In 2006, four out of ten (41%) active FDA regulated principal investigators were based outside the United States, according to an analysis conducted by the Tufts Center for the Study of Drug Development. Since 2002, the number of U.S.-based clinical investigators filing new Forms FDA 1572 has declined by 5.5% annually. During the same period, the number of active FDA regulated investigators based outside the United States has grown by 15% annually. 

But recent talk about the rapid growth of clinical trial activity overseas belies the realities of conducting studies there. It is hard to ignore Asia's 29% annual growth since 2001 in FDA regulated investigators, Latin America's 13% annual growth or Central and Eastern Europe's 16% annual growth when the number of U.S.-based FDA regulated investigators has declined during that same period. High overall regional growth fails to capture the subtleties and dynamics of individual countries within each region. Sponsors and CROs need to constantly monitor these details in order to anticipate and manage more effectively their increasingly global clinical trial activities. 

Take Central and Eastern Europe (CEE), for example. During the past decade, this has been the fastest growing region worldwide for FDA regulated principal investigators. CEE investigators last year accounted for 1793, or nearly 8%, of total active FDA regulated investigators. The region has experienced 41% annualized growth since 1996, when it was home to a mere 56 investigators. 

CEE offers a high volume of patients and well-trained clinical research professionals as well as cost advantages. A closer look at sponsor experiences in the region, however, reveals a number of unique conditions and challenges that must be managed. 

"CEE countries have made enormous progress," said Andras Madai, MD, Merck's regional medical director for CEE. "Many institutions in the region are absolutely comparable to Western institutions when it comes to infrastructure for clinical research." 

"The region is home to millions of patients, many of them receiving less than optimal health care services and drug therapies," said Madai, who was raised in Hungary. "Sponsors can find the patients they need by going to fewer institutions than in the West. Grant sizes are also smaller as a consequence of the overall cost structure in CEE countries. That adds up to an important difference in cost," said Madai. 

In CEE, Merck operates primarily in Hungary, the Czech Republic, Poland, the Baltic region, and Russia. The company is seeing a growing proportion of its total study volunteers coming from CEE. 

"A significant downside of doing clinical studies in the region used to be the lengthy wait for approvals by local regulatory and import agencies, hospitals, and ethics boards. Those time frames have grown substantially shorter over the past several years and are now close to the EU average. Most CEE countries complete approvals within 60 to 70 days. The speed of patient recruitment into studies more than compensates for any disadvantage in terms of regulatory approval time," explained Madai. 

"But the CEE is definitely not a single, homogenous region," cautioned Madai. "Individual countries have separate heritages, levels of development, and vocational backgrounds." As a result, growth in trial activity has been highly variable in the region. Since 2003, for example, Poland has experienced flat growth in the number of FDA regulated principal investigators. The number of them in Russia, on the other hand, has grown more than 25% during that same period. 

"Personnel at smaller country hospitals throughout the region also may have limited knowledge of GCPs," said Madai. Sponsor companies, including Merck, have yet to attempt much training on GCP in the Balkan countries. 

"As of March, regulatory authorities in Lithuania have mandated that all principal investigators take and pass a GCP course prior to conducting a clinical trial with any pharmaceutical company," says Michelle Metry, head of Merck's global training group. "It is one of the first countries in the region to identify a training need, and the requirements are quite specific. The local regulatory agency expects investigators to obtain a GCP certificate that includes names, place, and date of training, and signature of the sponsor or legal representative," added Metry. "A minimum of eight hours of basic training (four hours for refresher) is required, and the training organization must archive training materials for five years. But the regulation doesn't specifically say that the training needs to be provided by a pharmaceutical company." 

Metry explained that Merck has recently put together a global training organization that will, among other things, begin proactively offering nonprotocol-specific functional training to investigative site personnel. "The same curriculum will be offered in the CEE and Asia Pacific regions. Training topics will be determined by feedback from staff based in countries within these regions," she said. 

"In Europe, Wyeth's patient enrollment has been steadily shifting eastward," said Mark Ridge, the company's director of global enrollment planning and performance. "A few years back, CEE accounted for a mere 15% to 20% of European enrollment. But this past year, CEE has accounted for 50% of the Phase II and III patients from Europe." 

"Wyeth has a mature clinical research and development organization, particularly in Hungary," said Sheila Ronkin, MD, assistant vice president of clinical development. "Wyeth has created a global network of 15 sites (as of July '07), including two institutions in Hungary, which have agreed to accept a portfolio of Wyeth studies—global Phase II as well as Phase III, IV, and regional trials—under one master contract," she said. "Each of these clinical partners is capable of producing 300 to 500 patients per year, sufficient volume to justify having continuous on-site monitoring. Clinical trial approval times in Hungary are also favorable, allowing trials to start within three to four months." 

"At this time Wyeth primarily places studies in Hungary, as well as Poland and the Czech Republic," said Robert Maguire, MD, vice president of clinical development. "Wyeth is also doing more in the Ukraine, Bulgaria, and Russia." 

"GCP compliance in the CEE was problematic before 2004. We've seen considerable improvement since then, when the European Trial Directive was published and Wyeth implemented rigorous investigative site assessments and postinitiation compliance visits," said Maguire. 

"I think there's a lot of untapped potential, particularly in Russia at this time," added Maguire. "But the country presents several major challenges, including a sluggish regulatory approval process and potential GCP compliance issues. Hospitals also tend to be indication-specific, making them tough to build into a new global network. But I'm optimistic that Russia will end up being a nice place to do clinical trials. Wyeth just established a commercial office in Moscow and has plans to add R&D personnel in the region." 

For the past five years, Olympia, WA-based Western Institutional Review Board (WIRB) has been partnering with the World Health Organization to build the infrastructure for ethical review in developing countries. WIRB has been providing a six-month fellowship program for mid-career physicians. Two of the 50 fellows to date have been from Eastern Europe, "but we don't do anything on the ground with them," says WIRB President Angela Bowen, MD, citing concerns about political instability and a general lack of authoritative regulatory oversight. 

"Without enforcement, it's been hard to persuade investigators to do what they need to do," explained Bowen. "I have seen companies venture into places like these and, almost invariably, the quality of the data is not what they hoped to see. But recruitment is good, and that's what seduces them. It seems to our board that the recruiting in Eastern Europe is rather aggressive. The FDA simply does not have the resources to monitor and audit all these sites," she said. "Neither," she adds, "does the Office for Human Research Protection." 

An analysis of FDA investigative site inspection results supports WIRB's experience. Historically, the incidence of noncompliance and fraud is higher among principal investigators based outside the United States. 

Informed consent, drug accountability, and adverse event reporting are among the areas where  noncompliance is substantially higher for principal investigators not based in the United States. In addition, there is high variability in the incidence of investigator noncompliance and fraud between countries within a given ex-U.S. region. 

The Rate of Increase for FDA Regulated Investigators Around the Globe

Globally active sponsors and CROs must understand and be attentive to the details of each country in order to deliver development performance and economic advantages. "Every region has individual countries with unique characteristics," said Merck's Madai. "There are those places where the political situation may endanger clinical research work; the quality of data provided by a country's investigators varies between country; and regulatory and import authorities are not the same in each country."  

MS, MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Articles

Clinical Trial Insights

Individual countries hold the key to finding hot spots in growth regions like Central and Eastern Europe.

Global Clinical Trials Activity in the Details

A data and safety monitoring plan (DSMP) is an essential part of any clinical investigation. As outlined in National Institutes of Health (NIH) guidelines

  and Good Clinical Practice (GCP) Guidelines,

  DSMPs are designed to ensure subject safety and data validity. 

Despite their importance, DSMPs, in our experience, are often less well defined than other components of a research protocol, particularly when they are designed by investigators rather than by industry sponsors. Consequently, data and safety monitoring is frequently neglected during the study's duration. 

To assist investigators in developing and implementing proper DSMPs, the Partners Human Research Quality Improvement Program (QI Program) developed a set of guidelines, including a checklist, to ensure not only that all necessary elements of a DSMP are included in the protocol, but that they are implemented accordingly throughout the duration of the study. 

The purpose of this article is to describe and share these guidelines. They are likely to be relevant to anyone involved in designing, implementing or reviewing clinical research protocols, including investigators, study coordinators, research administrators, and IRB members at academic, medical, and research institutions. 

While there is an abundance of published literature concerning Data and Safety Monitoring Boards, the basic elements of DSMPs have gained considerably less attention. A few papers published to date emphasize the importance of developing DSMPs prior to the initiation of a study.

  The complexity of the plan will vary depending on the degree of risk involved; indeed, risk assessment is the pivotal first step in designing the DSMP.

  Once established, investigators should be prepared to modify monitoring plans based on findings by the Data and Safety Monitoring Boards, safety monitors, and/or the investigator's monitoring of study subjects.

As far back as 1979, NIH issued a policy stating, "every clinical trial should have provision for data and safety monitoring."

  In 1998, NIH published guidelines describing necessary elements for adequate data and safety monitoring for clinical trials.

  This document indicated that depending on the nature, size, and complexity of a study, various types of monitoring could be anticipated to evaluate the data quality and safety of the subjects. 

 Up Close: What a Good Data and Safety Monitoring Plan Looks Like 			

It further recognized that the principal investigator may be responsible for monitoring investigator initiated Phase I studies, while a committee of experts (e.g., a Data Safety Monitoring Board) may be responsible for Phase III studies. In 2000, NIH issued further guidance for Phase I and Phase II studies, including who is responsible for safety monitoring.

  In addition, the guidelines also stated that at a minimum, DSMPs should include a description of how adverse events will be reported to the Institutional Review Board, FDA, and NIH. 

The FDA regulations require that each clinical investigator is responsible for ensuring that a study is conducted according to the signed investigator statement, the investigational plan, and applicable regulations.

  The FDA also recommends that written procedures for monitoring clinical investigations be established to assure the quality of the study and that each member involved in the monitoring process carries out his/her duties.

  Furthermore, it recommends standardized general procedures that are supplemented by more specific monitoring procedures tailored to the individual study.

Despite the requirements outlined in the Code of Federal Regulations, FDA warning letters commonly cite investigators for failing to follow the signed investigator statement and the investigational plan. For example, investigators have been cited for not conducting follow-up safety procedures within specified windows, failing to report adverse events to the appropriate regulating bodies, and enrolling subjects who did not meet inclusion/exclusion criteria.

  These warning letters suggest that while the investigator may not be able to alter the provided industry developed protocol, a less well-defined DSMP does not absolve the investigator from responsibility for ensuring subject safety and data integrity. 

The general responsibilities of sponsors set forth in the federal regulations require proper monitoring of the investigation with assurance that it is conducted in accordance with the investigational plan and protocol.

  Therefore, investigators who hold an Investigational New Drug Application or Investigational Device Exemption and act as sponsors have the additional responsibility to establish monitoring procedures. 

  recognize that the study sponsor is responsible for adequately monitoring trials. Sponsors also should determine the appropriate extent and nature of the monitoring based on factors such as study size, complexity, and design. The protocol should outline plans to evaluate safety by incorporating the following measures into the protocol: safety parameters; methods and timing for assessing, recording, and analyzing safety parameters; procedures for recording and reporting adverse events and intercurrent illness; and the type and duration of the follow-up of subjects after adverse events. GCP guidelines also recommend a section on data handling and record keeping in the protocol, but do not specify what this section should include. 

An adequate DSMP should address four areas: safety monitoring, data monitoring, product accountability, and privacy and confidentiality. Each area includes a related set of elements. Table 1 illustrates these elements with examples. 

. Safety monitoring refers to the vigilant observations required to minimize threats to the safety and welfare of research subjects. A safety monitoring plan will be unique to each study; the monitoring activities are dictated by study-specific risks. In determining the type and frequency of monitoring required, sites should consider factors such as the study's purpose, design, population, procedures (including investigational products), sample size, and trial phase. 

Three essential elements make up a proper safety monitoring plan: important safety information, stopping rules, and  adverse event reporting. Safety monitoring itself should include collecting and subsequent monitoring of specific information/data that would indicate a threat to a subject's health and welfare. Parameters for each safety observation should be clearly specified in measurable terms. The frequency of safety observations should be defined for each variable and should be such that researchers are able to identify clinical or subclinical problems at an early stage. The person(s) responsible for reviewing safety data should be clearly identified. The FDA expects that the monitor "need not be a person qualified to diagnose and treat the disease or other condition for which the test article is under investigation, but somewhere in the direct line of review of the study data there should be a person so qualified."

Stopping rules include conditions under which an individual subject's study participation will be terminated, as well as conditions under which the entire study should be stopped or modified. The principal investigator is typically responsible for decisions of subject termination, whereas a Data Safety Monitoring Board or safety monitor may be responsible for making recommendations to stop and/or modify the study, depending on the phase of the investigation. 

The last essential element of the safety monitoring plan is an adverse event reporting plan. All studies are subject to unique institutional adverse event reporting requirements. At a minimum, the DSMP should indicate who will be responsible for reporting adverse events at the institutional level. In addition, adverse events occurring in clinical trials involving investigational drugs or devices must be reported to the FDA by the sponsor in accordance with relevant federal regulations. In the case of multisite studies, the coordinating center is responsible for reporting and distributing safety information to participating sites. 

. In contrast to safety monitoring, the purpose of the data monitoring plan is to ensure both adherence to the approved clinical investigative plan and the validity of the data collected. Its specific elements can include review of informed consent documentation, confirmation of subject eligibility, and verification of the accuracy of data transfer from source documents to case report forms. 

Data monitoring should be scheduled at intervals sufficient to keep up with subject enrollment and/or the expected volume of subject information. Unlike the safety monitoring plan, qualified study staff (not necessarily the principal investigator), such as a research nurse or study coordinator, can be assigned responsibility for conducting and/or overseeing data monitoring. In many cases, the person responsible for data review reports on a weekly or monthly basis to a principal investigator. 

The plan should additionally clarify how protocol deviations will be handled, such as filing appropriate reports to the IRB and instituting corrective action to minimize recurrences. It should be emphasized that despite qualified staff assignments to oversee data monitoring, the principal investigator remains ultimately responsible for data quality and integrity. 

 In studies that involve an investigational product, a plan for product accountability should be in place to ensure that all study drugs, biologics or devices are accounted for. This plan should provide for a record of receipt, distribution, and disposal of the product, as well as an overall inventory accounting for all investigational products. 

A person should be assigned responsibility for product accountability. Even if an institution-based research pharmacy assumes responsibility for these functions, the investigators are still ultimately responsible for product accountability and should still maintain records that document subject receipt of specified doses of the investigational product and return of any unused product. Devices can pose a greater challenge to research sites because the clinical research sites are typically required to manage accountability themselves. 

 In addition to plans to protect subject safety and adherence to the protocol, sites should consider plans to protect subject confidentiality. Breaches in confidentiality have the potential to lead to unanticipated problems, ranging from embarrassment to socioeconomic impacts (e.g., loss of insurance or employment). 

The HIPAA Privacy Rule, which took effect in April of 2003, requires that individually identified information (protected health information) created or collected during a study must be coded or de-identified.

  Legal consequences associated with violation of the Rule include civil fines and criminal penalties.

At a minimum, the DSMP should address how data will be protected, including how they are stored (password protected electronic records and/or paper files), who has access to the files, and what steps will be taken to prevent unauthorized access (e.g., contained in a locked office or large multistudy storage room). In addition, the plan may need to consider how investigators will protect subject privacy and confidentiality if the protocol calls for data or tissue samples to be shared with collaborators for the current or future research. 

To ensure compliance with FDA regulations, NIH policies, and GCP guidance, the QI Program developed a checklist that includes essential DSMP elements (Figure 1). Its main advantage for QI purposes lies in helping identify missing or underdeveloped DSMP elements when reviewing study protocols for study site initiated or IRB requested onsite review.

  Deficiencies can be easily detected, resulting in effective recommendations for corrective action. 

The checklist also serves an important educational purpose. Protocols for studies funded by government agencies, private foundations, and intra-institutional sources often lack the detailed DSMP descriptions characteristic of those developed by industry sponsors. To help investigators prepare more comprehensive DSMPs or improve existing plans in ongoing studies, we have conducted educational sessions to introduce the checklist. Investigators can use it as a template, supplemented by additional monitoring procedures specific to their study. Also, IRBs may use the checklist as a basis for evaluating the adequacy of DSMPs in protocols submitted for both initial review and continuing review. To standardize expectations for investigators or improve consistency in protocol reviews, some IRBs may wish to incorporate such a tool into institution-specific guidance documents available to their members as well as to the research communities they serve. 

Despite long-standing policies and available regulatory guidance, evidence found in FDA warning letters and reflected in our own experience indicates a persistent gap between DSMP regulatory expectations and reality. The FDA citations discussed earlier, illustrating that investigators commonly fail to follow the investigative plan, are just one example of this gap. Adequate monitoring would likely have identified lapses in protocol adherence, prompting corrective responses. It may also be necessary and appropriate for sites to exercise additional monitoring beyond that provided and/or required by the industry developed protocol. Investigators should use their judgment to decide if the protocol's DSMP is not as well defined as it should be. 

User-friendly tools are needed to help investigators, sponsors, IRBs, and quality assurance/improvement staff alike to translate regulating requirements into practice. The DSMP checklist presented here offers concrete guidance to help users incorporate all expected elements of data and safety monitoring into research protocols. It further provides a basis for evaluating regulatory compliance and improving study site performance. 

To be effective, DSMPs must be developed and in place prior to the onset of the clinical trial and modified as needed as the study progresses. Given the importance of DSMPs, tools such as the checklist described here can help to ensure regulatory compliance while promoting subject safety and data accuracy/completeness. We believe that this tool responds to a significant need for improved accountability as clinical trials come under closer scrutiny in both public and professional arenas.  

 1. National Institutes of Health, NIH Policy for Data and Safety Monitoring (NIH, Bethesda, MD, 1998). 

Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials

, Title 21, Part 312, Sections 50, 60 (US Government Printing Office, Washington, DC). 

, Title 21, Part 812, Sections 40, 100 (US Government Printing Office, Washington, DC). 

 5. International Conference on Harmonization, "Good Clinical Practice: Consolidated Guidance (ICH-E6)," April 1996. 

 6. N.T. Artinian, E.S. Froelicher, J.S. Vander Wal, "Data and Safety Monitoring During Randomized Controlled Trials of Nursing Interventions," 

 7. L. Slimmer and B. Andersen, "Designing a Data and Safety Monitoring Plan," 

 8. M.L. Terrin, "Evaluating and Implementing Data and Safety Monitoring Plans," 

 9. NIH Guide for Grants and Contracts, Volume 8, No. 8 (1979). 

Guideline for the Monitoring of Clinical Investigations

FDA's Electronic Freedom of Information Reading Room—Warning Letters and Responses

, Title 45 CFR Section 164.514 (U.S. Government Printing Office, Washington, DC). 

Feature Article

Guidelines and a checklist ensure those responsible for subject safety and data validity are doing their jobs.

Monitoring the Monitors

The new European procedure for compassionate use of medicines came into effect during the summer. The European Medicines Agency issued a finalized guideline in July on its role in the procedure, after more than five years of discussion. The move has been welcomed by patient groups and by the pharmaceutical industry—although there is a widespread feeling that the new rules do not go far enough. 

The European Cancer Patient Coalition had complained that European Union delay was hurting patients, with compassionate use "an unacceptable lottery" dependent on the measures taken by individual member states. "Many of our cancer patients' lives will depend on whether they can enroll in a clinical trial or are eligible for a compassionate use program," said the Coalition. It acknowledges the merit of the new procedure, but continues to indicate concern over whether it will have sufficient impact. 

Similarly, the European Federation of Pharmaceutical Industries and Associations compliments the European authorities on their initiative, but observes: "There is also a need in the longer term for greater harmonization of compassionate use approach and process across member states. The current initiative can hopefully be viewed as a first step towards that long-term objective." 

It was the major revision of European pharmaceutical legislation in 2001

  that opened up the possibility of compassionate use, as an exception to the general rule that medicines must be authorized before use or limited to use under an approved clinical trial protocol. A compassionate use program with a new treatment still under development became a formal treatment option for patients in the European Union suffering from a disease for which no satisfactory, authorized alternative therapy exists or who cannot enter a clinical trial. 

The new guidance makes clear that this facility is in no way intended to replace clinical trials. "From a methodological point of view, clinical trials are practically the only means of obtaining reliable and interpretable efficacy and safety data for a medicinal product," says the Agency firmly. Compassionate use programs may give rise to valuable safety data, but they "cannot replace clinical trials for investigational purposes. Compassionate use is not a substitute for properly conducted trials. Compassionate use should therefore not slow down the implementation or continuation of clinical trials intended to provide essential information relative to the benefit/risk balance of a medicinal product." In addition, "patients should always be considered for inclusion in clinical trials before being offered compassionate use programs." 

Although the option is permitted through EU legislation, compassionate use programs are governed by individual member state rules, whether for an individually named patient or for cohorts of patients. The EU role in all of this is to ensure that for medicines covered by the EU's centralized evaluation procedure, a common approach is followed in respect of the criteria and conditions. The European Medicines Agency can issue a non-binding opinion if a member state requests this before making its own decision. 

The rules lay down that the product can be provided only to "patients with a chronically or seriously debilitating disease, or a life threatening disease, and who cannot be treated satisfactorily by an authorized medicinal product" in the European Union. They spell out clearly how these terms should be interpreted. The severity of the disease needs to be justified based on objective and quantifiable medical or epidemiologic data. And while a life-threatening condition "is relatively easily recognizable," defining what conditions are chronic and seriously debilitating must take account of "morbidity that has substantial impact on patients' day-to-day functioning and will progress if left untreated"—such as cancer, HIV/AIDS, neurodegenerative disorders, and auto-immune diseases. "Chronic or serious debilitation or fatal outcome should be a prevalent feature of the target disease," the Agency says. 

Even "patients who cannot be treated satisfactorily" is redefined, to designate "patients left without treatment options or patients whose disease does not respond or relapses to available treatments, or for whom the treatments are contraindicated or inadequate." Whether patients can be treated satisfactorily or not will be assessed by the Agency, based on the review of authorized products and on the arguments as to why these are not considered satisfactory. 

The procedure to be followed is that a member state envisaging making a new medicine available for compassionate use notifies the Agency and indicates if it considers an Agency opinion would be useful. The Agency's Committee for Medicinal Products for Human Use may adopt an opinion that covers the conditions for use, the conditions for distribution, and the patients targeted for compassionate use; and in preparing its opinion, it may request additional data from the company. 

In terms of efficacy, the assumptions for compassionate use can be based on mature randomized Phase III trials (in cases where compassionate use and an application for marketing authorization are being assessed in parallel), but acceptable assumptions may also rely on promising early data observed in exploratory trials (such as uncontrolled Phase II trials). In terms of safety, the Agency recommends that all available data should be submitted if it might contribute to refinement of the conditions for use. 

The same rules on pharmacovigilance will apply in compassionate use as for any centrally authorized medicine, and the Agency is under an obligation to update opinions on compassionate use on a regular basis or when new data—such as on safety—triggers a review. Once a product has been authorized, updates of compassionate use opinions are, of course, no longer required. The Agency will also keep an up-to-date list on its Web site of the opinions adopted, including member states that have notified it; the names, active substances, dosages, forms, and conditions of use and distribution of products; the target population; and the name and contact details of the company. 

Meanwhile, the Agency has finalized a new book of rules for good clinical practice inspections—or rather, for the European inspectors who have to carry them out. The inelegantly termed "mandate, objectives, and rules of procedure for the GCP Inspectors Working Group" (the Agency has never given way to the temptations of snappy titles!) sets out what it should be doing, and how. 

GCP inspectors have been meeting in an ad hoc format at the European level for 10 years now. At the Heads of Medicines Agencies meeting in Lisbon in July 2007, it was decided that this configuration, with its regular quarterly meetings, should henceforward be called the GCP Inspectors Working Group. 

Its key role is developing and implementing procedures and processes that promote EU harmonization and mutual recognition of a high standard of GCP inspection. Since EU clinical trial and marketing authorization legislation covers all interventional clinical trials in humans, including both commercially and non-commercially sponsored trials and regardless of whether the active substance used is chemical, biological or herbal in nature, developments concerning GCP at the EU level affect a wide range of stakeholders. Under EU law, an inspection of GCP compliance carried out by one member state is carried out on behalf of the EU as a whole, and the results are recognized by all the member states. 

The group develops and agrees on GCP-related guidelines and high-level procedures for the conduct of GCP inspections, dealing with the selection of sites for inspection, and the coordination, preparation, conduct, and reporting of inspections, and any follow-up. It discusses practical implementation of GCP guidelines, common interpretation, and harmonization of GCP inspection approaches. It also maintains close links with the Agency's Pharmacovigilance Working Party, holding meetings specifically on pharmacovigilance inspection every six months, and liaises with the Good Manufacturing Practice Inspection Working Group and other Agency committees and working parties. 

Training of inspectors is another of its principal activities, which is seen as crucial to the development of harmonized procedures and practices, along with joint inspections. It shares experience through the review of anonymized inspection reports and findings, and holds discussions on problem issues and case reports. 

Meetings are chaired by a representative of the Agency's inspections sector, and its members are drawn from experts nominated by each of the national authorities. The group's rules stress that members should have "senior responsibility for and broad experience in the area of GCP inspections," and that membership implies "a commitment to participate actively" and to attend meetings regularly. The aim is to achieve consensus on issues discussed, but the chair may decide, in exceptional cases, that a vote is necessary. 

Each member state has one vote, and an absolute majority is required for a decision, with divergent positions being mentioned in the record of the meeting. The members and any experts co-opted may not have any direct interests in the pharmaceutical industry that could affect their impartiality, and all indirect interests must be entered in a register held by the Agency and accessible to the public. 

The group's mandate also allows for it to establish contacts, on an advisory basis, with a wide range of parties concerned with the manufacture and control of medicinal products, and there is explicit provision for the pharmaceutical industry, health care professionals, patients/consumers, and other interested parties to be given the opportunity to comment on regulatory developments. 

This column does not habitually flag upcoming meetings, but an exception is merited on this occasion, on account of the importance of the topic. On October 3, the EU and Agency are organizing a conference on "the operation of the clinical trials directive and perspectives for the future." The declared objective is to provide an overview of the experience to date with the operation of the directive and its implementing texts, to describe its impact and problems encountered, and to offer recommendations for the future. 

This promises to be an exciting event, since there are plenty of strongly held views in the clinical trials community across Europe about the topic. The authorities too have been conscious of the need for some serious rethinking about the way the directive is—or isn't—functioning. 

				So the conference is intended to be a stocktaking among all major stakeholders, and to allow an evaluation of "whether further work on the implementation will provide opportunities to resolve existing problems and whether a revision of the Directive is necessary."			

Don't pack your bags yet. As the program says, "attendance at the meeting will be by invitation only." But watch this space.  

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

1. Directive 2001/83/EC on the Community code relating to medicinal products for human use (November 6, 2001). 

View from Brussels

Industry and patient groups embrace new rules but acknowledge concern over initiative's impact across EU.

Compassionate Use Guideline Finalized

Legislation to reauthorize the Prescription Drug User Fee Act (PDUFA IV) includes a host of provisions designed to enhance FDA policies for ensuring the safe use of medications. These initiatives should provide more timely information on emerging concerns about certain medicines, but also could drive up the cost of new drug development and delay access to new treatments. 

The new measure will implement an FDA–industry user fee agreement issued last January (2007), as well as a similar user fee plan for medical devices. Because these fees have to be renewed by September 30, 2007, the legislation provides a vehicle for Congress also to renew incentives for manufacturers to study pediatric uses of drugs and devices, while further strengthening drug safety policies. The bill gives FDA authority to require postapproval clinical trials and to revise product labels within a set time frame. There is more funding to expand the agency's information systems for tracking adverse events and for detecting emerging safety problems. And manufacturers of more risky medications will have to spell out a range of pharmacovigilance activities to inform patients and prescribers of possible dangers and to ensure appropriate product use. 

In adopting PDUFA IV, Congress will boost the annual fees paid by pharmaceutical and biotech companies to adjust for inflation and the increased cost of overseeing the drug development and review process in an efficient and timely fashion. FDA and industry initially agreed on a new user fee program that would collect nearly $400 million a year in 2008, with steady increases over the program's five-year period. An additional fee program bolsters FDA review of drug TV advertising. 

However, the legislators are boosting drug user fees even more to broaden the range of activities that fall under postmarket safety review. The increased payments will support additional staffers in FDA's Office of Surveillance and Epidemiology (OSE) in the Center for Drug Evaluation and Research (CDER) and enhance the safety office's role in evaluating postapproval risk information and labeling changes. An important change in the PDUFA program, moreover, permits the use of fee revenues to support drug safety oversight and assessment throughout a product's life cycle—and not just during the first two or three years after product approval, as currently allowed. 

Although some parties feel that FDA already is overly dependent on user fees, the agency will need all the added fee revenues the legislators provide because FDA's appropriated funding is barely keeping up with inflation. 

An important drug safety measure in the legislation gives FDA added authority to require a Risk Evaluation and Mitigation Strategy (REMS) from sponsors when such an approach is needed to manage particularly risky products. Initially, the legislators wanted to require a REMS for all new drugs, but agreed with manufacturers that such a broad mandate could waste time and resources if applied equally to well-understood, low-risk products. 

For those drugs that raise increased safety concerns, manufacturers may submit a REMS plan in a new or supplemental application, or FDA may require this process based on new safety signals or information that raises concerns about the safety of a drug already on the market. A REMS would evaluate the need to: 					

conduct additional postapproval studies and clinical trials to assess a specific safety signal.

require labeling changes to disclose new safety concerns.

prepare and distribute a Medication Guide or patient package insert.

develop a communication plan for disseminating additional health care information to health care professionals.

seek FDA prereview of advertising and marketing materials to ensure that ads describe serious risks appropriately and fairly.

limit drug prescribing and distribution. FDA may determine that certain treatments should be prescribed only by health professionals that have special training or expertise and only for certain patients. Distribution similarly may be limited to select wholesalers and pharmacists. Such limited access programs also may require additional laboratory testing, patient monitoring and/or patient enrollment in a registry.

In addition to establishing a REMS for certain products, the legislation will give FDA authority to implement new oversight and disclosure policies for all drugs. A key provision requires sponsors to submit more information about ongoing clinical trials to the 

 Web site and mandates disclosure of the results of these studies, as discussed in 

's View from Washington last month. The bill also seeks to enhance drug safety by requiring: 

. Congress strengthens FDA authority to require manufacturers to make certain labeling changes to reflect new safety information. Under current policy, discussions between sponsors and FDA about the need to revise a product label may take months, or even years. The legislation sets time frames for negotiating such changes, including the need for black box warnings and additional information on contra-indications, precautions or adverse reactions. The label-revision system provides a process for sponsors to challenge a requested labeling change and for resolving such disputes. But if FDA insists on a certain change, it will have more teeth to compel manufacturer compliance. 

Timely completion of postapproval studies

. FDA currently may request additional clinical trials and analysis following approval of a new drug, but the agency lacks authority to levy fines and other penalties on companies that fail to complete these studies as expected. Sponsors claim that many studies that seem reasonable when a new product is approved for market later appear inappropriate, and many projects have trouble enrolling patients in trials after a drug becomes widely available. The new policy calls for discussion of postapproval study options earlier in the approval process to ensure that agreements are realistic and address important issues. FDA also can request more postapproval studies after a drug is on the market. Manufacturers will have to propose a timetable for completing studies, report periodically on their progress, and explain why they cannot meet set goals if problems arise—and should not be subject to hefty fines. 

. The legislation reflects Congressional concerns that too many members of FDA advisory committees have financial links to industry. Although policymakers recognize that these panels can benefit from input from well-known experts despite their conflicts, the bill aims to make advisory committees more objective on safety issues by limiting the number of waivers used to permit such testimony. Congress also wants FDA to more actively solicit scientists and medical experts without financial ties to pharmaceutical companies to improve the advisory process. 

A prime initiative for reducing drug safety problems is to modernize FDA's electronic information system. User fees have supported improvements in the agency's IT infrastructure for new drug review and oversight; now PDUFA IV will provide additional resources to establish an all-electronic regulatory submission and review environment over the next five years. The envisioned system will allow manufacturers to send in applications electronically with automated cross-links to previously submitted data, and FDA reviewers will be able to retrieve all relevant submissions and utilize tools for searching and analyzing data. The goal is a system that can handle two-way transmission of regulatory correspondence and other information. 

A modern IT system also would improve FDA's current adverse event reporting system (AERS) for collecting and analyzing adverse event reports from manufacturers, health professionals, and patients. Congress also supports FDA efforts to build a more robust active surveillance system instead of relying on spontaneous adverse event reports to identify emerging safety problems. 

Additional resources will permit FDA to contract with government health programs and private health plans to access population-based epidemiological data on millions of patients that can better inform postmarketing drug surveillance. Expanded collaboration with government and academic organizations and with the Centers for Education and Research on Therapeutics (CERTS) will enable FDA to learn more about how a drug works in real-world postmarket circumstances, including the extent and outcomes of off-label drug uses. The legislation notes that procedures should be put in place to protect the privacy of any individually identifiable health information in FDA drug use surveillance systems. 

To be able to use these new resources effectively, PDUFA funds also will support an expansion in FDA staff epidemiologists, safety evaluators, and programmers trained to utilize such IT resources. New research in this area should provide a better understanding of the role of epidemiologic analysis and use of databases in evaluating drug safety.  

View from Washington

Additional testing and monitoring requirements promise many changes for pharma R&D.

Legislation Expands FDA Oversight, IT Systems

Adaptive clinical trials, resulting in more rapid approval of safe and effective drugs and biologics, promises to open doors to available scientific advantages. The focus of this type of design is on finding early positive safety and efficacy signals, utilized for implementing "adaptive" changes in trials to shorten the time for new treatments to get to market. 

Is the industry ready to implement adaptive trial design? We are ready to discuss, define, and implement exploratory trials that incorporate adaptive features. In this evolving process, the industry needs to be cognizant of adaptive trial design complexity and careful and conservative in the approach until there is collective knowledge and experience. 

Adaptive clinical trial design will first emerge in early phase studies. Clinical study sponsors, contract service providers, and regulatory authorities will need to learn about implementing this type of trial design in Phase I and Phase II first within the Investigational New Drug (IND), and then, based on the learned experiences, features of adaptive design will be incorporated in the New Drug Application (NDA)/Biological License Application (BLA) Phase III clinical trials. 

Key implementation challenges facing the industry include the following: 

. Good decisions will be based on ensuring that there are the right data available to implement a change in the trial. These decisions will focus on conducting the adapted study with an enriched or sub population going forward in the clinical development process. 

Planning and conducting adaptive clinical trials

. Adaptive clinical trials will be extremely complex studies due to critical, rapid shifts required and the necessity for detection of early safety and efficacy signals. There must be a rapid response process for assessment and agreement among the sponsor, contract service provider, clinical sites, and regulatory authority to enable adaptation of the trial design. 

Ensuring both data integrity and unblinding

. A concern will be overemphasizing early observations with adaptations, which may introduce bias and result in potential data unblinding. To address these issues, the industry may need to introduce an independent Data Monitoring Committee to maintain and protect the integrity of the blind. 

Putting a regulatory structure in place for adaptive trials

. With the potential rapid changes in clinical trials, there may be multiple amendments sent into regulatory authorities. The regulatory structure must be able to receive and respond to amendments and assure that they conform to the prospectively planned protocol design. 

With adaptive trial design being an important part of the FDA Critical Path Initiative, open meetings between the FDA and sponsor groups, which have included developing a set of adaptive design tools for early, exploratory trial design/INDs, have moved the industry closer to implementing adaptive design features. Furthermore, the industry will need to adopt early design tools since the speed of information and detection of signals—enabled by technology, such as imaging results—will be critical to implement adaptive trial design. 

As the industry works together on adaptive design features for early phase trials, the goal is to separate the promising from the not-so-promising drugs/biologics. What we may see first is implementation of a narrower scope approach. If adaptive clinical trials are to be implemented across the full range, we may begin with limited features in what could be called innovative clinical trial design, which requires a new structure, technology solutions, a range of clinical development expertise, and regulatory experience. 

Ultimately, as the industry must enable new scientific advances, it should move forward with an iterative approach to implementing adaptive designs, while gaining the necessary complete safety and efficacy information.  

 is vice president, medical imaging consulting, for Perceptive Informatics, a PAREXEL company. 

Guest Commentary

Until adaptive trials are the norm, industry needs to proceed with care and an iterative approach.

Eyes Wide Open

Safety signal identification is founded on the recognition of a deviation from the expected background pattern of clinical events in a population of patients exposed to a product over time. A lack of understanding of the cumulative population of patients exposed, duration of exposure, and subpopulations of exposure by dose level is probably the largest pervasive deficiency in preregistrational safety event processing and interpretation. 

The population exposed is of equal importance to the presence of the event itself. The purpose of this article is to introduce a concept to aid in the determination of the total number of exposed patients (i.e., a rate denominator) in clinical trials. In this way, we will improve our understanding of adverse events (AEs) and their impact both on immediate patient safety for patients in the trial and, ultimately, potential drug efficacy when launched on the market. 

Current regulations and guidance documents only tangentially address exposure understanding as a dynamic and concurrent part of AE evaluation, especially as a prospective part of event evaluation. Current emphasis is on end-of-study or end-of-program summary. The explanation perhaps has less to do with intellectual resistance than a historical difficulty in pragmatically having exposure information available on a timely basis. 

Implicit in the structure of expectedness is a deviation in the frequency of an event. However, based on our experience, the submission of IND safety alerts, triggered by a change in frequency, rarely occur. During clinical trial drug development phases, patients progress from healthy volunteers, to relative health, to uncomplicated patients, to populations of patients reflective of patients with potentially higher risk. It would seem logical that an increase in the rate of AE occurrence would be observed through the development life cycle. But who knows, since the use of a radical concept called the rate seems to not yet be fully accepted in the pharmaceutical and biotechnology industries. 

The concept of a rate is widely used in a variety of industries to determine the significance of an event's occurrence. The use of rates to better understand and interpret the significance of AE occurrence, however, has been minimal. 

Typically, AE data is not fully studied or its ramifications understood until the end of the trial when all the trial data is available. If AE rates could be more accurately tracked and analyzed as a trial progresses, significant trial decisions could be made earlier. These decisions could improve patient safety and safeguard patient health. It could also be used to provide insight into a drug's performance earlier in the trial process. This insight could lead to critical trial changes, such as modifying the patient population or dose rates, among others. 

Why as an industry are we not embracing the interpretation of AE occurrence earlier in the drug development process? Among the most significant challenges in the interpretation of summary AE data is that both the actual number of AEs that have occurred (numerator) and the population of exposed patients (denominator) is unknown or difficult to gain access to during the course of the trial. Yet the key to unleashing this wealth of information has been in our hands all along. IVR technology already captures the necessary data; the only requisite is to recognize the power of the data that the technology holds. Using this technology, it's likely that the integrated use of exposure information will be established as a cornerstone of modern event processing. 

Identifying the actual number of exposed patients and the total duration of exposure is challenging.

  Some of the problems that have been identified include:

under-reporting of AEs by patients and practitioners

The challenges are especially daunting for spontaneous AE reporting.

  In the spontaneous arena, reporting is voluntary for health care providers and patients. Therefore, there is likely to be gross under-reporting, and in this case, even the numerator is unknown. Likewise, the population of exposed patients is unknown because there is no accurate way to determine how many patients receive prescription medication. There are firms that provide prescription data and sales data, but that data merely provides estimates of exposure and is inherently inaccurate. However, in this industry, accuracy is absolutely vital to patient health and is critical for determining denominator data for AE reporting. 

AE reporting is affected by many things besides the safety profile of a particular product. Some external factors that affect AE reporting include, but are not limited to:

adverse publicity associated with a particular product

litigation associated with similar products on the market.

In other words, reporting rate does not equal incidence. 

Before you can understand how an IVR system can aid in understanding AE profiles, we need to take a look at what an IVR system is and what information it captures. 

IVR systems utilize touch-tone telephony and user-friendly voice prompts to capture critical patient and drug supply management data in a centralized database. IVR systems were first used to optimize clinical trial management for pharmaceutical, biotechnology, and medical device trials in 1989 and is a widely used technology in this industry today. Frequent users of IVR systems include sponsors, investigators, site coordinators, monitors, and distribution centers. 

Sponsors use IVR systems for real-time updates. This real-time information can be used to monitor the performance of clinical sites, patient enrollment, drug supply re-ordering needs, and drug supply expiration. The data that IVR systems collect enable sponsors to manage clinical trial criteria. For example, IVR systems typically record inclusion/exclusion criteria, patient demographic data, randomization schemes, and enrollment levels. Real-time reports available to sponsors allow them to query for: 					

status by protocol, site, country or region

Sponsors are now also using IVR systems to monitor patient compliance to diary reporting and medication regimens. For example, if patients request resupply late, they may receive reminder calls reinforcing the need for maintaining their medication regimen. Sponsors may receive updates on patient compliance trends. Some IVR systems automatically call patients if they do not report diary information in a timely fashion. 

Sites are also actively using IVR systems. Enrollment levels are monitored, clinical trial personnel receive training/communication updates, subjects can be unblinded for emergency reasons, and sites can be updated with reminders. 

Additionally, patients utilize the IVR system to report information that was traditionally captured in paper patient diaries. In this way, patient symptoms (including frequency and severity), quality of life information, and safety/efficacy information is available in real-time, rather than waiting for diary information to be recorded and provided at the next site visit. Another benefit that can be employed when utilizing IVR patient diaries is to force patients to select from a list of possible answers, reducing ambiguity. By forcing patients to select one of several prompted choices, the information provided may be more expeditiously reviewed and analyzed. 

While IVR systems are now routinely used for patient enrollment, randomization, and drug supply, few sponsors have tapped into the breadth of benefits that the captured data can deliver to their clinical trials. One decisive yet untapped benefit is to utilize the captured data to improve the understanding of AE reporting. As detailed earlier, IVR systems are used to track the dispensing of clinical compounds. The system records exactly how often supply requests are received from investigators. Therefore, an accurate calculation of exposure can be determined with a thoughtful analysis of this data, and those AE challenges that were previously discussed can be overcome. 

The first challenge is data accuracy. The total exposure calculation derived from an IVR system is likely to be much more accurate than the data reported directly from those responsible for coding and collecting AE data. This is because IVR systems, when used for drug supply management, must be engaged for redispensing. In this way, a highly accurate record of exposure is achieved. 

The next challenge is gaining the numerator (incident occurrence) and denominator (population exposure) data. IVR systems capture the critical variables that will give you visibility into the characteristics of the patient population and will provide insight into possible unreported AEs. These variables include: 

Numerator data—Incident reporting: Patient discontinuations.

 IVR systems capture patient discontinuation information. A patient dropping out of the clinical trial or discontinuing the medication indicates a possible AE. By utilizing the discontinuation information captured in the IVR system, an AE can be recorded at the time patient withdrawal is known. 

 Because IVR systems capture requests for resupply, they may be used to track discontinuations or changes in dosing patterns. For instance, the absence of a resupply request would obviously suggest an issue, possibly a discontinuation or noncompliance with a medication regimen. Discontinuations during trials are often a predictor of similar trends and AEs for approved drugs. 

Denominator data—Population exposure: Age and gender

. IVR systems are able to provide records of the ages of exposed patients (and ages of those experiencing AEs). In the same manner, IVR systems are able to provide the gender data for both the exposed population in a clinical trial and also the population experiencing AEs. 

. IVR systems are often used for randomization. In other words, randomization schedules can be built into IVR systems so that patients are randomized according to predetermined disease variables. This stratification can then be analyzed for both the exposed population and the population experiencing adverse events. 

. IVR systems can be programmed to capture the geographic distribution of the exposed patient population. This is especially useful in global trials. For example, if clinical trial enrollment lags in one region, one should expect that the frequency of AEs reported in that region would also lag. By comparison, if enrollment is similar in multiple regions, one would expect AE patterns to be similar in those regions. If AE patterns differ (while enrollment remains similar), there are at least two possible causes: 					

There may be some ethnic, racial or other patient difference associated with the AEs being reported.

There may be a pattern of under-reporting or a challenge with monitoring in a region. This provides clinical staff with an opportunity to intervene and improve AE reporting processes.

Thus, IVR systems generate denominator data (or at least denominator approximations). They also enable subset approximations (e.g., age, gender, disease stratification). A researcher who is actively involved in the summation and interpretation of AE data should consider the value that an IVR system offers in providing exposure data, both in patients who experience AEs and in the total patient population. 

IVR systems can capitalize on exposure data and analyze adverse events much earlier.

Press One for Safety

All medicinal products introduced on the market are the result of lengthy and costly R&D conducted by pharmaceutical and biotech companies. 

Compassionate use programs facilitate patient access to promising medicinal products at an early stage in the drug development process, when the information already gathered for the drug benefit/risk profile suggests that patients will not be exposed to safety hazards. 

This article reviews the relevant legislative framework in Canada, the EU, and United States, and  highlights the applicable regulatory agencies' efforts to provide more efficient programs by revising their current regulation on compassionate use. 

What Canada, the EU, and United States are doing to update their compassionate use regulations.