For more on managing clinical trial data in today’s high-tech environment, check out the following articles: 

Integrating EHR with EDC: When Two Worlds Collide

Raising the Standards for Clinical Integration

There are significant opportunities to improve current methods of electronic data capture (EDC) in clinical research for both government and industry sponsored clinical trials. Current methods generally require investigators to keypunch data into EDC systems individually supplied by sponsors for each trial. While this is an improvement over paper-based methods, the current EDC model falls well short of possible efficiency improvements and, in effect, reinforces work redundancy at investigator sites. 

A far more effective approach would be for clinical investigators and sponsors to share a common system platform or, at least, for systems at investigator sites to be capable of directly supplying high-quality, auditable clinical trial data to sponsors and be in compliance with CFR Part 11.  

(PHOTOGRAPHY: DIGITAL VISION, EYEWIRE,    ILLUSTRATION: PAUL A. BELCI) 

For some time now, forward-thinking investigators and sponsors alike have suggested that extracting clinical trial data directly from the electronic health record (EHR) would be far more efficient. 

A thoughtful analysis of this opportunity, such as the March 2006 

 article "Integrating EHR with EDC: When Two Worlds Collide" by Paul Bleicher,

  rightly suggests skepticism about what's possible when EDC and EHR collide. 

In short, integrating EHR and EDC is not viable today unless source EHR data is first fed into CFR Part 11 compliant systems for clinical trial fulfillment—which is exactly what some researchers have begun to do. The approach is conceptually straightforward: Use one system solution that at once addresses the needs of investigators and sponsors. Such systems and integrated supply chains are in production today, conducting trials electronically from source data to sponsor submission. The approach is very similar to supply chains commonly found in other industries such as manufacturing. 

This article contains a description of how such fully integrated, clinical trial supply chains work from a systems perspective; the required systems technology; benefits for sponsors; supporting government and industry initiatives that are facilitating such integration; and some business model suggestions that will accelerate the evolution of integrated clinical research supply chains. 

There is a need to solve "the last mile" problem in clinical research. The notion of the last mile is most often associated with the telecommunications industry, where wiring the last mile—the cable or phone lines that go from the street into the house—is among the most time-consuming and expensive system infrastructure challenges. Notably, in that industry such wiring is also necessary to deliver meaningful system value. 

The analogy of the last mile also applies to clinical research, where the last mile problem is integrating research sites. Traditional EDC has gone part of the distance. To use the telecommunications analogy in the current model, investigators and their staffs using traditional EDC leave behind the systems and devices they use in their homes, walk to the bottom of their driveways or out to the sidewalk, log in to the system, enter trial data, and walk back into their homes and continue using whatever systems and devices they use on a day-to-day basis. 

As such, clinical research fulfillment is a broken supply chain. Indeed, some would argue that the current state-of-the-art systems introduced increase workloads for many research sites, which in turn adversely impacts sponsor productivity and contributes to the extended time periods required to conduct clinical trials and obtain related drug/device approvals. Few would disagree that the current supply chain and EDC model likely perpetuates tens of millions of dollars annually in costs and delays in clinical research execution. 

The only way to fix the supply chain is to solve the last mile problem. From an economic perspective, the constituency that stands to gain the most from a complete supply chain is research sponsors, particularly industry sponsors, simply because they generally have the most to gain economically from improved clinical trial execution. These gains in turn translate to better treatment options sooner for patients. 

The capabilities that need to be supported to enable an integrated supply chain include the following:  

The ability to support investigator and sponsor clinical trial information through one system platform.

The ability to manage data across studies and patients without changing systems for each study.

Integration capabilities so that individual consortium members can have source clinical data feeds, such as lab and demographics, from internal source systems to the EDC solution and on to the sponsor.

The ability to broadcast clinical trials to investigators with otherwise uniquely configured research systems.

A fully compliant FDA CFR Part 11 system validated by industry sponsors.

A pure Internet platform solution that is flexible, highly configurable, and affordable.

A number of EDC solutions do a solid job with individual studies, but few vendors address all the above needs. An integrated system designed from the ground up to support all the above capabilities is even more compelling. Simply put, the most effective way to eliminate redundant data entry and other widely documented inefficiencies in investigator–sponsor interactions is for investigators to use a system on a daily basis that also serves the needs of sponsors (see Figure 1).  

Figure 1. The integrated solution allows for investigatorâsponsor interactions to be less burdensome and more efficient. 

The general system specifications required to address all of the above needs include:  

A system architecture that is both patient- and study-centric.

A solution and system design that integrates study management via a clinical trials management system and EDC.

Advanced technology to support federated databases and research grids—a must to enable investigator utility and address the clinical research last mile problem.

A product that incorporates industry sponsor standards, such as Clinical Data Interchange Consortium (CDISC),

  as well as standards for government-sponsored trials, such as those of the National Cancer Institute's (NCI) Cancer Bioinformatics Grid (caBIG

) and hospital medical record system (HL7).

An integrated interface engine coupled with deep expertise and rich software libraries to support efficient, reliable EHR source data integration. 

Most or all the typical functions of a traditional EDC solution.

For sponsors, the process of implementing studies in a fully integrated supply chain is similar to conducting a clinical trial using traditional EDC. While extensive pretrial operations are also supported, for purposes of this article, this discussion begins from the time the study protocol and case report forms are IRB approved and ready to be configured in the system. 

 The first step is to configure the study in the system. The two general configuration activities are study set up and site participant set up. These activities are the same as those performed in a traditional EDC-based clinical trial. 

As compared to some EDC solutions, one difference may be that the system needs to be easy enough so that investigator staff can set up trials without vendor or systems personnel. This is because that same system must be usable and affordable to support other clinical trials, such as investigator-initiated trials that have more limited budgets than most industry-sponsored trials. It follows that such tasks can also be easily conducted by sponsor or CRO personnel. 

 In this step, called study broadcasting, the sponsor or its designate notifies site participants that the study is ready for patient accrual. Participating sites that already have the system receive the study in their local or vendor-hosted database. Authorized users at sites not already using the systems are given secure, on-line access to particular studies directly from the sponsor, CRO or lead investigator—very much like traditional EDC. 

 Next, sites accrue patients and carry out the study. There are three kinds of sites from a systems perspective. Sites with source system interfaces fulfill corresponding portions of the study electronically (i.e., no manual data entry for electronically sourced data). Where source system interfaces are not implemented, trial-specific data for individual trials is posted from within the system environment in use at the site, leveraging data and workflow already built into the application. Patient registration and scheduling, for example, are fully integrated with EDC and trial fulfillment. New sites (sites not already using the system) post trial data in the same manner as traditional EDC. 

Some investigators may adopt the system to manage clinical research across the department or enterprise and some may not. Either way, any sponsor-authorized investigator can participate in the clinical trial. 

Communications and workflow management tools also are required. These capabilities enable sponsors and sites to interact and monitor trial activity throughout the trial life-cycle. With traditional EDC, the bulk of the value and time savings comes around the time of trial database lock. In an integrated clinical trial supply chain, process and workflow improvement and system-based investigator and sponsor communications can occur throughout the study life-cycle. 

 When study or case report form data is completed and authorized through e-signature, study data is downloaded to the individual study database, which may be hosted by the vendor. The sponsor, CRO, lead investigator site or coordinating investigator site could also host the database. As such, sponsors can have continuous, up-to-the-minute access to study status information throughout the trial life-cycle. Complete CFR Part 11 compliant audit trails and compliance controls must be in place throughout the study life-cycle. 

 A wide range of easy-to-use system and workflow tools should support the entire research fulfillment process, including alerts and reminders, query management tools, ad hoc reporting, audits trails, and other tools. These system features help sponsors promptly and efficiently review data, compare site performance, interact and communicate with sites, review results, resolve queries, and ensure complete, accurate data for subsequent trial database lock. 

 The activities of posting trial data and supporting database lock are essentially the same as with traditional EDC. Data should be available in SAS, XML or any delimited sponsor specified format. In the case of trials sponsored by such large sponsors as the National Institutes of Health (NIH), study results can be posted directly to their trial databases. 

Not only is it feasible, it's being done today on a production scale in a variety of research contexts by both investigators and sponsors. One group of 14 networked medical centers is electronically downloading complete trial data in a federated database environment (meaning some members have separate physical database instances) to a large sponsor on 46 trials. 

Articles

Feature Article

The last mile in clinical research is integrating the research site to create a complete information supply chain.

A to Z Trial Integration

The shadow of TGN 1412 still hangs over Europe. The serious side effects experienced by volunteers in March 2006 during the first-in-man clinical trial of this monoclonal antibody continue to trouble the whole of the clinical trial community in Europe. In consequence, action is underway from industry, investigators, and authorities to avoid the risk of such dramatic events recurring in a first-in-man trial.  

As this column commented on earlier this year (View from Brussels, May 2007), the European Medicines Agency is drafting guidance on the subject—and following the draft document it published in March [http://

www.emea.europa.eu/pdfs/human/swp/2836707en.pdf

], it held a major consultation meeting during the summer to assess how to proceed. 

The initial draft guidance has been the subject of wide comment in the clinical trials community and beyond, and the Agency now has the delicate task of producing a final document that picks its way adroitly among the many opinions expressed—not all of them consistent. 

The concept of standardized guidance has met with general acceptance. "The draft appears to be very useful to elevate the safety of first-in-man trials," as the UK's Association for Clinical Pharmacology and Therapeutics put it. The European Clinical Research Infrastructures Network describes it as "a brilliant overview of a very complex issue." 

There are some common themes in the comments, and one above all stands out: The question of definitions. 

The draft guideline refers to "high-risk" medicinal products, raising the tricky question of just what that means. As numerous comments to the Agency point out, the definition will have to follow clear and narrow guidelines because once a product is considered to be a high risk, a large battery of additional studies and approval processes will be launched. 

The UK BioIndustry Association warns: "If the criteria are not defined precisely, there is a potential for misapplication. If the definition of high-risk products is applied too widely, this could have a detrimental effect on innovation [and] will create an excessively burdensome regulatory environment that will be damaging to the development of innovative medicines." 

Centocor Research & Development suggests getting around this problem by refocusing the guidance on risk management, risk mitigation strategies, and dose setting for all first-in-human clinical trials. "This would remove the need for a definition of 'high risk,' whilst still addressing appropriate risk management strategies," it says. 

The problem of definitions is spelled out at length by the Department of Clinical Pharmacology and Centre for Human Drug Research at Leiden University's Medical Centre, which cautions that "the guideline in its current form may do a disservice to rational and safe drug development" by its attempt "to dichotomize high-risk and nonhigh-risk compounds, which is impossible." It questions the distinction the draft guidance draws between "potential high risk" and "non-high risk" compounds, and rejects the guideline's suggestion that there are low risk compounds. "In fact, most new drugs explore novel mechanisms of action, and animal models are rarely fully predictive of the effects of the compounds in man. Therefore, classifying drugs as low risk may increase the risk for participants in trials, because it may result in performance of trials with less stringent rules than warranted." 

The European Federation of Pharmaceutical Industries and Associations finds that the major problem with the draft guideline is "the differentiation of 'high-risk' investigational medicinal products from the rest. Assigning a compound to one category versus the other could be viewed as being arbitrary. Risk is related to the doses administered in the clinical trials—not the product itself—and to the clinical trial design. 

The bottom line of many comments—particularly from industry—is that drug development may be delayed by excessive regulation, so there are repeated calls for a balance between ensuring the safety of trial subjects and making the European Union an attractive place for cutting-edge biomedical research. 

The verdict of the European Association for Bioindustries is harsh: In its current form, the guideline "will delay first-in-man clinical trial initiation." It is particularly concerned that the specific characteristics of vaccines, blood-derived products, and other immunotherapies are not catered for in the guidance. 

The view is echoed by Fresenius Biotech, speaking for the European Biopharmaceutical Enterprises: "A balance between the need to safeguard clinical trial subjects on the one hand and the need for continued development of innovative medicines on the other hand is important. An environment promoting clinical development is key to ensure public health by generating new treatments with the potential to address unmet medical needs...Compliance with this guideline could greatly increase both time and resources necessary to filing clinical trial applications and generate significant data that is potentially difficult to interpret and is of questionable value." 

				For the European Federation of Pharmaceutical Industries and Associations too, "Many points require clarification to avoid risk of misinterpretation, lack of flexibility, and a more conservative interpretation; this could imply unnecessary hurdles for drug development without leading to gains in safety."			

The other most common concern is that the proposed guidelines are not strict enough or sufficiently prioritized, and would not, as they stand, have prevented the TGN 1412 trial from going ahead as it did. According to Bristol-Myers Squibb, the draft's "inherent uncertainty leaves a degree of vagueness which, without further refinement or additional opportunities for timely and more specific guidance, may not provide the intended assistance to sponsors in transitioning from nonclinical to early clinical development, particularly regarding their planning of how, when, and where to conduct the First-in-Human study." Similarly, for the BioIndustry Association, "certain sections provide too general guidance that may be of little use to applicants" and "there is a lack of illustrative examples to provide practical guidance to all applicants in dealing with issues relating to transition from nonclinical to early clinical development." 

The Federation of European Cancer Societies finds the document "very general in its language," and urges improvements "by adding specific examples or indicating specific areas where, for example, patients would be more appropriate than healthy volunteers." Merck Sharp & Dohme (MSD) Europe shares the view that the document is "too general, open to interpretation, and does not provide specific guidance." In particular, "There are not clear definitions of the criteria for what a high-risk molecule is and importantly what a high-risk molecule is not. Specifically, the differences in requirements or considerations for a high risk vs. standard molecule are unclear." Instead, MSD suggests producing guidance that defines the limited circumstances for which concerns exist over the mechanism of action of the molecule or the relevance of preclinical evaluations to predict human toxicity. 

The same hunger for concrete guidance is evinced by the German Association for Applied Human Pharmacology: "We understand that an exact definition of different risk categories is not easy because such a classification depends on many individual factors. However, we propose that the guideline should be more specific and more obliging in terms of giving recommendations and instructions to sponsors and investigators." 

Meanwhile, Paul Jones, commenting on behalf of Cancer Research UK, remarks that the draft guidance focuses on healthy volunteer clinical trials. "There is no mention of how the guidance fits in with existing guidances on patient clinical trials and in particular cancer and HIV patient clinical trials. The guidance concentrates on the assessment of risk alone rather than the assessment of risk-benefit necessary in patient clinical trials." 

And there are views that go beyond the specific issues of first-in-man trials in high-risk products. Stephen Senn at the University of Glasgow, commenting on behalf of the Royal Statistical Society, makes the point that the draft neglects the question of informed consent, and says nothing about the risk information the sponsor should share with subjects in the trial or about statistical analysis. "If the results from such a trial are to be used, they will need to be analyzed and different designs will be suitable for different intended analyses and vice versa," he argues. 

Not considering the intended analysis would be unthinkable in the case of a Phase III trial, says Senn: "The fact that this has not been mentioned here is indicative of a mentality that this guideline will do nothing to dispel the unfortunate belief that Phase I studies are not really serious experiments. And that from the scientific point of view, no care needs to be taken in their design because in general they will not receive public scrutiny." 

The question of consent is also high on the agenda of the Standing Committee of European Doctors, which suggests that ethical issues receive more attention in the guidance. It proposes "a well-prepared information sheet for research subjects, emphasizing the background to existing animal studies, and the particular precautions that will be taken in the first human trials; a specific commentary that the product being tested is a high-risk compound, with a higher level of uncertainty than is usual; a more detailed explanation than is usual about the mode of action of the product and steps to be taken in the event of unexpected adverse reactions; and a sufficient period of time to be provided for a decision by participants whether to take part, and the opportunity for [subjects'] concerns to be shared with experts not associated with the trial itself." 

A similar emphasis on the ethical dimension comes from the European Forum for Good Clinical Practice: "This guideline concentrates very much on the scientific and technical aspects of first-in-man trials but does not sufficiently consider ethical aspects like information to subjects, indemnity coverage requirements, and medical safeguards during and after the study performance," it comments. Notably, when discussing clinical requirements, "more guidance should be given in terms of qualifications/certification of investigators and site personnel...A Phase I unit should be able to anticipate each type of life-threatening event...We are very much concerned that the required level of experience and qualification of investigators responsible for first-in-man trials are not specified in the guideline." 

It is also worth noting a contribution from The Good Clinical Practice Alliance–Europe, which underlines the impact of the increasingly tough commercial context for clinical trials. "Due to financial, market, and patient pressures, there is an increasing emphasis by sponsors on accelerating the development of molecules from bench to market," it says, adding that "the ongoing European attempts to streamline legislation and procedures testify to these pressures, often felt particularly acutely in the decision-making processes concerning the move to first-in-man studies." 

Globally, the pressure on such decision-making and risk analysis is also growing, argues the Alliance, and it also shows itself in the increasing globalization of Phase I clinical trials. "The European Union needs to strengthen its competitive edge in this highly pressurized and global market of first-in-man studies. The best way to do this is by providing public assurances of the sound scientific and ethical basis for the first-in-man studies approved and carried out within the EU," it says. "This proposed guideline should assist Europe in moving closer to the needed public assurances." 

Its comment is accurate—except that the nature of the proposed guideline remains unknown. The EMEA has a lot riding on how it cuts through this Gordian knot over the coming weeks. 

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

View from Brussels

Europe's clinical trial community has a lot to say about the EMEA's draft guidance on first studies in man.

Not Yet the Last Word on First-in-Man

Model Clinical Trial Agreements (mCTAs) were developed in February 2003 by the Department of Health and the Association of the British Pharmaceutical Industry (ABPI) with the dual aim of expediting and improving the contracting process to allow approved trials to begin more quickly. A further objective is to save money for the National Health Service (NHS), sponsors, and CROs by removing the need for legal review of trial-specific agreements. 

Revised versions of the mCTA for research sponsored by pharmaceutical and biopharmaceutical companies in NHS hospitals were launched on October 30, 2006. The revised mCTAs were further developed by a number of health care organizations, including the ABPI; the BioIndustry Association (BIA); the Department of Health for England; the devolved administrations of Wales, Northern Ireland, and Scotland; the Council Heads of Medical Schools; the NHS Research and Development Forum; and the UK Clinical Research Collaboration. The mCTA is based on English law and governance arrangements, but individual mCTAs have been adapted for use in Northern Ireland, Scotland, and Wales.  

(PHOTOGRAPHY: PHOTODISC    ILLUSTRATION: PAUL A. BELCI)			

The revised mCTAs build on the original versions and introduce changes to take into account new legislation and research governance requirements, changes that have taken place in the NHS (in particular, the creation of Foundation Trusts), and the NHS and industry's experience with the first versions. 

The mCTAs contain references to standards for the management and governance of commercial clinical trials that are either mandatory or reflective of industry agreed levels of good practice. These include the ICH-GCP harmonized tripartite guideline for good clinical practice; the good clinical practice guidance published pursuant to European Directive 2001/20/EC (relating to the implementation of GCP in clinical trials) and Commission Directive 2005/28/EC (also relating to GCP); the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended); various UK Research Governance Frameworks; and patient indemnity arrangements and accountability through NHS bodies' chief executives for clinical research involving NHS patients. 

				The mCTAs also deal with industry undertakings to register clinical trials and publish research findings (as set out in the Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases).			

The mCTA is designed to be used for Phase I to Phase IV trials undertaken in NHS hospitals involving NHS patients. It should not be used in connection with Phase I trials involving healthy volunteers; for noncommercial studies sponsored by charities, government departments or research councils; or for clinical trials performed by private institutions with patients recruited independently of their treatment within the NHS. 

The guidance issued at the launch of the mCTA explains that use of the model agreement is not mandatory for either NHS hospitals or member companies of the ABPI or the BIA. However, its routine use is "strongly recommended" by the Departments of Health in England, Wales, Scotland, and Northern Ireland. These bodies recommend that no changes be made to the mCTA other than filling in trial specific details such as the title of the trial, the contracting parties, the identity of the principal investigator, the financial terms, and the subject recruitment arrangements. 

In our experience, certain NHS Trusts have followed that guidance to the letter and have been reluctant to entertain any negotiations in relation to changes to the mCTA. They argue that the mCTA has been prepared by industry representatives, and therefore no changes should be required to the approved form document. This argument misses two points. 

The first is that sponsors of clinical trials did not personally take part in the preparation of the mCTA (even if they are members of one or both of the professional organizations representing the pharma industry), so they had no direct input into its content. The second is that the agreement is a model—only a model. Like all standard form contracts, it is open to amendment depending on the background circumstances to entry into the contract, the commercial objectives, and bargaining positions of the parties. 

The new mCTA contains a number of amendments that affect the bargain struck between the NHS Trust and the sponsor, particularly relating to the allocation of risk and intellectual property provisions. 

The key changes from the sponsor's point of view are the new limits on hospital liability. There are two caps, depending on the nature of the breach committed by the NHS Trust. 

In the event of willful and/or deliberate breaches of the agreement and any breach relating to clauses 6 (Confidentiality, Data Protection, and Freedom of Information), 8 (Publication) and/or 9 (Intellectual Property), the NHS Trust's liability is limited to a maximum of twice the value of the contract. The contract value is the total payment to be made by the sponsor to the NHS Trust if the targeted number of patients is recruited. The second cap covers all other breaches of the agreement by the NHS Trust and limits the NHS Trust's liability to a maximum of the contract value. 

These caps are clearly inadequate; the losses that sponsors may face if a clinical trial is not carried out in strict accordance with the protocol in the clinical trial agreement may be greater than the total contract value by several orders of magnitude. Furthermore, these clauses require a court to decide whether a breach of contract was deliberate, a concept that is rather alien to English law. The guidance issued with the new mCTA recognizes that: 

"...for a number of possible types of breach (for example, the loss of important Intellectual Property Rights or the release of strategically important information) it is arguable that these provisions might not fully compensate the sponsor to the extent of their loss. However, it is considered that paying compensation on the basis negotiated would be an additional incentive to encourage hospitals to take every reasonable precaution to prevent a breach. These precautions could include: having robust research governance arrangements; instituting training programs for researchers undertaking commercial trials; publicizing to researchers and their staff the crucial importance of protecting the integrity of sponsors' confidential information; and taking disciplinary action in the event of a willful or reckless breach of the provisions of clinical trial agreements."

These precautions are required to ensure the careful running of trials, but are not much comfort to sponsors in the face of substantial financial loss. The new mCTA places the onus on the sponsor to have deep pockets or rock solid insurance. 

The new intellectual property clause is based on the principle that each party retains ownership of any pre-existing intellectual property or know-how owned by it or licensed to it. The sponsor owns any intellectual property or know-how relating to the clinical trial, the investigational medicinal product or the trial protocol. The sponsor does not gain any rights to any clinical procedures or improvements to such procedures. 

This seems sensible in most cases, but may lead to difficulties if, for example, the method of administration of the investigational medicinal product is novel or complex. The NHS Trust and the principal investigator are obliged to disclose to the sponsor any know-how arising from the trial. 

Several changes were made to the new mCTA that may lead to disclosures that are to the detriment of the sponsor. The obligations relating to confidential information are restricted to a 10-year period in both clause 6.3.4 and clause 20. Lifting the obligations of confidence at the end of this period might well conflict with the sponsor's rights to data exclusivity. 

The new clause 6.2.6 of the mCTA, which was inserted to deal with the Freedom of Information Act 2000 (FOIA), is unbalanced. In particular, there are certain exemptions to the obligation to disclose information set out in the FOIA, but in the mCTA the decisions as to whether these exemptions apply is left purely in the hands of the site conducting the trial. The agreement should at the very least include a clause that permits the sponsor to make an application to the court or the Information Commissioner for the purpose of preventing a potentially damaging disclosure. This will be particularly important if the FOIA can be used by generic companies to obtain data relating to trials. 

Publications, recruitment, and terminations

In clause 8.4, there is a danger that publication of a summary of study results before publication of the full study might undermine the sponsor's right to preserve its intellectual property rights. As a result, the sponsor will need to ensure that the protocol deals comprehensively with the rights to publication. Note, however, under clause 3.6 of the new mCTA, in the event of conflict between the protocol and the mCTA itself, the terms of the mCTA prevail. 

The rationale behind clause 8 of the mCTA is that publications based on limited and perhaps unrepresentative subsets of data from one or a limited number of trial sites should not be published before the multicenter data. A dissenting interpretation of the trial's data may be published after the main report, if the procedures in clause 8 are adhered to. (The mCTA allows the sponsor a 60-day period for review of the publication, plus a delay of up to six months from the date of submission of the draft publication so that it can take steps to protect its proprietary rights, intellectual property, and know-how.) 

The mCTA does not deal with the issues of competitive recruitment between different sites or the consequences of a trial becoming full before the site that has entered into the mCTA has managed to recruit its proposed allotment of study subjects. This may have consequences on trial remuneration and expenses, which should be addressed. 

An amendment is required to clause 12.8 of the mCTA, which deals with early termination. The clause should state that termination of the mCTA is without prejudice to the accrued rights and liabilities of the parties under the agreement and to those rights and obligations, which are preserved 

pursuant to clause 20 or which by their nature are intended to survive termination.

 The additional wording (in italics) points to clause 20, which sets out the rights that are expressed to survive termination and widens the net to include any rights that are not included in clause 20 but should also survive termination. 

An additional issue is that the new mCTA does not oblige the NHS Trust to ensure that the principal investigator is aware of and complies with their obligations in the conduct of the study. 

As the principal investigator is not a party to the mCTA, the sponsor has no direct recourse against the principal investigator in the event that he or she breaches a term of the agreement. The NHS Trust represents that the principal investigator has the necessary skill and expertise to perform the clinical trial and that he or she is made aware of its obligations contained in Appendix 6 to the mCTA. However, the NHS Trust is not required to carry out any investigation to check that the principal investigator does not have any conflicts of interest. 

Aisling Burnand, chief executive of the BIA, commented at the launch of the new mCTAs that "the universal endorsement of this agreement is a tremendous achievement which will strengthen the UK's position as a world leading location for medical research. The use of this template contract will significantly accelerate the initiation of trials and allow patients faster access to innovative treatments." However, this optimism is tempered by the guidance issued with the mCTAs, which neatly sets out the problem faced by the UK: 

"In recent years, the performance of UK sites involved in these international clinical trials has declined in terms of the speed of trial site initiation, patient recruitment, and quality of data generated, while trial costs have, in general, risen faster than in comparable countries. With increasing competition from research sites in the developing world and states in Eastern Europe, it has become more difficult for pharmaceutical companies to justify the inclusion of UK sites. Unless their performance improves, the extent of UK participation in international trials will continue to decline, with possible adverse consequences for the UK Pharmaceutical Industry more generally, as well as the status of the UK as a centre of medical and research excellence." 

So, will the new mCTAs ultimately help or hinder the development of the UK pharmaceutical industry? 

The new mCTAs tip the scales in favor of the NHS Trusts to the detriment of sponsors. If a sponsor insists on adequate contractual protection in the form of indemnities, requiring the negotiation and amendment of the mCTA, then the attempted streamlining of the contractual process has backfired. 

We have seen sponsors dropping certain trial sites that are unwilling to make any revisions to the mCTA. This erodes the goodwill and connections established in prior collaborations between such sites and the sponsors and places future collaborations in jeopardy. Certain pharmaceutical companies are just not prepared to bear additional financial risks in what is already a risky business. If that reaction is widespread, the UK may become a less attractive location for clinical trials, despite its current reputation for clinical excellence. 

If in the long term fewer trials are being conducted in the UK, then British-based scientists may miss out on exciting new developments, which may ultimately undermine the UK's reputation for clinical excellence. 

 is a partner and head of the health care group at international law firm Ashurst, email: 

 is an associate in the technology and commercial department at Ashurst.

*To whom all correspondence should be addressed.

1. The Guidance on Use of the mCTA for Pharmaceutical and Biopharmaceutical Industry Sponsored Research in NHS Hospitals, paragraph 7.11 (2006 version), available at: 

The UK's revised model clinical trial agreements were launched, but have the changes saved time and money?

Model or Gospel

Companies engaged in clinical trials are seeing a paradigm shift in the very definition of clinical data management. What was once a paper-based, manual process focused on one trial at a time is evolving into a technology-based, automated process that operates across multiple studies.  

There have been an ever expanding number of data sources being incorporated into clinical trials, such as EDC, ePRO, IVRS, CTMS, as well as new types of electronic lab data. Sponsor companies have been attempting to take on the challenges of integrating and managing these data sources, and as a result, the technology—which in most cases is outside the scope of their core competencies. 

This makes for an untenable situation, which will continue to be a pressing issue for sponsor companies and CROs alike until a holistic approach to managing electronic data is implemented. 

What was once a "black box," where data went in one end and came out the other, is becoming a multidisciplinary process with new possibilities for access and visibility into the data.  But simply adding electronic to clinical data management is not going to close the process gaps that are being revealed as companies implement new technologies. 

In order to capitalize on the real value these new technologies offer, there needs to be a wholesale shift in the way we think about the possibilities of managing data electronically. 

If there is a new moniker, it is Electronic Data Lifecycle Management (eDLM): an approach to gain comprehensive visibility into the entire electronic data lifecycle that enables faster access to better quality data at each step—from FPI through archival. Instead of waiting for data to inform our decisions, an eDLM approach promotes proactive, real-time access to data (Labs, Sites, ePRO, CDMS, CTMS, safety, etc.), leveraging data repositories to provide upstream visibility into study metrics, enabling time-critical decisions and adaptive trial designs. Ideally, there would be a combination of in-house and outsourced expertise to manage eDLM. In-house staff would work across multiple studies with data project leaders savvy in automated trial design and data tracking and reporting tools. We would see a new breed of service providers, such as data integrators and aggregators, who would act as a trusted third party somewhere between the sponsor, CRO, and technology vendor. 

These service providers would integrate the data sources, design workflow, and aggregate data into repositories, providing a comprehensive view from which to extrapolate and cross analyze the data through the use of standards. 

With an increased number of vendors and diverse skill sets becoming involved in clinical research, the roles within the eDLM approach will demand strong interpersonal skills and the ability to manage seemingly disparate functions as one integrated team. 

All of these roles will require technological savvy and the ability to adapt in an ever expanding and complex environment. 

By combining the expertise of data, technology, and workflow to create a layer of services that acts as a bridge between the functionality of a software application and the sponsor's study design, between the sites and the CRO, and between the patient and caregiver, we will essentially create an IT model for trials that has been successful in every other major industry. 

These are exciting times for sure, but for those who think managing clinical data is a thing of the past, think again. While it may be very different, we will still have people managing data. The difference is that they will be managing the entire electronic lifecycle of the data, and no longer from a silo operation. Rather, they will be working along side the other functions as part of an integrated, multidisciplinary team. 

A Closing Thought

To capitalize on technology, a new approach to managing data is needed. Peg Regan, chief executive officer for PharmaPros Corporation, explains the concept of Electronic Data Lifecycle Management and how it will improve the quality of data and the time it takes to access it.

Electronic Data Lifecycle Management

As a change of pace, this issue's column isn't devoted to a cutting edge technology or process. Instead, we will explore a recent book, 

, by Nassim Nicholas Taleb (Random House, New York, 2007).  

Most people lead their lives assuming most observations, events or measures are distributed in a bell-shaped normal distribution. Of course, they probably don't even realize their assumption or even explicitly understand the normal distribution. Yet most of us expect and act as if events will unfold for us (and the world) roughly within the bounds of our limited experience and information gathering. These assumptions bring organization and comfort to our lives, but they may prevent us from avoiding catastrophic events as well as benefiting from spectacular opportunities. 

Consider your daily commute to work. You have likely developed a comfortable sense of the pattern of traffic and drive "defensively," prepared to act on the wide range of bad driver behavior you might expect. In the eyes of Taleb, you are living in "Mediocristan," where observations fall within a normal distribution of your experiences, and no individual event has a meaningful impact on your life. 

Suddenly, one morning you are faced with a very fast moving and erratic car hurtling directly toward you. A wrong lane driver is a completely unexpected and unpredictable event, so far off the normal curve that we might never have considered it possible nor worth thinking about. In fact, we had always been living (and driving) in "Extremistan," where highly improbable and infrequent events dominate in their impact on our lives. Most of us simply don't realize that we are. 

Our wrong lane, out of control driver is an example of a "black swan," as described by Taleb: an unexpected and unpredictable event that is so far from our aggregate experience that it has an effect far out of proportion to others. 

According to Taleb, most of us live our lives assuming that we are in Mediocristan when, in fact, we are always in Extremistan, where that unpredictable black swan can happen at any time. 

Taleb is the latest in a series of commentators who are thinking about the impact of nonGaussian distributions, particularly the power distribution, which model the way that infrequent events can have disproportionate impacts. He isn't just talking about number crunching or investments (where he has used these principles professionally), but in almost every aspect of our lives. It is worth a very general understanding of the power function before delving into its impact. 

The 80/20 rule (which is actually quite arbitrary and could be the 75/25 rule or other skewed fraction) actually fits a simple, mathematically defined law, known as the power probability distribution. If the normal curve resembles a bell, the power distribution resembles a hockey stick—the Y axis starting at its highest point at some X and rapidly descending to a long tail. 

Vilfredo Pareto (1848–1923) used the power distribution when studying the distribution of wealth in a society (still one of the most easily understandable examples, especially in contrast to a normally distributed measure). Many attributes of the human population are normally distributed, such as weight, height, and intelligence. The heaviest, tallest or most intelligent person you could think of, if lumped in with 100 randomly selected people, would barely budge the median value. However, the personal wealth of these same people is quite another thing. 

If we take the richest person we can think of (for example, that entrepreneur/philanthropist from Seattle with a net worth estimated at $56 billion dollars), his overall effect on the median would be staggering. In fact, it would shift the median up by $560 million dollars! Obviously, in sampling a population, medians of personal wealth have little meaning. Of course, you could argue that it would be highly unlikely for a random sample to include Bill Gates, but that is beside the point. Bill Gates is a highly improbable black swan when it comes to wealth. 

The power distribution is, in fact, a model of many different things. An often sighted example includes the frequency of words in books (a small number of words account for most text, and then many, many more are used occasionally). 

There are many reasons why most of us live in Mediocristan and are accustomed to thinking in Gaussian terms. To begin with, life has become exceedingly more complex than it was in the past, when humans developed their patterns of thinking. We tend to extrapolate from small numbers of observations, rather than the large number necessary to sample a complex environment. We are comforted by a consistent pattern of observations, confident that we can depend on them to continue ad infinitum. 

We are also taught from a young age to average observations without considering the distribution of what we are measuring. We consciously and subconsciously discard outliers as mistakes or incorrect observations and consistently make too few observations to sufficiently model outcomes. We fall prey to what Taleb calls the Ludic Fallacy: that we can use an observation-based model of reality (or "game") to make predictions (and choose actions) in our lives based typically on an expectation of a normal distribution of possible outcomes. 

Our struggle to make sense of the enormous and growing volume of data and information leads to two important adaptations that also keep us from seeing the extremes: confirmation bias and storytelling. 

Confirmation bias is simply the picking and choosing of information that confirms a pre-existing or developing bias. In a sea of information, our minds tend to seek out and emphasize that information which confirms our world views. In addition, our intense desires to understand and explain the world leads us to draw correlations where none may exist. Since positive correlations (for example, in clinical research) are notable, publishable, and fundable—and a lack of correlation is not—we work our way toward a world view that fails to represent its true complexity. 

Another important adaptation is the universal tendency to weave stories that explain current reality as a sum of past events. For example, historians explaining how we created computers or entered World War II weave a story that describes the events and milestones that form a meaningful progression toward these outcomes without including the thousands of false steps and (seemingly) meaningless diversions. These stories typically leave out the wholly unexpected, serendipitous events that were responsible for most of the progress. Outcomes are generally determined by black swans. 

The future will be shaped by black swans, and by their very nature they are unpredictable. Even if predictions may be seemingly correct in the short or medium term, a single black swan can make them worthless, and so they are generally worthless from the start (unless they are correct by shear accident, like a broken clock that tells the correct time twice a day). 

If black swans are impossible to predict, and predictions are generally worthless, how can we plan to maximize our advantage and minimize our downside exposure to these events? First, we need to be willing to say that we simply don't know when we don't—which is most of the time when predicting future events. And beware of those who do make predictions. 

Observe, question, form intuitions, and observe some more. Take actions based on observations, not on theory. In other words, it is ok to assume that the sun will rise tomorrow morning, but don't put all your eggs in the basket of, say, globalization of outsourcing just because somebody smart predicted that it would be "the future." 

Taleb argues that we should choose courses in our careers or lives that expose us to positive black swans and not negative ones. Working on projects and areas that have little upside (he cites catastrophe insurance and homeland security as two examples) exposes you mostly to the downside of black swans. However, investing time, money, and resources in areas where a black swan could bring windfall results is definitely worthwhile. 

For example, spend 85% of your time on projects or investments that are rock solid, stable, and have guaranteed returns, albeit small. Then, take the remaining 15% for highly speculative bets, projects or investments with very large payoffs. This creates a floor to the downside, but exposes you to the potential for the large gains achieved by those rare positive black swans that come from the 15% of speculation. 

Finally, positive black swans don't come along every day. When an opportunity—or something that looks like an opportunity—arises, seize it. We shouldn't wait for these opportunities to drop into our laps either, but we should actively go out and seek them. 

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

Technology Viewpoint

A reminder to observe, question, and observe more, taking action based on observations.

Living at the Extremes in the Information Age

As the Medicare prescription drug benefit heads into its third year, analysts are applauding the program's success in providing pharmaceutical coverage for millions of elderly patients. Surveys show a substantial expansion of benefits, particularly for low-income seniors. Expenditures are less than anticipated even though formularies are broad. Beneficiaries appear generally satisfied with their plans, and the much-feared "donut hole" has not been a major problem.  

The Centers for Medicare and Medicaid Services (CMS) reported earlier this year that almost 40 million Medicare beneficiaries now have prescription drug coverage through a Part D prescription drug plan (PDP) or other program, a substantial increase from 27 million the previous year. 

Similarly, a national survey of 16,000 seniors found that 90% had some kind of prescription drug coverage in 2006, up from less than 50% in 2005. Half are in Part D plans, one-third obtain coverage from employers, and about 10% have benefits from the Veterans Administration or military, according to this analysis by the Kaiser Family Foundation (KFF), the Commonwealth Fund, and Tufts-New England Medical Center [published online by Health Affairs, August 21, 2007, 

]. Part D plans have higher proportions of low-income members that were automatically enrolled by CMS, and seniors with chronic health conditions and high drug use were more likely to obtain coverage than low-drug users. 

Of importance to the pharmaceutical industry, this big jump in benefits is boosting drug utilization for a key patient cohort. The 24 million seniors enrolled in Part D plans filled approximately 486 million prescriptions in 2006—almost 15% of the total retail prescription drug market, according to IMS Health [see 

]. About 37 million prescriptions filled under Part D were written for individuals who would have had to pay for the drug out-of-pocket in 2005, generating significant cost savings for those previously uninsured. 

The Medicare program has boosted utilization of most chronic therapeutic classes, particularly those for asymptomatic conditions such as hypertension and high cholesterol. Hypertension drugs got the biggest chunk of the pie, accounting for 122 million prescriptions, or one-fourth of all the drugs provided under the program. Lipid regulators came in second with 7.4% (36 million scripts), and antidepressants accounted for 25 million prescriptions for a 5.1% share. Other leading therapy classes with more than 20 million prescriptions include treatments for diabetes, pain, and ulcers. Rounding out the top ten were anti-infectives, thyroid hormones, antithrombotics and seizure treatments. 

Providing drug benefits to some 3.4 million seniors who previously lacked coverage also has had a particularly noticeable impact on utilization patterns and compliance. For example, patient use of proton pump inhibitors (PPIs) increased by 2.7% due to new prescriptions, many written for patients with new coverage who switched from over-the-counter drugs to prescription products, IMS notes. Similarly, prescriptions for angiotensin II antagonists increased by 1.5% due to new therapy starts, and by another 2.4% due to improved compliance. CMS also requires formularies to cover "all or substantially all" drugs in six protected categories (antipsychotics, antidepressants, antiretrovirals, immunosuppressants, anticonvulsants, and antineoplastics), which also boosts prescribing for these treatments. 

Increased demand for treatments for chronic diseases is likely to boost R&D in drug categories most important to elderly patients. In light of its expanded involvement in prescription drug reimbursement, CMS also is clarifying its policy for covering the cost of routine patient care for seniors enrolled in clinical trials [see sidebar: Medicare Clarifies Coverage for Trials]. 

Medicare Clarifies Coverage for Trials			

However, pharma companies recognize that as participation in Part D rises, program spending is sure to increase. With that will come more aggressive utilization management by Part D plans and increased demand for cost-effectiveness information from industry. Congress and Medicare analysts support strategies for obtaining data that compares the safety, efficacy, and cost of medical products and procedures [see June 2007's View from Washington], and sponsors acknowledge that studies must produce comparative information to obtain favorable coverage decisions from plans and payers. 

PDPs already are moving to manage formularies more aggressively in order to improve their position at the negotiating table. Three-fourths of Part D plans have formularies with four or more tiers that set higher co-pays and restrictions on use for more costly brand products, including specialty drugs. CMS wants all PDPs to cover the 200 top drugs used by the elderly, but allows plans to utilize a range of formulary tools that can help them obtain favorable discounts. 

A prime strategy for plans is to encourage physicians and patients to use less costly generic drugs. CMS reports that nearly 60% of Part D prescribing is for unbranded generics, slightly higher than for the total retail market. PDPs push generics by eliminating deductibles, reducing co-pays, and requiring pharmacists to notify patients if a low-cost generic is available, according to analysis by Avalere Health. Generic drug use should rise even more as additional popular treatments lose patent protection. The first generic statins appeared in 2006, and more generic versions of major brands are on the horizon. 

If plans can't obtain sufficiently low prices from pharma, some members of Congress want the government to do so. Earlier this year, Congress debated legislation to eliminate the "noninterference" clause in the Medicare program, which prevents the federal government from entering drug price negotiations. The bill failed, largely because the Congressional Budget Office and other analysts predicted that public disclosure of drug prices and rebates would save little money and might even discourage deep discounts from manufacturers. 

Even without legislation, program critics are keeping a close watch on Medicare drug costs, looking for evidence that plans are overpaying for drugs. PDPs, for their part, now have at least one year of drug utilization data on enrollees to provide evidence that they can move market share. Furthermore, continued consolidation among Part D plans is likely to give insurers more clout in demanding lower drug prices. 

All these strategies for managing Part D costs have allowed PDPs to maintain relatively low plan premiums for the 2008 open enrollment period this fall. Even so, a certain number of PDP members incur high out-of-pocket costs compared to other retiree benefits. More than one-fourth of all seniors report spending at least $100 a month on medications, and 8% dole out $300 or more, according to the Kaiser survey. Individuals hit with such costs are more likely to ignore or drop a prescription, especially for chronic conditions with no visible symptoms. 

In coming years, all parties will look back at the first few years of Part D as the "golden years for enrollees and branded pharmaceutical companies alike," predicts IMS. The future promises higher premiums and cost-sharing for beneficiaries; increased scrutiny of plan benefits and costs by Congress; sharper focus on drug prices in shaping formulary listings; and more competition from generics in important categories. Even without federal price controls or a national formulary, Medicare Part D will set the tone for coverage and payment decisions throughout the U.S. market, which will shape pharmaceutical R&D and information strategies. 

View from Washington

Expanded access to drugs for seniors has increased demand, focusing more attention on medical costs.

Medicare Drug Benefit Shapes Pharma R&D

Clinical trials conducted in developing countries are usually not legally bound to adhere to Good Clinical Practice (GCP), and GCP is not mandatory as long as the data are not needed for regulatory purposes by the sponsor. Nevertheless, sponsors usually require that clinical trials are conducted in accordance with the ethical principles and quality standards that underpin GCP. There is some debate about how stringent the implementation of guidelines should be in these circumstances. 

In essence, GCP "is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are accurate and credible."

(PHOTOGRAPHY: COMSTOCK    ILLUSTRATION: PAUL A. BELCI)			

In an attempt to unify the various standards of GCP formulated over the previous 30 years in the European Union, Japan, and the United States, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) provided a new, tripartite GCP guideline.

  The ICH GCP Guideline came into force in 1997 and is probably the most frequently referenced document pertaining to GCP in clinical trials. In the United States, Japan, and Europe, for example, the guideline is already implemented in national legislation. 

The objective of the ICH GCP Guideline was to "facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions," but it was further suggested that the "principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects."

Although GCP is well recognized in the ICH regions, it was questioned whether the ICH GCP Guideline is utilizable outside these countries.

  This article explores these issues in the context of studies carried out in sub-Saharan Africa, in general, and in The Gambia in particular. It addresses ethical issues surrounding informed consent, vulnerability of study participants, and post trial treatment, and also considers data quality issues in trials such as GCP, other needs in sub-Saharan Africa, and routine monitoring.  

It has often been questioned how much and which information might be understood by a potential trial participant who is illiterate. According to an investigation by Krosin et al., in West Africa about 90% of trial participants did not understand withdrawal criteria and the existence of side effects, and nearly 75% did not understand that they were enrolled in a study as opposed to receiving therapy.

These findings are in agreement with results of an interview with 189 parents who were asked to let their children participate in a trial of a Haemophilus influenza vaccine in The Gambia in 1995. Although there was good knowledge of the purpose of the vaccination, only 10% of those who participated in the trial were aware of the placebo control group.

A comprehensive sociological study by the UK's Medical Research Council (MRC) of trial participation in The Gambia was recently published.

  The trial was designed to test the efficacy of a pneumococcal vaccine in preventing childhood pneumonia, and mothers attending infant welfare clinics throughout the eastern half of the country were invited to enroll their children. From 800 mothers whose infants were recruited, 45% of respondents in the sociological study later claimed that they did not know, had not been told or had forgotten the purpose of the study. Only 6% mentioned pneumonia or the phrase "pneumococcal vaccine trial." 

But the understanding of information given to trial participants is not solely a matter of concern in developing countries. Caldwell et al. reported that many parents of children who were asked to participate in a clinical trial in Australia had little knowledge about randomized controlled trials, misunderstanding the concept of randomization and the rationale for placebo use.

A major contributory factor to the poor retention of important information is likely to be the large amount of information presented; it is not uncommon for information sheets to run to 15 pages for industry-sponsored trials—a daunting amount of information for anyone to comprehend.

This situation arises in part from Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) in sponsors' countries insisting on certain information being included, even though the ability of potential participants to understand may be limited, particularly those who are illiterate. 

For example, information about compensation or data protection is unlikely to be understood or remembered by most people in developing countries. Detailed explanations of the possibility that a test product may protect against asymptomatic infection is also unlikely to make sense to someone unfamiliar with the germ-theory of disease. Presenting such information often leaves potential participants overwhelmed. Further high-quality studies comparing the trial consent process in developing and developed countries would be useful. 

If informed consent concepts vary in different societies, then the best methods for obtaining it may also differ, and GCP procedures should be modified accordingly. For example, it is irrational to translate written subject information sheets into local languages for illiterate subjects, when such languages are usually only spoken. Tape recorded translations of the information given to subjects in their local languages and the means to replay them could help to improve the process, keeping in mind that a straight translation might not be understood by the people involved. 

In many developing countries, permission from community leaders, elders or spouses must be sought before individuals can consent to take part in studies.

  Furthermore, patients in many societies in developing countries are not accustomed to questioning doctors, while locally employed fieldworkers may be perceived as being more approachable by the communities in which research is being carried out.

Getting past consent and ethical issues endemic in underserved populations to ensure quality GCP.