After months of speculation, the White House finally nominated its lead health policy advisor, Mark McClellan, as Food and Drug Administration commissioner. McClellan, a physician and economist, has been a member of the White House Council of Economic Advisors, where he has served as the key Bush administration spokesperson on health issues. As an MD with no direct ties to the pharmaceutical industry, he fits the basic criteria set for confirmation by the Democrat-controlled Senate.

Talk of McClellans appointment to head FDA circulated through Washington for several months, but he was too involved in negotiations over Medicare policy and prescription drug coverage to change hats earlier. The 25 September announcement set the stage for the Senate to approve the nomination quickly enough to allow McClellan to move into the FDA post this year.

The new commissioner differs from his predecessors in that he has little direct experience with FDA regulation and policy, having been more involved with health payment and cost-effectiveness issues. But his credentials for the job are strong, and he benefits from deep ties to Texas politics and the White House. His mother is Texass state comptroller, and his brother, Scott, is the current White House press spokesman. McClellan has an MD from Harvard and a PhD in economics from the Massachusetts Institute of Technology (MIT). He previously held a post in the Clinton administration and is not considered a political ideologue. In fact, he garners praise on all sides for being open-minded and conscientious, traits important for anyone overseeing an agency that regulates a broad range of critical consumer products.


As commissioner, McClellan will have to tackle a number of difficult administrative and policy initiatives while also managing a growing agency. In the absence of a permanent leader, these tasks have been handled by FDA deputy commissioner Lester Crawford, who has demonstrated strong leadership skills and a willingness to address thorny issues. McClellan would do well to encourage Crawford to continue as his right-hand aide, a role that may compensate for the commissioner nominees own lack of administrative experience. 

In August, Crawford launched a major FDA reexamination of good manufacturing practices (GMPs). This move is part of a broader shift to risk-based regulation at the agency, an approach that aims to focus FDAs limited resources more on high-risk products and activities. At the same time, the agency has experienced its biggest growth in the last 30 years, Crawford noted at the PDA/FDA Joint Regulatory Conference in September. FDA has gained 800 employees to support antibioterrorism activities. The agency has also been granted authority to hire another 450 staffers under the Prescription Drug User Fee Act (PDUFA), which Congress reauthorized in June. That measure is expanding FDA surveillance of new drugs during their first years on the market.

Another important initiative is FDAs reexamination of its legal authority to regulate commercial speech related to drugs and other regulated products. The agency is reviewing comments on this topic as part of a broad review of its policies regarding prescription drug advertising, product labeling, drug marketing to physicians, and additional communications issues affecting public health.


Probably the most challenging initiative on FDAs plate is the proposed transfer of oversight for therapeutic biotech drugs from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER), which was announced 6 September. The plan is for CBER to retain authority over vaccines, blood and blood products, and a new office overseeing gene therapies, somatic cell products, tissues, and other cutting-edge technologies. Monoclonal antibodies and proteins are slated to go under CDERs oversight next year, along with the staff, laboratories, and resources to support regulation of these products.

The shift aims to allow CBER to focus its expertise on vaccines and blood products that are critical for our homeland defense, Crawford commented at the PDA conference. In the face of growing criticism of the change, Crawford took pains to highlight CBERs important role in encouraging development of new therapies and vaccines to counter emerging disease and protect public health. Crawford explained that shifting therapeutics to CDER made more sense than completely combining the two centers, and he emphasized the importance of retaining five centers at FDA.

Crawford acknowledges that consolidating the review of drugs and biologics under one roof is a very sensitive undertaking. The first challenge of the high-level transition team headed by FDA senior associate commissioner Murray Lumpkin is to determine which biotech products should shift to CDER. The stated objective of the change is to consolidate FDA review of medical products that are similar in clinical development, clinical data analysis, and use in medical practice. Whether or not therapeutic protein vaccines or recombinant blood products should remain in CBER or move is not clear.

Decisions on which product categories go where will affect the assignment of CBER reviewers among CDER new drug review offices and also determine which CBER compliance and advisory functions shift to CDER, including personnel responsible for providing advice on clinical trial design and for postmarketing surveillance. Crawford emphasizes that no staff reductions will be made due to this consolidation, but considerable uncertainty exists in the agency about how the change will affect CBERs research-review model. Several observers predict a major brain drain from the agency as top scientists leave for academia, research institutes, and industry.

Although manufacturers publicly support the consolidation, some privately acknowledge that they never envisioned such a major organizational change. Their complaints about slower application reviews and problems clarifying drug development requirements in CBER were intended only to improve CBERs management and systems, they say. During PDUFA negotiations earlier this year, industry had argued for policies to improve CBERs record for approving applications in the first review cycle and for reaching agreement with sponsors on product development programs. The issue gained the spotlight during the Congressional investigation into ImClones development of the colorectal cancer therapy Erbitux. At a hearing before the House Energy & Commerce Committee in June, members of Congress criticized CBER officials for permitting the company to file a license application on what appeared to be an inadequate therapy development program. The investigation by the House panel into the resulting insider trading scandal prompted further Congressional inquiries into significant differences between CBER and CDER regulatory practices.

Shifting regulation of biotech therapies to CDER has raised concerns among scientists as well as other observers. At a CBER Symposium held at the National Institutes of Health in September to commemorate 100 years of federal regulation of biological products, gene therapy researcher French Anderson, now director of the Gene Therapy Laboratories at the University of Southern California, termed the breakup of CBER shortsighted and irresponsible. He acknowledged that working with the agency is often difficult, but said that a good many of CBERs demands are important. Jay Siegel, director of CBERs Office of Therapeutics Research and Review (OTRR), maintained that product approval times from his office compare favorably with those for other drugs and that no therapies approved by OTRR have been recalled for safety reasons.

Although it may be logical to merge the medical and clinical review of biotech therapies with oversight of drugs that treat similar conditions, a much trickier task will be to transfer to CDER responsibility for reviewing and evaluating CMC (chemistry, manufacturing, and controls) data on biotech products. Clinical testing of drugs and of biotech therapies have become fairly similar, but production methods for biologics remain very different from those for conventional drugs. 

Probably the biggest fear of biotech companies is that the shift to CDER will open the door to generic biologics. Manufacturers welcomed assurances from Crawford that no changes would be made in statutes governing biologics, which currently set a high barrier to generic versions. However, these products now will be regulated by CDER officials who are very familiar with generic drug policies and have indicated more interest in exploring options for the development of therapeutically equivalent biotech therapies.

FDA officials expect to have a plan for implementing the new regulatory structure for drugs and biologics before the end of the year. Deciding what programs and personnel will go where is not an easy task. Different standards for electronic submissions between CBER and CDER are a problem, as are different field inspection programs. CBER funding will be a critical topic, because that center stands to lose about three-quarters of its user fee revenues. Biotech companies planning to file new license applications in the next few months fear a slowdown in the approval process. The long-term expectation is that a more streamlined regulatory and review process should spur biotech R&D, but change is always disruptive and will present new challenges to regulators and to industry. 


Greg Koski, MD, PhD, is returning to Harvard University after two years as the director of the Office of Human Research Protections, DHHS.

Koski insists the move is not politically motivated. But the research community will be watching to see who the administration chooses as his successor.

The move follows the recent publication of the Institute of Medicine (IOM) report, entitled Responsible Research: A Systems Approach to Protection of Human Research Participants, which confirms and supports OHRPs efforts to broaden federalprotections for human research participants.

Koski said, Serving as the first director of the Office for Human Research Protections has been an extraordinary challenge, privilege, and honor, and wishes to thank his friends and colleagues for their support.

 He is scheduled to leave at the end of November.	
JW

Uncertain time for research ethics oversight


The Bush administration raised eyebrows in the medical research community when it allowed the National Human Research Protections Advisory Committee (NHRPAC) to go out of business. The panel was established formally in June 2000 with a charter that expired in two years, unless renewed. Committee members were told privately by Health and Human Services officials last summer that the panel would continue, perhaps with some changes, and were shocked to learn otherwise with little warning. An HHS spokesperson says that secretary Tommy Thompson is not killing the committee but, in fact, will reconstitute it with a broader mandate and some changes in membership.

However, many concerns have surfaced about how and when a new NHRPAC will emerge. If indications that the new panel may have fewer than its previous 17 members prove correct, then forming committee working groups might become more difficult. Senators Edward Kennedy (Democrat, Massachusetts) and Hillary Rodham Clinton (Democrat, New York) sent a letter to Thompson in September expressing their deep concern about reports of a wholesale replacement of experts on NHRPAC and other HHS scientific advisory committees. The comments also referred to HHS eliminating its Advisory Committee on Genetic Testing and replacing most members of a panel that advises the Centers for Disease Control and Preventions National Center for Environmental Health. These developments bolster critics who believe that the changes at NHRPAC may reflect Bush administration opposition to panel recommendations for added limits on clinical research, for tighter conflict-of-interest rules, and for opposing new policies to protect the unborn.

At its last meeting in July, the old NHRPAC issued final reports regarding research on children and obtaining informed consent from the decisionally impaired. Developing a guide for IRBs to evaluate human genetics research proposals is one of several unfinished projects. Although any administration enjoys the prerogative to select advisory committee members who reflect its interests and inclinations, such advisors should be qualified experts, and panel changes should aim to minimize disruption in ongoing work.
	JW

SIDEBAR: McClellans confirmation held up by unrelated issue 


Although a Senate committee on 9 October unanimously approved Mark McClellans nomination as FDA commissioner, the expected quick confirmation did not materialize. Instead, a group of senators led by Senator Jeff Bingamin (Democrat, New Mexico) is blocking the nomination until Health and Human Services Secretary Tommy Thompson explains why he withdrew backing for a bill that would make pregnant women eligible for the State Childrens Health Insurance Program.

Abortion-rights activists say they see Thompsons withdrawal of support as an effort to undermine reproductive rights for women, according to a report in National Journals Congress Daily. 
ACT staff report            

Articles

View from Washington

The agency is shifting regulation of biotech therapies to its drug center, a streamlining initiative to be implemented by a new FDA commissioner.

FDA Faces New Leadership and Major Changes

Most developing countriesand all Third World activistsconsider last summers World Summit on Sustainable Development in Johannesburg, South Africa, to have gone off with more of a whimper than a bang. As far as health care is concerned, the summit provoked few cheers from the champions of greater access to medicines for poor countries. But in the specific area of clinical trials, the European Union used the Summit as a shop window for a project it has been developing over recent months, and which may yet prove to offer some enduring assistance to the populace of countries still ravaged by disease.

The initiative is called the European and Developing Countries Clinical Trials Partnership (EDCTP), which brings together the 15 EU member states and Norway, the developing countries, and the pharmaceutical industry in a joint effort to combat poverty-linked diseases. Nongovernmental organizations are also to be involved where these are effective ways to engage with communities directly affected by these diseases, the EU said when announcing the plan. The EDCTP could provide support for prioritized clinical trials of new drugs and vaccine candidates against HIV/AIDS, malaria, and tuberculosis (TB), which are urgently awaiting clinical testing.


The concept of a long-term partnership between Europe and developing countries is a new oneand this is also the first time the EU has taken the initiative of bringing together the clinical research activities and programs of several member states in pursuit of a common objective. The problem it aims to address is well known. The vicious circle of disease and poverty causes a fundamental public health and economic crisis in developing countries, particularly in sub-Saharan Africa. HIV/AIDS, malaria, and TB alone account for more than five million deaths every year, 95% of these in the developing world.

For years, critics of the drug industry have highlighted what they claim as consistent failures by profit-oriented companies to devote resources to development of medicines for markets that are likely to offer little commercial return. Leaving aside the complex debates that have raged across international forums in the World Trade Organization or the United Nations Commission for Trade and Development over the respective roles and responsibilities of government and private enterprise in facing these problems, one thing has become crystal cleareven when potentially useful medicines might be made available, serious obstacles make it difficult for clinical trials to validate the medicines efficacy in the conditions that they would have to be used in. And this is where the merit of the new partnership lies.

To increase the chances of success, the initiative is based on sharing problems and potential solutions from the earliest stage. The EDCTP is intended to be a true partnership, in that it will evolve under the guidance of developing countries as the drivers of the real needs. So EDCTP has ensured that African clinicians and health system representatives are to take part from the very early stages, enabling them to assume a leading role in its further development. A committee with five European and five African representatives in consultation with the stakeholders drafted the strategic plan. At the same time, the European pharmaceutical industry is setting up an Industry Forum as the EDCTPs industrial focal point to encompass the essential expertise that only industry can provide in the clinical development of new drugs and vaccines.


The EDCTP is a response for more and better research and development activities to fight three major diseases. The intention is to rapidly launch a first set of urgent measures. In practical terms, the EDCTP program envisages central European and African management facilities, measures to improve networking of European clinical research programs, support for clinical research capacities in developing countries, and a training scheme for local researchers and clinicians that will strengthen the locally available human resources to guarantee the long-term sustainability of the EDCTP program.Networking and pooling of national trials activities in the EU could include the infrastructures needed in the EU to support these trials (notably Phase 1 trials). Supporting trials activities in developing countries would also cover networking, upgrading trials infrastructures, and transferring know-how and technologies in clinical research. To sponsor these clinical trials, officials plan to put together financial packages that attract external sources of co-financing, particularly in partnership with the pharmaceutical industry.

Experts from Europe and also a growing number of African scientists have been working together on the project for the past few months, under the leadership of the Hospital Clinic of Barcelona. EDCTP differs from many other international initiatives in this field because of its long-term relationship with the beneficiary countries, and because of its conception as a NorthSouth partnership. Other poverty-related diseases and other geographic regions may be included later.

Clinical interventions to be tested through the EDCTP could include simplified combinations of therapy using existing drugs, reformulation of existing drugs, and development of new drugs. Development of new drugs and therapeutic strategies against HIV/AIDSrelated opportunistic infections are also envisaged. So too are immune-based interventions against all three diseases, including development of prophylactic or therapeutic vaccines, combinations of vaccines, and combinations of antiretroviral and immunomodulatory-based strategies. Applicants will be able to apply for EDCTP funds for the conduct of Phase 1, 2, 3, and 4 studies.

Networking is important to win agreement from national programs for support of the clinical trials framework, to identify duplications or gaps within national and/or international activities, and to add value to national activities by bringing together complementary activities in EU countries for expedited clinical trials with clear endpoints for selection of superior clinical interventions for further development.

EDCTP clinical trials sites will be defined. They will have to be able to conduct clinical trials in accordance with ICH GCP regulations, at a level where trials will be accepted by the regulatory authorities for registration and licensing. In developed countries, sites will mean a network of clinical and other research structures to cover the skills required for the design, conduct, and analysis of clinical trials related to HIV and/or TB and/or malaria, under GCP and GLP (good laboratory practice) conditions. Staffing would have to cover principal investigators, physicians, nurses, laboratory staff, data managers, and regulatory experts. A site could be located at one single place, but because of the different skills and facilities needed for some clinical trials, a site could also be developed from the networking of complementary structures to allow efficient use of resources.Developed countries will assess the types of clinical interventions that are required, with timelines for their introduction. The countries will set up a framework to identify the development pipeline, the probable numbers per year, the state of development (Phase 14), and the capabilities and capacities of clinical sites that will be required. They also will assess the infrastructure required to conduct GCP clinical trials (hospital wards, field sites, clinical laboratories and equipment, data management and data filing, repositories for storage of material, and IT support).


The European Union is going to put E200 million into the EDCTP this year. The program requires E600 million to workand plans call for an additional E200 million worth of activities, which will come from the participation of national clinical research programs in the involved countries. Other donors and the drug industry are expected to deliver E200 million more.

The EU calculates that its member states and Norway will invest a total of more than e1 billion over 20022007 in biomedical research at the national level to develop new clinical means to cure or prevent HIV/AIDS, malaria, and TB. However, while important new research results are obtained, they are not immediately put to use for the development of new health-improved tools that can be applied in developing countries, the EU said in a statement accompanying the launch of the project. It went on to say,
More concretely, new medicines or vaccines emerging from clinical research may prove highly promising in preliminary small-scale clinical trials but may not be developed further into market products in the absence of sufficient funds and/or facilities for the necessary large-scale trials. Such large-scale trials have to be conducted in the diseases-endemic countries under local clinical and social conditions, in order to obtain relevant results that benefit needy populations.

The underlying organizational idea is that the scale of research needed to develop new interventions may be better addressed at a European level than nationally. The EDCTP would thus add value and coherence to national R&D programs and activities such as clinical trials. And success could attract more resources into developing these interventions, potentially accelerating candidate products through the developmental pipeline, and boosting the capacity and capability in developing countries to test their efficacy.

The first major outputs from the strategic plan will include a definition of diseases and a related geographical focus, a needs assessment by the developing countries, and an understanding of potential partnerships of sponsors, scientists, and clinicians for clinical trials, particularly in sub-Saharan Africa. One of the central tenets for action is that EDCTP should not support development of new interventions without a strategic clinical planwhich should include a clear understanding of the basis for cooperation with existing or future industry objectives, a commitment to advance clinical interventions of benefit to sub-Saharan Africa (but also including trials in other clinically relevant geographical areas if required), and a degree of risk-taking to support new interventions that may not otherwise attract private or public funding.


The EU is playing the project up for all it is worthpartly out of legitimate pride at a humanitarian action, partly because it could serve to validate some of the EUs repeated declarations about its commitment to broad and worthy goals such as science and North and South cooperation, and partly, perhaps, so that it can be seen to be offering something positive in the course of a major international debate about drug provision in which Europe, and the rest of the developed world, is not looking too generous. The negative publicity about the attempts of European and U.S. drug firms to prevent erosion of intellectual propertywhich peaked last year when a clutch of drug firms eventually backed down from a battle with the South African government about compulsory licensinghad repercussions on the broader attempts by the EU to win over hearts and minds to the need for protecting patents. That battle is still being played out in the continuing discussions of how to implement the so-called Doha Agreementthe deal reached at the 2000 World Trade Organization conference on the way rich countries should share technology with poorer countries. And the background to that conflict is the much wider issue of how to promote free trade at the world level.

The EU knows that it and its developed world partners face an uphill struggle to remove international trade barriers, because its arguments that free trade will promote worldwide growth are still interpreted by many opponents as naked attempts to exploit third-world markets. The spectacle of AIDS orphans, or of entire countries half-crippled by disease among the most active sectors of society, sits uncomfortably alongside speeches by well-fed European diplomats and officials preaching the merits of free trade and enhanced prosperity for all. So anything that can be done to mitigate the contrast could be a valuable contribution to support the positions put forward by developed countries on the bigger arguments.

This is doubtless why, while in Johannesburg, European Research Commissioner Philippe Busquin described the EDCTP program as an initiative that shows our commitment to help developing countries  and to make treatment cheaper as well as adapt it to the needs of the poorest countries. He called EDCTP a perfect example of the functioning of the European Research Area.            

View from Brussels

The World Summit on Sustainable Development may have fizzled, but a promising new long-term clinical trials partnership between the EU, industry, and developing countries is in the works.

Taking European Clinical Expertise to Africa

Effective clinical research requires attracting the attention of individuals with treatable medical conditions, then screening them and enrolling them into a clinical study. Subject recruitment has turned into an industry in which the environment is tumultuous and the competition is stiff. Sponsors are continuously developing and refining their techniques to reach out to appropriate patient groups and are becoming more sophisticated consumers of recruitment services; vendors continue to refine their service offerings; and site personnel are dedicating increased resources to recruiting and enrolling subjects. Although the subject recruitment sector is maturing, it is far from delivering predictable and successful outcomes.

Three elements influence the recruitment process: the protocol, the investigative site, and the patient population. We believe the reason that most recruitment programs fall short of expectations is that they do not address these factors and the relationships between them. Understanding and avoiding common mismatches between the protocol design, site infrastructure, and prospective subjects interests and needs will make recruitment easier.


Just as you would not purchase an expensive wedding gown or suit off the rack and expect it to fit without going through the painstaking fitting and alterations process, you should not expect a recruitment program to be successful without undertaking similar measures to ensure a good fit between the study protocol, the participating sites, and the target patient population. Mismatches between these three core elements can result in an ill-fitting and ineffective recruitment program.

 For example, the team responsible for subject recruitment may have created a very effective media awareness campaign that results in a high response rate from interested candidates. Yet if the site has insufficient staff to screen prospective subjects via the telephone or doesnt promptly respond to patients referred by a centralized call center, this may result in a low yield of subjects. In such cases, it is common to blame the recruitment team for not delivering successful results. The media campaign was likely very successful in attracting the attention of interested participants, but the site didnt have sufficient resources to respond to the high volume of calls. 

 Another common mismatch relates to the strictness of the subject eligibility criteria. Failure to secure input from the sites on the inclusion and exclusion criteria often leads to enrollment delays and protocol amendments. Recruitment of subjects into a study is a shared responsibility between sponsors and sites. Sponsors should validate the number of potential subjects available, and sites should not accept studies without doing a thorough feasibility assessment of their access to the appropriate patient population.

 A further illustration pertains to the site selection process. Investigators are often selected based on medical expertise and past experience, which may or may not relate directly to the ability of the research site (as an entire entity) to implement the protocol. A thorough evaluation of the site capabilities, resources, and facilities for a specific protocol, in addition to validation of the sites access to the appropriate patient population, are critical steps. Interviewing several staff memberssuch as the investigator, clinical research coordinator, and site administratorto confirm subject availability estimates and site capabilities is an often overlooked but essential activity to ensure recruitment success.

The box, Fitting Together the Components of a Clinical Trial, highlights elements that should be addressed during the protocol design, site selection, and recruitment planning phases of study implementation. Early assessment of these variables is essential to understanding the recruitment challenges of each study and identifying the most suitable interventions.


Recruitment issues can be assessed as part of the routine site selection and subject recruitment planning processes.

 Sites should conduct a thorough feasibility assessment of the protocol, including retrospective and prospective analyses of their patient population. This may be done by conducting database searches and reviewing medical records over a period of time to identify subjects who meet the eligibility criteria. This should be accompanied by a careful review of past enrollment performance metrics for the disease in question to evaluate what the most successful strategies were for recruiting subjects in past and similar studies. In the United States, sponsors and CROs have access to more sophisticated informatics vendors, such as Acurian (www.acurian.com), the MedStat Group (www.medstat.com), Quintiles (www.quintiles.com), and others, who use prescription and medical claims databases to validate site enrollment projections and model the disease prevalence rates in given geographic regions. These evidence-based techniques provide an aggregate view of disease prevalence by geographic area and practitioner/prescriber, preserving patients confidentiality while validating that the sites selected truly have access to the patient population of interest.

 Sites should then undertake detailed subject source mapping and recruitment planning, outlining all possible sources of subjects (for example, existing medical practices, referral physicians, and the public at large) and estimating the percentage of subjects likely to be drawn from each source. The table above provides an example of a subject source map. Such a map can be used to identify which sources are most likely to yield the most subjects and help prioritize the types of outreach and awareness programs most likely to reach each source.

The subject source mapping and recruitment planning exercise is also extremely valuable for resource planning and allocation. For example, if the primary source of subjects will be the investigators own pool of patients, additional staff resources may be required to conduct chart reviews to identify potential candidates. If the primary source of subjects will be referring physicians, the site will need to define the resources and materials required to identify and educate potential referring physicians and assess their access to suitable subjects for a given study. Up-front planning such as this will ensure that adequate funds are secured to implement the strategies and that sufficient time is allowed for development and ethical review of clinical trial awareness materials.

 If the primary source of subjects will be the general public, all stakeholders (sponsors, CROs, recruitment vendors, and sites) should consider investing in some type of market research activity. Market research techniques (including focus groups and the profiling of population subsets by demographic, socioeconomic, and lifestyle interests) can shed further light on unique characteristics of the patient population, such as their hobbies, interests, and media use habits. This information can be used to create the most effective eye and ear catchers and help sites target their media placements more strategically. Such techniques may reveal, for example, that senior citizens in central Florida who suffer from type 2 diabetes are 10 times more likely to listen to light jazz radio stations than all other stations, whereas the same population in Seattle is more likely to listen to talk radio programs or is more effectively reached through another medium such as a home magazine. Members of a target patient  group start to react to an advertisement when it appears before them three or more times, and market research can help ensure that advertisements are placed with the right message in the right media so that members of the target group are exposed to the message repeatedly. A combination of various outreach methods may yield the best response of interested subjects for a study.

Market research can provide further insight into the motivation of potential subjects for participating in clinical research. For some subjects, the prospect of relief of symptoms is the key motivation, whereas other subjects reasons may be altruistic. Understanding potential subjects concerns can have a significant impact on the protocol design itself, in addition to awareness of the study. For example, if the target patient population is of working age, then it will be important to consider the number and duration of study visits to minimize the overall burden to the subject. Otherwise, all the efforts to attract the appropriate patient population will be wasted if the subjects arent able to comply with protocol visits.

These are but simple illustrations of the type and depth of information that can be uncovered through market research techniques. All too often sites or media vendors may have the proper message, but it is placed in the wrong medium, or vice versa. Sophisticated information about potential subjects lifestyles and media techniques will ensure that recruitment budgets are spent wisely.

 Beyond designing clinical trial awareness programs that are media-focused, it is also important to consider other channels for recruiting subjects. Not only is it important to understand what potential subjects read, watch, and listen to, it is also important to understand where and how they live, what activities they participate in, and so forth. Religious-, work-, and school-oriented disease educational programs; health fairs; and other activities can be just as effective as advertising, if not more effective, in raising awareness about a potential study, particularly in countries and communities where direct-to-patient advertising may not be allowed or considered appropriate. Several minority organizations and patient advocacy groups in the United States and around the world are getting involved in developing patient education materials to help raise awareness about the value of participating in clinical trials, in addition to including information about clinical trials in their newsletters, posting information on their Web sites, and sponsoring community-based awareness programs.

Bringing treatment to patients is increasingly possible through the use of mobile mammogram and blood donation units and visiting nurse services. Similarly, mobile research units can be used to bring research to the subjects and provide the opportunity for potential subjects in remote and underserved areas to participate. Telemedicine interfaces, such as those developed by Frontier Medical research (www.frontiermedicalresearch.com) are also being applied in the clinical research environment to reach previously untapped patient populations.


Selecting the most appropriate and cost-effective approach to reaching potential subject populations is complex and multifaceted. What works for a private practice physician investigator in New York City will be quite different from what works for a professional research center based in the midwestern United States, and different further still from what works at an academic medical center in Seattle. Techniques that are appropriate in France may not be transferable to Thailand, and so on. While it goes without saying that any recruitment program must adhere to all levels of regulatory and ethical compliance, it is important to recognize that international regulations and guidelines dont begin to address the site- and protocol-specific needs and issues that affect recruitment for a given study.

Gaining an appreciation for the fact that each site is structured differently and operates in different environments, and that every potential subject has different needs, will go a long way toward developing more effective subject recruitment programs. Although the protocol and subject definition criteria for a given study are consistent, the study is being implemented at many different sites, all of which have different and unique infrastructures, environments, personnel, and needs. Although the patient population in general may be the same age and be suffering from the same conditions as required by the study, each potential subject is unique in terms of his or her interests, needs, motivations, and media use habits. Outreach programs that use the wrong media, or clinical trial awareness messages that fail to target different lifestyle segments and cultural sensitivities, will miss the opportunity to reach the largest audience possible. Successful recruitment requires sensitivity to site, geographic, cultural, and community differences and a willingness to tailor the recruitment program, where possible, to accommodate these differences.

SIDEBAR: Fitting together the components of a clinical trial

Ensuring a good fit between sites, protocol, and patient population requires careful assessment of many factors.

 Past experience conducting trials in a similar patient population and assessment of past enrollment performance metrics.


 Personnel resources including the number and type of personnel available, their functional responsibilities, and their relationships to other institutional departments, referring physicians, and community organizations. Financial resources to support hiring and training of additional staff if needed


 Appropriate delegation of responsibilities among personnel with sufficient qualifications to perform the protocol procedures involved.


Ethical review committee policies and procedures.

 Ethical review committee attitudes toward patient outreach programs (for example, restrictions on media messages), subject reimbursement, and so on. 

Between the sites and the patient population

Disease prevalence in the geographic region of the site.

Access to the appropriate patient population.

 Is the investigator a treating physician who can draw on patients from his or her existing practice, or a dedicated clinical trialist who sees only research subjects?


 Existence of any competing trials and their expected dates of completion of enrollment.


 Subject-friendly facilities (comfortable waiting room); efficient scheduling; extended clinic hours to accommodate subjects work schedules; transportation support, subject reimbursement, and compensation amount and procedures. Type of screening procedures (clinical chart review, phone, mail, face to face).
 

 Are the individuals who will be screening and interviewing potential subjects and obtaining informed consent skilled at verbal communications (and in which languages) and responding to subjects questions and concerns? Are site staff focused on creating a pleasant customer service experience for the subject?

Between the patient population and the protocol

 How restrictive are the criteria relative to the existence of patients with the disease or condition being studied? How closely do protocol procedures and treatments resemble standard medical practice?


 How invasive and burdensome are the procedures? How demanding is the visit schedule in terms of visit frequency and duration?     

Feature Article

Successful recruitment requires a good fit between the subjects, the sites, and the protocol. Here?s how to assess the necessary tailoring of procedures.

Successful Subject Recruitment: One Size Does Not Fit All

On 14 August 2002, the U.S. Department of Health & Human Services approved final amendments to the so-called Privacy Rule, the privacy regulations issued by HHS in December 2000. With regard to research recruitment and the need for an authorization for disclosure of protected health information to third parties, the language in the preamble to the final amendments is intended to clarify the following: Although 45 CFR 164.512(i)(1)(ii) allows use or disclosure of protected health information for research preparatory activities, including recruitment, on the hospitals site, the protected health information may not be removed from the hospitals site by the researcher for such activities without the patients authorization or waiver, or without alteration thereof by the institutional review board (IRB).

When can researchers view protected information about patients?

 Under 45 CFR 164.512(i)(1)(ii), a hospital may permit researchers to view protected health information about its patients for purposes of the researcher preparing the research protocol and recruiting subjects provided that the researcher demonstrates, either in writing or orally, that


	the use or disclosure is sought solely to review protected health information as necessary to prepare a research protocol or for similar purposes preparatory to research.

	no protected health information is to be removed from the hospital by the researcher in the course of the review.

	the protected health information for which use or access is sought is necessary for the research purposes.

When can researchers record and remove protected information?

 The researcher may record and remove protected health information from the hospitals premises only if the hospital either waives or modifies  authorization requirements (and appropriately documents this) or obtains an authorization from the patient. Alternatively, the researcher may remove de-identified information, or the hospital may disclose a limited data set to the researcher, provided the hospital and the researcher enter into a data use agreement relating to the limited data set.

A health care attorney clarifies how amendments to the HIPAA Privacy Rule bear on the recruitment of clinical trials subjects.

The HIPAA Privacy Rule Affects Subject Recruitment

Many professionals involved in the execution and management of clinical trials see electronic data capture as a tool that can enhance the quality of data obtained during a trial. In addition to high data quality, EDC offers another benefitreal-time access to data. Both project managers and clinical research associates can benefit from such access during the trial. EDC allows managers to track and analyze the project progress in terms of deliverables and milestones, and to control the project budget with less time and effort. Using EDC means having real-time access to current project status and on-the-spot ability to generate accurate, up-to-date reports. Hierarchical reporting structures, the availability of the CRA, and time zones no longer need frustrate project managers.

Those familiar frustrations may be replaced by new ones, however, unless project managers and CRAs plan for the problems that can arise when EDC is implemented. Based on the challenges that I have encountered on EDC projects, I offer some issues to anticipate.


The workload in an EDC study is distributed over time differently than it is when paper CRFs are used. In EDC projects, the start-up phase is more challenging than it is in conventional paper case report form (CRF) projects. Getting started on EDC trials requires up-front planning and training in addition to software and capital equipment selection.

Project managers must keep in mind that data management tasks, such as database setup or programming of validation checks, must be completed by the time of site initiation, and sufficient time has to be planned for CRA training. Such planning requires intense collaboration with the departments involved, but will definitely pay off during the project life.

Unlike managers, who must plan for more work at the start of a study, CRAs will find that the use of EDC will result in a more balanced workload from site initiation through recruitment phase, and from the last subjects last visit to database lock.

 An EDC study requires more time at study start for training. Familiarizing site personnel with an electronic case report form (eCRF) will take as much time as it does to familiarize them with a paper CRF.

In addition to study-specific training on the protocol, CRAs will need to acquire basic computer skills and become familiar with the monitoring tools available on the system. CRAs also will have to be familiar with basic computer tasks and solutions in order to provide training to site personnel assigned to the study after initiation.

 With both a correctly functioning system and appropriately trained on-site personnel, CRAs will discover that using EDC leads to positive changes to the work on site. Having direct access to the data at their sites, CRAs can determine the workload they can expect at their next monitoring visit. The direct access to site data will help CRAs plan visits in accordance with recruitment and performance of the site, thus resulting in more efficient visits. Data can be reviewed for quality purposes before the monitoring visit, and queries can be generated and ideally resolved by site personnel before the visit. When the CRA arrives on site, he or she can perform source data verification on clean data. Certainly the time required for source data verification will remain the same. But appropriate validation checks and automatic queries will significantly improve data quality and reduce the number of queries.

These changes will reduce the time the CRA spends on site and also the number of monitoring visits, subsequently resulting in less travel time.

The time savings on activities associated with the use of paper CRFs is also significant. Paper CRFs require printing, distribution, collection, and tracking. Using EDC, CRAs are spared the need to retrieve pages of CRFs and/or data clarification requests, separate originals and copies, complete tracking logs, pack and send originals to data management, and search for missing pages.

Visit follow-up activities, such as sending reminders to the site and generating reports, will be simplified because basic information is available on the system and will not have to be duplicated.


Despite these potential benefits when an EDC study goes well, technical difficulties can quickly cause an EDC study to fall behind schedule. In the last six years I have had the opportunity to experience a variety of platforms and software applications, and both vendors and sponsors solutions. Most projects in which I was involved were multinational, multicenter trials in both Western and Eastern Europe, Australia, and Southeast Asia. Entering the world of EDC meant dealing with a variety of new challenges.

Because my first EDC projects took place at familiar and experienced sites, my team had validated historical data on the expected recruitment rate and data reliability to allow an estimate of the projects duration. Prestudy visits covered technical and information technology issues, and the investigators were asked to provide detailed information regarding technical status. Hardware and equipment were individually tailored for all sites.

 After this initial halcyon period, we found that in reality, the majority of sites had problems with technical infrastructure that led to unexpected delays in study start-up. Some sites had no Internet access on the wards, in the departments, or in the treatment rooms where subjects were actually evaluated. Where local equipment was used, auditing local hardware and software was necessary to determine the need for upgrade and updates. This raised contract and confidentiality issues.

Some hospital telecommunication systems did not allow direct dialing to numbers outside the clinic, and when connections could be made, lines sometimes broke down.

 Once sites were set up and initiated, a new set of unexpected issues arose. Staff persons at sites working offline often missed entering data. Sometimes this happened because, for insurance purposes, sites stored laptops in locked cupboards with restricted access.

Sometimes data were entered on time but not actually transferred because setting up a communication line (that is, unplugging phones or fax machines in use during the regular working hours) presented too many difficulties.

On-line systems were often not accessible or were otherwise unacceptably slow. 

 Even if the technical infrastructure was satisfactory, users often had difficulty solving problems with the system. Navigation through eCRFs was time-consuming, and the help desk not always available. Investigators faced with frozen screens simply gave up. Those sites that already had experience with more user-friendly systems refused to tolerate a step backwards.

 As a result of these problems, site personnel were reluctant to enter data, instead waiting for the study monitor to complete the eCRF. Data were never completely available for the project manager or the CRA. The information captured in the system represented only a fraction of the data available on site. Consequently, CRAs spent more time on site for monitoring and made more monitoring visits. More contacts were also necessary to motivate the site staff.

The rejection of the EDC system led to a declining recruitment rate and extension of the project duration. Additional efforts and costs were necessary to select and initiate new sites.

Time for source data verification was actually doubled by using a worksheet as well as eCRFs and subject records. Far more inconsistencies were found, of course, and more time had to be spent on clarifying those. Queries relating to data inconsistencies tended to remain unresolved over time, therefore accumulating. 

Furthermore, CRF insufficiencies had to be compensated for by comments, and eCRFs were not adjusted to reflect protocol amendments. Additional paper CRFs were introduced halfway through the study. This meant additional working hours for everybody involved, and enormous unexpected logistic efforts.

Ongoing site personnel changes and reduced use of and practice with the system resulted in a need for repeated training sessions. In short, our teams assumption that monitoring visits would require less time once the first visits were done was proven wrong.


Faced with challenges like these, both project managers and CRAs must respond. To keep their teams motivated and the project on schedule, project managers must be prepared to help sites overcome technical obstacles. CRAs, for their part, must get used to changes in their duties.

 Only if site personnel accept the EDC system will project managers and CRAs have the opportunity to reap the benefits EDC can offer. Investigator and initiation meetings are an opportunity to demonstrate to investigators, study coordinators, and study nurses the potential for the reduction in the number of queries and the gain in time for all involved in the performance of the study. The message must be clear that the industry is not abusing site personnel as data entry staff.

This message must be backed up with adequate technical support. Providing a user-friendly CRF and equipment that can transmit data at an acceptable line speed is crucial.

 Our working environment demands from us a capability to adapt to new electronic systems. CRAs will have to get used to the overlap of data management tasks, to source data verification and consistency checks on a screen, and to data listings, that is, cross-references for site payments, sample logs, and so on.

It is also sometimes necessary to accept navigating through eCRFs that are not user friendly, and working with unsatisfactory monitoring tools.


EDC potentially offers more than just high-quality data. The added value for project managers and CRAs comes with appropriate monitoring tools, validation, and consistency and plausibility checks.

Provided that sufficient thought is given to the initial expenditure on planning, training, software, and capital equipment selection, the cost of EDC can be recouped many times over in more efficient and effective project control, leading to faster project completion.

Good organization and technological support are needed to bring the benefits of electronic data capture to a clinical trial.

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