Chapter 7

Resources

MANPOWER

Managing manpower, or what is more politically correctly termed humanresources, is no easy juggling act. Nevertheless a project manager should be ontop of this aspect of the job. Once again the approach is a continual cycling ofthe plan, track and adjust loop. If you like linked spreadsheets, then this activitywill be a joy for the duration of the project.

The first step is to identify the work categories required. For a small clinicalteam, this may look something like this:

Project physician Project manager Clinical team leader Senior CRA CRA Project assistant

Next you will need to need to decide how many FTEs of each work category arerequired in each unit activity planned (See Chapter 5 on Budgets and Chapter 6on Time). Then convert your unit activity timeline to weekly totals of FTEcommitment (ie all unit activities/work category).

The FTE profile of each work category will of course shift like desert sanddunes as time progresses. During the planning and set-up phase there will be ahigh level of project physician and project manager input. Then as the studyprogresses into clinical treatment, clinical team leader and CRA involvementwill grow, peaking at last-patient-out. From then on, emphasis will turn to datamanagement staff, statisticians and medical writers as the project draws to aclose.

The map of this changing demand needs to be matched to staff availabilitywithin the matrix management system (see Chapter 3). If other project managershave made similar resource projections, it should be apparent to line managerswhich periods represent under-resourcing and vice versa. This may lead todecisions to hire new staff, outsource to a CRO, retrain staff, or even downsize.

It is inevitable that conflicts will arise between the resourcing needs ofdifferent projects, particularly if they are running on similar timelines (eg end-

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of-year database lock). There needs to be a mechanism for efficiently resolvingsuch situations by prioritization. When comparing the needs of two projects, ifone resource demand is for a critical path activity (see Chapter 6), then thisshould take precedence over a non-critical activity.

If both requirements are critical, then a decision should be taken at a seniorlevel as to which study should receive the resource. This may reflect thecommercial importance or risk of one study over another. Equally, it may bejudged that time lost on one project can be recovered later by over-resourcing asubsequent activity.

In common with other aspects of the project, it should be possible to track theactual time spent by staff in completion of unit activities. This normally involvesteam members completing daily electronic timesheets, in which they code theactivities performed. Wide area networking technology then makes it possiblefor a project manager to review timesheet summaries compiled from manyinternational offices.

This serves two purposes. First to check that tasks are being performed by theappropriate categories of staff, and second that estimates for resources requiredto complete activities are accurate. Deviations in either case would prompt youto analyze and correct the problem.

DRUG SUPPLIES

The management of investigational product (study drug) is a resourcing activityunique to clinical studies. It is generally handled by a specialized studyproduction support department or contractor, in liaison with the formulationteam. These staff will be working within Good Manufacturing Practice (GMP)regulatory guidelines to ensure that the product is manufactured as specified,cross-contamination is avoided, and that there is full traceability of allingredients, as well as the finished product.

The study design requirements should be shared as early as possible with theproduction group, to give them time to set up. They will need to know theproject timeline, number of countries, number of investigators, dose regimen,treatment period, and number of patients planned.

If the drug is still in early development, then supplies production is likely tobe a critical activity. The manufacturing process is probably yet to be finalized,particularly if adjustments are still being made to the formula and dose strength.Production will have to be scaled up from the lab bench to factory, andrevalidated with test batches before study supplies can be generated. This willinclude stability testing of the finished product. It is a perennial issue that therewill thus be only a minimum of stability data available at the study start, and thatsuch testing will be ongoing. At this stage, storage specifications are oftenjustified by accelerated stability testing. Following the Arrhenius principle,

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analytical results obtained from 40 and 50C shelf studies will be used to fast-forward time and predict the long-term chemical behavior of the formulationat normal temperatures.

As part of GMP QC, the bulk product will be analyzed against a physico-chemical release specification, and a Certificate of Analysis generated. Incertain regulatory environments (eg EU), local laboratory retest of the bulk orpacked drugs may be required on importation. This is something to take earlyadvice on from your regulatory colleagues. Given the novel nature ofinvestigational products, their analysis is not always straightforward. I onceexperienced a months delay on a timeline because a British laboratory was notfamiliar with the methodology developed by the Japanese manufacturer fordetermining their active agent.

Phase III studies are generally conducted under double-blind conditions, withthe medication presented in such a way that neither the patient nor investigatoris able to tell which treatment is being administered. Placebos or differentstrength study drugs should thus be manufactured so as to appear the same. Thisis simply achieved for medicines which can be prepared in standard capsuleshells, identical size tablets or clear liquids. As necessary, dyes and flavoringscan be employed to mask characteristics of the drug which may otherwiseunblind the treatment.

This becomes more complex however when a marketed comparator agent isinvolved. One approach is to purchase the standard product, grind it down, andfill into standardized capsules or dissolve in solution. The problem with this isthat time-consuming bioavailability and stability studies then have to beperformed to validate the new product.

A second strategy is the double dummy method. Here matching placebosare prepared for both presentations. For example, if the study involves a studydrug capsule and a comparator tablet, then all patients would take one capsuleand one tablet. Depending upon treatment allocation, one of the units would beactive, and the other a placebo.

As is the case with the study formulation, packaging will usually be thatintended for the marketed product, to avoid further stability and bioequivalencetesting. As child-resistant devices are increasingly being demanded bygovernment agencies, your regulatory department needs to check for whichcountries these are required.

The investigational product will normally be packed in sets of individualpatient supplies (ie sufficient for each throughout the study), identified by aunique code number. For randomized studies, these will often be in a secondaryshipping box, containing a statistically balanced block of treatments. Forexample supplies may be provided in groups of six patient supplies: within eachare 2 placebo, 2 50 mg, and 2 100 mg, randomly assigned to a sequenceof code numbers. Thus in order to be able to pack the supplies, the productionsupport group need the finalized randomization schedule from biostatistics.

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Indeed it is customary to dispatch the randomization emergency code-breakenvelopes to the investigator with the drug shipment.

The labeling of investigational products is controlled by regulatoryauthorities. Thankfully this is largely harmonized internationally. The followingexample label is compliant with both FDA and EU guidelines.

Figure 7.1. Clinical Studies Label Format.

Nevertheless it is generally required that labeling should be in the locallanguage. Time should thus be allowed for translation and back-translation oflabel copy. In some countries (eg Belgium, Israel) more than one language maybe required. Once the product is labeled in a given language then you arecommitted to using it in that territory. Increasingly labels are provided in multi-lingual booklets to provide flexibility in this respect. Even so, it is advisable tomaintain a reserve of unlabeled product as a contingency should it be necessaryto introduce a new country to the study.

This brings us to another issue, the management of supplies distribution. In anideal world, all the investigators in a study would enroll patients (ie consume drugsupplies) at the same rate. The reality however is that some will never recruit apatient, while others enrol prolifically. This presents two problems: First, how toprovide adequate supplies to all investigators without wasting materials at the lowperforming sites. Second, how to avoid the unbalancing of treatment allocationswhich follows if randomization blocks are not completely used.

The answer to both questions is centralized treatment allocation. In thisenvironment the investigator contacts a central facility before dispensinginvestigational product, in order to receive the treatment code number to use.The designation will follow a scheme such that across the study centers as awhole, medication is dispensed in a balanced sequence (ie 1, 2, 3, 1, 2, 3, 1, 2,3). This is generally achieved using a telephone automated IVRS.

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The act of centralized randomization also provides for accurate tracking ofpatient recruitment. The first spin-off from this is that the data can then beaccessed by the project manager to generate up-to-the-minute status reports.These in turn can be used to monitor investigator stock levels, and trigger timelyproduct resupply from local distribution centers on an as needed basis.

The last banana skin in drug supplies management is the product expiry date.We saw earlier that clinical studies will usually start when there is only minimalstability data available on the new formulation. We also noted that as withmarketed drugs, regulatory agencies require that the product expiry date isincluded on the label.

It is thus typical to find that nine months into the study, the labeled expiry dateis reached. By this time however, the formulation group will have accumulatedfurther stability test data. If the results of this do not support extension of theshelf-life, it may mean that the original product has to be replaced. So it is crucialthat the retesting occur early enough to allow manufacture, QC, packaging anddistribution of new supplies before the original materials expire.

If the retest result is positive, all that is required is relabeling of the supplieson site with a revised expiry date, justified by the new certificate of analysis.

To summarize, the study production support group should be involved at theearly stages of protocol planning, so that they can make provision for the dose/placebo formulations required, manufacturing scale-up, stability testing andbulk materials production. When it come to packaging, input will also berequired from biostatistics in terms of the randomization schedule, andregulatory affairs for label copy.

Using a centralized IVRS randomization system, statistical balance ismaintained across the study in the allocation of treatments, and reports are usedfor recruitment tracking, and triggering just-in-time re-stocking of investigators.The formulation group will also have an ongoing role through the study:monitoring batch stability, providing retest certification and, where necessaryorganizing manufacture of replacement materials.

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ContentChapter 7 ResourcesMANPOWERDRUG SUPPLIES