A MANAGER’S GUIDE TO THE DESIGN AND CONDUCT OF CLINICAL TRIALS - PART 7 pot

Here is how this works: If a client tion were to open a file stored on a file server directly, it would need applica-to retrieve and transfer every record across the network just applica

perform the operations The server reduces the risk of data file ruption, because only the server writes to the database; a crash orpower outage on a client desktop—a not infrequent occurrence—willnot leave the database in an incomplete state.

cor-A database server takes advantage of the client-server architecture

to lower network usage Here is how this works: If a client tion were to open a file stored on a file server directly, it would need

applica-to retrieve and transfer every record across the network just applica-to filterout the ones it really needs Instead, the database server filters outthe unneeded records and only sends out over the network the datathat really matter Microsoft’s PC-based Access®is a relational data-base, but it is not a database server MS-SQL, SQL Anywhere®,DB2®, and Oracle®are both relational databases and databaseservers

One Size Does Not Fit All

Bumbling’s Clinical Affairs Department insisted that all studies usenot only the same data management system but the same databaseconstruction, the rationale being that this would further reduce devel-opment costs Here’s what actually happened:

• The cost of developing the data analysis software doubled because of the constant need to extract and merge subsets before any analysis could be performed.

• Because so much of each file was waste space, devoted to ables not in the current study, retrieving the information proved enormously time consuming and almost brought the corporate mainframe to its knees.

vari-• Information Systems kept buying larger and larger hard disks, but invariably ran out of space as the files with their hundreds of dummy variables were an order of magnitude larger than they should be.

• The complex keying instructions that resulted when several pieces

of information had to be combined into one to “fit” the standard design introduced a large number of errors that had to be corrected.

• Programmers had to work overtime during the analysis phase designing programs that would unpack the data that had been combined and recoded during the keying process.

COMBINING MULTIPLE DATABASES

For the reasons discussed in the preceding sections, we need to divideour data up among several files (or databases) and then find some

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way of linking these files together How should we divide the

data up? A good rule of thumb is to combine all the information collected by a single individual at a single point of time in the samefile

We link the disparate files with the aid of keys A key is an

element of information common to several databases that serves totie the databases together One obvious key is the patient ID;

another is the date on which a particular examination was

completed

The key item must be stored in each of the files it is to link Apatient’s name is not a good choice for a key as it is something wewish to keep confidential and thus stored in as few locations as possi-ble A patient’s sex, the length of a target lesion, or the dosage of thedrug the patient is receiving are not good choices because their pres-ence in more than one database would be redundant

A good rule of thumb is to use the patient ID as a primary key totie all the databases together and to use an examination date or someother value as a secondary key to tie together information that isclosely related An example of related data might be the adverseevent form on which the need for a certain action was recorded alongwith all the databases containing the information related to thataction

A RECIPE FOR DISASTER

In Chapter 8, the importance of providing detailed instructions wasillustrated with an example from an almost-successful study The

“almost” came about when Bumbling Pharmaceutical acquired the

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Every time you have a column whose

value must come from a known set of

values you have a “domain” for that

column Your domain may be as simple

as the day of the week (SUN, MON,

TUE, SAT), as lengthy as a list of

anatomical sites, or partially unknown

as the set of adverse events Domain

tables reduce storage requirements by

associating an ID (or code) to a name or

description Whether the investigator

enters a symptom name or its

abbreviation, only one of the two (your choice) is permanently stored.

In addition to providing the benefits

of flexible data entry (accepting “close” misspellings such as “asperin”), domain tables provide faster queries, faster sorting, lower storage, and ease in updating They’re a standard part of most relational systems, present in both the least and the most expensive.

trial’s sponsor shortly after the trials were under way Severe errors

in database construction (resulting from forcing the data to fit into the standard corporate data model) led to a subsequent

failure to locate and recapture information essential to the

analysis of treatment effects Recovery was labor intensive and time consuming, resulting in substantial delays in completion of the study

The company’s first error lay in adopting an older hierarchicaldatabase management system in use by accounting The rationale wasthat the product was already in use so the database programmerswould not need to be retrained Of course, these same programmerswere already tied up with their work in accounting, so a whole newgroup had to be hired and trained in a system generally considered

to be obsolete

Bumbling’s second and incurable error lay in setting up the base Each of the case report forms was split into a half-dozen parts:investigator’s signature and date to one file and the dates of variousevents to another One whole file was reserved for keeping the dates

data-of patients’ visits Unfortunately, there was no way (other than thedates themselves) to link these visits with the various follow-upforms

An intricate coding system using a page name and an “event”would have worked had, for example, the one-month follow-up actu-ally taken place exactly one month after the start of the intervention.But it never did, except on rare occasions

If the occasional form did not get entered in the database (andbecause Bumbling was using paper forms for initial data entry, therewere always forms that did not get entered in the database), onecould never be sure which form went with which date in the visit register

Although not explicitly stated in the original sponsor’s protocol (as

it ought to have been), good medical practice required that thetaking of a repeat angiogram precede revascularization The dataindicating a repeat revascularization had been performed were(mainly) stored in one file whose possible keys included the patient’s

ID, an “event” ID, and the date of surgery The data for the sponding angiogram were stored in two separate files, neither ofwhich contained the date on which the angiogram had been taken.The keys for these two files included the patient’s ID, an “event” ID,and a “page” name

corre-A different coding system had been used for the event IDs thanthat used in the revascularization file, so it was impossible to

CHAPTER 11 DATA MANAGEMENT 153

reconcile the two Fortunately (?), there was a fourth file in whichthe dates of patient visits were often recorded; its possible keysincluded the patient ID, an “event” ID (using approximately thesame coding system as the files), and the date of the visit For revas-cularizations, the recorded visit date might or might not coincide withthe date of surgery.

The only data that could be utilized for the automated (computer)analysis were results for which there was an unambiguous linkbetween the angiogram and the revascularization The angiograms forapproximately 5% of the patients in the trial had simply fallenthrough the cracks

Fortunately, after a lengthy inspection of the original records byhand, almost all were located The programs used for analysis weremodified to incorporate explicit reference to the individual patientrecords and to maintain a clear audit trail for the regulatory agency.The losses in money and time were absorbed in the company’s profitand loss statement

Bottom Line: Despite having a computer that could process arecord every millisecond, the company ended up doing hand counts

at a rate of one per minute Kind of reminds you of the 2000 Florida Presidential election

Transferring Data

Transferring the data entered at each physician’s and each tory’s computer to the central database can be done in one of threeways:

labora-1 Enter directly at each physician’s computer.

2 Transfer the data automatically at day’s end via telephone to the central database.

3 Copy the data each day to a CD; at the end of the week the CD is mailed to your staff to be entered into the database.

Direct entry at each investigator’s cite to the master database isruled out because of the impossibility of maintaining a continuouslink to multiple disparate computers that may be hundreds, eventhousands of miles apart

Which of the last two options to adopt will depend upon thevolume of data you expect to receive from each treatment center

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35 As with so many of Bumbling’s efforts, no documentation was ever found for either coding system Apparently, it had been left to each employee who quit, retired, or transferred to another department to brief his replacement.

With either alternative, a second data entry program “reads” thetransmitted files and enters the records into the database Humanintervention is required only to start the program and slip the CDinto the host computer’s CD drive.

Separating the two stages of data entry guarantees that tors’ contact with the database is strictly limited They can enter theirdata in the database, but they cannot modify it once it is entered Norcan they access the database and be exposed to findings that mightcolor their own observations

investiga-Data Entry Via the Internet A fourth alternative is to have the

data collection forms stored on a single central computer to beaccessed and completed via the Internet The chief advantages of thisapproach are that updating and distribution of trial protocol and datacollection forms can be accomplished at a single location so thatfewer monitoring visits and monitoring personnel are required (SeeLallas et al., 2004; Lopez-Carrero et al., 2005; Marks et al., 2001).The offsetting disadvantages include:

• High-speed Internet connections are required at each teminal.

• Real and perceived security threats may inhibit both patients and study centers from participating.

• The intervening Internet service providers as well as the Internet itself may be unavailable for varying periods.

• The industry is far from stable Third-party Internet resources may cease to exist before the completion of the study.

Note also that when data collection and verification is conductedvia the Web, new data management methods and software may berequired See, for example, Brandt et al (2000) and Wübbelt,

Fernandez, and Heymer (2000)

QUALITY ASSURANCE AND SECURITY

Maintaining Patient Confidentiality

The patient’s name, address and other identifying information should

be stored in one file only, and access to that file should be severelyrestricted References to patients in other files should be by coded

ID only

Access to Files

Although the ability to write to and modify a clinical database can

and should be restricted to a privileged and responsible (and readily

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monitored) few, everyone with a need to know (CRMs, project

leaders, project physicians) should be able to access and read from

the database and, moreover, to do so in a manner no more difficultthan the manner in which data are entered into it

Your data management software should permit you to establishprivileges on a file-by-file basis for every individual who will haveaccess to the system Too often, data managers and statistical analystsfunction as some kind of primitive priesthood, issuing proclamationsthat they and only they shall be privileged to access the clinical data-base But with today’s databases, security can be readily maintainedwhile giving those with a need to know immediate access to the datathey need

A single individual, normally the database manager, is entrustedwith issuing passwords and security levels to all those seeking access

to the database.36

Full access would include the ability to read from, write to,

update, and even delete files These privileges are necessities whilethe database is still under construction Full access after the database

is constructed should be limited to the database manager and hisassistants

Access should be granted on a file-by-file basis Access to the filecontaining a patient’s name, address, and other identifying informa-tion and to the file containing the treatment assignments should beseverely restricted Read-only access to most of the other files should

be made on a need-to-know basis Here are two examples:

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36 Security levels are assigned both to individuals and to automated applications.

Although the date of discharge from

the hospital was included on the

case report forms, Bumbling

Pharma-ceuticals decided not to include this

information in the database The

ratio-nale for this deletion was lost after the

database designer was promoted Later,

when it was realized the date of

dis-charge was essential to a comparison

of adverse events in the two treatment

groups, the preliminary analysis had

to be done by hand rather than by

computer.

To avoid bumbling yourself, always

• Begin with your reports.

• Plan for and collect the data you’ll need for your reports.

• Store the data you collect.

• Store the data as they were entered.

• Design the database in terms of one file or table for each set of data that was entered by the same person at the same point in time.

1 The pathology laboratory should be able to both read and write to the file containing pathology reports.

2 Until the trials are complete, investigators should not be given

direct access to the database, not even to their own data Instead, they would submit a request to the CRM and the CRM would

provide them with any needed data that is consistent with the

guidelines you and your data manager have established.

While the database is under construction, the database manager

normally makes all the decisions regarding who should have access tothe database, the level of access they should have, and the files theyshould be permitted to access Just before the start of full-scale dataentry, the database manager should submit a chart similar to Figure11.4 to you for your approval Thereafter, all decisions as to access tothe data will be yours alone

Maintaining an Audit Trail

To avoid even the appearance of fraud, and to satisfy government

regulations, all changes to the database must be automatically

tracked and recorded by the system

they want to know Other information they will attempt to glean

from your employees.37

To protect the database, you will need to backup (copy) and testyour data on a regular basis and store at least some of the backup

CHAPTER 11 DATA MANAGEMENT 157

FIGURE 11.4 Tonto Project: Database Access Privileges.

37 The best solution to this latter problem is to ensure employee loyalty through

ongoing effort See Gandy (2001) and Mendes (1995).

Mike Chuck Statistician y y

Seri Shanti Programmer y y y

copies in a remote location Standard practice is the cycle of 3 times 5, and sometimes 7).

(some-Backups are made on the evenings of days 1, 2, and 3 On the night

of day 4, the backup of day 4 is sent to a remote location and thecycle is restarted; the backups of days 2 and 3 are discarded as days 5and 6 backed up

Although backing up the database and storing the backups at aremote location are essential, you’ll need to do more Backing updata that is already contaminated is pointless You’ll need to run tests

on your database before a backup is made These tests are larly important during the early part of the trials when you areunlikely to be accessing the data on a regular basis

particu-Tests should be made on a file-by-file basis Possible tests include:

• Selecting five records at random from each file

• Counting the total number of records

• Printing out the minimum and maximum of at least two of the fields

FOR FURTHER INFORMATION

Brandt CA; Nadkarni P; Marenco L; Karras BT; Lu C; Schacter L et al (2000) Reengineering a database for clinical trials management: lessons for

system architects Control Clin Trials 21:440–461.

Date CJ (1999) An Introduction to Database Systems (Introduction to base Systems), 7th ed San Francisco: Addison-Wesley.

Data-Garcia-Molina H; Ullman JD; Widom J (1999) Database System tion Upper Saddle River, NJ: Prentice Hall.

Implementa-Gandy BG (2001) 30 Days to a Happy Employee: How a Simple Program

of Acknowledgment Can Build Trust and Loyalty at Work New York:

Fireside.

Kelly MA; Oldham J (1997) The Internet and randomised controlled trials.

Int J Med Inform 47:91–99.

Lallas CD; Preminger GM; Pearle MS; Leveillee RJ; Lingeman JE; Schwope

JP et al (2004) Internet based multi-institutional clinical research: a

con-venient and secure option J Urol 171:1880–1885.

Lopez-Carrero C; Arriaza E; Bolanos E; Ciudad A; Municio M; Ramos J; Hesen W (2005) Internet in clinical research based on a pilot experience.

Contemp Clin Trials 26:234–243.

Marks R; Bristol H; Conlon M; Pepine CJ (2001) Enhancing clinical trials on

the Internet lessons from INVEST Clin Cardiol 24:V17–V23.

Mendes A (1995) Inspiring Commitment: How to Win Employee Loyalty in Chaotic Times New York: McGraw-Hill Professional Publishing.

Paul J; Seib R; Prescott T (2005) The Internet and clinical trials: background,

online resources, examples and issues J Med Internet Res 2005 7(1):e5.

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Prokscha S (1999) Practical Guide to Clinical Data Management Englewood,

CO: Interpharm.

Rondel RK; Varley SA; Webb C (2000) Clinical Data Management, 2nd ed New York: Wiley.

Wübbelt P; Fernandez G; Heymer J (2000) Clinical trial management and

remote data entry on the Internet based on XML case report forms Stud Health Technol Inform 77:333–337.

CHAPTER 11 DATA MANAGEMENT 159

Chapter 12

Are You Ready?

CHAPTER 12 ARE YOU READY? 161

T HIS CHAPTER IS INTENDEDto serve as a master checklist before you startthe actual study Hopefully, most of the points touched on here, many

of them quite minor, have already been disposed of by your staff But

as with a vacation whose first few days are ruined because you forgotthe mosquito repellent, a few extra moments of reflection beforeyour departure can yield large dividends

We begin by reviewing the basis of your study, the pharmaceuticals

or devices that will be used in the intervention—you do have a fullsupply on hand?—and then go over points to be covered with yourinvestigators and site coordinators, the final field tests of your ques-tionnaires, data entry software and hardware, and uniform instruc-tions to be issued to participants

PHARMACEUTICALS/DEVICES

• Preferably, all devices and drugs used in the study should be drawn from the same lot and set aside before the start of the study Obvious exceptions include prohibitively expensive devices that are normally manufactured on a just-in-time basis and phar- macological agents whose potency deteriorates quickly.

• Controls should be matched to the active intervention on the basis of both appearance (size and color) and taste The matching should be verified by your staff.

• All vials should be labeled with the patient’s name, the patient’s

ID, and (if applicable) instructions for self-administration (e.g., twice a day with meals).

A Manager’s Guide to the Design and Conduct of Clinical Trials, by Phillip I Good

Copyright ©2006 John Wiley & Sons, Inc.

• To monitor compliance, the patient should only be supplied with the amounts of pharmacological agents needed for use until the next scheduled checkup.

• The initial labeled supplies should have been shipped to the investigators.

SOFTWARE

• Data entry software is completely debugged and tested.

• The variables and layouts of the interim reports have been determined.

• Software for tracking recruitment is in place and has been tested.

• Established the identity of the single individual who will be responsible for ensuring the orderly collection and monitoring of data.

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• Conducted training programs for the chief investigator and all individuals who will have contact with patients or be involved in data entry.

• Provided copies of procedures manuals and of the forms to be given to patients These latter include informed consent, study overview, and any instructions needed to ensure compliance.

• Supervised the installation of the data entry computer and field tested the software, the hardware, and the communication links with your office.

• Duties determined (As an example, the safety committee will classify all adverse events as to whether or not they are treatment related.)

• Meeting arrangements determined (For example, the members of the safety committee will each make an independent review, then teleconference monthly for a final determination.)

• All committee members recruited.

PATIENTS

• Recruitin g quotas determined for each treatment site.

• Recruiting methods determined subject to ongoing review.

• Patient instructions ready for field test.

REGULATORY AGENCY

• Agency has approved the trials.

TEST PHASE

In most case, it can be advantageous to hold a preliminary test phase

at one or two sites to ensure that all systems are fully functional Theevaluation would include field tests and possible revision of

CHAPTER 12 ARE YOU READY? 163

• Drug/device delivery procedures

• Data entry software

• Transfer of data from the investigator to central storage

• Transfer of samples from investigator to external laboratory and

of data from external laboratory to central storage

• Physician and laboratory manuals

• Recruitment procedures

• Patient instructions

A report on these tests with a list of proposed modifications should

be made to the implementation committee

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