PAGE 32 MARCH 2004JOURNAL OF VASCULAR NURSINGwww.jvascnurs.net

Research Column

An overview of clinical trialsKathleen Rich, MS, RN, CCNS

The development and release of a new drug, interventionaldevice, or therapy is not a haphazard process. The Food andDrug Administration (FDA) must approve all research thatinvolves a new medication, treatment, or device.1 The company(referred to as the sponsor) submits an application to the FDAthat details the plan (known as the study protocol) for conductingthe research on human beings. The protocol details a series ofcontrolled studies on human volunteers. These studies are knownas clinical trials and evaluate the safety and efficacy of thetherapy. There are several different types of clinical trials. Thosethat involve drugs or devices are referred to as treatment-typeclinical trials. Other types of clinical trials include: investigatingissues relative to quality of life, early screening for the presenceof specific disease, or prevention strategies to minimize thedevelopment of a condition.2 The purpose of this article is toprovide an overview and description of the various phasesinvolved in clinical trials. As the majority of persons associatedrugs and devices when describing a clinical trial, the focus willbe on the treatment-type clinical trial.

A clinical trial is considered prospective research, meaningthere is a well-defined starting point and all subjects are followedup over a specified period of time.3 There are certain basiccharacteristics that clinical trials share in common. A clinicaltrial examines the effect(s) of the intervention(s) on a specificpopulation, frequently known as the treatment group. The inter-vention is applied in a standardized manner to all subjects withinthe group. The treatment group that received the interventionmay be compared to another group of persons known as thecontrol group. The control group is defined as those individualswho did not receive the specified intervention.4 The controlgroup may receive one of the following therapies depending onhow the clinical trial is structured. They may receive the currentusual and customary treatment for the specified condition, aplacebo, or no active intervention at all. Randomization is

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typically another requirement for clinical trials. This is a methodby which the subjects in the clinical trial are assigned on thebasis of chance to a specific group. Randomization reduces therisk of selection bias.5 Last, many clinical trials also includeblinding in the study design. A blinded study means there is alack of knowledge regarding what therapy is received. Whenonly the subject is not aware of which treatment is beingdelivered, it is known as a single-blind study. A double-blindstudy means that neither the investigator nor the subject hasknowledge of what therapy is rendered.3 The treatment identifi-cation is controlled through a central location. Blinding is onemethod that reduces the risk of Hawthorne effect occurrence.The Hawthorne effect is a change in the subject behavior as aresult of being part of a research study, rather than due to thetreatment rendered.4

Before beginning a clinical trial, the pre-clinical researchperformed in the laboratory (in vitro testing) and animal studies(in vivo testing) must indicate that the treatment is safe enoughto warrant further studies on human beings.6 There is no set timeframe for completion, which is dependent on the drug/device.The pre-clinical findings are included in the study protocolsubmitted to the FDA to support the proposed new treatment.1

Clinical trials have 4 phases. The first phase, known as aphase I trial is the introduction of the drug or device into ahuman being.1,7 Phase I trials consist of a small number ofsubjects (from 20-80).1 Depending on the purpose and diseasebeing studied, the subjects may be either healthy volunteers orpatients. The purposes of a phase I trial are to develop a safetyprofile on the drug/device, to determine if there are any adverseeffects and if it is a drug, to determine how the medicationshould be given and the dosage range.8 Additionally in medica-tion phase I clinical trials, the pharmacokinetics (absorption andelimination) of the proposed agent are closely studied. Blindingand placebo use may occur depending on the drug/device beingstudied. Phase I trials last approximately 1 year and may beconfined to a single site.8 An example of a phase I trial was thestudy by Brener et al9 of a new adjustable endovascular graft forabdominal aortic aneurysms sponsored by Teramed (MapleGrove, MN). The primary objective was to evaluate devicesafety. Fifteen patients in the United States had the deviceimplanted. A 1-month follow-up revealed no complications.9

A phase II trial confirms the short-term safety and efficacy ofthe drug/device on the basis of the results obtained from thephase I trial. The number of subjects may be somewhat largerthan phase I (between 100-300). The subjects in a phase II trial

2

have the disease being researched. The treatment is examined

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for effect. If it is a medication, the dosage established in thephase I trial is evaluated. The incidence of short-term adverseevents is also studied. A placebo may be used and blinding iscommon, both single and double. A phase II trial providesevidence of the clinical significance of the drug/device.1,8 Thenumber of sites involved is typically limited. The average lengthof a phase II trial is 2 years. In a phase II trial, Desai et al10

studied the clinical response rate on the addition of oral thalid-omide to weekly gemcitabine and continuous fluorouracil infu-sions in patients with metastatic renal carcinoma. A 43% inci-dence of venous thromboembolism subsequently occurred inthese subjects. The authors recommended against using this3-drug combination.

A phase III trial proves the safety and efficacy of thedrug/device over a long period. Additional information is col-lected to evaluate the overall benefit-risk relationship of theintervention.8 Continued monitoring of adverse effects (includ-ing identification of rare side effects) is done. In a phase III trial,the proposed new therapy is compared with the current standardtreatment (if one exists).7 The number of subjects ranges fromhundreds to thousands recruited from multiple testing sites. Inphase III drug trials, randomization, placebo-control, and doubleblinding are customary. Because of these design issues, phase IIItrials may last several years.8 The Carotid RevascularizationEndarterectomy versus Stenting Trial (CREST)11 is an exampleof a phase III trial. The purpose of this trial (scheduled to endDecember 2003) is to evaluate carotid stenting (the investiga-tional therapy) against the gold standard treatment of carotidendarterectomy.11 It is multi-center and includes 2 treatmentstrategies. CREST also has a recruitment aim of 2500 subjectsrandomized to either therapy arm.11 Phase III represents the lastclinical trial before FDA approval.

Reports are submitted to the FDA throughout this process,including preliminary findings and subjects that have experi-enced adverse effects. The FDA or study sponsor may close thetrial prematurely either if it is determined that the proposed newtherapy is not safe or effective or if it has been shown superior

7

TABLE I

CLINICAL TRIAL PHASES

Phase Purpose Number o

I Determines safety/dosage 20

II Confirms treatmentsafety/efficacy shortterm

100

III Proves treatment safety/efficacy long term

Hundreds to

IV May be multiple: Va

Expand safety profile

Specify new indications

Educate researchers

Fulfill mandates

to the existing treatment. During or after phase III trials, the

sponsor prepares a new drug/device application for FDA sub-mission. This includes a summary of all aspects of the newtreatment including results of the clinical studies and pre-clinicalresearch. It also details how the drug/device will be manufac-tured including methods, facilities, controls, processing, andpackaging.8 Amendments to the application frequently occur.The FDA takes an average of 12 months to review the applica-tion. The approval, modification, or rejection by the FDA of theproposed treatment is communicated to the sponsor.8 If changesare suggested, the approval process will take longer. It takesapproximately 8 years and may cost millions of dollars tocomplete all 3 clinical trial phases.1

A phase IV trial occurs after the FDA has approved thedrug/device for use.2 There may be several goals in a phase IVtrial. These include specifying new indications for use, expand-ing the safety profile, gathering new information about thetherapy, educating clinical researchers, and fulfilling a regulatoryedict.12 Cost effectiveness may also be explored. A phase IV trialmay also be a pilot study for other potential product indications.It may be conducted at single or multiple sites and last months toseveral years. There is usually no control group and the numberof subjects varies depending on the objective. The participantsmay be as few as those in a phase I trial or as many in a phaseIII trial.12 A phase IV trial was conducted by Chiu et al13 onintravenous tissue plasminogen activator (t-PA) for acute isch-emic stroke. The study examined the feasibility, safety, andefficacy of t-PA in the first year after the FDA had approved theuse of the drug for this patient population. Thirty patients withacute ischemic stroke from 3 sites were included. Findingsconfirmed the safety and efficacy of t-PA were comparable to theprevious National Institute of Neurological Disorders and StrokePhase III t-PA study.13 Table 1 summarizes the 4 phases ofclinical trials.

A clinical trial may be conducted in almost any setting, froman academic medical center to a physician office. All are re-quired to comply with stringent governmental guidelines before

bjects Duration (years) Number of sites

Approximately 1 Single site

Average 2 Few sites

usands Several Multiple sites

Months to years Single tomultiple sites

f su

-80

-300

tho

ries

approval. By understanding the different clinical trial phases, the

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nurse will be able to better answer questions and provide supportfor the patient considering enrollment in a clinical trial.

REFERENCES

1. Food and Drug Administration: the new drug approvalprocess. Available at: http://www/fda.gov/cder/handbook.Accessed October 4, 2003.

2. National Institutes of Health: introduction to clinical trials.Available at: http://www.clinicaltrials.gov. Accessed Octo-ber 6, 2003.

3. Polit D, Beck C, Hungler B. Essentials of nursing research.5th edition. Philadelphia: W.B. Saunders; 2001. p. 166-75.

4. Burns N, Grove S. Understanding nursing research. 3rdedition. Philadelphia: W.B. Saunders; 2003. p. 214-8.

5. Allen M. Randomized clinical trials: attention to bias. JWound Ostomy Continence Nurs 2002;29:127-8.

6. Liang B. The drug development process II: investigationalnew drug application. Hosp Physician 2002;38:36-8.

7. Sims J, Miracle V. Phases of a clinical trial. Dimens CritCare Nurs 2002;21:152-3.

8. Liang B. The drug development process I: drug discoveryand initial development. Hosp Physician 2002;38:1-21.

9. Brener B, Faries P, Connelly T, et al. An in situ adjustableendovascular graft for the treatment of abdominal aorticaneurysms. J Vasc Surg 2002;35:114-9.

10. Desai A, Vogelzang N, Rini B, et al. A high rate ofvenous thromboembolism in a multi-institutional phase IItrial of weekly intravenous gemcitabine with continuousinfusion fluorouracil and daily thalidomide in patientswith metastatic renal cell carcinoma. Cancer 2002;95:1629-36.

11. Roubin G, Hobson R, White R, et al. CREST and Caress toevaluate carotid stenting: time to get to work! J EndovascTher 2001;8:107-10.

12. Liang B. The drug development process III: phase IVclinical trials. Hosp Physician 2002;38:42-4.

13. Chiu D, Krieger D, Villar-Cordova C, et al. Intravenoustissue plasminogen activator for acute ischemic stroke: fea-sibility, safety and efficacy in the first year of clinicalpractice. Stroke 1998;29:18-22.

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