During the past 15 years, good clinical practice (GCP) has developed from operational guidelines for industry-sponsored research to national legal and ethical frameworks against which all research involving human subjects is measured and appreciated. During the same period science and industry witnessed a rapid globalization of stakeholders and contributors to pharmaceutical, genetic, and indeed all biomedical research. GCP has become the common denominator for regulating, carrying out, and evaluating research around the world. 

As an evolving standard for science and ethics in the implementation and execution of  research, GCP represents a shared understanding of correct procedures for arriving at sound research conclusions for public health decisions while protecting the dignity and well-being of research participants. It is GCP's ability to marry science and ethics in research that makes it so convincing for society and the organizations and individuals engaged in research. 

The ongoing development and implementation of GCP into all aspects of research involving human participants, in all regions and areas of research, provides the fundamental pillar on which society can build trust in the research process and its results. Trust in research and in researchers has been seriously shaken over the past few years, however legitimately, by a growing list of reports of failures to follow appropriate standards and procedures in clinical trials. Behind each of these failures, whether viewed as an anomaly or as systemic, society senses a fundamental failure in individuals to accept or exercise certain responsibilities. 

Amid all of today's skepticism, controversy, and finger pointing regarding trials, GCP provides the only complete framework for industry, academic, and government accountability. GCP is fundamentally concerned with identifying and assigning responsibilities in clinical trials: the ethics committee's responsibilities, the investigator's responsibilities, the sponsor's responsibilities, and even the regulator's (government's) responsibilities. To paraphrase the FDA, GCP makes all parties in research responsible for science and ethics. 

However, the responsibilities so clearly outlined in GCP mean very little in the abstract. They are most cogent and convincing, but also extremely difficult, in the concrete: "What is my responsibility?" 

As a research director, monitor, or auditor—or as an investigator or GCP inspector—you need to ask yourself: "How do my activities in this specific research project contribute to accurate scientific results while providing the highest concern and protection for participant safety and well-being?" As an educator or member of an ethics committee, DSMB, or an international association dedicated to promoting and developing clinical research, you should ask: "What is my responsibility toward the protection of research participants and the promotion of science in the interest of public health?" and "What is my bottom line?" 

Perhaps the first paragraph of every GCP guideline (law or handbook) should read, paraphrasing Helsinki, "The duty of every person engaged in biomedical research is to promote and safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this duty." 

"My responsibility" is the most challenging and, at times, the most disturbing part of the GCP equation. No amount of oversight or review can substitute in clinical trials for individual commitment to reconciling knowledge and conscience in each step of the research engagement. Good research organizational and systematic structures cannot substitute for personal integrity; rather, these structures need to be built on responsible engagement in ways that promote transparency and accountability. 

And what if this reconciliation eludes us? What if alongside the demand to fulfill this duty, our jobs or our organizations somehow threaten to put our engagements in conflict with good science or good ethics? What then is my responsibility? How should I decide? 

Personal integrity is the finality of GCP. Personal integrity is also an achievement; it cannot be found in a guideline or regulation. Perhaps it is only one achievement among others. From the points of view of science and ethics, however precarious, GCP remains my responsibility.  

, Director General, Good Clinical Practice Alliance-Europe, 

A Closing Thought

Personal integrity is what we need to insist on as the finality of good clinical practice.

GCP's Finality: Personal Integrity

Central and Eastern Europe (CEE), including the European part of Russia, constitutes a significant part of the European continent with its population of approximately 340 million people (see Figure 1). Good clinical practice (GCP)-compliant research that began in this region in the early 1990s reveals good-quality data and predictable patient recruitment.

  The presence of clinical trials in CEE countries has always been highly valued by the medical community and patients due to the range of opportunities they provide, in particular access to innovative therapies for patients and doctors. 

Photography: Comstock, Eyewire    Illustration: Paul A. Belci 			

On 1 May 2004, eight Central and Eastern European countries (the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Slovenia) joined the European Union (EU). Poland, with a population of 38.5 million people, is the biggest country among the new CEE EU Member States (see Figure 1), which together have approximately 74 million inhabitants. There was a huge legislative effort to adopt thousands of regulations pertaining to almost every field, including those directly and indirectly related to clinical research (import of goods, insurance law, taxes, etc.) in all of these countries prior to accession to the EU, which itself coincided with the implementation date of the European Union Clinical Trials Directive 2001/20/EC (EU CTD). 

In this article, the author explores the impact of the EU CTD on clinical research practices in the new CEE EU Member States from the perspective of a regional (CEE) project leader. The author also refers to CEE countries that are not EU Member States, such as Romania, Bulgaria, and Croatia. 

GCP rules were published and followed in most CEE countries in the 1990s, despite not being legally binding. Transposition of the EU CTD into law in the new CEE accession countries commenced in 2002, long before they joined the EU in May 2004 and before the European Commission Guidance Documents were published to give more in-depth clarification to the expectations of the directive. 

Belated publication of the Guidance Documents resulted in the need for regulations to be revised in some countries that had already started legislative transposition (e.g., Hungary, the Czech Republic, and Poland) in time to meet the European Commission deadlines. 

Today, all the new CEE Member States have implemented the key principles of the directive, including those principles related to the protection of minors and incapacitated adults. Nevertheless, from a regional perspective it is clear that this has not yet brought about a "harmonisation of administrative provisions governing clinical trials," as intended by the directive's authors. 

It is worth mentioning that certain CEE non-EU countries such as Romania also have their clinical trial law in line with the EU CTD.

Ethics Committees (ECs). All the new Member States (and Romania, Croatia, and Russia) have the procedures and legal framework for accepting a single EC opinion binding for all sites in a multicenter study (see Figure 2). However, in individual countries (e.g., the Czech Republic), this single opinion was added to the opinions previously required of local ECs. In Hungary, the recent law revision introduced a "true" single EC opinion for both ongoing and new trials; however, local ECs will still be involved in site and investigator assessments. 

Figure 2. CEE EU countries-Ethics Committee Review.			

A parallel review carried out by the Competent Authority (CA) and EC(s), and timelines imposed by law, made the 60-day review timeline realistic in all new CEE Member States. In Hungary, where the CA acts as a go-between for the sponsor and Central EC, the submission is made to the CA only (with the CA decision and review duration depending on the opinion and actual timelines of the Central EC). 

Competent Authority (CA). The regulatory process related to clinical trial authorization has not been truly harmonized despite the EU CTD implementation in CEE. Differences exist not only with respect to the application process (format, language, and submission mode—electronic vs. paper) and the attachments required, but most importantly also with respect to the CA's view of their role, responsibilities, and power. 

Some CAs focus mostly on a scientific review of the study concept, and others center around an investigational medicinal product (IMP) and its dossier (the Hungarian CA requires IMP samples as part of the submission). Nevertheless, the majority of CAs perceive their role as a purely administrative one, which results in either a smooth and predictable CA review process (in most new CEE Member States) or a lengthy and unpredictable one, as a consequence of the most stringent interpretation of formal requirements. 

In Poland, for example, the CA has added a new bureaucratic layer on top of the legal guidelines by requesting originals or notarized copies of documents such as company (sponsor, CRO) registration data or a GMP Compliance Statement. For over a year, the final signed contracts for all participating parties were required as part of a valid submission, which led to extension of the time-to-submission in Poland. The question regarding what the benefits of such an approach might be for subjects and society remains unanswered. 

Apart from varying perceptions of their own roles and review processes at the CA, it is clear that there is no common understanding and approach to EU CTD terms such as substantial amendment, or implicit approval, despite the fact that one of the major EU CTD objectives is harmonization of administrative provisions across the EU. 

In Poland, where implicit CA authorization is a legally binding rule (in line with the EU CTD), the CA considers that even a minor question during the review process (not in itself a reason for refusal according to & 11 of the Preamble to the directive) transforms the clinical trial application into an exceptionally complex case. Such cases require explicit written authorization even if 60 days have passed after valid submission. 

In many CEE countries, implicit approval is not allowed at all. But this is not an issue as long as the 60-day review timeline is respected, which is usually the case. 

The Association for Good Clinical Practice in Poland asked major companies in the region to provide data on EC and CA approval timelines between 1 May 2004 and 1 March 2005 in the new accession countries plus Romania and Bulgaria (in Bulgaria, parallel submission to the local ECs and CA is not allowed). Eleven big sponsors and CROs operating in the region answered the survey, giving an optimistic view of approval timelines in postdirective CEE (see Figure 3). In most countries the ethical review took far less than 60 days, and the CA review took between 30 and 60 days. However, in individual countries such as Poland, CA approval timelines were longer after 1 May 2004, from approximately 40 days pre-directive to approximately 75 days postdirective, with no clear reason and contrary to the new regulations. 

Figure 3. CA and EC approval timelines after May 1, 2004 (survey GCPpl). CA review time was counted from valid submission to written or implicit approval (clock stop periods subtracted).			

In most CEE EU Member States an IMP import permit is issued as part of the CA approval for a specific study. Depending on the country concerned, the procedure for obtaining the import permit and its definition differ, for example: 					

An import permit for IMPs imported from a non-EU country (a third country) is only required in Hungary.

A single, collective import permit for all IMPs imported for a study is required in Poland regardless of whether the IMP is from a third country or EU territory.

Separate import permits for every IMP shipment in a study are required in Estonia and Latvia, regardless of whether the IMP is from a third country or EU territory.

In most cases, the import permit is issued after CA approval is granted, which may potentially prolong the review process. The import permit seems to be an example of old pre-EU and predirective regulation that has survived despite substantial legislative revision. Import permits that condition the supply of IMP from EU territory are in disagreement with the EU CTD. 

The EU Directive regulates who should be in charge of IMPs in a Member State (article 13) and requires that this body (a person or legal entity) be holder of an authorization for IMP manufacture or IMP importation (from outside the EU). Legal frameworks and procedures for obtaining authorization have been implemented in most new CEE Member States, but requirements again differ from country to country. 

Labeling requirements are, with minor exceptions, very similar in EU CEE countries and in line with the European Annex XIII, dated July 2003. 

Clinical trial insurance is mandatory in all CEE countries. There is a variety of different, country-specific requirements, such as who is in fact insured (sponsor, investigator, patient), the type of insurance policy, policy terms, and the place of issue—for example, a local clinical trial insurance policy is required in the Czech Republic, Lithuania, and the non-EU countries Bulgaria, Croatia, and Russia. 

In most new CEE EU Member States (and also in Romania, Bulgaria, and Croatia) there is a legal obligation to report Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) in an expedited manner. However, this is the only uniform safety reporting rule across the region. Regulations pertaining to expedited safety reporting differ with respect to: 					

Scope of reporting—what should be reported (all SUSARs for IMPs, all SUSARs that occur in the study in question, all SUSARs that occur in a Member State concerned)?

Time of reporting—notification of death and life-threatening SUSARs within seven days, all SUSARs within 15 days?

Recipients—CA, Central EC, Local EC, investigators?

In some CEE countries (e.g., Slovenia) the law does not specify sponsor or investigator obligations related to adverse events/reactions reporting to the CA/EC. In other countries (e.g., the Czech Republic) regulations are very detailed and describe several reporting scenarios; these scenarios depend on the IMP regulatory status, the origin of the report, the report recipient, etc. Only a few countries managed to adjust their regulations to the European Commission Guidance Document on Adverse Events,

  which was published just one day before the EU CTD came into force. 

The CAs have—or should have—an institutional base for processing safety information derived from clinical trials. At the same time, many Institutional Review Boards (IRBs)/ECs are overwhelmed by the number, volume, and complexity of reports. Some IRBs/ECs seem to have neither the expertise nor the time to review this information. One might have the misleading feeling that the large volume of data coming every day from different sponsors to ECs is analyzed, and thus subjects' safety is better protected. The effort made by sponsors to comply with divergent, and in many cases, stringent reporting requirements seems to add little real value. 

There needs to be a greater search for solutions that support ECs in fulfilling their obligation of continuous monitoring of patient safety (e.g., a safety Web page, periodic listings, etc.). True harmonization of safety reporting rules and ethical review procedures, including safety vigilance, could increase the comparability and quality of EC operations. An Annual Safety Report is required in all new CEE EU Member States. 

In CEE, as in many other EU countries, the situation of academic research worsened after implementation of the EU CTD.

  Inevitably, the number of valued noncommercial clinical trials will continue to fall because of the new and mostly administrative requirements that are difficult to comply with due to organizational reasons and limited funds. 

The EU Directive on Clinical Trials forced the creation of a legal framework for GCP and GMP in all new CEE Member States. It helped systematize national regulations and review systems, leading in most countries to increased predictability of the review process in terms of requirements and timelines. 

Unfortunately, EU Directive implementation resulted in only a limited harmonization of procedures across the region. In practice, to a large extent it has increased the paperwork requirements—an increase that is also due to a more precautionary attitude among some CAs in the postdirective era. 

EU Directive requirements were merged with existing regulations and review systems in CEE, resulting in implementation outcomes that differ between countries. Obviously all the parties involved (the CA, EC, legislators) and all the countries concerned are still in a learning stage. It is not certain, however, that they will ever meet at the same point. 

The EU Directive's objective to harmonize and simplify the administrative procedures that govern clinical trials could be achieved by implementation of a single CA approval process across the EU. Apart from uniformity of the regulatory view on different aspects of clinical research, this could also result in the elimination of a portion of the repetitive paperwork that tends to obscure the patient in the clinical trial process. 

Another effect of the directive has been a legal instability in new CEE EU Member States, which has increased uncertainty and the need for legal advice. Taking into account the recent issue of updated or new European documents (e.g., the Directive 2005/28/EC), one has to admit that the changing clinical trial environment is not a transitional difficulty but a long-term reality. It is of course more noticeable for those operating on a regional level (e.g., project leaders). 

Feature Article

The impact of the EU Clinical Trials Directive on current clinical research practices

Revisiting the European Union Directive in CEE

Pharmaceutical companies recognize the benefits of carefully managing the quality of data from their drug development and clinical trials. To ensure clinical data accuracy and integrity, it is necessary to thoroughly review these data, to assess the validity of outlying data points, and to carefully document query identification and resolution throughout a study's duration. 

 Photography: PhotoDisc  Art Direction: Paul A. Belci			

Maintaining accuracy and quality throughout a clinical study is a continual, dynamic process.  Although study requirements are carefully set forth initially in detailed documents such as an approved clinical protocol, a data management plan, and an accompanying project plan, expectations and requirements can change during a study. This ongoing process requires revising mechanisms and communicating these revisions clearly to all investigators and support staff. 

Quality: the total set of characteristics of a product or service that affect its ability to satisfy a customer's stated or implied needs. 

Quality system: the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management. 

Quality assurance (QA): the systematic and independent examination of all trial-related activities and documents. These audits determine whether the evaluated activities were appropriately conducted and that the data were generated, recorded, analyzed, and accurately reported according to protocol, standard operating procedures (SOPs), and good clinical practices (GCPs).

Quality control (QC): periodic operational checks within each functional department to verify that clinical data are generated, collected, handled, analyzed, and reported according to protocol, SOPs, and GCPs.

The ongoing challenge in managing the quality of clinical data is to continually monitor data collection procedures and data management practices at every level of the study. This includes: 					

ensuring that data generated during the study reflect what is specified in the protocol (case report form [CRF] vs. protocol)

comparing data in the CRF and data collected in source documents for accuracy (CRF vs. source documents)

ensuring that the data analyzed are the data recorded in the CRF (database vs. CRF).

Quality surveillance continues after the trial has ended and plays an important role in ensuring that: 					

data presented in tables, listings, and graphs (TLGs) correctly match data in the database (TLGs vs. database)

data reported in the clinical study report (CSR) are the data analyzed (CSR vs. TLGs)

all aspects of the data management processes are compliant with SOPs and GCPs.

The quality plan describes how the quality control and quality assurance processes will be applied throughout the clinical trial. It definitively defines the various quality-related tasks in the study. A quality plan documents specific quality practices, resources, and activities relevant to a specific project. This includes both operational QC and QA activities. 

It is critical that trial managers develop a QC plan for each key operational stage of the study that defines standards against which QC will be conducted, including: 					

data source to be used for QC at each operational stage

appropriate methods to report and distribute results.

During the study design phase, QC personnel provide an independent review of the approved proposed protocol. The QC plan includes comparison of the study's CRF to the objectives set forth in the protocol to ensure that it is designed to collect all necessary data. A requirement to review CRF completion guidelines is also an element of the QC plan. 

For overall site management, a complete QC plan addresses the following: 					

investigator selection and qualifications

– experience in conducting clinical trials

– experience with the specific indication

– not on the FDA's restricted or debarred lists

– subject informed (signed informed consent form)

– subject's eligibility (inclusion/exclusion)

– adverse events (AEs) and concomitant medication

– completed data clarification forms				

ACT 101

A system of checks and examinations that helps ensure the quality of clinical trials.

Quality Control and Assurance in Clinical Research

So you've decided you need a clinical trial management system (CTMS). You're in the process of sourcing bids from companies that profess to offer such things. You may well have started your search by asking peers and colleagues "Who do you know that makes a good CTMS?" or searched online for CTMS and came up with a list of names. You're not alone. A recent survey of 839 key pharma decision makers indicated that 57% of those surveyed who are involved in clinical trials saw CTMS as the most important technology initiative in their area.

  But before you bask in the warm fuzzy glow of affirmation, STOP. Begin with the end in mind. You don't necessarily need a CTMS. In fact, you may actually want a 1/2-inch hole. 

How are a CTMS and a 1/2-inch hole the same? They both relate to what you actually need, rather than what you use to achieve it. It's an old marketing adage that "Customers don't buy 1/2-inch drill bits, they buy 1/2-inch holes." This sage wisdom is used to remind marketers (and by them to remind companies) that the focus should be on what customers actually need—in this example, a hole—rather than the product itself, which merely helps them achieve that end. Focusing on the product runs the risk of ignoring a needs-satisfying solution that may be cheaper/faster/more convenient because a product focus is inherently narrowed in on that thing to the exclusion of all else. It's an easy trap to fall into, presupposing the answer to a need is to be found in a known product. 

Try going into a store and asking for sunscreen. You'll probably get exactly what you asked for. Now, go to the same store and talk about your need: facial freckle avoidance. You may well walk out with a broad-brimmed hat that will do a better job of meeting your need. 

So, why don't more people take the time to talk about their need rather than a product that they think will meet their need? Two primary reasons: 					

They want to appear to be informed consumers (so they don't get taken for a ride, are respected by their peers as knowledgeable, and can succinctly explain to their manager why they need an increased budget).

They don't know what they don't know, but they do know (or presume to know) item X will probably work.

How does this relate to a CTMS? Let's start with what is actually needed from a CTMS. Basically, visibility into operational metrics and strategic management of clinical trials, with the goal of getting studies up and running quickly and smoothly and increasing the likelihood of success. The components that make up those broad topics of metrics and management include: site documentation, recruitment rates, overall data quality, IRB status and renewal, clinical product distribution and tracking, resource allocation and utilization, budgets and payments, visit and outcomes monitoring, and more. 

These are laudable goals. But standalone CTMS products suffer greatly for the fact that they are inherently overlays onto a variety of disparate systems. That means that someone from your clinical staff has to take time to enter summary information into the CTMS, which necessarily takes time away from their core function of running the study.

  Some systems can draw data from the underlying programs, but as one large pharma company discovered, making that work effectively is a lengthy, time-consuming, and at best ROI-neutral process.

It has historically been problematic to get software to "talk" to other software. And the simple act of changing the version of one of the underlying software elements in a CTMS may throw everything into chaos when it no longer communicates. The solution to that problem is to stick with the original version of the underlying element, which may condemn large segments of the organization to use obsolescent, bug-ridden early versions for which support may no longer be available. Technology integration or lack thereof is thus a major problem. 

Some industry analysts predict that an inability to exchange data with underlying applications will actually cause some established CTMS market players to fail in the relatively near-term.

  So, if we concede that standalone CTMS products are not without their problems, what to do? The future, available now from a few leading companies, is actually very bright indeed if we focus on the 1/2-inch hole (AKA the need). And it comes in the form of liquid soap. 

SOAP is an old sales acronym for "Sell Only Available Product" used to focus salespeople on what the company has to offer rather than what they don't have, or may possibly get in the future. The trouble with soap, especially as regards a CTMS, is that you could end up with a product that doesn't fit anyone's needs particularly well, except the salesperson's need to bring home the bacon that month. 

What is needed is liquid soap that penetrates into all the nooks and crevices to do its job, rather than a hard scratchy bar that rubs the hands raw trying to achieve the same end. All of that is an obtuse way of saying the product you select to meet your need should be flexible enough to adapt to your specific circumstances, rather than be an "out-of-the-box" standard offering that necessarily descends to the lowest common denominator. And that product may not bear the label "CTMS." 

Does such a product exist with respect to meeting the need for a CTMS? Yes, it's called EDC. Not your common or garden variety EDC mind you, but highly advanced state-of-the-art EDC that in fact forms a functional CTMS by its very nature—in short, EDC systems that produce operational metrics as a by-product of their operation

  and either integrate other systems into their overarching schema or replace those systems entirely. The most advanced EDC systems perform like liquid soap, gently adapting to your specific needs and processes, and they do a far better job of achieving your goals than older, inflexible EDC systems that force sponsors to adapt to them—that's the hard, scratchy, and somewhat painful experience most people would rather avoid.  

				"These systems leverage EDC within the setting of an automated, integrated, clinical trial workflow...[such] Clinical trial management systems provide more efficient and cost-effective functionality than their component technologies, increasingly driving pharmaceutical and biotech companies toward adoption."			

A state-of-the-art advanced EDC will obviate the need for staff to enter summary data. The real-time availability of data in a Web-based system can roll up the information, across multiple initiatives, without the need for human intervention. Instances have occurred where development of specific modules within the EDC offering actually obsoleted the sponsor's existing system, such as control of clinical product inventory and distribution. The EDC CDMS/CTMS controls shipments, receipts, returns, and which patients get allocated what product, and it articulates seamlessly with the distribution company.

  Of course, the sponsor can view where any product is at any given point in time through a by-product drug/device accountability log. 

But even advanced EDC must be able to integrate with, or at least talk seamlessly to, other systems within the sponsor corporation. Simply obsoleting other systems won't work in some instances. Such an instance might be the generation of investigator payments via the corporate accounting system—it's highly unlikely a corporation will use the advanced EDC system to pay its bills! A good example is my own experience at Guidant Corporation (2003–2004) in clinical applications research studies.  

We used advanced EDC to track investigator honoraria due (which the system could feed into a single report that described which forms were complete, which were unsigned, which required deviations, etc.), which we then had the vendor turn into an electronic file that could feed directly into the corporate SAP financial system. What happened then was many hundreds of checks poured out the other end each quarter, replete with a cover letter letting the physician know what they were getting paid for. The reduction in staff burden amounted to some 3.0 FTE headcount. We had similar experiences with monitoring, contact tracking, data quality, and other key elements. 

Some authors contend that advanced EDC will never replace standalone CTMS products because they can't handle budgeting and contract management or monitor visit scheduling.

  A quick scan of the industry, however, indicates otherwise. Various companies are now offering an advanced EDC CDMS/CTMS that does in fact cover these bases, as my own experience from two years ago bears out—and those companies may not be the ones you're thinking of. As one pundit put it in late 2004, "It's Oracle and Phase Forward's market to lose."

So, in Covey's immortal words, "Begin with the end in mind."

  When you've decided that you need a CTMS, step back and ask yourself the 1/2-inch hole question. Look for a system, regardless of what it's called, that offers you real-time visibility into operational metrics and strategic management capabilities, as well as the flexibility (or liquid nature) to adapt to your specific needs—including the ability to produce such operational efficiencies as obsolescence of existing systems and leverage of broader extant corporate systems. Remember, you don't need a CTMS, you need a 1/2-inch hole.  

PhD, is chief marketing officer & principal scientific advisor with  MedNet Solutions Inc., Carlson Parkway, Suite 605, Minnetonka, MN 55305, (877) 212-8320, 

1. E. Julian, "What Pharma Wants from IT Today," 

2. D. Fishbach, "Does EDC Herald the End of CTMS?" 

3. R. Case, "In Search of the Holy Grail," 

4. J. Hanover and E. Julian, "U.S. Clinical Trial Management System 2004–2008 Forecast and Analysis," 

5. P. Fadden, Director of Project Management & Customer Service, MedNet Solutions, personal communication, August 2005. 

Guest Commentary

A story about 1/2-inch holes and the power of liquid soap

The CTMS Story: Focusing on Need

As part of its campaign to streamline the drug development process, the Food and Drug Administration is encouraging sponsors to conduct simpler, safer, and less costly exploratory clinical trials before launching traditional Phase I studies. Its Exploratory IND (investigational new drug) policy allows researchers to examine whether very low doses of a candidate drug has a pharmacologic effect before investing in the full battery of preclinical in vitro and animal testing required for usual safety studies. By quickly examining a large number of candidate compounds, scientists will be able to cull out those that show promise and merit further testing in more science-based trials. 

FDA also seeks to better inform physicians and patients about the safe and appropriate use of prescription drugs by overhauling the format and content of approved drug labeling to make it more accessible [see sidebar]. The agency published a long-awaited final rule on labeling for drugs and biologics in January that adds a controversial "highlights" section to prominently display the most important prescribing information. All labels now will present clinical trial results and toxicology information, among other additions and revisions. 

By identifying promising drug candidates more quickly and efficiently, FDA's early-into-man initiative aims to speed up pharmaceutical R&D, reduce research costs, and avoid unnecessary and possibly toxic testing in both animals and humans. Nine out of ten compounds fail in human studies, reported FDA Acting Commissioner Andrew von Eschenbach in announcing the new policy in January. FDA aims to reduce this high failure rate as a prominent part of its Critical Path Initiative. 

The Exploratory IND guidance [available at 

] describes the process for conducting early trials: Administer very low doses of a drug to very few individuals (less than 20) for a short period of time (under seven days) in studies intended to have no therapeutic or diagnostic benefits for the participant. Such trials may test very low microdoses (less than 1/100th of the dose calculated to yield a pharmacologic effect) or slightly higher doses that do not produce a pharmacologic or toxic effect in the participant. Single-dose studies may collect pharmacokinetic information or perform imaging studies, while short, multiple-dose trials may test pharmacologic endpoints. 

Even with such low doses, researchers will be able to use modern imaging technology and analytical methods to detect whether a test substance hits a target organ or metabolizes in a certain way. Traditional Phase I studies, explained FDA Deputy Director Janet Woodcock, escalate doses for trial participants until they reach a toxic level, but usually provide information only on what dose patients can tolerate. 

Sponsors of exploratory studies still have to file an IND with FDA, but this may be modified. Early study INDs may briefly describe the research program and anticipated outcomes, including a rationale for selecting the test compound and for adopting a certain study plan. Chemistry, manufacturing, and controls (CMC) information can be presented as a summary report that describes the product's characteristics, source, therapeutic class, dosage form, route of administration, formulation, method of preparation, manufacturer, and composition. A certain amount of analytical testing should demonstrate the identity, structure, purity, and potency of the candidate product. And preclinical animal testing may involve only toxicology studies in one species. FDA always will require some animal study data, Woodcock noted, but this policy creates opportunities to spare animals from testing. 

To make early trials even easier, FDA also issued a new rule that permits sponsors to produce Phase I clinical supplies without complying with good manufacturing practice (GMP) requirements. The GMP exemption applies to all Phase I studies, except those that involve an already approved product, and it does not apply to drug production for Phase II or III trials. This modification of GMP requirements is "incredibly important," says Woodcock, because it will allow researchers in labs to produce small quantities of a test product without adopting policies for large-scale commercial manufacturing. Industry sponsors may continue to produce clinical supplies in GMP-compliant facilities, but this modification may help move products from the lab to the clinic, which would overcome a major bottleneck in drug development. 

Cancer researchers are particularly enthusiastic about FDA's modification of GMP requirements and the exploratory study option, which National Cancer Institute (NCI) officials helped develop. Up until now, pointed out NCI Chief of Surgery Steven Rosenberg, NCI scientists who wanted to test a promising compound in human trials had to find a company with GMP-compliant facilities to produce it. 

The GMP exemption goes into effect this spring if no one objects to it. If, however, a third party files "significant adverse comments," FDA will have to launch a notice-and-comment process to make this change, which could take months, if not years. 

Even with the GMP exemption, researchers still must establish systems and maintain records to ensure the quality and safety of test products. A companion draft guidance to the GMP rule [

] advises sponsors to keep complete records of production processes, including equipment maintenance, analytical tests, distribution, reagents, and components. It also offers recommendations for preventing the contamination of investigational biologics and sterile products. 

If an exploratory low-dose study shows promising results, sponsors have to start all over. Before launching conventional Phase I studies, researchers will have to conduct additional animal and in vitro testing and file a new IND. At this point, though, scientists should be moving forward only with those products that appear most likely to have a positive effect on human health. 

Although some skeptics regard the new policy as merely a way for drug companies to cut costs while creating additional risks for patients, Woodcock maintains that this approach will save people from being exposed unnecessarily to higher and more risky doses. Von Eschenbach emphasized that the new policy does not compromise standards for clinical trials or laboratory testing, but offers a way to use modern diagnostic tools to gain more insight. Instead of changing FDA's rules, Woodcock noted that the new policy advises researchers on "how they can take advantage of the inherent flexibility in the current regulation." 

 is the Washington editor of Applied Clinical Trials, (301) 656-4634 

View from Washington

FDA seeks to reduce clinical research failures and make drug labeling more useful.

Early Studies Aim to Spur Development

Conduct in clinical trials involving human subjects is regulated by international, regional, and national guidance, legislation, and frameworks, which pharmaceutical companies then translate into detailed internal standard operating procedures (SOPs). Recruitment of subjects to take part in clinical research trials, at the core of which lies the informed consent process, is therefore subject to the most stringent guidelines. From the point of view of someone taking part in clinical research, however, even a fully regulator compliant set of processes and documentation is often not the most subject-friendly. In addition, high-profile media attention and negative publicity have impacted pharmaceutical companies conducting clinical trials in developing countries such as Nigeria.

 Photography: PhotoDisc Illustration: Paul A. Belci			

But it's not just trials in developing countries. Although Swedish participants had been "aware that they were taking part in a clinical trial, the quality of information understood and recalled by the participants varied, and in many cases did not meet the guidelines of the Declaration of Helsinki."

  And a recent survey of 1900 subjects at 16 U.S. research institutions revealed that 53% were not even aware that they were part of a study.

The Department of Health in the United Kingdom has initiated its own review in this area and disseminated the findings through the National Health Service.

  New regulations in the United States such as the HIPAA privacy regulation

 have impacted upon subject information in U.S. trials. 

In 2002, Roche's Clinical Pharmacology Department conducted an audit of its own clinical trials' "supply chain," mapping out the processes and stakeholders involved from conception to completion of a trial. A potential risk was identified around the informed consent process. The sponsor of clinical trials is removed from this process. However, if issues were ever raised about the way informed consent had been carried out in one of its trials, as the most well-known organization in the supply chain, the damage to reputation would focus on the sponsor—although not directly responsible. 

Feedback from regular investigator satisfaction surveys carried out by Roche also demonstrated the need for change. It stressed the need for more educational materials to aid subject understanding, improved paperwork, and better support for investigators and subjects.

  Roche began an initiative in September 2002 to explore the issues surrounding the informed consent procedure and subject information. The company commissioned an independent research organization, Article 13, to carry out a research program, initially with a UK focus. 

Given the focus of the inquiry and the ultimate objectives, the research clearly fell within the realm of social research, so it was designed to be as participative as possible. Sampling involved a range of relevant stakeholders using purposive sampling where appropriate (sponsor's employees, investigators, trial subjects, and regulatory and patient advocate organizations). 

The initial aim of the research was to define clearly the key issues around informed consent. Was a concern emerging around how informed consent was carried out and the role of the subject within the process? And were these issues relevant to the sponsor? The research started with a review of key literature

 (current national, regional, and international guidance documents

 ) and semistructured interviews by telephone with carefully selected key informants that included senior individuals in regulatory, government, and advocacy organizations. 

This first phase, the problem definition phase, produced the following findings: 					

definitions of informed consent concentrate on the giving of information by the researcher rather than on the understanding by the subject

the whole process needs to address the subject's understanding of the information

surveys conducted among doctors showed that many thought their patients rarely understood all of the information given to them

the commonest cause of ethics committee deferral was the informed consent form (ICF)

information is often too technical or pitched at a reading level too advanced for many subjects

the understanding of subjects is not always tested

the process does not engage subjects with what they want to know or what they think they need to know

there is variation in how quickly or easily different subjects absorb the information given to them (e.g., some subjects need more "explaining" time)

subject understanding (or lack of) can have an impact on the effectiveness of the trial.

The findings clearly showed that the informed consent process was too focused on a one-way flow of information and that the information was not suited to the audience. 

The findings were taken forward to a second phase, which used an approach called Participatory Action Research.

  The following questions were addressed: 					

If there were concerns in the health sector around the informed consent process, how did the industry currently perform?

Did the company need to change its processes?

Could action be taken at an individual company level, or did it need an industry-wide approach?

A series of separate workshops was conducted with key stakeholder groups. The aim was to find out what currently happened at the various stages in the informed consent process, starting from when sites were briefed through the preparation of the written material and informed consent form, to when informed consent was actually carried out with subjects. Workshops were held with the following groups: 					

multifunctional staff at Roche who were involved in writing ICF and subject information, liaising with investigator sites, and overseeing quality and compliance with international guidance

investigators who were either working or had worked with the sponsor and were directly responsible for taking consent from subjects or overseeing the process

clinical trial subjects—separate workshops were carried out with healthy volunteers and with patients, each with a mix in terms of gender, age, and clinical trial experience.

The findings demonstrated several key disconnects in the following areas: 					

in timing—when the subjects wanted information and answers to their questions and when the informed consent procedure required information to be provided

in what information was provided for—and used for— between what the investigators and sponsor wanted and what the subjects wanted

between new subjects and experienced subjects and what information they required.

The particular issues that surfaced for the sponsor during this second phase were: 					

there is an assumption that the informed consent process is carried out consistently and transparently by all parties; however, this was not supported by evidence or an audit trail, representing a potential risk to the sponsor

an emerging risk lies within the theme of subject understanding and the additional information subjects' desire during the trial.

The findings from the Participatory Action Research phase were reviewed by a working group of Roche staff to assess the implications for the sponsor and recommend actions to address them. The Roche working group produced a set of guidelines (i.e., an action plan), which included: 					

process recommendations setting minimum standards for what the sponsor should expect of investigator sites and ensuring increased transparency in the informed consent process

best practice recommendations for writing user-friendly subject information

The ICF was accredited with a Crystal Mark by the Plain English Campaign, an independent UK organization

 promoting the use of clear and easy-to-read language in documents for the public. 

The new processes, guidelines, and associated training with sponsor staff were assessed to establish whether they had made a genuine difference. This evaluation consisted of questionnaires and in-depth interviews with: 									

sponsor staff (email questionnaires and semistructured telephone interviews)

investigators (email questionnaires and semistructured telephone interviews)

subjects (freepost and questionnaire cards).

The key issues uncovered by this stage of the research evaluation centered around the subject. The responses concurred with the need for the informed consent process to focus on the subject and their requirements. The in-depth interviews also confirmed the need for the process to ensure the understanding of the information received by allowing time for volunteers to take in the information, as well as the need for methods such as active questioning of the subject. 

A common set of rules for ensuring a two-way flow of information and addressing subjects' needs.

The Importance of the Subject in Informed Consent

When the European Forum for Good Clinical Practice  (EFGCP) starts to express concerns over the prospects for the pharmaceutical industry in Europe, it is time for everyone to start worrying. 

Alarming statements from associations representing the European pharmaceutical industry are a matter of course—it is almost their job to spread warnings. EFGCP, that much more thoughtful platform on science and ethics, has until now tended to stay close to its clinical practice roots, from which it sprang over a decade ago. But its 2006 Annual Conference in late January focused on the broader question of the chances of seeing Europe regain its former prowess in medicines research and development. 

"Since the end of the last century Europe has clearly lost its leading role in research and development of medicines to the United States," says EFGCP in flagging up its anxieties. And under the title "Retooling European Medicines Development for Leadership," it debated the effectiveness of the many national and pan-European initiatives undertaken over the last five years to stop or reverse this trend. 

The European pharma industry struggles to regain its former prowess in R&D.

Applied Clinical Trials-03-01-2006