3.1A-Bolton; 2007

CHRONIC WOUND CARE, 4th Edition 57

C o n t rolled Clinical Trials Versus CaseS t u d i e s : W hy Wound Care Pro fe s s i o n a l sNeed to Know the Diffe re n c e

Laura Bolton, P h D ; Pe g gy Dotson, R N , B S ; M o rris D. Ke r s t e i n , M D

I n t ro d u c t i o n

In keeping with rapid changes in healthcare,wound careresearch has made great strides. Product availability hasbranched from few options to a multitude of selectionsnow classified in product categories. Likewise, expecta-tions regarding treatment choices have progressed from itworked before approaches to research-based decisionmaking.13 Solid rationale for established or modified treat-ment plans separates a knowledgeable healthcare providerfrom a haphazard one. Given the abundance of publishedliterature and sales materials, all claiming product superi-ority, how does one discern the legitimacy of the claimsbeing made? It is the responsibility of the clinicians on theinterprofessional team not to accept these claims at facevalue but to scrutinize the quality of information receivedand to use it properly.4 When they can identify the differ-ent types of research and understand what conclusions canbe drawn from each, practitioners are better prepared tobase care decisions solely on the accurate claims.The goalof this chapter is to provide wound care professionals thetools needed to identify the various types of clinicalresearch that support wound care product claims and toselect only the legitimate conclusions derived from each asthe scientific backing for their wound care decisions.

Definitions and ScopeDifferent types of clinical research aid medical decision-

making in different ways. The US National Institutes ofHealth website at www.ClinicalTrials.gov classifies clinicaltrials by function: Treatment trials test new or experimental treatment

modalities, drugs, or approaches to surgery or radiationtherapy

P revention tri a l s e x p l o re modalities, lifestyle change, o rp ro c e d u res to prevent the onset or re c u rrence of disease

Diagnostic trials explore improved diagnostic tests orprocedures for a disease or condition

Screening trials optimize detection of diseases orhealth conditions

Quality-of-life or supportive care trials exploreways to improve comfort and other quality-of-life fac-tors for those with chronic illnesses.Ta ble 1 lists types of clinical study design from strongest to

we a kest ev i d e n c e, with content and conclusions that can bed r awn from each type. M o re detail can be obtained ath t t p : / / w w w. ve t m e d . w s u . e d u / c o u r s e s - j m g ay /G l o s s C l i n S t u d y.htm or http://www. mu s c. e d u / d c / i c re b m /c l i n i c a l t ri a l s . h t m l . Each type of re s e a rch is va l u a ble if the con-clusions are consistent with the study design and methods.

Bolton L, Dotson P, Ke rstein M. C o n t rolled clinical trials ve rsus case studies: w hy wound care professionals need to know the differe n c e. I n :Krasner DL, R o d e h e aver GT, Sibbald RG, e d s . C h ronic Wound Care : A Clinical Source Book for Healthcare Pro fe s s i o n a l s. 4th ed. M a l ve rn , Pa : H M PC o m mu n i c a t i o n s , 2 0 0 7 : 5 7 6 6 .

C H A P T E R 7

O b j e c t i ve sThe reader will be challenged to: Differentiate between controlled clinical trial evidence of wound care product efficacy and case series or

studies and describe product use Use 3 sources of evidence on product efficacy and safety in clinical pra c t i c e Design a controlled clinical study of wound care product efficacy and safe t y.

58 CHRONIC WOUND CARE, 4th Edition

Bolton, Dotson, and Kerstein Controlled Clinical Trials Versus Case Studies

The strongest support for decision-making is the ran-d o m i z e d , c o n t rolled trial (RCT). Hallmarks of a well con-ducted RCT are that the experimental and contro l l e dgroups are matched on initial laboratory and demogr a p h i cvalues as well as wound characteri s t i c s . R e t ro s p e c t ive stud-ies should be avo i d e d . T h ey may be biased by omittingpatients who we re discontinued due to pro blems with themodality or protocol of care. Each type of study descri b e din Ta ble 1 answe rs a different kind of question with poten-tially useful evidence for the interp rofessional team. In theabsence of higher quality ev i d e n c e, even case studies canbe useful to the wound care team, p a rticularly to intro d u c estaff to usage or performance of a new product or an exist-ing product on a new indication. H oweve r, a n swe ri n gquestions of comparative performance or efficacy re q u i re sa properly conducted RCT or cro s s - over tri a l . In additionto individual studies, meta-analyses of all studies that meas-

u re specific outcomes (eg, i n f e c t i o n ) ,1 5 l i t e r a t u re sum-m a ri e s ,16 and systematic rev i ews like those cited at theCochrane website (http://www. c o c h r a n e.org) are helpfulin aiding clinical decision-making. If an inadequate scien-tific basis exists for including a particular treatment modal-ity in ones protocol of care, one can test its comparativeefficacy in achieving measurable goals by conducting ac o n t rolled clinical trial of the treatment ve rsus an accepteds t a n d a rd or control tre a t m e n t .5 , 6 R e s o u rces abound withthe h ow - t o s of clinical re s e a rc h .1 7 , 1 8 F rom these, one canl e a rn more about the different types of re s e a rch and howto conduct a study.

W h a t ever type of study is conducted, one should notfocus solely on the wound to the detriment of the patient.Treating ulcers without proper diagnosis and managementof the patients comorbid conditions or fa c t o rs that con-t ri bute to tissue bre a k d own is a waste of va l u a ble re s o u rc e s

Table 1. Types of clinical research and conclusions that can be appropriately derived from each (beginning withstrongest evidence)

Type of Study Content Conclusions

Experimental Studies Investigator assigns modality

Prospective, randomized Prospective comparison of measured Comparative safety and efficacy of modalitiescontrolled trial5 (RCT) effects of randomized, 2 or more modalities evaluated for outcomes measured if groups

on patients randomly assigned by were initially similar on all related measuresinvestigators to groups and risk factors

Prospective, randomized, Similar to RCT, except that all groups Same as for RCT, only this and the RCTcrossover trial6 receive successive treatments according provide evidence of product efficacy and

to a randomly assigned schedule safety

Prospective, nonrandomized, Similar to RCT except that patients are not Potentially biased unless groups arecontrolled trial7 randomly assigned to groups rigorously matched on all relevant

features on enrollment

Observational Studies Treatments naturally selected

Prospective cohort study8 Measured outcomes are correlated with Correlation between treatments and healthtreatments or diagnostic modalities outcomes; useful for testing validity ofadministered prospectively diagnostic tools, testing product safety, or

generating hypotheses

Retrospective, Clinical outcomes of the proportion of Odds ratios are calculated that a givencase-control study (RCC)9 cases with 1 risk factor or treatment are treatment or risk factor is associated with

compared to those of patients in the same the measured outcome; high potential forpopulation without it bias; may support product safety in selected

patients

Ecologic (aggregate) study10 Similar to RCC, performed on an aggregate Similar to RCC, with we a ker ev i d e n c eof mu l t i p l e,d i verse populations u n l i ke ly to be re l evant to any individual patient

Cross-sectional Descriptive study of relationship between a Such studies can describe outcome trends(prevalence) study11 condition (eg, confined to bed) and a health over time but lack information about

outcome (eg, having a pressure ulcer) at 1 exposure to causative factorspoint in time

Survey of clinical practices or Information gathered by interview or Frequency of a specified practice or incidenceoutcomes over time questionnaire over a specified period of a clinical outcome (eg, nosocomial(incidence study)12 of time, usually in months or years pressure ulcers or infections)

Case series13 Description of treatment and outcomes of Weak evidence of safety because patienta series of patients receiving the same selection may be biased; may providetreatment modality information on product performance

Case study14 Anecdotal description of 1 patients course Weakest evidence; describes how othersof disease and (ideally) measured outcome managed this condition and clinical outcome


Controlled Clinical Trials Versus Case Studies Bolton, Dotson, and Kerstein

and time. All studies from the RCT to the case studyshould include normal standard laboratory values whilealso assuring that the patients had adequate nu t rition (eg,p re a l bumin or albumin for protein sufficiency, t r a n s f e rri t i nfor iron transport from the gastrointestinal tract), we re noti m mu n o s u p p ressed by virtue of a normal lymphocytec o u n t , and had controlled blood glucose as indicated by an o rmal hemoglobin A1c for patients with diabetes. Pa t i e n t sshould have adequate hydration and renal function, a n dtheir disease state(s) should be under control sufficiently toa l l ow wound healing before they are enrolled in the study.E ven the best controlled clinical study cannot diagnose andmanage the cause of a chronic wo u n d ; this re q u i res ani n t e rp rofessional team.

R e s e a rch also should be clinically re l evant if it is to sup-p o rt conclusions that have bearings on healthcare practice.The more similar to ones own clinical practice a study is ins e t t i n g , wound type, p a t i e n t , and treatment va ri a bl e s , t h em o re clinically re l evant it is to ones use and decision-making pro c e s s .Though the scope of this chapter includesonly clinical studies, remember too a wealth of pre c l i n i c a lre s e a rch exists that also can aid decision-making to theextent that it is clinically re l evant to ones practice. I n - v i t r ostudies are the least clinically re l evant because they are basedon responses by cells in culture, separated from their norm a le nv i ronment rich in growth fa c t o rs , e n z y m e s , and other nat-

urally occurring molecules in the body. I n - v i vo studies onanimals can be especially va l u a ble when they parallel clini-cal phenomena (eg, acute animal wound healing parallelsthat of humans; p re s s u re-ulcer animal models simu l a t ehuman pre s s u re ulcers ;1 9 and ischemic ulcers can be gener-ated in animals by prolonged ischemia).2 0 Clinical re l eva n c eshould be carefully assessed before extrapolating from animalto human studies, or when generalizing from one type ofclinical wound to another (eg, f rom donor sites to diabeticfoot ulcers ) . Animal models for chronic wo u n d s , such asthose mentioned prev i o u s l y, a re more clinically re l evant toc h ronic wounds of similar morp h o l ogy and etiology than ahuman acute wo u n d , such as a donor site, would be.H oweve r, the most re l evant re s e a rch on which to base clin-ical wo u n d - c a re decisions is the controlled clinical study ofpatients similar to those who re c e ive the care. Most pro f e s-sionals turn to controlled trials on the etiologies and depthsof wounds they manage, when ava i l a bl e, as a basis for pro t o-col choices because of the question of clinical re l eva n c e.

Conducting a controlled clinical trial is not as forbiddingas it sounds. It can be fun and open new horizons of patientcare and communication with colleagues. Getting involvedin some form of research helps the new researcher learn theprocess. However, a basic understanding of various researchmodels is essential in establishing the foundations for clini-cal practice.A format for conducting research follows in this

Table 2. Evidence reviewed by the FDA in support of wound care products

Product Classification Product Description Evidence Required

Class I medical devices are low risk; this Product is not life supporting or life The FDA has classified wound careincludes most wound dressings and sustaining and does not present a products as low risk and for the mostostomy supplies reasonable source of injury through part do not need premarket approval

normal usage21 before distribution

Class II medical devices are higher risk, May support or sustain human life, and The FDA may examine and identifyand a majority require data to assure there is enough information for controls and tests adequate to assuresafety and effectiveness performance standards safety and effectiveness in a premarket

application (PMA)

Class III medical devices are high risk Support or sustain human life; are of Requires PMA with sufficient, valid,for which there is not sufficient substantial importance in preventing scientific evidence to assure the deviceinformation to place them into a Class I impairment of human health or present is safe and effective (clinical studies,or II category or to establish a potential unreasonable risk of weighing health benefits and risks)performance standards illness or injury

Over-the-counter (OTC) drugbased on Regulated by FDA based on compliance Safety and efficacy of OTC drugs, suchprior research, the FDA has agreed on a to therapeutic monograph labeling21 as skin protectants or certain topicalsafe, effective ingredient or combination and the assumption that their benefits antimicrobial or antifungal agents, isof ingredients, doses, labeling, claims, and outweigh their risks; potential for misuse based on manufacture to FDAindications for more than 80 therapeutic and abuse is low therapeutic monograph specificationscategories

Prescription drugs include oral or topical Drugs include substances with Drugs require proof of both safety andagents requiring a physicians prescription; pharmacologic or other direct effect in efficacy relative to standard agents orthis class would include debriding agents the diagnosis, cure, mitigation, treatment, treatments that may be submitted toand non-OTC antimicrobial agents or prevention of disease or to affect the the FDA in a New Drug Application

structure or any function of the human (NDA) or, in the case of a genericbody. . .22 drug, an abbreviated NDA (ANDA)



chapter. This chapter discriminates between the 2 mostcommon types of studies reported: uncontrolled case orproduct studies and controlled clinical evaluations.With thisbasic knowledge, readers will be able to use the evidencethey glean from published and unpublished professional andsales literature with a clear understanding of exactly whateach form of evidence means for their practices and theirpatients well being.

Making the Most of Av a i l a ble EvidenceEvidence for product safety and efficacy already may have

been rev i ewed by gove rnment authorities or by other pro f e s-sionals in search of answe rs .This evidence may be ava i l a ble inp roduct package insert s , in the published literature, in postersor presentations at professional meetings, or in unpubl i s h e dp roduct literature.W h a t ever the sourc e, the afore m e n t i o n e dtools and definitions will help the clinician draw his or herown conclusions about the clinical re l eva n c e, s a f e t y, and effi-cacy of products based on ava i l a ble literature.

Product package inserts. In the United States, theFood and Drug Administration (FDA) reviews supportingevidence for claims, indications, warnings, and contraindi-cations before giving clearance to market for some woundcare products. Different classifications of products requiredifferent supportive evidence before they can be marketed(Table 2). Understanding these requirements for each classof product helps wound care professionals to be aware ofthe research base that already exists for each product andhelps one interpret marketing claims of relative efficacy orconfidently request evidence to support these claims.

Evidence ava i l able from industry. Food and Dru gAdministration clearance to market most wound dre s s i n g sis based on substantial equivalence to another dre s s i n g ,p reclinical safety studies, and assurance of consistent qual-i t y, but it does not support conclusions of clinical pro d u c tp e r f o rmance or re l a t ive efficacy of the pro d u c t .2 1 , 2 2 I nsome cases, studies of clinical performance characteri s t i c sm ay have been performed for a wound care device toe s t a blish substantial equivalence to another dev i c e, bu tthese are not re q u i re d . In general, it is not safe to assumea wound care dressing has been tested clinically before itis marketed unless the company provides that ev i d e n c ewith the product literature. In the absence of publ i s h e dclinical ev i d e n c e, wound care professionals are encouragedto contact companies that market the devices for ev i d e n c es u p p o rting product claims.

Comparative efficacy studies of most wound care devicesalso are not required before marketing clearance is given.For example, if manufacturer C develops an alginate dress-ing substantially equivalent to manufacturer Bs alginatedressing, manufacturer C may produce and market its algi-nate dressing in compliance with regulations without con-

ducting a clinical study on its own alginate dressing.Manufacturer C may use the substantial equivalence prop-erty to support clinical performance, using the same refer-ences pioneered by manufacturer B to support product Csclaims, even if product C was never used on clinicalwounds. This practice benefits society by encouragingchoices in each dressing category and reducing costlyresearch. However, wound care professionals should notassume that supporting evidence exists for relative clinicalperformance of the 2 alginates. If assertions are made aboutcomparative clinical efficacy of the 2 dressings, referencesshould be provided in the associated literature.Wise profes-sionals will review these references for accuracy or requestthem from the company for verification.Evidence support-ing comparative clinical claims can be provided only by aclinically relevant evaluation that compares the 2 dressings.

Evidence from literature and professional meet-ings. In addition, independent or corporate-sponsoredresearch may provide evidence for wound care decisionsbeyond that evident from product package inserts and rou-tine FDA-required data.These can be acquired by readingor searching the wound care literature, networking withother wound care pro f e s s i o n a l s , attending pro f e s s i o n a lmeetings, and critically reading posters. If the evidence isnot available from any of these sources, resourceful woundcare professionals can do their own research to answer ques-tions about how wound treatments perform, their optimaluse, and which treatment modalities work best.23

Format for Conducting a Research StudySpecifically, research is investigation or experimentation

aimed at the discovery and interpretation of facts...24 Anattempt to answer any question can be considered research.If good scientific method is used to attain the answer, it willpredict patient outcomes accurately and reliably.The formatfor the process of conducting research normally proceedsthrough the following stepssimilar to those involved inbuilding a house: Formulate the question to be answered (decide on the

function, type, and location of the house) Search prior literature on the question (assess the site and

prepare the foundation) Develop this question into a specific objective for study

(devise a general plan) Write the protocol (draw the blueprint) Set up the study (obtain a building permit)

o Obtain resources, such as funding, equipment, andproperly licensed personnel on the interprofessionalteam required to conduct the study

o Obtain permissions and approval for the study proto-col from appropriate supervisors and the institutionalreview board (IRB)



Conduct the studyapply treatments and observe andrecord the effects (build the house)

Analyze the results (certify that the structure meets codesfor occupancy)

W rite up the conclusions so others can benefit(enjoy/assess the house).These steps have been described in greater detail else-

where.4,17,22 They will be used here to illustrate the differ-

ences between clinical evaluations and case studies (Figure 1).Research begins with a question. The answer will add

information to the foundation of knowledge about thatquestion. Be sure to ask a clear, narrow question that willdetermine a research objective feasible to answer using theresources and subjects at hand.A literature review will helpyou assess the research environment to build on a securefoundation of others findings.The research objective deter-

Questions Literature Search

Objective Compare treatment effects Types of wounds Outcomes explored

Objective Describe treatment effects Types of wounds Outcomes explored

Methods Patients included/excluded Time line:

Retrospective Prospective

Setting Good clinical practice Treatment applications and duration Follow-up

Design

Controlled Experimental vs. standard protocol Randomized, stratified Randomized Nonrandomized

Results measured Valid, reliable Comparative analysis Clinically relevant to objective

ConclusionsExperimental is/is not safe andefficacious vs. standard protocol

Uncontrolled Experimental protocol only

Results measured Valid, reliable Before/after analysis Clinically relevant to objective

Conclusions Product or protocol safety Performance to use

Case StudyClinical Evaluation

Figure 1. Differentiating controlled clinical evaluations from case studies.



mines the outcome and setting of a study in much the sameway that initial choices of function, type, and site shape ahouse.The site must be consistent with the anticipated pur-pose and structure. A researcher will need to select thequestions to ask in order to determine the study methods.For example, in an environment subject to frequent flood-ing, it may be prudent to build the house on stilts.Knowledge regarding the use and construction of the stiltsis acquired by re f e rring to previous experi e n c e. T h eresearcher will find this experience by searching the litera-ture related to his or her topic. Just as the environment andpast experience influence a buildings structural design, aliterature review helps the researcher refine the question,select the most useful methods to answer it, and build onthe established body of scientific evidence.

With a clear question or objective in mind, t h ere s e a rcher can formulate a focused re s e a rch objective,specifying the type of wo u n d , p a t i e n t , s e t t i n g , t re a t m e n t ,and measured outcomes. Just as a weak foundation eve n-tually results in instability of the stru c t u re, an unclearo b j e c t ive can lead to weak or unclear re s u l t s . A clearre s e a rch objective is the foundation of the studys generalp l a n , d e s c ribed in detail in the study protocol or design.The study protocol specifies the inclusion/exclusion cri-t e ri a , t re a t m e n t s , t reatment duration, va ri a bles measure d ,and anticipated analysis. Just as the bl u e p rint of a housemust be precise and clear and match the ow n e r s vision,the study objective and protocol must clearly and accu-rately address the inve s t i g a t o r s question in order to derivere l evant answe rs at the end of the study.

Before setting up a study for market-approved products,the researcher should read the product package insert(s) forthe material(s) carefully, making sure that the products havebeen cleared by the FDA or an equivalent agency for useon the type(s) and depth(s) of wound(s) being studied. Ifasked by a manufacturer to perform a study investigationfor FDA approval to market the product, the protocol andindications are all reviewed and approved by the FDA andthe researchers own IRB before study commencement. Ifa manufacturer requests an investigation of a marketedproduct for an unapproved indication, the clinician is legal-ly responsible for adverse events. Manufacturers may spon-sor studies only for FDA-cleared indications of their prod-ucts.4 If this is not the case, the researcher and his or herinstitution bear responsibility if using the product outsidenormal indications.

Approvals and permissions can provide valuable tools forthe success of a study, assuring access to experts in studydesign and conduct. Facilities, whether acute care hospitals,long-term care facilities, or home health agencies, eitherhave their own IRB or have access to one.The IRB regu-lates research to assure safety and ethical standards. It is pru-

dent before initiating any investigation to check IRBrequirements.The degree of IRB involvement in a proto-col may be influenced by whether the evaluation is exper-imental or involves further study of an already approvedi n d i c a t i o n . E x p e rimental testing invo l ves pre m a r ke t e dproducts or a marketed product for indications that havenot been approved. One additional approval to obtain isthat of the patient. Guidelines regarding the necessaryinformed patient consent are also obtainable from the IRB.Patient-informed consent is more than a formality; it is thepatients right, guaranteed by the Helsinki Accord, and acornerstone of quality research by assuring patient under-standing of and compliant participation in the study. Byinforming and gaining support of colleagues and the facil-itys administration, the researcher will also garner cooper-ation and moral support from individuals who may providevaluable assistance, feedback, and tips on valid, reliable tech-niques for measuring or conducting the study. Additionalresources of financial support and materials may includegovernment agencies and corporations.4 Just as a buildingpermit assures cooperation by ascertaining conformance tolocal codes and standards, these approvals help to assure thestudy conforms to good clinical practices and the specificstandards of the researchers professional environment.

Conducting the study with integrity and diligence isanother key to success. As the strength and quality of ahouse depend on builder adherence to the blueprint, so toodoes a well conducted study follow its protocol as closely aspossible. Anyone involved in the study requires adequatetraining to assure uniform treatment application, patientmonitoring, and measurement of outcomes. All profession-als should keep patient welfare as the highest priority whileconducting the study.

C o m p a ring case studies with RCTs. Early phases ofthe re s e a rch process do not differ for case studies and clini-cal eva l u a t i o n s .The question sends the curious re s e a rcher tothe literature to explore and learn from the experience ofp rior re s e a rc h e rs . H oweve r, the objective of a case study,which explores effects of a single tre a t m e n t , is clearly differ-ent from that of a clinical eva l u a t i o n , which compares mu l-tiple tre a t m e n t s . If the objective is to determine pro d u c tsafety or to describe perform a n c e, effects of a single tre a t-ment will be explored on a given wound care outcome in acase study paradigm. Case studies are time-honored ve h i c l e sfor informing colleagues about unusual responses or adve rs ereactions to treatment modalities. For example, m a ny jour-nals feature special sections for case studies, which spaw nn ew re s e a rch and alert professionals to new clinical findings.

If comparative efficacy is to be determ i n e d , 2 or moret reatment groups will be compared in a clinical evaluation oftheir comparative effects on the specified outcome(s). T h ep rotocol will specify the treatments to be compared and



techniques for applying each treatment and measuring out-c o m e s .The study design flows from the objective. I d e a l l y, t h et reatments will va ry in only 1 aspect of care, and patients willbe assigned in a random or other unbiased way to each tre a t-ment gro u p. In a well-designed clinical eva l u a t i o n , wo u n dand patient characteristics are measured before and aftert reatment for a given duration to allow conclusions about thec o m p a r a t ive safety and/or efficacy of the treatments applied.

The process of setting up and conducting the study issimilar for clinical evaluations and case studies. Both requireresources, materials, and cooperation of, or permissionfrom, the IRB, administration, colleagues, and patients inorder to succeed in meeting their objective. Including afunctioning interprofessional team in the research process isvital to the success of patient management25 and is a hall-mark of a well-managed clinical study.

Analysis of results for a case study involves descriptivestatistics before and after treatment of the following: Patient variables (eg, age, sex, mobility, nutritional status,

risk factors) Wound variables (eg, area, depth, necrosis, exudate, sur-

rounding skin, pain) Environmental elements (eg, caregiver, financial con-

straints, footwear).If more than 1 patient completes the study, p a i red statistics

can be used to compare pertinent measures before, d u ri n g ,and after treatment and optionally after a follow-up peri o dspecified in the pro t o c o l .This process provides re a d e rs with aconclusion of product or protocol safety during treatment aswell as durability of its effects. Clinical evaluations comparethese 3 types of va ri a bles for the treatment groups studied,which assures similarity before the experimental and contro lt reatments or pro c e d u res are implemented. N e x t , the differ-ences in the progre s s ive treatment effects on these va ri a bl e sas well as the subsequent durability of these effects duri n gf o l l ow-up intervals are measure d . C o m p a r a t ive statistics, s u c has t-tests or analyses of va ri a n c e, a re used for the continu o u s ,n o rmally distri buted va ri a bl e s , w h e reas chi-square or othern o n p a r a m e t ric statistics are used for discrete or skewed data.The results yield direct information about differences ine f f e c t iveness of the tre a t m e n t s .

Conclusions derived from a case study re p o rt the cours eof events when 1 or more participants use a product orp ro c e d u re. For example,Wilson et al1 3 p e r f o rmed a longi-tudinal (over time) study of 7 patients with systemicm e t h i c i l l i n - resistant S t a p hylococcus aureus (MRSA) infec-tions whose leg ulcers we re dressed with hy d ro c o l l o i dd re s s i n g s .All patients we re isolated to prevent the spread ofthis pathogen until its presence was detected only in thewo u n d .With the dressing isolating the wo u n d , the patientsresumed normal hospital-room residence without spre a dof the MRSA, which eventually disappeared in all but 1

p a t i e n t .W h e reas the study established safety of the pro d u c ton microbially contaminated wo u n d s , it did not extrapo-late comparative efficacy of the treatment because it wa snot compared to an altern a t ive treatment method. B ye s t a blishing product safety, the case study may set the stagefor further investigations to compare this treatment modal-ity to other management methods.

Although safety questions are wo rt hy re s e a rch objectives toa d d re s s ,m a ny professionals want more than assurances of safe-ty for their wound care pro d u c t s . For instance, when makingselections in the building scenari o, 2 brands of window shadesv i ewed individually may visually keep out the suns ray s .H oweve r, only by comparing them under the same sun expo-s u re at the same time of day and using a thermometer toobtain an accurate temperature can one ascertain which win-d ow shade provides more protection against the heat. B o t hbrands wo r k , but which one is more effective? In a wo u n dc a re study, after safety is establ i s h e d , re s e a rch answe rs questionsabout issues, such as comparative efficacy of healing, d e b ri d e-m e n t , and pain re l i e f, by comparing products under similarconditions side-by-side or in parallel to control tre a t m e n t s .The more specific the investigation is to the condition ofintended product use, the more accurate and clinically re l e-vant the results will be. Results are only as good as the re l i a-bility (repeatability) and validity (clinical re l evance) of themethods by which they are obtained and may apply only tothe ori ginal objective set out to be discove re d . One must bec a reful to generalize only to the kind of population studied.For example, if an objective is stated to determine the com-p a r a t ive efficacy of 2 enzymatic debriding agents in re m ov i n gn e c rotic tissue from pre s s u re ulcers , the conclusion may gen-eralize only to pre s s u re ulcers , not to art e rial ulcers , b e c a u s et h ey we re not included in the eva l u a t i o n . R e s e a rc h , l i kebuilding a house, must proceed in specific sequence of clear-ly designated steps, without omitting a single step or exceed-ing its intended boundari e s , if its integrity is to be maintained.

Conducting Your Own StudyWith the framework of a literature search-based question

and objective established, what are the details that direct theoutcomes? This is where the customizing (interior design)takes place, which will differentiate case studies from prod-uct evaluations. The following need to be included in aresearch design in order to produce sound results.

Study design and methods. Inclusion criteria identi-fy who is being studied (eg, nu rsing home residents withsacral pre s s u re ulcers ) . R e l evance of medications, d i s e a s ep ro c e s s e s , patient status, a g e, g e n d e r, e t c. va ries according tothe objective. N a rrow inclusion cri t e ria limit the number ofva ri a bles influencing the outcome but will also limit generalapplicability of the re s u l t s . Exclusion cri t e ria identify patientsnot studied to whom the results cannot be generalized.



The number (N) of participants contributes to the powerof the study.The more participants included, the more cred-ible the results will be at the completion of the investiga-tion. Obviously, the reported safety of a product after 350applications is more convincing than a report on 25 appli-cations.The number of participants also affects the statisti-cal significance when the results are analyzed for differencesin treatment effects on the wounds. For a given magnitudeof difference in treatment effects, the more patients in astudy, the lower the probability that the observed differenceresulted from chance alone.The statistical significance, oralpha probability, sometimes called P, is the probability ofincorrectly concluding that the treatments caused differenteffects on the wounds studied.

The setting should be relevant to the objective. Forinstance, is the researcher comparing the practicality of 2different products in the home environment? If so, com-mon sense would determine that the study should takeplace in the participants homes. Otherwise, extrinsic factorsmay influence the relevance of the results.

All re s e a rch re q u i res a method of data collection that isre l i a bl e, va l i d , and objective. Reliability re f e rs to a method ofdata collection that achieves consistent, re p e a t a bl e, and accu-rate results of observa t i o n s . If data collection is re l i a bl e, it canbe replicated accurately at different times by the sameo b s e rver or by another observe r. An evaluation should usevalid tools that actually measure the clinical outcome beingi nve s t i g a t e d . O b s e rvations must be measurable in order forthe study to be objective. For instance, if the part i c i p a n t sd e gree of risk for developing a pre s s u re ulcer is determ i n e dsolely by the inve s t i g a t o r s assessment rather than with the useof a va l i d , re l i a ble tool, the observations are not likely to beaccurately duplicated, which reduces data re l i a b i l i t y.

What data collection timeline is used? A re t ro s p e c t ivestudy examines specified past events during a given peri o dof time. R e t ro s p e c t ive studies are commonly conducted bymeans of chart rev i ew s .P recise re c o rds are essential for accu-rate data collection. In a simple illustration, a re t ro s p e c t ivestudy using length x width as the healing measures mu s th ave these measurements re c o rded consistently at re g u l a rtimeframes for all wounds assessed. P ro s p e c t ive re s e a rc h ,h oweve r, evaluates that which will take place.The re s e a rc hdesign is based upon an objective, and participants area c c rued or actively enrolled into the study. If the timelineselected is pro s p e c t ive, the re s e a rcher must determ i n ewhether the study will be controlled or uncontro l l e d .

The control refers to the gold standard of the treatmentprotocol. This standard is usually the best known or mostwidely used method of care.An uncontrolled or case studyinvestigates the performance of a new product withoutcomparing it to a standard protocol. It could also examinethe use of an established procedure in a new situation.

Under either circumstance, the experiment can concludeonly that the product or procedure is safe. All participantsincluded in an uncontrolled study (product or case study)re c e ive the same treatment pro t o c o l . No compari s o nagainst another product or procedure takes place; therefore,no conclusions regarding superior efficacy versus that ofanother product or procedure can be claimed.A product orcase study is beneficial in providing the professional infor-mation regarding product use, performance, and outcomes,such as ease of use. Properly designed and appropriatelyreported, such case studies can provide valuable informationto assist in decision-making and deciding whether or notfurther research is needed.

On the other hand, a controlled clinical trial utilizesc o m p a risons and carries more power by discerning bothsafety and comparative efficacy of a product or pro c e d u re.H e re, the objective is to evaluate the experimental pro d u c tor pro c e d u re against a standard contro l . Depending onre s o u rc e s , f u n d i n g , t i m e, and participant ava i l a b i l i t y, e x p e r-imental and control treatments may be applied to differe n tp a t i e n t s , to different wounds on the same patient, o r, i fa p p ro p ri a t e, to different parts of the same wo u n d . T h ere s e a rcher must commit to a lengthy patient accru a lp rocess to obtain a significant number of patients for ac o n t rolled study in treatment of rare diseases, such asn e c rotizing fa s c i i t i s , w h e reas a controlled study of pre s s u reu l c e rs in a nu rsing home may take less time because thelatter are more abu n d a n t .

Patient or wound assignment.When using a control,the method of participant assignment must be determined.Nonrandomized treatment assignment allows the investiga-tor to determine what treatment is used on which partici-pant.Although this permits treatment comparison, it intro-duces a bias into the evaluation thereby influencing objec-tivity and affecting outcomes. A less biased, more powerfulassignment method is randomization.Webster defines ran-dom as being or relating to a member of a set whosem e m b e rs have an equal probability of occurri n g .2 4

Therefore, patients will have equal probability of beingassigned to each treatment group according to a preselect-ed random pattern, thus eliminating investigator bias. Astratified random pattern further defines subgroups andrandomizes treatment assignment accord i n g l y.1 5 Fo rinstance, 2 treatment groups of trochanteric pressure ulcersmay each be subdivided into age-related subgroups, andtreatments are then randomized within each subgroup sothat half the patients over 65 years of age are randomlyassigned to receive each treatment, half the patients 45 to 65years are similarly assigned to treatments, as are half thepatients younger than 45 years.

E valuation of re s u l t s . Unbiased evaluation of re s u l t si m p roves the accuracy of a study.This is done in a bl i n d e d



evaluation or experi m e n t . A single-blinded evaluation iswhen the subjects are unawa re of whether they we reassigned to the control or experimental group or pro c e d u re.In contrast, a doubl e - blinded experiment obscures know l-edge of control ve rsus experimental assignment from boththe subject and the investigator who evaluates the outcomes.This significantly reduces the possibility of opport u n i s t i cbiases during treatment and outcome measure m e n t .

Analyzing and re p o rting re s u l t s . The results shouldonly cover the outcomes cited in the study objective, n om o re or no less.The data re p o rted are obtained strictly bythe investigation and not surm i s e d .Validity and reliability ofoutcome measures determine the quality of the re s u l t s . D othe outcome measures address the ori ginal objective? A we l lconducted study should also measure and re p o rt pro d u c timpact on quality of life and costs of care, including coste f f e c t iveness if feasibl e. This information can inform yo uabout what types of patients and settings may be optimal forthe product(s) studied.A re the nu m b e rs of patients sufficientto give power to results? The results section should containthe appro p riate analysis of all va ri a bles re c o rd e d , b e gi n n i n gwith a section ascertaining that the treatment groups we reinitially similar on pertinent patient characteri s t i c s , such aswound size, d u r a t i o n , and depth.The key tests for differe n c e sin treatment effects should be appro p riate to the data and onindependent subsets of data.T h ey should be presented suc-cinctly in figures and tables that clearly illustrate the level ofstatistical significance of findings. Treatment details shouldva ry only re l a t ive to treatment specifics.When comparing 2p ri m a ry dre s s i n g s , the dressings themselves are ideally all thatshould differ. Cleansing pro c e d u re s , s e c o n d a ry dre s s i n g s , a n dtaping methods should be equivalent in order to isolate thespecific dressing as influencing the outcome. P ro c e d u re sassociated with 1 treatment but not the other could caused i f f e rences in patient outcomes erroneously attri buted sole-ly to the tre a t m e n t s .

F i n a l l y, the conclusion is the summation of the study.Although the conclusion is based on the inve s t i g a t o r si n t e rp retations of the re s u l t s , it should still accuratelyreflect the results obtained and not include assumptions.One cannot assume in the conclusion that the re s u l t sa p p l i c a ble to the population studied can generalize to theexcluded group or to other settings.4 For example, if thee f f e c t iveness of a pre s s u re - reduction surface is establ i s h e din a hospital setting, it cannot be assumed that the re s u l t sapply to the home-care population. C a re giver time andtraining level in critical are a s , such as repositioning orp re s s u re re l i e f, m ay va ry from setting to setting.

S u m m a ryT h rough scientific re s e a rc h , the wound care pro f e s-

sional is able to make inform e d , k n ow l e d g e a ble tre a t m e n t

d e c i s i o n s .This re s e a rch may be in the form of publ i s h e dor unpublished literature or studies conducted withino n e s own institution. W h a t ever the sourc e, only know l-edge and application of the re s e a rch process can help oned e rive or interp ret quality information to improvepatient care.To make the most of this inform a t i o n , a wisewound care professional will scrutinize the results as we l las the conclusions that can be legitimately drawn fro mthe context of the re s e a rch design: A re the results consistent with the objective and

method? Do efficacy claims need to be discounted because the

study was uncontrolled? R e s e a rch need not be intimidating. Become fa m i l i a r

with the floor plan, s t a rt at the gro u n d , and build up. S e trealistic goals that will support your clinical practice. It isi m p o rtant to remember that re s e a rch objectives will nota lways culminate in a final answer but may lead to anoth-er question. In the context of wound and skin care, c a s estudies and case series may provide early evidence of pro d-uct safety and descri p t ive functions, but only contro l l e dclinical trials ideally support final decisions about the bestt reatments to use in achieving wound care outcomes.

A c k n owledgment The authors wish to acknowledge the work of Geraldine

Mayoros in providing graphics for this manuscript.

Self-Assessment Questions1.Which is stronger evidence of product efficacy?

A. P ro s p e c t ive, r a n d o m i z e d , c o n t rolled study on 20patients

B. 20 clinical cases

2. Most wound care products do not need premarketapproval before distribution.

A. TrueB. False

Answers: 1-A, 2-A

Ta ke Home Message for Practice Responsible clinical professionals on wound care

teams will scru t i n i ze product indications, c l a i m s , a n ds u p p o rting literature and recommend only productss u p p o rted by the strongest and most clinically rele-vant evidence.



R e fe re n c e s1. Bergstrom N, Bennett MA, Carlson CE, et al. Clinical Practice

Guideline Number 15:Treatment of Pressure Ulcers. Rockville, Md: USDepartment of Health and Human Services. Agency for HealthCare Policy and Research; 1994.AHCPR Publication 95-0652.

2. Panel for the Prediction and Prevention of Pressure Ulcers inAdults. Clinical Practice Guideline Number 3: Pressure Ulcers in Adults:Prediction and Prevention. Rockville, Md: US Department of Healthand Human Services.Agency for Health Care Policy and Research;1992. AHCPR Publication 92-0047.

3. Association for the A d vancement of Wound Care (AAW C ) .Summary algorithm for venous ulcer care with annotations of avail-able evidence. Malvern, Pa: Association for the Advancement ofWound Care (AAWC); 2005.

4. van Rijswijk L. Nursing research and dermatology: where to start.Dermatol Nurs. 1990;2(3):158161.

5. Arnold TE, Stanley JC, Fellows EP, et al. Prospective, multicenterstudy of managing lower extremity venous ulcers. Ann Vasc Surg.1994;8(4):356362.

6. Berg K, Seidler H. Randomized crossover comparison of adhesive-ly coupled colostomy pouching systems. Ostomy Wound Manage.2005;51(3):3036.

7. Barret JP,Wolf SE, Desai MH, Herndon DN. Cost-efficacy of cul-tured epidermal autografts in massive pediatric burns. Ann Surg.2000;231(6):869876.

8. Bolton L, McNees P, van Rijswijk L, et al.Wound-healing outcomesusing standardized assessment and care in clinical practice. J WoundOstomy Continence Nurs. 2004;31(2):6571.

9. Oien RF, Hakansson A, Ahnlide I, Bjellerup M, Hansen BU,Borgquist L. Pinch grafting in hospital and primary care: a costanalysis. J Wound Care. 2001;10(5):164169.

10. Ochs RF, Horn SD, van Rijswijk L, Pietsch C, Smout RJ.Comparison of air-fluidized therapy with other support surfacesused to treat pressure ulcers in nursing home residents. OstomyWound Manage. 2005;51(2):3868.

11. Ballard-Krishnan S, van Rijswijk L, Polansky M. Pressure ulcers in

extended care facilities: report of a survey. J Wound OstomyContinence Nurs. 1994;21(1):411.

12. Mayberry JC, Moneta GL, Taylor LM Jr, Porter JM. Fifteen-yearresults of ambulatory compression therapy for chronic venousulcers. Surgery. 1991;109(5):575581.

13. Wilson P, Burroughs D, Dunn LJ. Methicillin-resistant Staphylococcusa u r e u s and hy d rocolloid dre s s i n g s . P h a rmaceutical J.1988;243:787788.

14. Parnell LK. Up close and personal with deep vein thrombosis.Ostomy Wound Manage. 2006;52(3):6672.

15. Hutchinson JJ, McGuckin M. Occlusive dressings: a microbiologicand clinical review. Am J Infection Control. 1990;18(4):257268.

16. Bolton L, Fattu AJ.Topical agents and wound healing. Clin Dermatol.1994;12(1):95120.

17. Bolton L. Clinical studies and product evaluations: how to maxi-mize their va l u e. O s t o my Wound Manage. 1 9 9 5 ; 4 1 ( 7 ASuppl):88S95S.

18. Chow SC, Liu JP. Design and Analysis of Clinical Trials: Concepts andMethodologies. Hoboken, NJ: John Wiley & Sons, Inc; 2004.

19. Salcido R, Donofrio JC, Fisher SB, et al. Histopathology of pressureulcers as a result of sequential computer-controlled pressure sessionsin a fuzzy rat model. Adv Wound Care. 1994;7(5):2328.

20. Constantine BE, Bolton LL.A wound model for ischemic ulcers inthe guinea pig. Arch Dermatol Res. 1986;278(5):429431.

21. Code of Federal Regulations. Title 21, volume 8, section 860.3.Revised April 1, 2006.

22. Code of Federal Regulations. Title 21, volume 5, sections 314.3314.50. Revised April 1, 2006.

23. Day A, Dombranski S, Farkas C, et al. Managing sacral pressureulcers with hydrocolloid dressings: results of a controlled, clinicalstudy. Ostomy Wound Manage. 1995;41(2):5265.

24. Gove PB, ed. Websters Seventh New Collegiate Dictionary. Springfield,Mass: G & C Merriam Co; 1972.

25. Department of Veterans Affairs. Assessment and Prevention of PressureUlcers. VHA Handbook 1180.2. Washington, DC: Department ofVeterans Affairs; 2006.

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