IntraLinks' Internet-driven electronic document system allows management solutions for all of a trial's forms

IntraLinks (New York, NY) offers a multifaceted database for a clinical trial staff with different uses for everyone from the sponsor on down to the CRA. More importantly, they also have experts on hand to guide each team member through whatever questions they have.		

With IntraLinks, users have access to all the regulatory forms they'll need, all in convenient PDF format. Site contracts, budgets, 1572s, protocol documents-all included, all distributable to anyone in the process along with a reminder note to ensure they get filled out. Sending out a safety notification is as easy as forwarding an email. It's all done via the Internet, so any computer with a modem becomes a possible access point.	

The software tracks which parties receive each document, and stores/archives completed versions of forms for audits. Adaptable permissions let each person who logs in see only the documents he or she needs. The 128-bit security feature ensures that no one who isn't supposed to be looking around will be. Running a report will let an investigator know exactly how much progress has been made. And if anyone isn't sure about how things work, a 24/7/365 tech support can offer guidance in over 140 languages.	

A study simulator that predicts the unseen trial problems lets PIs fix their mistakes before they're made

Pharsight Corp. (Mountain View, CA) knows that much of the work in a successful clinical trial is done before the first site has gone into action. Simulating the action, like a practice game, lets the people in charge anticipate problems before the occur. 			

The company's Pharsight Trial Simulator lets a sponsor considering a trial create a virtual environment to have a "trial" clinical trial. In one PTS option, compare two series of doses to see which one, on which dosage schedule, would deliver more useful information about the drug's efficacy and safety. And with percentage results based on how clearly you've defined your goals, you can ensure that the multisite trial about to begin runs smoothly.	

No one wants to realize halfway through a long expensive trial that they should have better formulated an assumption, or aren't collecting the correct amount of data points. The simulator gives sponsors and investigators a "trial" trial run of sorts, to practice design skills for the big show.	

Pharsight's other products include PK Automation for pharmacokinetic data, Pharsight Knowledgebase Server for PK/pharmacodynamic data, and education via training and consultation.	

Two new reference materials give the clinical trial world both a phone book and an encyclopedia of the industry

Thomson CenterWatch (Boston, MA) has created two databases which almost anyone involved in the clinical trial world could put to good use.			

The first, Drugs in Clinical Trials Database, lists over 2000 drugs in over 800 different conditions, from asthma to zinc deficiency. The drugs are indexed by formulation, manufacturer, phase status, and more. The online reference is updated daily for new FDA approvals and trial announcements, so it's always fresh. 	

The second new database, eDirectory of the Clinical Trials Industry, is a massive list of over 1400 clinical trial professionals. Besides listing over 140 pharmaceutical and biotech companies, it includes over 170 CROs, over 30 IRBs, 800 sites, 80 SMOs, and over 200 consultants. It was previously only available as a printed document, but now is accessible on the Internet.	

Articles

News

IntraLinks' IntraLinks, Pharsight Corp.'s Trial Simulator, and Thomson CenterWatch's Drugs in Clinical Trials Database and eDirectory of the Clinical Trials Industry

eShowcase

IRBs often set an arbitrary grade-level requirement-such as sixth or eighth grade-at which consent forms are supposed to be written. A recent review

 of 114 Web sites of U.S. medical schools found readability standards between fifth and tenth grade, although actual grade levels of their consent form templates averaged almost three grades higher than their recommended grade levels.	

The assumption behind such recommendations is that subjects who can't understand a consent form at a third-year college level will understand one written at an eighth-grade reading level. Sometimes this recommendation comes from data showing that average Americans read at an eighth-grade level; sometimes it comes from intuitive beliefs that anything written at a lower grade level simply must be easier to understand. But this recommendation is flawed for at least two reasons. The first is that writing at an eighth-grade level is very hard; the Flesch Reading Ease Score

 describes materials at sixth-eighth-grade reading level as having 14 to 17 words per sentence and 139 to 147 syllables per 100 words. This translates into many one- or two-syllable words. Second, how should writers measure a consent form's grade level? Many IRB Web sites recommend readability software, often suggesting the Flesch-Kincaid formula in Microsoft Word. But Microsoft's version of that formula is flawed; any score at grade 12 or above is reported as grade 12, plus its reported grade level is affected by the document's format.

 Although the Flesch-Kincaid scores up to grade 17, Microsoft's version is too unreliable and inaccurate to recommend or use since researchers can not reliably verify the grade level of a consent form. 	

Few studies have been done on the impact of rewritten materials on reader comprehension. Table 1 summarizes nine studies comparing comprehension of higher grade level documents that were rewritten to a lower grade level. The nine studies include informed consent as well as other rewritten materials spanning over 20 years.		

Table 1.  Summary of reading comprehension and reading grade level	

 compares an investigator-developed consent form with one developed by focus groups for a U.S. Veterans Administration study on Gulf War Illnesses. Although the focus group made seven significant changes, such changes (see Table 2) were not reflected in an independent statistical readability analysis (using Prose: The Readability Analyst, Grammatik 6.0, and WStyle) of the two versions. 	

Although the two versions were almost statistically identical, changes recommended by the Focus Group may still produce differences in understanding. And this may depend on whether the researchers' questionnaire is sensitive enough to detect such differences.	

 Most study populations are college-educated people who should have better reading and comprehension skills than those without a college education. This is because they have more years of formal education, which includes better-developed abstract thinking skills, larger vocabularies, and more experience reading complicated text. For this reason, some consent form comprehension studies may show better understanding simply because these subjects are better educated. What are needed are comprehension studies that include a broader range of subjects, whose educational attainment matches U.S. census data. College-educated subjects may not find easy-to-read consent forms more comprehensible, but subjects with high school or junior high school educations might.				

 Psychological principles require comprehension measures to be both valid (i.e., they measure what they are supposed to measure) and reliable (i.e., repeated testing produces similar scores). "Face validity," in which an instrument only looks like it measures what is it supposed to measure, has no scientific value.	

 addressed the content validity of their comprehension measures, but did so in very vague terms. They stated only that "Consent validity for the measure was high, as evidenced by the judgments of a panel of experts who reviewed the questionnaire"

 or that three experts reporting,  "Agreement was reached in each of these areas,"

 but neither discussed the statistical specifics of those assessments. Plus, these two papers were the only ones that addressed reliability of their comprehension measures. Without any document validity or reliability data for their comprehension measures, the others studies are scientifically questionable, since they are based only on "face validity." 		

Table 2.  Readability of investigator-developed vs. focus group-developed consent form	

Different researchers use different methods for measuring comprehension, so there's no way to compare findings from different studies. Researchers have used true-false questions,

 or have asked subjects to paraphrase documents and answer questions.

Both true-false and multiple-choice questions are flawed because subjects can get a percentage of answers correct by guessing. Because a true-false test is simply a multiple-choice test with only two possible answers, subjects can get 50% correct by guessing. For multiple-choice questions, subjects can get 20% correct with five possible answers, 25% correct with four, and 33% correct with three. Such methods for measuring subject comprehension may not be sufficiently sensitive to detect true understanding. 	

Since multiple-choice questions include the correct answer among the incorrect alternatives, they measure consent form recognition, not recall. Consent researchers seem unaware of this important distinction. As a result, comprehension scores may be higher on a multiple-choice test than they would be if subjects were asked to tell researchers what they remembered and understood about the consent process. While these issues are not discussed in the informed consent research, they are well known in the psychological testing literature (which is similar to informed consent testing process), and can be found in undergraduate textbooks such as Anne Anastasi's renowned 

Psychological measurement demands that comprehension measures be both valid and reliable. Of the nine studies, only two addressed the content validity of their comprehension measures, but did so in very vague terms.

. stated only that "Content validity for the measure was high, as evidenced by the judgments of a panel of experts who reviewed the questionnaire,"

 (p. 837) but did not include specifics of those judgments. Cardinal, who used three experts, reported that "Agreement was reached in each of these areas" (p. 296), but did not discuss specifics of that agreement.

 Coyne and Cardinal were the only researchers to address reliability of their comprehension measures. Without validity or reliability for their comprehension measures, such studies become scientifically meaningless.	

 One study using multiple-choice questions

 found a statistically significant difference in understanding between a Low Reading Level consent form (grade 6) and a High Reading Level consent form (grade 16). But the actual difference in comprehension was a difference of only one more answer correct! Subjects with less than a high school education answered 12.88 questions correctly; those who attended college correctly answered 13.95; those who graduated college correctly answered 14.31. Based on 21 multiple-choice questions (the number of alternatives was not given), subjects correctly answered 61% to 68% of the questions. Does that demonstrate "comprehension?" In an academic setting, that would be a "D" grade. 	

In another study that measured legal contract comprehension,

 which can be compared to an average consent form, subjects correctly answered 65% of the questions about the plain-language version versus 51% of the legal contract version. This 14% difference in comprehension was statistically significant, but does 65% correct demonstrate "comprehension?" The authors suggest because legal documents are complex, or don't fit with people's understanding of the law (or what they've seen on television), plain-language legal contracts may not lead to major changes in comprehension. The same might be said of consent forms.	

A study asking subjects to paraphrase jury instructions

 found about 40% to 54% correct responses, concluding that conceptual difficulty accounted for much variation in comprehension scores. Sentence length had no effect on subject comprehension, but educational attainment did, with the best comprehension demonstrated by those subjects with the most years of education. A second study of rewritten jury instructions without problematic construction problems found 43% correct answers with modified instructions versus 32% with the original. While this 11% difference is statistically significant, the question still remains: Does 43% correct really demonstrate understanding?  	

A vaccine information pamphlet study5 found that subjects better understood (by 15%) a university-designed pamphlet at a sixth-grade reading level compared to the CDC's tenth-grade version. Comprehension was measured with nine questions; subjects correctly answered 72% (six and a half of nine questions) on the university pamphlet and 56% (five of nine questions) on the CDC version. Is a statistically significant difference of 1.5 answers on nine questions meaningful? 	

Plus, the authors reported that the lengthy (18,117 words) CDC version took subjects about 14 minutes to read-that equals a 1,294 words-per-minute reading speed. The university pamphlet was 332 words long. Subjects took an average of about 4-1/3 minutes to read it, which is equal to an average reading speed of 74 words per minute. At that reading speed, it would have taken subjects 4 hours to read the very long CDC pamphlet. Subjects could not have read the entire CDC form in 14 minutes, suggesting that poorer comprehension on the CDC form might be due to the fact that they didn't read the entire pamphlet. 		

Table 3.  Readability factors in informed consent	

A study of information about an HIV vaccine trial

 found that on a 20-item multiple-choice comprehension test (with three alternatives), subjects correctly answered 83% (about 17) of the questions on a simplified version, but 70% (about 14) on the standard version. Subjects could have gotten six to seven answers correct (20% to 35%) by guessing. But the standard version, developed by the National Institute of Allergy and Infectious Diseases, was 22 pages long (4,059 words). The simplified version was about 2,521 words. This study differed from the others insofar as the subjects were read the vaccine materials out loud and could follow along if they wanted. Results may be confounded because some subjects may have only had the materials read to them; others may have heard it and read along. Two inputs might be better than one. 	

 suggested a minimum level of understanding, assuming that scores of 70% or above on the cognitive test demonstrated minimum comprehension. Using that 70% cutoff, none of the above studies demonstrated even minimal understanding for plain-language consent forms or legal documents. 	

Do subjects really understand what they are reading? 

The answer to that question depends on how "comprehension" is measured. Most of the studies involved having subjects answer true-false or multiple-choice questions, a task which some subjects might find difficult if they have reading problems. If they can't read and understand the questions, how well can they answer them? There might be differences in comprehension depending on whether subjects are given a paper-and-pencil comprehension "test" or whether the questions are asked verbally, so the subjects can give an oral response that does not involve reading test questions. Without comprehension criteria that are decided upon before the study is done, there's no benchmark for low comprehension, average comprehension, or above average comprehension.				

 Some studies used short consent forms, perhaps only 300 words. But clinical trial consent forms typically range from about 1,000 to 3,000 words-averaging about 2,000 words14-before new required HIPAA elements are added. With HIPAA, future consent forms may range from 2,500 to 4,000 words long or longer (a recent consent form that came to our IRB was 5,260 words long). As a result, that reading level may be offset by problems with information overload.	

The U.S. Department of Health and Human Services

 has developed model language for researchers to use when explaining how they share protected health information. This document notes that "The authorization must be written in plain language." But this authorization is not in plain language (see sidebar).				

Table 3 compares five basic readability factors for the HHS "Optional Elements," as well as 20 HIPAA notices (averaging 900 words) from consent forms submitted to North Memorial Health Care's IRB and from online HIPAA notice templates and examples. 		

Since most sponsors want to be HIPAA compliant, they will probably use the HHS sample language, which means that subjects will be given even more written information they can't easily understand. In their audits, FDA will review HIPAA privacy notices if they are embedded in the consent form (both requiring a single subject signature); they will not review HIPAA privacy notices if they are an addition to the consent form (requiring two subject signatures).	

 FDA requires eight basic elements and six "when appropriate" elements for informed consent, and HIPAA regulations may add five to 12 more to that sum. Thus, current clinical trial consent forms may have up to 26 elements that have to be explained-more topics than typical subjects can read, remember, and understand. 	

But readability research doesn't address all FDA-required elements of informed consent, often asking only 10 or 20 questions about the research project. Thus, there's no way to identify which FDA-required elements are understood completely, partially, or not at all. So much for the statement "I have read and understand this statement of informed consent...," usually found just before the subject's signature on the consent form; subjects may read consent forms, but they apparently don't understand them. 	

What do subjects want in an informed consent form?

As part of a study on the desired features in multimedia consent forms, Jimison and her colleagues

 asked 29 patients with potential cognitive impairments (depression, schizophrenia, and breast cancer) to read a sample consent form and to suggest improvements to that form. These patients said that the consent form was too long, with too many complex words and confusing details. Table 4 summarizes their nine recommendations for an improved consent form. Jimison 

l. found that eight IRB members and 15 researchers made similar recommendations.		

Table 4. Suggested improvements to consent forms 				

Since only one of the nine recommendations-that of using lay language-is measured by readability formulas, it's fair to say that consent form "readability" isn't the sole problem or the sole solution to improved understanding. While most current consent forms appear visually to have been merely typed but not designed, perhaps future consent forms can better incorporate important (but unused) features of the word processing program used to write those forms.	

What can IRBs do to improve subject understanding? 

Unless they're willing to do their own research, there is little that IRBs can do to actually improve subject understanding, since understanding consent forms may have less to do with reading grade levels and specific words than with the sheer amount of information that potential subjects are expected to read and understand. IRBs can continue to insist that consent forms be written at junior high reading levels even though there's no evidence that such rewritten consent forms will do much to improve reader understanding. What is needed is more research on the consent process itself and insights into those strategies that actually improve subject understanding. Unfortunately, there is no method for writing a clinical trial consent form that significantly improves subject understanding. Given the nature and amount of information that must be communicated to subjects, perhaps that's an impossible task.				

1. M.K. Paasche-Orlow, H.A. Taylor, F.L. Branca, "Readability Standards for Informed-Consent Forms as Compared with Actual Read     ability,"

3. M. Hochhauser, "Flesch-Kincaid in Microsoft Word is Flawed." (Online letter 10/7/03). CA: 

http://caonline.amcancersource.org/cgi/letters?lookup=by_date&days=365

4. R.P. Charrow and V.R. Charrow, "Making Legal Language Understandable: A Psycholinguistic Study of Jury Instructions," 

5. T.C. Davis, J.A. Bocchine, D. Fredrickson et al., "Parent Comprehension of Polio Vaccine Information Pamphlets," 

6. D.A. Murphy, Z.H. O'Keefe, A.H. Kaufman, "Improving Comprehension and Recall of Information for an HIV Vaccine Trial Among Women at Risk for HIV: Reading Level Simplification and Inclusion of Pictures to Illustrate Key Concepts," 

7. C.A. Coyne, R. Xu, P. Raich et al., "Randomized, Controlled Trial of an Easy-to-Read Informed Consent Statement for Clinical Trial Participation: A Study of the Eastern Cooperative Oncology Group," 

8. M.E.J. Masson and M.A. Waldron, "Comprehension of Legal Contracts by Non-Experts: Effectiveness of Plain Language Redrafting," 

IRBs often set an arbitrary grade-level requirement?such as sixth or eighth grade?at which consent forms are supposed to be written...

Informed Consent: Reading and Understanding Are Not the Same

Central call centers can relieve sites of tedious scheduling and record keeping, freeing them to focus on physical exams and other core tasks.


Your study seemed so promising. Your recruitment marketing was compelling and cutting-edge. Your toll-free number was swamped with callers. Yet you still havent enrolled enough qualified subjects. Whats a trial site to do?

Unfortunately, this scenario is all too common in todays clinical trial environment. Its a given that subject enrollment and retention are two of the most important components of the recruitment process, but they can also be the least effective and most costly.Even though the number of trials is increasing, the subject drop-out rate remains an alarming 40%. Most study coordinators

a full 70%continue to manage their own subject enrollment programs,

 often to the detriment of efficiency and strong trial outcomes. If competent third-party companies can provide such services in an efficient, affordable manner, why, then, are less than a third of clinical research outfits using them?

One of the biggest culprits in this scenario of failure is leaving the initial screening responsibility with the sites, especially if advertising is employed. The sites more than frequently cannot handle referrals in a timely fashion. Consequently, back logs build up and significant numbers of participant prospects are lost. In addition, the sponsor has no control over the database of ineligible respondentswhich could be used (if respondent consent is acquired) in future trial recruiting programsbecause sites are notorious for not providing timely and accurate feedback.

A simple fix for this important part of the problem is utilizing a central call center to do the initial screening. A great many of the initial screening questions can be administered over the phone, leaving blood work and physical examinations to the sites. And the call center can actually schedule appointments for examinations by the nearest site for callers who pass the initial screening. This sends only qualified prospects to the sites and relieves them of the headache of schedule record keeping.  

But to many, outsourcing this part of the process is an anathema. It should not be. The litany of typical objections to outsourcing could include: perceived lack of control, potentially improper screening techniques, and questionable credentials of call representatives. These are understandable reservations. After all, we are dealing with serious matters, some of which can concern life and death.

However, there are call centers that specialize in handling and making healthcare-related calls, and have experience in screening potential trial participants responding to advertising, promotion, and community outreach efforts. In these programs, a single toll-free number is used either in centralized advertising efforts or in efforts created and executed by individual sites.


Using common toll-free numbers results in a central database in which an up-to-date picture is available at all times that details calls received by media, numbers of referrals to individual sites, the resolution of referrals to sites, numbers of randomized subjects, and reasons for failure to randomize, among others. Study coordinators end up having one central source of data that provides a complete picture.

Call centers that have recruiting experience do not hire minimum-wage communicators. They pay premium wages and typically use people with healthcare backgrounds who can efficiently administer applicable inclusion/exclusion questionnaires over the phone. Some use healthcare professionalsregistered nurses, pharmacists, nurse practitioners, physicians assistants, and medical technicians.

These call centers also have sophisticated and secure data systems that collect, store, refresh, mine, and report. And, they are completely conversant and fully compliant with HIPAA and Part 11 regulations.

Daily reporting of call volumes and referral rates provide the sponsoring company with more than a measure of control. Report content and frequency can be structured to client requirements. With the above knowledge in hand, a site visit to one or more call centers that put management personnel through their paces should allay the litany of fears.The preliminary screening and the setting of the first site appointment is a hassle for most sites. What many people fail to realize is that the time and expertise needed to effectively obtain appropriately screened subjects often represents wasted energy and resources that would be better spent managing the trials themselves. Several publications, including CenterWatch, have suggested that sluggish enrollment represents one of the primary causes of trial delays. Yet too many trial sites have been slow to explore the option of outsourcing the job to a company that can sign up suitable candidates promptly and efficiently.

Responses and referrals can be accurately tracked, altering appointment schedules can be easily done, and questions can be answered quickly. Such a centralized screening and appointment-setting process can reduce the no-show rate by as much as 50 percent.A recent survey conducted among physician offices indicated that the barriers to introducing centralized screening and scheduling to sites might not be as thick as one might imagine. The purpose of the survey was to determine what, if any, Internet access capabilities these offices have, and whether or not they would like to have a centralized call center make screening appointments for them for potential subjects who have passed a preliminary phone screen. The survey was conducted via telephone. Personnel responded to the following questions: 

 Does your site have an Internet connection?

 Do you allow an outside company to make appointments?

 Would you prefer to have access to a secure Web site to obtain appointment information?

The survey sample size was 100 sites involved in a large type II diabetes trial. The survey found that 92% of respondents said they have access to the Internet, and 65% said they would rather get referrals through a Web site. Another 70% said they would prefer not to have to deal with appointments.

These views suggest to us that, properly positioned, a centralized call center would not be too hard a sale to most sites, especially if the sponsor were to take a strong position that stressed the benefits to the sites.


1. K. Getz, CenterWatch Review of 19992001.

2. K. Getz, CenterWatch surveys of investigator sites, 2001.

3. Alliance Healthcare Information, Inc., Survey, 2002. 

is president and chief operating officer with Alliance Healthcare Information, Inc., One Ivybrook Blvd., Bldg.  100, Ivyland, PA 18974, (215) 347-1100, fax (215) 347-1110, email: msabogal@alliancehealthinfo.com, www.alliancehealthinfo.com.

SIDEBAR: Questions to Ask in Evaluating a Third-Party Call Center


Having the answers to the following questions will help you identify which call centers are best suited to execute centralized preliminary phone screening: 

 How many clinical trial recruiting programs has the call center completed? 


 Can the call center provide a list of the audiences and disease states? 


 Can the call center provide a perspective on the size of these trials in terms of numbers of participants sought, number of sites involved, size of media budgets and media choices, and urgency of the sponsor in enrolling participants? 


 How many inbound stations does the call center have? What is the capacity of the stations that can be assigned to this program? How would you handle spikes in volume due to media response? 


 Does the call center have a switch, also known as an Automatic Call Distributor, or ACD? (This is critical; it allows calls to flow evenly to call representatives and enables call tracking and reporting so that you can control costs by measuring productivity, service levels, and average call length for each representative.) 


 How familiar is the call center with using the Internet to recruit participants? 


 Have you executed programs where your call center has scheduled the first appointment at the appropriate site for qualified potential subjects? 


 What kind of back-up systems does the call center have for power, light, computer hardware, and phone systems? How long would it take to be back in operation in the event of a fire, flood, or other disaster? 


 What knowledge and/or medical background does the call representatives have related to essential information about inclusion/exclusion questionnaires, research sites, protocols, study coordinators, investigators, CROs, CRAs, IRBs, MedWatch, etc? 


 Do your project managers know how to flow the most useful information to call representatives in a timely manner? 


 Is every single call floor station computerized? 


 What will your hours of operation be? What do you consider to be acceptable service levels? 


 Do you have a staff of computer programmers on hand at all times for emergencies and to help adjust the call guides, appointment schedules, enrollment tracking and site information database as necessary? 


 Can you give us an example of your previous performance? 


 Do you currently have a subject recruiting program in operation that we could call into so that we can take your company for a test drive?


Feature Article

Reconsidering Third-Party Companies for Subject Enrollment

The passing of the EU Directive deadline next month is unlikely to quell the stormy debate over its far-reaching impact.

The traditional childrens Mayday song of Here we go gathering nuts in May could well be drowned out this year by loud expressions of buts rather than nuts. May 1 is the deadline for implementing Europes new clinical trials rules, and growing concerns over the impact on clinical research are going to ensure the date does not pass unremarked.

Many of the anxieties that have underlain the 10-year genesis of these rules remain unresolved, even in the final weeks before the rules are due to come into effect across the 25 member states of the European Union. Most notably, in an appeal to the authorities for more understanding, nearly a thousand scientists and doctors from 33 countries around the world have signed up to an expression of concern over the impact the new rules will have on their work. 

From Australia to Serbia, and from Egypt to Norway, 837 specialists with experience of multicenter international trials conducted by academic clinical research organizations have argued that important problems for academic research have not been adequately addressed.

The appeal, orchestrated largely by the European Organisation for Research and Treatment of Cancer, focuses attention on the way that the EU Directive on clinical trials poses threats to vital aspects of noncommercial clinical trials.

Specific difficulties are anticipated in relation to sponsorship: the pharmaceutical industry may not be willing to provide its products for noncommercial trials if this is perceived by competent authorities as some sort of sponsorship of the trial.

More generally, the directive is expected to result in increased administrative work and expensesuch as fulfilling requirements on on-site monitoring, or through fees to ethics committees and authorities. The fundamental anxiety is that the directives focus on commercial clinical research is ill-adapted to the realities of noncommercial research and will impose intolerable burdens on the scientific community, leading to the discontinuation of much valuable work. If implemented without caution, the Directive will prevent important research from being conducted, the appeal states. 

The blind implementation of the directive in Europe could drain the interest for research in the health care sector with more research being conducted outside of Europe. This is already the case for commercial research (drug development) and EU member states are about to set the rules to also push noncommercial research away from the European area, warns Patrick Thrasse of EORTC.

In support of its case, the appeal cited examples of important clinical trials which would not be conceivable under the future legislation. The data for this approach come from a January 2004 snapshot review by the EORTC of all its trials recently closed, currently open, or about to be activated. The review projected the consequences of the directive on this set of 127 clinical trials, and found that in the worst case scenario, if the directive was strictly implemented, approximately 60% of all academic drug trials would not have taken place. 

 This translates into a significant amount of critical research no longer being conducted and important improvements in health care would not have occurred, the appeal continues.

Worse, although this embarrassing situation is recognised by the European Commission as well as by the legislators in most member states, no real solution has yet been proposed, it says.

With characteristic resourcefulness, however, the signatories to the appeal have come up with a possible way out of the jam. While it is too late to repeal the directive itself, which has been adopted by the EU member state governments, the appeal suggests that changes should be made to the detailed notes for guidance produced by officials in the European Commission, which deal with the practical implementation of the directive. These can be amended at any time and national authorities have some flexibility in the implementation of the text, the appeal argues.


The appeal even offers a trial product for evaluation: the Belgian approach to implementing the rules. In Belgium, the appeal says, constructive interaction between academia and competent authorities has resulted in a national implementing text that addresses some important problems identified for academic clinical research. Above all, the Belgian text makes some explicit provisions for excluding academic research from the most onerous requirements of the directive.

The signatories to the appeal want all EU member states to urgently consider the Belgian proposal as a model, so as to avoid blocking most academic clinical research. All national legislation should provide special conditions for academic noncommercial research, including simplified procedures and conditions for using marketed drugs. They say this could form a basis for a harmonization at the EU level of the application of the Directive for academic research. They also urge specific corrective detailed notes for guidance to be developed to address other problems faced by academic research. And they would like to see formal dialogue between academia, industry, competent authorities, and the European Commission to cover the way this directive is implemented and the drafting of any new legislation in this area. Academia needs to be formally represented directly and indirectly in talks with the commission, they insist.


Some of the concerns over the impending implementation of the directive have already percolated through to the EU institutions. In discussions in February in the European Parliaments committee on environment, public health and consumer protection, U.K. member and committee chair Caroline Jackson raised the diffi-culties facing noncommercial research.

The Irish government, which holds the rotating Presidency of the EU for the first half of 2004, said it was fully aware of the problems with this directive, and that it  had received comments from research institutes operating in the area of cancer. Nothing should undermine this kind of research, says the responsible minister, promising to raise the matter with the European Commission in order to get clarity and ease the concerns.The coming weeks will show how far the Irish Presidency can act on its promise.


Meanwhile, the EU is continuing its efforts to mobilize clinical research that could more effectively combat diseases in developing countries. During February, European Research Commissioner Philippe Busquin followed up his visit to southern Africa last year with a trip to Senegal, for the formal launch of the E600 million European and Developing Countries Clinical Trials Partnership program that the EU has been promoting.

The visit also aimed at encouraging West African countries to join the initiative, in which the EU is funding clinical trials, and fostering clinical research in developing countries. The EU has pledged E200 million, with a focus on the three major poverty-related killer diseases of sub-Saharan Africa: AIDS, malaria, and tuberculosis. Another E200 million will come from EU member states, and a further E200 million will be funded by other international donors and industry. The EU is also devoting E200 million to basic preclinical research in this field. 

Research into treatments for diseases does not just mean working in laboratories; it also means working with the sick and infected in their own communities, said Busquin before he left Brussels. By visiting Senegal, one of the exemplary countries in the fight against HIV/AIDS, I hope to highlight what the clinical trials program means in real terms: European countries working in partnership with developing countries and the pharmaceutical industry to reduce suffering and poverty.

SIDEBAR: Studies that the Directive Would Have Prevented 


Some of the EORTCs examples of trials that would have proved impossible if the proposed rules were already in force:

A pyriform sinus cancer study demonstrated the benefit of a neo-adjuvant chemotherapy to reduce the tumor burden before surgery and enable the preservation of the larynx during the surgery without compromising the long-term survival of patients. Since this trial was published, patients operated can keep their natural voice instead of having to speak with artificial means. 


A randomized trial of two regimens of chemotherapy in operable osteosarcoma demonstrated that the administration of a 2-drug regimen as opposed to a complex 10-drug regimen (which was the standard treatment) was shorter in duration, better tolerated, and as efficacious. Beyond the clear benefit for the patients, this trial also illustrates the possible economic impact academic trials may have for the societythe appeal arguespointing out that for obvious reasons, no pharmaceutical company will ever support such initiative.


And a study of the effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer demonstrated that the combination of radiotherapy and cisplatin (a marketed drug for other indications) increased significantly the overall survival of patients as compared to the standard treatment, which was radiotherapy alone. Cisplatin in this setting has been used to increase the sensitivity of tumor cells to radiations. The dose of cisplatin used in this setting is largely inferior to the dose normally prescribed in other malignant indications for which cisplatin is used as a cytotoxic agent. However, in this trial cisplatin is used outside of its registered indication.

If the drugs used in these studies (all of them being marketed for other indications) had to be provided by the researchers, the studies would not have been possible, says the appeal. And if other conditions required by the new legislation had applied, at least one and probably two of these trials would not have been conducted.POD

SIDEBAR: Inside the Black Box of EU Rule-Making


Nothing is simple in EU rule-makingleast of all when it comes to clinical trials. But the essential features of the EUs complex system can be summarizedas follows:

 The perception of an EU legislative void or incoherence can trigger action by the  European Commission (the EUs principal administration) to propose new rules. There was (and is) plenty of incoherence in national rules on clinical trials in Europe, so the commission started drafting a directive in the late 1980s.

A formal legislative proposal (such as a directive) from the Commission is examined by the EU Council of Ministersthe formal representatives of the member states governmentsand by the European Parliament. They can (and usually do) amend the initial proposal, and they can even reject it. The clinical trial draft directive went through numerous changes during its lengthy review by council and parliament before it was finally adopted in 2001.

When a directive is adopted, it still has to be transposed at the national level into the legislation of each of the EU member states; the directive fixes the objectives to be attained, but leaves it up to each member state to find the precise legislative tools to attain the objectives. A transitional period is invariably allowed for this stage of the process. For the Clinical Trial Directive, the deadline for implementing the directive is 1 May 2004.

Some directivesparticularly those dealing with complex technical subjectsare accompanied by guidance from the European Commission, aimed at ensuring effective and accurate transposition throughout the widely differing legislative frameworks of the 15 (and from 1 May 2004, 25) member states. For the Clinical Trial Directive, more than a dozen such guidance notes have been created by the commission. These guidance notes do not have the force of law, and can be relatively easily updated and modified as circumstances dictate.

After the implementation deadline has expired for a directive, the European Commission checks on whether the member states have fully and accurately put into effect the new rules they signed up to implement. If it finds noncompliance, it can (and does) take legal action against offending member states requiring them to implement the rules properly. If member states still do not cooperate, the commission can drag them before the European Court of Justice, which may impose fines if it concludes that a member state is failing in its obligation to implement the rules. For the Clinical Trials Directive, none of this checking can even begin before 1 May 2004and action is often painfully slow, with delays of years before recalcitrant member states are brought into line.POD            

View from Brussels

Gathering ?Buts? in May

McClellan shifts to head Medicare after delivering new proposals to block counterfeits, add bar codes, and assess drug imports.

After weeks of insider speculation, the White House announced in February that commissioner Mark McClellan would be leaving the Food and Drug Administration to become administrator of the Centers for Medicare and Medicaid Services (CMS) in the Department of Health and Human Services (HHS). A top priority for the Bush administration clearly is to begin implementing the Medicare prescription drug benefit to quell complaints from seniors before the November elections. As a physician and economist, McClellan knows a lot about drug pricing and reimbursement and their impact on biomedical innovation. He is also skilled in navigating the political minefields of Washington, which will be important in building public understanding and confidence in this very complex and untested Medicare policy.

As FDA commissioner, McClellan has demonstrated a broad interest in drug coverage and access, as well as issues affecting research and development of new therapies. Before coming to FDA in fall 2002, he was White House health policy advisor as a member of the Council of Economic Advisors; in recent months he advised administration officials on various issues in the Medicare legislation related to pharmaceutical coverage and quality of care. 

Establishing a Medicare drug coverage program will require CMS to issue dozens of new rules and policies. The upcoming legislation also promises to make significant changes in health care delivery and innovation, as seen in provisions to promote electronic prescribing, develop more evidence on product safety and effectiveness, and provide more useful information to patients and health professionals. 


In shifting McClellan to CMS, the administration also calculated that FDA could weather the change. Deputy commissioner Lester Crawford, who already served as acting commissioner during the first two years of the Bush administration, will resume that position. 

During his first stint at the agencys helm, Crawford launched programs to modernize good manufacturing practices and to consolidate regulation of biotech therapies with drugs. In recent months under McClellan, Crawford has been heading up FDA programs to enhance food safety, curb obesity, prevent the spread of BSE (bovine spongiform encephalopathy) and promote antibioterrorism initiativesprime HHS concerns.

McClellan made the smart move last fall of detailing Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), to the Office of the Commissioner (OC) to help implement many of his risk management and strategic plan initiatives. Now Crawford has asked Woodcock to remain as one of three acting deputies instead of returning to CDER in April as planned. Woodcock will be deputy for operations; Murray Lumpkin deputy for special programs; and Amit Sachdev deputy for policy. Scott Gottlieb will coordinate OC initiatives with CDER and the centers for biologics and medical devices as director of medical policy development.

Woodcock says she can extend her stay in the Office of the Commissioner because CDER is in good hands under acting director Steven Galson. Main priorities for Galson are to continue integrating biologics staffers into CDER and prepare for the move to new offices at White Oak next year. Another challenge, Woodcock notes, is dealing with a constant bombardment of lawsuits related to generic drugs.

In the Office of the Commissioner, Woodcock plans to remain in charge of initiatives to update good manufacturing practices and to develop guidance on protein characterization, among many others. One specific priority is to develop an agency proposal for dealing with genericor follow-onbiologics, which is expected this spring.

Although FDA will continue to function well, McClellans departure leaves a big hole at the agency. As one of the more activist and outspoken commissioners, he advocated for policies to spur medical innovation, including more equitable global pricing of drugs as one way to reduce U.S. prices. He also has been particularly enthusiastic about FDA collaborative efforts with the National Cancer Institute and other organizations to streamline clinical research and spur development of new critical therapies.


The main criticism of McClellan has been his tendency to propose dozens of initiatives without the resources to follow up and implement them. McClellan leaves FDA with a mountain of unfinished business, but also with a strong list of accomplishments for someone at the agency less than 18 months:

  More useful DTC advertising. FDA issued draft guidances in February that offer new approaches to communicating drug risks to consumers. One proposal encourages pharmaceutical companies to replace the tiny-print brief summaries in print advertisements with more comprehensible and useful information formats. A companion guidance encourages marketers to support more educational advertising using FDAs help seeking format.

Action against dietary supplements. FDA developed sufficient evidence in the past two years to pull ephedra off the market. The move may face legal challenges, but it represents a ramp-up in enforcement of policies to limit claims by supplements experiencing  serious safety problems.

 Campaign to block counterfeit drugs. Working on a tight time frame, an FDA task force issued a final report on Combating Counterfeit Drugs in February. The centerpiece of the plan calls for manufacturers to insert tiny radio frequency identifier (RFID) chips in drug labels and packages in order to track a product as it moves through the drug distribution system.

 Support for bar codes. FDA also published a final rule requiring manufacturers to print linear bar codes within two years on packaging for most drugs, vaccines, blood products and some over-the-counter drugs used in hospitals. The bar codes do not have to carry lot numbers or expiration dates, and the rule doesnt mandate unit-of-use packaging; however, demand from hospitals and other purchasers is prompting manufacturers to move in that direction.

 Monitoring of financial claims. FDA recently announced plans to work more closely with the Securities and Exchange Commission (SEC) to better identify false or misleading company financial announcements related to FDA review decisions. FDA and SEC officials have streamlined processes for requesting and exchanging confidential information from companies developing and seeking approval of new drugs and medical products. A new centralized system under Office of Regulatory Affairs chief John Taylor aims to eliminate redundant paperwork and clarify responsibilities of FDA staffers. FDA says it will protect confidential information from regulated firms, but companies that issue misleading statements could face public release of proprietary data if the feds take them to court.


FDAs plan to combat drug counterfeiting envisions an RFID-based tracking system that would create a de facto electronic drug pedigree in three or four years. This technology would eliminate the need for a tracking system based on paper records, as required by the Prescription Drug Marketing Act (PDMA) of 1987. This was scheduled to become effective April 1 of this year, but FDA instead is encouraging industry to establish an electronic tracking system. 

The anticounterfeiting initiative also calls for stiffer criminal penalties for parties that produce bogus products, stronger regulation of drug wholesalers by states, and increased involvement of health professionals and consumers in identifying and reporting suspect prod-ucts. FDA also asks manufacturers and other parties to do more to ensure the security of their operations and sites to prevent theft and diversion of products likely to facilitate illegal production activities. 

One question is whether it makes sense to require bar codes now when e-chips used to prevent counterfeiting may make the linear codes obsolete over the next decade. However, HHS secretary Tommy Thompson wanted to implement the bar code system now as one way to spur formation of a national electronic health information system. Ultimately, an e-health network would track drugs through the distribution system, identify outliers and counterfeit products, facilitate recalls, detect prescribing errors, and ensure the safe and appropriate use of prescription drugs.


New electronic technologies that can distinguish between genuine, approved medical products and those that are adulterated, unapproved or illegal also might address some of the safety concerns held by manufacturers and regulators about the current drug import surge. While not all illegal imports are counterfeits, FDA believes that Internet purchasing opens the door for bogus products to enter the U.S. market. 

The increase in shipments of unauthorized drugs to U.S. customers has prompted an FDA crackdown. Data from IMS Health shows that sales of prescription drugs reimported from Canada to the U.S. topped $1 billion in 2003 vs. $500 million the previous year. An FDA sting operation in January netted evidence of counterfeit and mis-branded products being mailed to Amer-icans and led to actions against Texas importers. The tension heated up in February when several state and local governments launched new efforts to help citizens obtain drugs from Canada. 

FDA objected strongly that these state initiatives could threaten patient safety by opening the door to more misbranded and counterfeit therapies. FDAs oppo-sition to broader drug importing has prompted some members of Congress to propose legislation that would legalize lower cost imports of prescription drugs. In addition, several senators threatened to block McClellans appointment to CMS until he explained his anti-import stance. 

While Congress debates drug import proposals, FDA analysts are examining what resources the federal government would need to make drug re-importing safe, as required by the new Medicare reform legislation. HHS secretary Thompson recently established a special Task Force on Drug Importation to examine more publicly what kind of policies and initiatives are needed to import drugs safely and how such activity would affect medical costs and development of new therapies. Surgeon General Richard H. Carmona will be chairman, replacing first pick McClellan, who drew criticism from Congress. The task force includes representatives from CMS and other federal agencies such as the Bureau of Customers and Drug Enforcement Administration. 

The task force plans to meet with consumer groups, health care professionals, purchasers, state officials, and manu-facturers to estimate what agency resources would be needed to adequately inspect pharmaceuticals entering the country. The agenda also calls for assessing whether anticounter-feiting technologies could assure product safety and analyzing how increased drug importing would affect development of new medical products.            

View from Washington

New Leadership, New Policies at FDA

Although the worlds of EMR and clinical trial technologies are similar, they have quite a few differences as well.

 is that there is a parallel world, coexisting with ours, but not apparent to any of us. This concept has long been part of science fiction, great literature (the short story The Garden of Forking Paths, by Jorge Luis Borges), and has now taken a place in modern physics with the gradual acceptance of string theory. 

The idea of a parallel universe is a very nice metaphor for the two worlds where technology touches clinical dataour world of clinical trial technology and the parallel universe of electronic medical records (EMR). These two worlds are so close to one another that the general public assumes that they are, in fact, one and the same. The primary end user is the same (the physician and nurse), the data collected is very similar, and the requirements for privacy, security, and data quality are more or less equivalent. Once we recognize that these two worlds exist, we have to wonderhow are they the same? How are they different? And, where is the most logical point of connection between them? 

Adoption technology in the two worlds has run in parallel as well. Until a few years ago these technologies were used for less than 5% of data collection, and there were tens to hundreds of vendors offering technologies that were difficult to distinguish from one another. However, with the emergence of the Internet, enterprise computing, and the general societal adoption of electronic technologies, the adoption of these technologies is rapidly rising and the spectrum of vendors is narrowing to a smaller number of larger vendors.

Despite the obvious similarities, the EMR and clinical trial technology worlds are very distinct from one another. The most obvious reason is that the end consumer of the data is very different in each case. In the world of the EMR the consumer is either another physician or third-party payors. Therefore, these systems are bought by hospitals, clinical practices, and insurance companies. 

Clinical trial technology, in contrast, is typically purchased by pharmaceutical, biotechnology, and medical device companies who are conducting clinical trials. The types of data collected are very similar, but quite differently structured; while clinical trial data is highly structured by visit schedule and expected content, EMR systems must be able to capture a much larger collection of data types with far less standardization.The result of the differences in buyers and purposes is that EMR and clinical trial technologies have developed in parallel (driven by the availability of technology and process needs) but almost completely apart from one another.

My feet are firmly planted in the clinical trials technology universe where I typically spend my waking hours. If you dont live and breathe clinical trials technology, you can always get a good sense of it by walking the exhibit hall floors at the Drug Information Association Annual Meeting in June. The floors are filled with technology companies from large corporations to small entrepreneurs. All companies on the floor work hard to showcase the latest technology that they have developed. If you spend some time looking at the booths, you will understand the state of the art of technology in clinical trials for the coming year.

The parallel of the DIA annual meeting for the EMR is the HIMSS meeting, held annually in February. I attended HIMSS this year, and had the opportunity to walk the halls and experience this parallel universe. The HIMSS meeting is truly impressive in scope and scalein headcount alone it is over three times the size of the DIA, approaching 20,000 attendees. My expectations of the parallel but nonintersecting nature of this universe was confirmedthere were very few people from the pharmaceutical industry that I saw, and almost no presence or acknowledgement of the industry on the trade show floor. The exhibit floor itself was teeming with technology vendors displaying applications that were very similar to those shown at the DIA. Yet, the companies were almost entirely different entities than those at the DIA.

The general feel of the meeting was that of an industry in transition from individual point solutions to an integrated, enterprise suite of applications addressing the entire patient life cycle from registration, scheduling, patient input, physician data, lab data, record archiving, billing, referrals, third party payments, and notifications. Each of these has existed as standalone solutions, but companies like GE Medical Systems, Eclipsys, IDX, and Siemens are weaving these together into integrated solutions for practices and hospitals. The true value of these products is becoming apparent to institutions more as a suite than as individual solutions. This trend also parallels the adoption of technologies in many industries in the pastincluding financial services, customer relationship, supply chain management, and of course typical desktop applications.

Another notable trend was the very prominent presence of major companies in the information technology industrycompanies like Microsoft, IBM, and Hewlett Packard. The news coming from the upcoming DIA show is similar. Clearly, health care IT and pharmaceutical IT have reached the level of attention of these giants. With that comes much innovation from smaller, more fleet-footed, entrepreneurial companies. This kind of attention brings long-term benefits to the buyers of this technology.

Amidst the sea of exhibits, I was able to discern a few very revealing trends in the health care industry that clearly have parallels in the pharmaceutical clinical trial market.


As more and more processes in health care become fully automated, decision makers are beginning to demand near real-time information from most of these.  In the past, this meant opening each applicationsome legacy and some newand using the native reporting tools available to view and explore information. This process is frustrating and painful for the average business user, and most industries are moving towards an integrated view of the various systems and data available through an enterprise portal. You can think of an enterprise portal much like a My Yahoo, whereby a Web page is broken down into 612 component sections. A user might think of this as a single Web page, but each of these sections represents a view of a particular data source, which is probably functionally distinct from the other sources, and may even be geographically distant.

An enterprise portal can tie together information from dozens of different systems and display this in a uniform environment. One section of the portal may represent a document room, with key forms and information available for viewing, printing, or editing as necessary. This could serve to provide consistent, centralized information or provide a central file storage for collaborative projects. Another section might be a window into secure emailwhere encrypted, secure, HIPAA-compliant email could be viewed, sent, and archived. A third section might have news and conference information, streamed from other Web sites through RSS Web services. Finally, one or more sections may be dedicated to reports from enterprise applications. 

When designed well, the views can have three levels. First is an alert level which has little information, but can keep managers abreast of overall status of a project. Think of a company that manages a group of hospitals across the country and needs to monitor bed availability. The alert level might be a set of gauges indicating percent occupancy of individual hospitals colored red, yellow or green to indicate the presence of an issue. 

Next is a report level with information summarized in tabular form, for example a list of hospitals and units within these hospitals with bed occupancy, and types of patients (male/female, medical/surgical, etc.). This more detailed view may be available to an upper-level administrator by clicking on an alert level indicator, or it may be the opening screen for an operational project manager. Finally, a click on an individual unit could lead to the third levelthe data level. Here you would view individual patients, with ID numbers, diagnoses, etc. This information might only be available to some users, depending on their rights within the system (and identified by their login authentication username/password).

The development of enterprise portals is an intermediate step in the true integration of systems and processes. These portals dont require systems to be fully integrated; they only need the ability to query and display information from a variety of disparate applications. Whether they are 20-year-old accounting systems or state-of-the-art EMR systems, they can appear to be part of a single integrated system through an enterprise portal.

Enterprise portals are being designed and implemented for pharmaceutical applications as well.


The next trend is true system integration, an ideal that is becoming more achievable through the development of standards; in the case of health care this is being led through the HL-7 effort. Beyond the standards, though, is the development of integration broker technologies, often based in XML standards. In the past, connecting individual software applications required direct plumbing between the two applicationsa manual job that required adjustment or even a complete redo every time one or the other application changed. When considering a hospital system with dozens of applications, the work of integrating these applications grows at an exponential rate. Enter the integration broker.

Integration brokers work through managing messaging through a common information bus. The broker listens to data coming from one application, transforms it into a data schema that is understandable by another application, and routes the newly transformed data to its target. By providing bidirectional messaging between applications, the integration broker makes it possible to weave together software solutions so that they work together. Thus, a physician order entry system can communicate with a drug safety system, a clinical pharmacy robot, and a billing system through an integration broker, ensuring that drug interactions are noted and that the proper drug is dispensed and billed to the patient.

The advantages of integration brokers are not lost on pharmaceutical clinical trial technology. More on that in a future column.

Applied Clinical Trials-04-01-2004

eShowcase

Informed Consent: Reading and Understanding Are Not the Same

Reconsidering Third-Party Companies for Subject Enrollment

Gathering ?Buts? in May

New Leadership, New Policies at FDA

Parallel Universes?Technology in Health Care and Clinical Development

Subject Recruitment and Retention: Barriers to Success