Tool places sponsors in control of their patient recruitment programs  with real-time data reporting

 (Newton, MA) has a new suite of recruitment tools that are flexible and customizable for individual trial needs. TCN e-Systems produces real-time data designed to maximize clients' recruitment programs and cut enrollment times.  

The main features of TCN e-Systems include: enrollment projection modeling; real-time tracking of recruitment tactics, inquiries, and referrals; accurate measurement of site and CRO performance; and control of clinical trial costs. The solution is applicable whether sponsors want to manage and/or deploy efforts for an entire therapeutic category, a specific protocol, or a single clinical study site. TCN e-Systems is comprised of six modules: Study Forecaster, Site Organizer, Patient Generator, Study Materials & Approval Tracker, Retention & Compliance, and Study Message Center.   

Articles

eShowcase

Tool places sponsors in control of their patient recruitment programs with real-time data reporting

eShowcase: TCN e-Systems

Democrats are back on top in Congress and are mapping out a broad agenda that puts drug pricing and access high on the priority list. The biomedical research community is optimistic that the new leadership will boost support for embryonic stem cell research and other scientific undertakings. At the same time, pharmaceutical R&D could be stymied by demands for more intense oversight of clinical research, broader disclosure of research programs, and challenges to new research approaches.  

The bottom line for sponsors and researchers will be more and larger clinical trials. Regulators want more data to document drug efficacy and safety; payers seek more comparative analysis to support premium prices for new products; and all parties demand more postapproval studies to address safety issues in real-world patients. Clinical trial registration and results disclosure will be championed as ways to protect trial participants and patients, but may make research programs more cumbersome and costly. 

Legislators and regulators are examining a host of research activities and issues under the umbrella of assuring patient safety, while a number of government watchdog agencies are pursuing a range of investigations. Some of the hot topics include: 

. Members of Congress have attacked the Food and Drug Administration's approval of sanofi-aventis' antibiotic Ketek (telithromycin) based on data from non-inferiority trials. This has led to a broader scrutiny of whether innovative study designs may harm trial participants as well as subsequent patients. Sen. Charles Grassley (R-Iowa), who has been highly critical of many FDA activities as chairman of the Senate Finance Committee, blocked confirmation of Acting Commissioner Andrew von Eschenbach for several months to pressure FDA to respond to questions related to his probe of Ketek. The new Finance panel leader, Max Baucus (D-Mont), has supported Grassley's concerns, and the Government Accountability Office (GAO) is investigating these issues. 

. FDA is reassessing its 10-year-old policy that permits research on patients without informed consent under certain pre-specified emergency situations. FDA held a meeting in October to discuss possible revisions in a new draft guidance to assist investigators, sponsors, and institutional review boards (IRBs) in developing and conducting such research protocols. 

. The HHS Office of the Inspector General (OIG) is examining FDA's clinical trial inspection process as part of ongoing scrutiny of IRBs, study recruitment practices, and the integrity of research data. Similarly, FDA's Office for Good Clinical Practice is revising guidance on inspection of clinical investigators. 

. A rising number of investigator disqualifications is prompting FDA to develop guidance on its enforcement procedures. Separately, the OIG is assessing whether sponsors and the FDA adequately monitor financial interest disclosures of investigators. 

. Industry's poor record for posting information on new trials on the 

 Web site has prompted legislative proposals to mandate such listings. Along these lines, the OIG is investigating how well sponsors submit trial protocol information to the Web site, the completeness of registration information, barriers that might prevent full listings, and government monitoring capability. 

. FDA is working with other government agencies and professional organizations to encourage wider use of central IRBs and more streamlined review of adverse events. These efforts are addressing IRB concerns over liability and resources to build support for innovative approaches to research oversight. 

. A prime target for Congress and federal investigators is industry's low rate for fulfilling postapproval study commitments. The OIG issued a report last July calling for FDA to develop better systems for tracking the status of postmarketing study commitments and for assessing adequacy of resulting reports. Several bills before Congress would authorize FDA to levy fines on firms that fail to meet report deadlines. 

. It's no longer a question of whether to disclose research results, but the scope and timing of such data disclosure. Key issues are whether disclosure applies to all early trials vs. Phase III and IV; covers proprietary information such as trial enrollment and endpoints; and how long sponsors can delay disclosure in order to publish results first in peer-review journals. 

While it will be a challenge to respond to Congressional probes and to oppose damaging legislative proposals, the larger task for the pharmaceutical industry is to gain Congressional reauthorization of the Prescription Drug User Fee Act (PDUFA) before the program expires Sept. 30, 2007 [see sidebar: New Faces in Charge]. A PDUFA bill also would renew user fees for medical devices and continue the pediatric drug exclusivity program, which has greatly expanded the volume and scope of clinical trials involving children.  

With Democrats and Republicans unlikely to agree much on health care legislation, both sides will eye any PDUFA bill as a ready vehicle for enacting broader measures on drug safety, generic drug access, and drug importing. There may even be a move to give FDA the authority to regulate tobacco. 

Members of Congress have proposed drug safety legislation that changes FDA pre- and postapproval assessment of safety issues. These measures levy penalties on firms that fail to register clinical trials to disclose results appropriately and to adequately report adverse events. One proposal would expand the scope of risk management plans for new drugs with potential safety concerns, while others want to establish new FDA offices to monitor drug safety. 

Another goal of many Congressional leaders is to speed more new generic drugs to market. The current debate centers on whether to give FDA specific authority to approve generic versions of biotech therapies, an admittedly more complex task that could require more clinical testing of candidate products. 

 "All these issues will be in play," acknowledges Jim Greenwood, president of the Biotechnology Industry Organization (BIO) and formerly a leading Republican on the House Energy & Commerce Committee. Industry's task is to identify a working majority in the House and Senate that can "deal with these issues responsibly," he says; with PDUFA, "we can't play veto games." 

FDA and industry leaders have been discussing user fee issues and options for several months. As with the last three re-authorizations, the agency aims to present an agreed-on user fee plan to Congress early this year. This will include proposed fees, timelines for application processing, and the range of FDA activities that fees will support. 

The new five-year agreement is expected to boost user fees by one-third to reach about $400 million, bringing the cost of filing a new drug application well over the $1 million mark. Added fees will support more timely review of pharma company advertising and marketing materials and also significantly expand FDA drug safety oversight activities.  

View from Washington

Shift in Congressional control opens door to probes into research practices & expansion of PDUFA legislation.

Clinical Research Faces Scrutiny in Year Ahead

In 2001, when news about the human genome was first published, much speculation ensued about the impact it would have on new therapies and treatments. One area that drew a significant amount of attention was pharmacogenomics, especially as it related to what many described as a revolution in drug development and commercialization: Personalized medicine. 

While significant advances have been made in the field of pharmacogenomics over the past five years, detractors are quick to point out that not all of its initial promises have materialized. Unmet expectations have been a result of the field's inherent limitations, as well as inaccurate information regarding possible applications of pharmacogenomics-related technology. 

The study of an individual's genetic profile to better predict the toxicity, safety, and efficacy of drugs was first heralded as the next revolution in medicine due to its potential to help the pharmaceutical industry redefine the blockbuster model. At the core of this model is the assumption that a single compound can treat most patients suffering from a particular condition. However, at best most drugs are only effective in about 60% of the population. 

The advent of pharmacogenomics led several analysts and members of the media to conclude that personalized medicine was the answer to this inherent flaw in the blockbuster model. At first, many believed that pharmaceutical companies would develop dozens of tailor-made formulations designed to match patients' genetic codes. However, research has shown that drug response is typically associated with fewer than four to six different phenotypes. Using pharmacogenomics to develop a large number of drugs targeting the same condition would not only be impractical from a cost perspective, but it would also be unnecessary. 

Another challenge the industry is facing with regard to the blockbuster model is the escalating cost of drug development. The constant dollar amount to develop a new drug increased 5.8 times between the 1970s and 1990s. In addition, only 9% of drug candidates ever reach an NDA filing. It has become increasingly difficult for companies to justify the high costs and risks associated with developing a new blockbuster drug. 

Pharmacogenomics has helped the pharmaceutical industry tackle this challenge in three basic ways: by facilitating the elimination of unfavorable drug candidates at earlier stages of development; by enabling companies to design clinical trials that more definitively prove drug efficacy; and by providing researchers with genomic data that can be used to rescue some drugs from failed clinical trials. 

  report, 58% of drugs that failed during development were terminated because of efficacy or safety issues. Today, more pharmaceutical companies are using pharmacogenomics to recruit responders for clinical trials and to eliminate subsets of patients whose phenotype makes them likely to suffer from adverse reactions. Trial sponsors are now able to obtain more specific results using smaller patient populations and avoid the high cost of product failure later in the clinical testing process. 

Some pharmaceutical companies have also started to see the benefit of using pharmacogenomics to demonstrate a drug's efficacy on a specific subset of patients. This process, called "enrichment" by the FDA,

  has the potential to rescue some drugs that fail in clinical trials. Enrichment strategies work to the extent that an underlying pharmacogenomic trait is really responsible for some patients responding, while others do not. We have to keep in mind that disease, age, sex, lifestyle, and race also play a part in drug efficacy. 

Today we know that personalized medicine will never completely replace blockbuster drugs. Simply put, not all therapies are a good match for pharmacogenomics. The human genome has provided us with a roadmap. It has taken the industry a few years to realize that knowing the roadmap does not mean we know exactly what path each patient will travel. 

1. PriceWaterhouseCoopers, Personalized Medicine: The Emerging Pharmacogenomics Revolution (February 2005). 

A Closing Thought

While not a panacea, pharmacogenomics is still a valuable trial tool that can make the recruitment process more efficient and eliminate the high costs associated with late-stage product failure.

Beyond Blockbusters

This article describes AstraZeneca's (AZ) experience in implementing the EU Clinical Trial Directive 2001/20/EC, which came into force on 1 May 2004. In particular, it is based on Articles 2, 16, 17, and 18 and Revision 1 of the associated guidance document, ENTR/CT3, "Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use." 

Directive 2001/20/EC establishes specific provisions regarding the conduct of clinical trials, including multicenter trials on human subjects involving medicinal products as defined in Article 1 of Directive 65/65/EEC, in particular relating to the implementation of good clinical practice.  

Directive 2001/20/EC does not apply to noninterventional trials (i.e., studies where the medicinal product(s) is/are prescribed in accordance with the terms of the marketing authorization). 

In this discussion of the directive, AZ comments are noted where there have been changes in practice and standard operating procedures (SOPs) in the Articles and Revision 1 of the associated guidance. If there is an explanation of the directive with no comment it is considered good current practice at AZ and there is no impact on SOPs.

This guidance applies to all clinical trials on medicinal products for human use conducted within the European Community. It applies to all investigational medicinal products (IMPs) for human use, independent of their marketing authorization status in any Member State whether or not IMPs are used under the conditions of the authorization. It sets out detailed guidance on the collection, verification, and presentation of adverse event/reaction reports arising from such trials. In addition, it sets out the responsibilities of the concerned parties (see sidebar "Setting Out Investigator and Sponsors Responsibilities").  

Setting Out Investigator and Sponsor Responsibilities			

The sponsor has to keep detailed records of all adverse events (AEs) reported by the investigator(s) and perform an evaluation with respect to seriousness, causality, and expectedness. 

On request of a Competent Authority (CA) in whose territory the clinical trial is being conducted, the sponsor should submit detailed records of all AEs that have been reported by the relevant investigator. Each individual AE should be evaluated by the investigator and by the sponsor, including seriousness and causality. 

The sponsor shall determine the expectedness of an adverse reaction according to the reference document, as defined in the protocol (e.g., the investigator's brochure (IB) for a nonapproved IMP or summary of product characteristics (SmPC) for an authorized IMP in the EU).  

All AEs judged by either the investigator or the sponsor as having a reasonable suspected causal relationship to an IMP qualify as adverse reactions. The expression "reasonable causal relationship" means in general that there is evidence or argument to support a causal relationship. 

The causality assessment given by the investigator should not be downgraded by the sponsor. If the sponsor disagrees with the investigator's causality assessment, then both the opinion of the investigator and sponsor should be presented.  

All SUSARs (suspected unexpected serious adverse reactions) related to the IMP (i.e., the tested IMP and comparators) that occur in the concerned trial(s) are subject to expedited reporting. This includes: 					

SUSARs that occur in another trial conducted by the same sponsor either in the European Community or in non-European Community countries

SUSARS identified from spontaneous reports or from a publication(s)

SUSARs transmitted to the sponsor by another regulatory authority

The minimum criteria for the expedited reporting of SUSARs are: 					

an AE assessed as serious and unexpected, and for which there is a reasonable suspected causal relationship

a unique clinical trial identification (EUDRACT number or in the case of non-European Community trials the sponsor's trial protocol code number)

a unique case identification (i.e., the sponsor's case identification number).

As a general rule treatment codes should be broken by the sponsor before reporting a SUSAR to the CA and ECs of the concerned Member States. 

Electronic reporting should be the expected method for the expedited reporting of SUSARs to the CAs. The CIOMS-1 form is a widely acceptable standard for adverse drug reaction (ADR) reporting. However, no matter what form or format is used, it is important that the basic information/data elements described in Annex 3 of ENTR/CT3 are included in any expedited report. The latest version of MedDRA should be applied. 

AZ comment: Electronic reporting is new for AZ and implementation of electronic reporting had a major impact on our systems and processes. Despite reference to the CIOMS-1 form, most EU Member States require transmission via E2B.

Other important safety issues may also qualify for expedited reporting when they might materially alter the current benefit–risk assessment of an IMP or when they would be sufficient to consider changes in the IMP administration or in the overall conduct of the trial, for example: 					

single case reports of an expected serious adverse reaction with an unexpected outcome such as a fatality

an increase in the rate of occurrence of an expected serious adverse reaction, which is judged to be clinically important

poststudy SUSARs that occur after the patient has completed a clinical trial and are reported by the investigator to the sponsor

a new event relating to the conduct of the trial or the development of the IMP likely to affect the safety of subjects, such as:

			– an SAE associated with trial procedures that could modify the conduct of the trial

			– a significant hazard to the subject population such as lack of efficacy of an IMP used for the treatment of a life-threatening disease

			– a major safety finding from newly completed animal studies (such as carcinogenicity).						

AZ comment: Expedited reporting of expected serious adverse reactions with an unexpected outcome (e.g., a fatal outcome) is new for AZ, and this change had a significant impact on our SOPs/processes as the safety database and listed table had to be amended to facilitate this change.

				For fatal/life-threatening SUSARs, the CAs and ECs in concerned Member States should be notified as soon as possible, but no later than seven calendar days after the sponsor has first knowledge of the minimum criteria for expedited reporting (IMP, SUSAR, identifiable reporter, and subject).			

Follow-up information should be sought and communicated to CAs and ECs in concerned Member States as soon as possible but no later than an additional eight calendar days. 

AZ comment: Expedited reporting of SUSARs to ECs is new for AZ. This had a major impact on our SOPs, processes, and personnel. Compliance with submitting follow-up information within an additional eight calendar days was a challenge, and our SOPs/processes were amended to accommodate this new requirement.

All other SUSARs must be reported to the CAs and ECs in concerned Member States as soon as possible, but no later than 15 calendar days after the sponsor has first knowledge of the minimum criteria for expedited reporting. Further relevant follow-up information should be given as soon as possible. 

Feature Article

AstraZeneca's interpretation of the EU Clinical Trial Directive: An industry perspective

Roadmap to Implementing the EU Directive

System treats compliance as a single, repeatable process to ensure organizational quality

 (Florham Park, NJ) has released an end-to-end closed-loop compliance solution for life science companies. The QUMAS Compliance Closed-Loop Process™, which the company says is the first product of its kind in the industry, automates the tracking and management of compliance, business, and quality issues enterprise-wide.  

The solution integrates various tasks with other processes critical to regulatory compliance. Rather than treating compliance as a series of silos that vary with department and/or product lifecycle stage, the Compliance Closed-Loop Process treats it as a single procedure.  

The QUMAS approach automates the generation of internal or external complaints, product nonconformances, deviations, audits, investigations, and all other compliance actions. The tool captures, records, routes, and verifies completion and approvals while auditing each step in a sponsor's quality management process.  

eShowcase: QUMAS Compliance Closed-Loop Process

, MS, is vice president, preclinical and clinical quality assurance at UCB Pharma, Smyrna, GA. In this role, he leads a global organization of quality professionals based in the United States, Europe, and Japan. Aaron partners with UCB's Development and Medical Affairs organizations to establish robust Quality Systems that ensure GXP compliance while streamlining business processes and maximizing efficiencies. In addition, Aaron's organization executes field surveillance for safety and efficacy studies to ensure trial subjects' safety and rights are protected and that data generated from these studies are accurate and reproducible.  

Aaron F. Bartlone, MS, vice president, preclinical and clinical quality assurance, UCB Pharma			

Prior to joining UCB, Aaron was head of quality operations-product research & development, with Eli Lilly & Company, Indianapolis, IN, responsible for developing the strategy and framework for Lilly's product research & development quality system. 

Aaron's earlier positions with Eli Lilly include European quality director-global product development in Mont-Saint Guibert, Belgium (2001–2004), where he led the delivery of quality assurance services across European drug development sites. Aaron had a staff of quality professionals located in Belgium and Germany, and worked closely with his U.S. counterparts to institute global processes and quality systems commensurate with international regulations and industry-best practices.   

Prior to working at Lilly's Mont-Saint Guibert, Belgium, location, Aaron held numerous positions with Lilly in Indianapolis, IN: quality control manager-global product development (1999–2001); head of quality-biotechnology quality control and quality control laboratories (1998–1999); quality control team leader-oral and parenteral clinical products (1997–1998); senior compliance auditor-corporate quality assurance (1996–1997); and laboratory group leader-quality control laboratories (1994–1996). 

From 1992 to 1995, Aaron was an associate professor at Ivy Tech State College, Indianapolis, IN, where he taught chemistry, physics, and mathematics, and participated in the design of a new laboratory teaching facility. Earlier, he was a clinical toxicologist with South Bend Medical Foundation, South Bend, IN, performing laboratory procedures for substances of abuse and forensic investigations. 

ACT Editorial Advisory Board

Get to know the newest ACT Editorial Advisory Board member.

Meet the EAB: Aaron F. Bartlone

It could be a happy new year for clinical trials in Europe. The European Union agreed—just in time—on its research support program for 2007–2013. The agreement, reached only in December and which came into effect on 1 January 2007, allocates more than €54 billion ($64 billion) to European research over the program's seven-year life.

It isn't all scheduled for clinical trials, however. The money is to be shared among a wide range of European research priorities. But the program does make substantial provision for life sciences. There will be more than €6 billion specifically for health, with further allocations for biotechnology, nanosciences, and nanotechnologies. 

It will also provide support for initiatives such as European networks of advanced clinical research centers; bio-banks and genomic resources; high security laboratories for emerging diseases and threats to public health; and model testing facilities for biomedical research. 

The European Parliament, which had a hand in the preparation of the program and has many members with sharp sensitivities over ethical considerations, did oblige the EU member states to accept some limits on medical research. But the compromise reached imposes conditions that are less severe than had been feared by many researchers earlier in the year. And Parliament also insisted on boosting the focus on research into children's health, respiratory diseases (particularly those induced by allergies), and neglected diseases.  

EUÃÂ´s Compromise on Research Ethics			

Among the last-minute modifications to the provisions on health research, the Parliament insisted on support for: 

"Translating the results of clinical research into clinical practice including better use of medicines (e.g., with a view to avoiding the development of antibiotic resistance), and appropriate use of behavioural, organisational and public health system interventions and health therapies and technologies. Special attention will be given to patient safety, including the side-effects of medicines; to identify the best clinical practice; to understand decision making in clinical settings in primary and specialised care; and to foster applications of evidence-based medicine and patient empowerment with a view to enhancing patients' personal and social autonomy. Focus will be on the benchmarking of strategies; investigating outcomes of different interventions including medicines and new health technologies, taking into consideration pharmacovigilance evidence, specificities of the patient (e.g., genetic susceptibility, age, gender and adherence) and cost benefits in terms of health, quality of life and good practice." 

Some of the program's broader aims will also offer potential backing for different aspects of clinical trials and drug development. These include support for cooperation between universities, industry, research centers, and public authorities, and training and career development of researchers. The program will also set up an autonomous European Research Council to support investigator-driven "frontier research," and it will promote coordination and development of research infrastructure, regional research clusters, and smaller firms. 

This isn't the EU's first multi-annual research support program. There have been six since 1984, and they have each helped produce some results in clinical trials. But they have in the past been heavily criticized by researchers for their procedural complexity. Many laboratories and firms have stopped applying for grants under the programs because they found the gains didn't justify the pains. 

This new version of the program aims to avoid the same trap. 

The new year brings another change to the European Union: it has grown to 27 member states—with Bulgaria and Romania taking their place alongside the 10 other new members that joined in 2004. This may make the European medicines market bigger, but it brings new complications with it too. And in preparation for this new expansion, the European Medicines Agency felt it appropriate to issue new enlargement-related guidance for sponsors of orphan medicines. 

The EU's legislation on orphan medicines, with its procedure for designating medicines as orphans and its incentives for their development and launch, has been in force since 2000. But the rules apply only if the sponsor is "established" in the EU. From 1 January 2007, the EMEA has made it clear that individuals or companies from the two new member states will be considered as meeting that eligibility requirement. 

That's fairly straightforward. But because one of the qualifying criteria for orphan status is limited European prevalence of a condition, the calculations of prevalence have to be adapted to the new situation, too. 

Bulgaria and Romania between them bring some 30 million new citizens into the EU—almost a 10% increase. The calculation inevitably changes for the number of persons affected by the condition in the EU at the time the application for designation is submitted. The new rule is that for applications submitted from 1 January 2007 onward, prevalence calculations must be based on the population of the enlarged European Union—and that means 27 member states (as well as Iceland, Liechtenstein, and Norway, which are not EU members but who years ago chose to throw in their lot with the EU on these questions). 

The same enlarged EU will be the reference base for another of the eligibility criteria for orphan status—the nonavailability of methods for diagnosing, preventing or treating the condition targeted by an application. It is the responsibility of the sponsor to establish that no satisfactory method of diagnosis, prevention or treatment of the condition has been authorized in the EU (or that, if a method exists, the medicinal product will be of significant benefit to those affected by the condition). So from the start of 2007, sponsors will be required to include and review existing methods in the new 30-country market. 

For translations, life also becomes a little bit more complicated, since Bulgarian and Romanian have become official EU languages with the accession of these two countries. At the time an application for designation is made, the agency requests translations into all the official languages of the European Union for not just the international nonproprietary name of the substance but also the proposed orphan indication. 

That means the information must appear in all the following languages: English, Bulgarian, Czech, Danish, Dutch, Estonian, Finnish, French, German, Greek, Hungarian, Italian, Latvian, Lithuanian, Maltese, Polish, Portuguese, Slovak, Slovenian, Spanish, Swedish, Romanian, Norwegian, and Icelandic. 

And there's no easy escape for applications submitted before the latest enlargement became a fact. Decisions on orphan designations granted after the start of 2007 will have to be translated into all the official languages, including those of the new member states, plus Icelandic and Norwegian. 

The only relief is that decisions on orphan designations granted prior to January 2007 have been automatically extended to Bulgaria and Romania on the day they became member states. Similarly, EU marketing authorizations for orphans automatically extend to the new member states from their date of accession. And the EU-wide market exclusivity granted to an orphan extends automatically to Bulgaria and Romania. 

The European Union faces a huge problem in adapting its own operating mechanisms in its enlarged form. And so far, it has come up with very few sustainable ideas about how to do this. The attempt to win agreement on a new constitutional treaty for the enlarged EU was severely wounded by public rejections in referendums in France and The Netherlands in 2005. 

Germany, which took over the rotating presidency of the EU at the beginning of 2007, has promised to do what it can to find consensus on new operating rules—but warns no one should expect miracles. The complexities in conducting trials in Europe are therefore likely to persist until resolution is found on broader and deeper political questions in Europe. 

Watch this space. You will be the first to be told when the skies start to clear. Meanwhile, Happy New Year! 

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

1. European Union Seventh Research Framework Programme; details on: http://

View from Brussels

Patient safety, orphan medicines featured in EU's six-year research support budget.

New Year Brings New Opportunities

If clinical trial organizers had to nominate a single subject that rates as their current priority, it would probably be safety. This topic certainly dominated much of the agenda at the 

 European Summit, held in Amsterdam from 17 to 19 October 2006. 

Safety groups should have a higher profile and a more prominent role in the strategic aspects of benefit–risk optimization, noted John Ferguson, vice president of pharmacovigilance (PV) at Millennium Pharmaceuticals. Such groups should be first in line to receive safety information, adequately resourced, independent, an equal partner, decision-makers, and well-connected. They must be able to communicate complex information in simple terms, determine when and how to inform the public and other stakeholders, strike the right balance ("no warning without informing"), and anticipate/manage unintended consequences. 

Ferguson thinks chief safety officers should have the same standing as the lead for medical research under a chief medical officer. Also, they should be able "to go toe-to-toe with medical doctors in clinical development and medical affairs on their turf." They need a sound understanding of analytical and observational research designs and an ability to prioritize and negotiate change. They should be flexible individuals with high numeracy IQ. 

Successful risk communication requires looking at issues from the patient's point of view and building up an understanding of how the public perceives risk. Communicating accurate, timely, and balanced information is also essential to enable all stakeholders to make informed decisions. 

"The bottom line is that successful benefit–risk management requires that safety personnel have the stature, vision, expertise, independence, bandwidth, leverage, and relationships needed to effect change at the level of the enterprise," said Ferguson. "A collegial relationship with agencies and the media makes a huge difference in managing potential crises. Cultivate your relationships with regulators and the media before you have a potential crisis." 

"Compliance inspections are the way of the future, and they need to be a routine activity for industry," said Vicki Edwards, director of pharmacovigilance at Abbott Laboratories in Maidenhead, UK. "They should be viewed as a partnership and an opportunity for both parties to learn and shape the future process. There is also a need for better mutual appreciation of the challenges on both sides, and more clarification of interpretation of regulations" (see sidebar: Five Keys to Compliance). 

Edwards described an inspection in which she participated. The UK Medicines and Healthcare products Regulatory Agency (MHRA) issued the inspection plan 10 days before their arrival. There were four inspectors, some of whom were in training, plus an observer. A significant amount of time was spent on reviewing documents, the database was studied, and a live interrogation of data was requested. There were more than 160 requests for documentation, and 22 staff members were interviewed. 

"It was a very intense experience," she said. "The interviews were very detailed and probing, with a focus on interfaces and group interviews. Departmental visits were very focused and quite stressful." 

At the end of the inspection, inspectors gave verbal feedback on their findings and observations and provided interviewees with an opportunity for questions. There were no real surprises, and everything was fixable. Overall, the inspection was an excellent opportunity to raise the importance of PV within some functions of the business, noted Edwards. 

A sponsor must be able to demonstrate its PV systems, and should ensure that the documents reflect what the company does and not what it would like to be doing. Among the procedures that should be described are the activities of the qualified person, case processing, follow-up reports, expedited reporting, and signal generation and risk–benefit assessment. Copies of procedures need to be available within two working days. Inspectors may request further details on databases, links with other organizations, training, documentation, and quality management. 

The European Union's Clinical Trials Directive (CTD) was implemented more than two years ago, and it has brought some benefits, according to Dr. Ingrid Klingmann, president of Belgium-based Pharmaplex and co-chair of the European Forum for GCP's ethics working party. Implicit study approval for competent authorities in all EU member states now takes less than 60 days, and explicit approval is only needed for "complex" products. Also, one ethics committee opinion is needed per member state, GCP applies for all studies, data protection rules have been clarified, and the same requirements exist for labeling of study medication. 

Dr. Ingrid Klingmann, pictured here posing a question from the Summit floor, says progress has been made on the harmonization of EU regulations but considerable work still remains.			

However, a great deal of harmonization work still needs to be done, particularly in the field of ethical review, Klingmann said. In reality, different procedures persist in all EU nations, and the requirements of ethics committees (ECs) for information vary greatly. Sponsors must still contact virtually the same number of committees, and the need for translations is practically unchanged, while fees paid by sponsors have risen. Furthermore, real timelines are not always improved because interpretation of start time varies. 

"Reporting requirements for SUSARs (suspected unexpected serious adverse reactions) are in conflict with international reporting requirements for SAEs (serious adverse events), resulting in global SOPs requiring the reporting of SUSARs and SAEs," Klingmann said at the opening plenary session. "Clinical trials in Europe have not been successfully harmonized by the CTD, and the attractiveness of Europe for clinical research has not increased. However, the need for improvement has been broadly recognized by all stakeholders of the clinical trial process. Efforts are made to achieve harmonization in little steps." 

New developments such as the EU regulations for pediatric trials that are due to come into force in early 2007 may lead to greater harmonization. A special committee at the EMEA has overseen the pediatric legislation, and it requires special expertise in ECs and competent authorities, as well as special rules for transparency, Klingmann said. 

The new regulatory framework has contributed to a significant decrease in the number of clinical trial authorizations in Western Europe, noted Jean-Pierre Tassignon, group executive vice president of PSI Pharma Support International. Between May 2004 and April 2005, 1250 authorizations were made in Germany, compared with 1700 a year earlier. The comparable figures for the UK were 857 and 1700, and for France 1200 and 1045. During this period, the total number of authorizations for these three countries fell from 4600 to 3151, amounting to a 30% drop. 

Academic research has faced particularly acute challenges, but over the long term the regulations will improve quality and strengthen its capacity to develop public–private partnerships, believes Prof. Jacques Demotes-Mainard, coordinator of the European Clinical Research Infastructures Network (ECRIN) and advisor to the French Ministry of Research. 

Philippa Smit-Marshall (PharmaNet) chats with fellow presenters Ken Getz (right) and Pieter Guelen during the Speakers Lunch.			

"This requires appropriate infrastructures and funding," he said. "Public institutions should develop their capacity to act as a sponsor in national and international academic studies. Protection of patients and credibility of data should not be restricted to clinical trials on medicinal products, but extended to any type of clinical research. Also, new EU legislation and guidance covering any type of clinical research should be prepared by DG (Directorate-General) Health, DG Research, and DG Enterprise, with contributions from academic researchers." 

Another fast-changing area is clinical trial registries. They offer easier and better organized access to trial information for everybody involved in clinical research, but many of the users are competitors who want to keep an eye on other sponsors' activities, said Dr. Beat Widler, global head of clinical quality assurance at F. Hoffmann-La Roche in Basel, Switzerland. In addition, risks and threats are posed by a "mushrooming" of registries, different (and at times conflicting) standards and requirements, and their use as a political tool. 

"They should facilitate subject recruitment, but the numbers that we have recruited in this way can be counted on one hand. Patients announce their interest in participating in a trial, and physicians should follow up, but they don't always do it," Widler said. 

Widler thinks industry needs to become more active in shaping the development of guidelines for registries. He fears that they suffer from a lack of quality control, and only active engagement can help manage the complex process and ensure quality. Some guidelines and standards do not serve patients and physicians' needs, and the governance of trial registries should not be related to for-profit status, Widler said. Quality control procedures should be more clearly defined. A step forward would be to organize a workshop with all stakeholders under a neutral chairperson. This would help to identify gaps and issues in the current process, align expectations and objectives, and drive the development of future guidelines. 

 European Summit will be held in Berlin, Germany, from 29 to 31 October. For more details, visit 

is the European Editor of Applied Clinical Trials.

Safety issues come under close scrutiny at Amsterdam meeting.

ACT European Summit Report

There are compelling reasons to stop a trial early because of harm or futility. Both subjects and future patients will be protected from harmful or useless medical interventions. At first glance, early trial stopping for benefit seems to provide also undoubted advantages: required sample sizes may be lower, financial and management resources will be saved, and the results will be available earlier. 

Compared to trial stopping due to harm or futility, the social implications of early trial stopping for benefit are quite different: rapid drug approvals and exciting publications (mainly in the 

, which attract high-level attention by the medical community) may lead to accelerated and widespread use of a new therapeutic option.

Do prematurely stopped trials for benefit always provide a sound basis for future treatment decisions? Firstly, the overall database of a trial will be reduced by preventing more patients from being enrolled or by shortening the median follow-up period. This may dilute conclusions on the safety of a new intervention, as related risks sometimes show up only in larger patient populations, after long-term use,

  or even first in daily clinical practice.

  Secondly, a relevant proportion of enthusiastic, highly cited clinical research trials were later followed by clinical trials with moderate or even contradictory results.

  The risk of overestimating efficacy is further increased if conclusions are based on interim results—because the play of chance becomes more important. The following article demonstrates some pitfalls with early trial stopping for benefit. 

The UK Medical Research Council Acute Myeloid Leukemia Trial (AML12) compared five courses of chemotherapy with four.

  Two interim analyses (on 340 and 480 patients, respectively) showed large and highly significant survival benefits in favor of the additional treatment course. The Data Monitoring Committee (DMC), however, considered the findings too large to be clinically plausible and recommended that the trial continue. At the end of the trial, the analysis on 1078 patients provided a "null result." The continuation of the trial therefore prevented future young AML patients from receiving an ineffective and toxic 5th course of chemotherapy. "Be skeptical about unexpected large apparent treatment effects"—so stated the publication title of the final results.

Another randomized trial evaluated the efficacy and safety of tifacogin (a recombinant tissue factor pathway inhibitor) in patients with severe sepsis. The second performed interim analysis in 722 patients demonstrated a 10% absolute survival benefit for tifacogin over placebo with respect to the 28-day mortality rate. Like the previous example, the DMC recommended to continue the trial as originally planned. When a total of 1754 patients was analyzed, treatment with tifacogin had no effect at all on mortality.

  Because the trial was not stopped, future patients with severe sepsis were prevented from taking a useless treatment with a higher bleeding risk. 

  consisting of three separate randomized trials comparing the A-II blocker candesartan with placebo in chronic heart failure patients, provides a third example. The prespecified stopping criterion for the whole program was met by the 4th interim analysis, when candesartan reduced all-cause mortality by 24% relative to placebo. Following the DMC decision, the three trials continued. In the final published result, the difference in mortality had shrunk to 9%.

  This example again illustrates the importance of continuing a trial to its scheduled completion unless there is proof beyond a reasonable doubt.

  Not stopping the CHARM trials early avoided any exaggerated claim of a survival benefit.  

Stopping Trials Early: Lessons Learned			

In all three examples, interim analysis was at a "random high" of benefit, but by the collection of further data a "regression to the truth" occurred.

When it was probably not useful to stop early

In contrast to the previous examples, the following trials were actually stopped early for treatment benefit. 

Bisoprolol reduces peri-operative mortality and myocardial infarction (MI) in patients undergoing major vascular surgery. This was the conclusion based on a total of 112 patients on either betablocker or standard therapy after the trial was stopped early.

  Only two patients in the bisoprolol group died compared to 18 patients in the standard therapy group who either died or had a MI—leading to a relative risk reduction of more than 90%. Is this "too good to be true," as these data were inconsistent with results of previous trials? The meta-analysis of V.M. Montori et al. on a set of randomized trials stopped early for benefit

  could also show that small trials with only few events yielded, in general, greater treatment effects than large trials with a high number of events. 

Southwestern Oncology Group (SWOG) Trial 9701 compared a three-month paclitaxel treatment versus a prolonged maintenance 12-month paclitaxel treatment in patients with advanced ovarian cancer in first clinical remission.

  When an interim analysis revealed a seven-month progression-free survival (PFS) advantage in favor of the 12-month treatment, the trial was stopped early. In the final analysis, however, long-term treatment had no survival benefit but induced grade 2 and 3 neuropathy in a quarter of the patients. Nevertheless, the authors concluded the PFS advantage to justify a 12-month maintenance paclitaxel treatment.

  The early trial termination, however, makes it difficult to appropriately interpret the data, as the three-month treatment might indeed be equivalent—with less toxicity—since patients still may have prolonged survival through the use of second-line paclitaxel at time of relapse.

In a third clinical trial, adjuvant treatment with intra-arterial radio-labelled lipiodol (a fatty acid ethyl ester) was assessed in patients after curative resection of hepatocellular carcinoma.

  After 30 patients had been enrolled, an interim analysis showed a 48% reduction in cancer recurrence as compared to untreated control patients. Until the decision was drawn to stop the trial early, 13 more patients were randomized. In order to increase the follow-up time of the recently enrolled patients the data analysis was postponed. In the final analysis (based on 43 patients), the absolute difference in the recurrence rates shrank to 30%. What would have happened if the trial had finished the planned recruitment of 120 patients? A comment to this trial stated

: "It is a fundamental problem that most cancer clinical trials are far too small. Even if the study had reached its intended sample size, it would have lacked statistical power to detect realistic treatment benefits." 

To stop or not to stop—The ethical dilemma

Decisions by a DMC to stop a trial early have potential implications for three groups of patients: patients who have already been enrolled in a trial, prospective patients to be enrolled, and the current and future population of patients who may be treated or not treated with a drug based on the trial results. The obligations to minimize the risk and maximize the benefit in each patient group occasionally conflict with each other.

  The ethical dilemma is to protect patients in a trial while also  protecting society from ineffective and unsafe treatments or, in other words, to save the social value of a trial.

The Blood Pressure Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA

) is an example of this dilemma. Although the DMC recommended in October 2003 to possibly terminate the trial early (as atenolol treatment was associated with more deaths than amlodipine treatment at an early interim analysis), the investigators decided to continue the trial—the treatment differences could have been related to differences in high blood pressure management and might have evened out over time. However, when a further interim analysis in December 2004 showed a relative 24% higher mortality with atenolol, the trial was immediately stopped. "Would you go to court and say you carried this for another two years knowing that the death rate was higher in one side than in the other?" one of the investigators (who initially was strongly in favor of continuing the trial) later said in an interview.

In addition to the clinical considerations previously mentioned, there is also a critical challenge with respect to ethics: finding the appropriate balance between maximizing the scientific validity and social value of a trial and the obligation to protect the trial subjects.

All major clinical trials should have an independent DMC.

  The main risk with early stopping for benefit is overestimating treatment effects. If a clinical trial is going to be stopped early for benefit following a scheduled interim analysis, stringent statistical stopping boundaries for benefit are necessary. The actual final decision to stop a trial early based on the available preliminary data, however, is a clinical and ethical decision. Without doubt: Trial participants need to be protected. But it is also an ethical demand to protect future patients from ineffective and unsafe treatments. Therefore, a trial should remain conclusive about the true treatment effects—which means that stopping a trial early for benefit is not always the best alternative. 

 MD, FFPM, Swiss specialist in pharmaceutical medicine, is medical director with PFC Pharma Focus AG, Chriesbaumstrasse 2, CH-8604 Volketswil, Switzerland, email: 

Editorial material for this article was presented at the 

 1. V.M. Montori, P.J. Devereaux, N.K.J. Adhikari, K.E.A. Burns, C.H. Eggert, M. Briel et al., "Randomized Trials Stopped Early for Benefit. A Systematic Review," 

Journal of the American Medical Association

 2. S.J. Pocock, "When (Not) to Stop a Clinical Trial for Benefit, "

 3. R.S. Bresalier, R.S. Sandler, H. Quan, J.A. Bolognese, B. Oxenius, K. Horgan et al., "Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial," 

 4. D.N. Juurlink, M.M. Mamdani, D.S. Lee, A. Kopp, P.C. Austin, A. Laupacis, D.A. Redelmeier, "Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study," 

 5. J.P.A. Ioannidis, "Contradicted and Initially Stronger Effects in Highly Cited Clinical Research," 

Journal of the American Medical    Association

 6. K. Wheatley and D. Clayton, "Be Skeptical About Unexpected Large Apparent Treatment Effects: The Case of MRC AML12 Randomization," 

 7. E. Abraham, K. Reinhart, S. Opal, I. Demeyer, C. Doig, A.L. Rodriguez et al., "Efficacy and Safety of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) in Severe Sepsis," 

 8. M.A. Pfeffer, K. Swedberg, C.B. Granger, P. Held, J.J.V. McMurray, E.L. Michelson et al., "Effects of Candesartan on Mortality and Morbidity in Patients with Chronic Heart Failure: The CHARM-Overall Programme," 

 9. S. Pocock, D. Wang, L. Wilhelmsen, C.H. Hennekens, "The Data Monitoring Experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program," 

10. S. Pocock and I. White, "Trials Stopped Early: Too Good to Be True?" 

11. D. Poldermans, E. Boersma, J.J. Bax, I.R. Thomson, L.L.M. van de Ven, J.D. Blankensteijn et al., "The Effect of Bisoprolol on Perioperative Mortality and Myocardial Infarction in High-Risk Patients Undergoing Vascular Surgery," 

12. M. Markman, P.Y. Liu, S. Wilczynski, B. Monk, L.J. Copeland, R.D. Alvarez et al., "Phase III Randomized Trial of 12 versus 3 Months of Maintenance Paclitaxel in Patients with Advanced Ovarian Cancer After Complete Response to Platinum and Paclitaxel-based Chemotherapy: A Southwestern Oncology Group and Gynecologic Oncology Group Trial," 

13. S.A. Cannistra, "The Ethics of Early Stopping Rules: Who Is Protecting Whom?" 

Real examples from recent studies illustrate the risks associated with making such a delicate decision.

Applied Clinical Trials-01-01-2007