costs are justified if the system provides value in terms of shortening cycle times, improvement of efficiency, and quality. Disappointments and frustrations of measuring clinical development productivity in the early days due to insufficient system support, duplicate records, and manual tracking can now be avoided. With suitable software, a thorough understanding of underlying business processes, and a commitment to continuous improvement, these challenges can be met.  

Implementing a performance metrics system will be of great value now and in the future. Focusing on performance indicators that drive change and positively impact productivity while remaining in full regulatory compliance is an unwavering principle. The sum of all efforts at all levels across companies will eventually reduce cycle times in clinical development and bring innovation sooner and in a larger scale to those who need it most—the patients. 

Certain clinical project metrics are heavily influenced by country-specific regulations or conditions, such as IEC review times.

Measures of Success

A recent conference featured debate on the role of research ethics committees.


Last month this column briefly remarked on the conference in Brussels on "Research Ethics Committees in Europe: Facing the Future Together." It was a significant first gathering of hundreds of representatives of local and regional ethics committees (ECs) from all across Europe. In view of its importance, it is appropriate to offer a snapshot of how far the meeting went in raising understanding between researchers, regulators, and ethicists about the challenges that ECs face.

The challenge is apparently huge. Even after research ethics committees (RECs) have been reviewing clinical trials for 20 years, fundamental questions about their role, scope, and structure remain a matter of debate, not consensus.


A workshop on the organization, infrastructure, and role of RECs at the country level revealed differences on everything from assuring independence to expertise of members, and from mechanisms of funding to levels of transparency. 

If RECs are to play their role as guardians of the dignity of research subjects, insisted Dr. Jiri Simek of the Institute of Medical Ethics at Charles University in Prague, they must keep their independence from sponsors, researchers, institutes, regulatory authorities, and even from central ECs. Methods of nomination, qualifications for membership, and training are crucial influences on independence, he argued.

There were strong defenders of the voluntary approach to REC membership as a guarantee of independence. With ethics review seen as a matter of adventure rather than bureaucracy, it was recognized that some controls were required. Some saw the evolution towards greater professionalism as a guarantee of independence. Others viewed it as a threat to independent thinking. 

Differing views were expressed on how to cope with the risk that independence might be compromised by close relationships between local committees and local investigators and sponsors, or by payment of REC members. Institutional RECs were depicted as being closer to--and more confident in--investigators, entailing the need for independence to be guaranteed by supervision. By contrast, regional committees may enjoy a greater detachment from investigators, but may be subject to influence from their appointing authority.

Caroline Trouet, of the Belgian pharmaceutical industry association pharma.be, noted the increasing complexity of the tasks facing RECs, their gradual assumption of legal status, and their subjection to national and EU legal controls and even legal liability. But she also highlighted the diversity of responses countries had adopted to meet these new circumstances, and the consequent challenges posed by any attempt at harmonization or standardization.

Overall, although some participants considered the composition of RECs to be insufficiently precisely laid down in the EU clinical trials directive, some consensus emerged. The merits of wide membership of RECs were both to boost independence and also to provide the widest possible range of expertise to cope with ever more sophisticated demands.

Easier communication between RECs was described as part of a move away from a system of secrecy and lack of mutual confidence to a sort of "peer review" system in which RECs routinely justify their opinions. A general raising of standards was also desirable to prevent REC-shopping by sponsors looking for a lax assessment.

Cristina Avendao-Sol offered an overview of the development of the Spanish RECs system in the wake of the EU clinical trials directive. It has brought a new level of coherence and transparency to the review process by establishing a "lead" REC to give an opinion on a multicenter trial. There is obligatory consultation among all other RECs involved, and an online register of multicenter trials. 

Sigrid Skavlid of the central secretariat for RECs in Norway also provoked widespread interest. She told of the new electronically based application system in operation there since the start of 2005, aimed at bringing greater transparency into clinical trials review procedures.


Much of the discussion focused on how to fund RECs adequately--and from what sources. Workshop examples suggested RECs' fees ranged up to E2500 per assessment, with many concessions made to academic research. Many participants saw a risk to impartiality if there are direct payments from clients to RECs for services provided. "You don't pay the judge to get justice," observed Bert Vanderhaegen of the Ghent University Hospital EC.

But payment from the state was merited, it was argued, since the state was demanding the service. The clinical trials directive has not only required a central opinion on a multicenter trial, but has required a fast turnaround time which is often difficult to meet. RECs need administrative support to be able to meet their new obligations.

And even where new systems have been set up by the state, there are often serious resource problems in making the system function. In Spain, the authority that inspects and demands performance from RECs is not the one that provides the resources. There is a resource gap because of an institutional gap.

Professor Dominique Sprumont of the Institut de Droit de la Sant of the Universit de Neuchtel emphasized the emergence of a formal legal view of the role of RECs. This was exemplified by a landmark Swiss court ruling that their function is not to help researchers seeking funding for research projects, but to carry out what is a state duty to review clinical trials in respect of the public interest.

There was vigorous debate over how the imposition of new responsibilities on RECs was also creating increased liability for them. It was suggested that the state--and even researchers themselves--might be delegating more responsibility than they should onto shoulders that were ill equipped to carry such a burden. And it was pointed out that risks of liability were a strong disincentive to potential recruits to RECs.

The questions extended to the scope of ethics review (and even the scope of the meeting itself)--should it cover only interventive trials with medicines, all trials with medicines, or even wider, and at what cost? It was pointed out that clinical trials with medicines no longer hold a monopoly on discussions of ethics--even engineers nowadays conduct high-quality ethics assessments of new projects. Rainer Gerold, director at the European Commission, noted the wider need for discussions beyond bioethics--in nonmedical primate research, in nanotechnology, and the full range of EU-funded research projects.SOPs for RECs

A workshop on standard operating procedures and quality assurance examined how far RECs already follow standardized procedures and how far regulatory authorities are involved. Spain, Italy, the Netherlands, and the United Kingdom already accredit or inspect RECs, and wide support was expressed in the workshop for the idea. But it was stressed that care is needed in the balance between national and local powers, and in making clear the role of RECs in relation to other authorities. 

Unanswered questions ranged across who should carry out site-specific assessments not based on ethical issues, on how to fix the limits to REC requests for further information from applicants, on the status of international guidance documents in quality assurance, and whether one REC refusal invalidates all parts of a multinational trial.


How RECs should and should not interact with other parties was the focus of another workshop. Involvement of external expertise is often necessary, but there are potential risks in relation to confidentiality and security of data. Divergences of view between the REC and the national authority could create confusion among researchers and sponsors, increasing the risk of lawsuits against the RECs or the national authorities. And with the pharmaceutical industry, better dialogue is needed--and caution, particularly in respect of gifts, grants or other funding from the industry. Since most trials are commercially sponsored, financial interest is often bound to influence the design and planning of clinical trials. 

Interaction with researchers was also, it was suggested, inadequate, and could be usefully boosted by better communication, including through better harnessing the power of the Internet. And some argued that laypersons on RECs should be genuine representatives of the local community.


Training and dissemination of good practices was examined in one of the workshops--and revealed agreement on the merit of training, but practical difficulties in organizing and funding it. 

Accurate targeting of training was emphasized, since different kinds of training are needed to match the different needs of REC members and administrators, and their different levels of experience. And the danger of professionalization of committee members was repeatedly raised: it was recognized that it is no easy task to promote a culture of ethical thinking that also maintains a healthy diversity of informed opinion.

Those who wish to know more can download the presentations and conclusions in full, from http://www.europa.eu.int/comm/research/conferences/2005/recs/programmetable_en.htm. Should they wish, they can also watch videos of the presentations, including the workshop summaries by your columnist, who was a rapporteur at the meeting.

But, as this column also suggested last month, the key performance indicator of the success of this meeting is what will come out of it. How many answers are found to the many questions raised? And that is something that will emerge only over the coming months and even years.

"The diversity of methods to respond to new circumstances is a challenge to harmonisation."--

Caroline Trouet, deputy director of Pharma.be (the Belgian pharmaceutical industry association)


"The function of RECs is not to help researchers seeking funding for research projects."--

Dominique Sprumont, Institut de Droit de la Sant of the Universit de Neuchtel


"Ethics review should be a matter of adventure rather than of bureaucracy."--

Jiri Simek, Institute of Medical Ethics, Charles University, Prague


"Moving from secrecy to a sort of 'peer review' system."--

Cristina Avendao-Sol, Puerto de Hierro hospital, Madrid


"You don't pay the judge to get justice."--

Bert Vanderhaegen, Ghent University Hospital

View from Brussels

The Future of Ethics: A European Perspective

Clinical trials may take longer and become larger as proposals emerge to strengthen regulatory policies.


Members of Congress, patient advocates, and some industry experts say it is time to re-evaluate Food and Drug Administration approval and postapproval operations. Safety concerns about prescription drugs continue to mount, along with charges that new drugs are coming to market without adequate testing and that postmarket surveillance has suffered. Some legislators want to give FDA authority to require postapproval studies and labeling revisions. FDA officials maintain that recently proposed internal initiatives can fix most of its problems. 

The Senate Health, Education, Labor, and Pensions (HELP) Committee held hearings last month to discuss FDA's drug approval process. Panel chairman Mike Enzi (R-WY) and lead Democrat Edward Kennedy (D-MA) plan to develop bipartisan legislation addressing drug safety issues and FDA procedures, but appear willing to take their time to weigh all options. 

Kennedy complained that it took five years for the public to learn that Vioxx may double the risk of heart attack or stroke, and suggested that user fees have allowed FDA to review new drugs much more quickly, while oversight of post-approval drug safety has lagged. But Kennedy also agreed with Enzi that "overreacting could be as dangerous as doing nothing," and that it is critical to "find the right approach."


FDA officials are trying to fend off proposals that would radically change the drug approval system, partly for fear that more onerous study requirements would not really improve the process. FDA acting deputy director Janet Woodcock pointed out that sponsors now are conducting more clinical studies than 10 or 15 years ago. Vioxx and Celebrex had more people in trials than any other anti-inflammatory drug, and sponsors still did not learn about serious side effects until much later.

The clamor over drug safety has widened the debate over just how long and how large clinical trials need to be to document safety and efficacy. Bruce Psaty of the University of Washington told the Senate committee that the pre-approval evaluation of COX-2 inhibitors was inadequate, and that medicines that will be used by millions of Americans for long periods of time should be studied in large, long-term clinical trials.

Woodcock acknowledged that drugs designed to treat a visible symptom such as pain usually are not studied very long in the pre-approval stage, compared to trials for drugs to treat asymptomatic conditions such as high cholesterol. It is hard to tell how long a study needs to be, Woodcock commented, adding that there would be no drugs to treat asymptomatic conditions at all if study requirements are too burdensome. 

One proposal for improving the current approval process is to grant "conditional" or "staged" approvals followed by extensive postapproval study requirements. Ray Woosley of the University of Arizona described a plan that would allow limited approval of a new drug for a carefully defined patient population following comprehensive Phase II testing. This first study phase would involve about four years of trials based on more complete characterization of dose-response relationships and targeted drug interaction studies. The product's label would be expanded following several years of additional larger trials and intensive safety assessment. Woosley points out that this approach would make needed drugs available faster while also strengthening postapproval oversight and safety examination.

Sponsors generally oppose conditional or limited approval designations for fear that lingering safety concerns would stymie marketing efforts and raise legal liability concerns. And FDA officials do not seem highly enthusiastic about leaving a product's approval status uncertain.


In addition to revising pre-approval requirements, reformers want to overhaul FDA oversight of postmarket safety surveillance. The main proposal is to establish an office to oversee drug safety issues that is separate from FDA's new drug review operation. 

Some FDA critics want the drug safety operation totally independent of the agency, similar to organizations that review transportation accidents. But most are willing to keep the new entity within FDA, just separate from the Office of New Drugs in the Center for Drug Evaluation and Research (CDER). Legislation developed by Sens. Chris Dodd (D-CT) and Charles Grassley (R-IA), chairman of the Senate Finance Committee would do just that. 

FDA officials oppose creating a separate drug safety agency, and most experts seem to agree. Woodcock explained that it is important for the people who evaluate a drug in the first place to play a role in monitoring the product over its full life cycle. She described drug review and oversight as a continuum between pre- and postmarket monitoring, a process that requires input from experts familiar with the drug and its whole class. Most new drugs are approved for narrow indications with the expectation that further clinical trials, including studies on children, will lead to broader labeling.

She also rejected suggestions that reviewers who approve a drug would be conflicted about later efforts to remove it. FDA uses a team approach for application reviews, and if serious safety issues arise more people become involved and the review process opens up. A separate drug safety office would suffer from a lack of familiarity with the drug's benefits, in addition to its risks.

FDA has proposed several initiatives to address fears that drug safety problems fail to gain a full hearing at the agency. A new drug safety oversight board composed of experts from FDA offices and from other federal agencies is being formed to provide an objective perspective on the safety of marketed drugs. A new grievance process will provide a forum for dissenting FDA scientists to air their concerns. 

Another FDA plan involves posting the latest drug safety information on the new Drug Watch Web site. FDA acknowledges that it took an unusually long time to reach agreement on needed labeling changes for Merck's Vioxx after cardiovascular adverse events emerged, but believe that the new site will prevent delays between when FDA learns about a safety problem and when that information reaches prescribers and patients.

 Critics contend that the safety board and Web site are just window dressing and will lack real teeth in addressing serious safety problems. They are examining a number of additional proposals to give FDA more power:

* Strengthen FDA authority to require labeling changes on approved drugs.

 While FDA usually reaches agreement quickly with sponsors on needed warnings and other labeling changes, the Vioxx case shows that such negotiations can take months. 

Sandra Kweder, deputy director of CDER's Office of New Drugs, acknowledged at the first Senate hearing that the ability to require changes in labeling would be "very helpful" to the agency. Kennedy expressed the growing sentiment that "negotiations with a drug-maker should never delay accurate information for patients and doctors."

* Mandate completion of post-approval studies.

 FDA now can require sponsors to conduct additional studies only for drugs approved under its accelerated approval process. Otherwise, the agency may ask a sponsor to conduct certain Phase IV studies as a condition of market approval, but it lacks authority to impose penalties if such commitments are not fulfilled. Kweder said it would be helpful for FDA to be able to require a clinical trial to address safety issues that emerge after a drug is on the market. 

An FDA analysis of industry performance of Phase IV study commitments in 2004 shows that sponsors completed about 15% of about 1700 planned postapproval studies each year. Most are pending, about 50 studies fall into the "delayed" category, and a little more than 200 were submitted to the agency.

? Boost FDA authority to remove problematic drugs from the market.

 Most drug withdrawals are voluntary, but often result from FDA urging. FDA has legal authority to pull a drug off the market if it can show that the product poses an "imminent risk," but that is usually difficult to do. Critics contend that withdrawal discussions can take a long time and want to give FDA authority to levy fines or impose other penalties on manufacturers who fail to comply quickly to postapproval safety concerns. 

 Congress wants to strengthen and expand clinical trial registries to better inform the public about investigative drugs under study. There also is a push for public disclosure of clinical trial results, including those that end up producing unfavorable data. Pharmaceutical companies say they are posting more research data voluntarily, but most observers believe that a specific mandate is needed to gain full access to important safety information. 

 Many observers feel that FDA's budget is too lop-sided, with most resources devoted to new drug approval and too little to post-approval monitoring. The administration's budget plan for 2006 proposes to expand funding for drug safety surveillance, but that amount still would be far below levels needed to conduct more proactive safety analysis and epidemiological studies. 

The official FDA policy is that Congress should hold off on legislative change until the agency's internal reforms have a chance to address these problems. FDA is finalizing three draft guidances on managing the risks in medical products, which were issued almost two years ago. One guidance addresses the scope of clinical assessment of safety issues in the premarket study phase; another describes when special risk management plans are needed for certain drugs.

FDA also is working with the Institute of Medicine on a review of the drug approval process. The project should begin in six months and be completed within two years. Meanwhile, more legislative proposals are likely to surface, and more inquiries will be held. FDA officials believe that innovative research methods and cutting-edge analytical approaches could greatly enhance the safety of new medical treatments, provided that poorly designed legislation does not discourage risk-taking in the drug development process. 			

View from Washington

FDA Approval Process Under Scrutiny

A multimedia Webinar program lets experts teach investigators across the country, or across the globe 

 (Franklin, TN) acts like a teacher's college of sorts for study investigators. Managers ensure their staff acts properly in every location, making each independent site unified in its approach to the clinical research at hand.  

TrialTrainerPlus is a Web conferencing and on-demand learning program which allows rich media presentations to be shown at the viewer's convenience. Video files, PowerPoint slides, rolling transcripts and other text-based materials all can interact to reinforce important points.  

Presentations can even be done live, and saved to be viewed by people unable to watch the real-time version. Much of the money saved is from unneeded hotel rooms and cross-country flights. 

The idea is similar to electronic informed consent tools; if everyone hears and sees the exact same thing, they will be unified by their shared perspective on it. And that translates to multiple sites acting as a franchise, if only for this trial. 

The company has offered online learning programs for everyone from the Department of Defense to GE and banking and accounting firms. It is used by 18 of the top 20 pharmaceutical companies. 

This mental diary to capture the moods of manic-depressive subjects has been 30 years in the making 

 (Fullerton, CA) is a nonprofit organization working to increase the understanding of mood disorders.  

ChronoRecord is an electronic version of the ChronoSheet, developed in the '70s to help follow mood fluctuations of patients with manic-depressive illness. It was revolutionary then, and still not widely enough used now. 

The mechanics of ChronoRecord are familiar to those with EDC experience. Patients or subjects using ChronoRecord fill out a daily form on their computer describing mood, sleep, medications taken, and life events. That information can either be emailed to the site or saved on a floppy disk. Or, nontechnical users can record the info in a paper diary and have it data-entered at the site. 

Since ChronoRecord is a nonprofit, it only charges what it needs to cover manufacturing and distribution. Costs are no more than $150 per patient. 

Back when ChronoSheet premiered, mood disorders were not clearly seen as treatable illnesses. Now that such disorders have had some of their stigma removed, it is important to have records of mood to go alongside other medical records for a proper data analysis.  

ChronoRecord Association, (714) 773-0301, 

There is now a way to determine how many subjects a site screens and enrolls before the trial is over

 (Brentwood, TN) created PraxisDirect as a program to let sponsors or sites monitor every step of a subject's recruitment in a clinical trial. 

The first step is the subject decision whether to be involved at all. Recruitment information of their initial prescreening responses goes into the system. The medical info of those who did not sign an informed consent will never be associated with the person. 

After the subjects are qualified and enrolled, their metrics go into the same database that held the prescreening info. Fields include referral source, inquiry, and disqualifications at a screening visit.  

Sponsors can also check out weekly activity reports, numbers of inquiries and respondents per site, and average enrollment times. An updated list of referrals ensures that no possible subject will fall through the cracks. This data is obviously much more useful to receive during a trial than after it is over.  

PraxisDirect uses VeriSign Secure Site Pro, a Cisco firewall, and physical security to ensure that private information stays that way.  

eShowcase

DigiScript (Franklin, TN) acts like a teacher's college of sorts for study investigators. Managers ensure their staff acts properly in every location, making each independent site unified in its approach to the clinical research at hand.


As a psychologist, it strikes me that the COX-2 televised drug company-FDA public meeting was full of relevant psychological implications that probably weren't recognized. It's been too easy to cast some researchers as "bad guys" and some as "good guys," as if that label addresses or resolves any of the COX-2 problems. The real problem is that highly educated and well-intentioned researchers are trying to make decisions under conditions of uncertainty--a psychologically difficult task. Perhaps what we've seen in the televised meeting was due to: 

As I recall, all the presenters offered statistics via what looked like PowerPoint. But PowerPoint is not a completely neutral presentation format. In his 2003 booklet "The Cognitive Style of PowerPoint," MIT information expert Edward Tufte (http://www.edwardtufte.com/) notes that "In particular, the popular PowerPoint templates (ready-made designs) usually weaken verbal and spatial reasoning and almost always corrupt statistical analysis." (p3) In a 1999 study

 of how different data displays affected accuracy of physician researchers' decisions to stop a hypothetical clinical trial, researchers found that such decisions were affected by both the type of data display (icons, tables, pie charts or bar graphs) and the framing (positive or negative) of tabular data. Since interpretation of statistical data can't be separated from the presentation style of that data, it's possible that presenting the same COX-2 data in different displays may have lead to different committee recommendations. 

Applied Clinical Trials-04-01-2005

Reporting Adverse Reactions to Clinical Trial Investigators in the ICH Regions: Key Differences

Measures of Success

The Future of Ethics: A European Perspective

FDA Approval Process Under Scrutiny

eShowcase

Letters to the Editor

Subject Diversity Is Good for the Business of Medicine

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