Análise de problemas e desafios em estudos psiquiátricos CH40_537-546

7/27/2019 Anlise de problemas e desafios em estudos psiquitricos CH40_537-546

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I S S U E S I N C L I N I CA L T R I A L D E S I G NS

J O H N M . K A N E

The introduction of the randomized, double-blind, clinicaltrial was one of the major advances in the development ofmedical science. In the arena of psychotropic drug develop-ment this approach has proven to be of enormous valuein advancing a field in which laboratory tests and strictlyobjective methods for diagnosis and outcome assessmentare not currently available.

Designing trials in the treatment of schizophrenia high-lights some of these challenges. Schizophrenia is a complexillness affecting to varying degrees a range of functions, in-cluding cognition, affect, behavior, mood, and motivation.The fact that this disorder affects so many different do-mains, varying from individual to individual, and to someextent within individuals over time, makes development ofpharmacologic treatments even more challenging. Althoughthere are core features of schizophrenia that involve percep-tion (hallucinations), cognition (attention, working mem-ory, etc.), motivation (avolition), inferential reasoning (de-lusions), and affect (blunted or inappropriate), there is no

pathognomonic sign or symptom of the disease. This hasimportant implications for the diagnostic process, which isalso complicated by the fact that the evaluation of somecore features (e.g., hallucinations and delusions) relies solelyon subjective reporting, the accuracy of which is potentiallyinfluenced by the very symptoms themselves as well as byother social situational and personality variables.

In addition, the fact that such an array of domains andfunctions is disturbed in this illness creates a challenge fordrug development. The tendency has been to conduct anarray of assessments to evaluate drug effects in a number ofdomains concurrently, when in fact different domains mayrequire different study designs, patient selection criteria, du-

rations of treatment, etc. In the future, more attention willbe given to those issues, and it is possible that multipletreatments will be studied rather with the goal of findingcombinations able to improve outcome across a variety ofdomains. It is hoped that new treatments will be developed

J. M. Kane: Department of Psychiatry,Hillside Hospital,Glen Oaks,NewYork; Department of Psychiatry and Neuroscience, Albert Einstein College ofMedicine, Bronx, New York.

with a focus on specific domains such as negative symptomsand cognitive dysfunction. Although a better understandingof basic mechanisms should facilitate further treatment ad-vances, our current knowledge of pathophysiology remainslimited. Advances in imaging techniques and pharmacogen-omics are also important potential developments on thehorizon that could have enormous impact on drug develop-ment and clinical evaluation.

Each area of psychotropic drug development has its ownchallenges in terms of rates of spontaneous remission, pla-cebo response, patterns of relapse, domains of assessment,etc., but, in general, challenges of design and methodologyinvolve issues that cut across the diagnostic domains.

DESIGN ISSUES

There are a number of critical issues in general design thatneed to be addressed in both the individual study as well

as the particular program of drug development. A drug de-velopment program needs to be comprehensive as well asadaptive so that early results can inform subsequent evalua-tion. Although even when a drug is marketed there are stilllimitations in the amount of knowledge available to clini-cians, several fundamental questions should have been atleast partially addressed: (a) What benefits are likely to resultfrom the drug? (b) What are its risks? (c) What dosage isindicated? (d) How does the new drug compare to alterna-tive treatments? (e) Are there specific patients most likelyto benefit from the drug?

There are a number of specific concerns that should beaddressed when designing clinical trials of psychotropic

drugs. Some of the most salient issues include dose finding;efficacy vs. placebo; efficacy vs. a standard reference com-pound; acute and long-term adverse effects; continuationand maintenance treatment efficacy; and relative efficacy oradverse effects in specific subgroups (e.g., early-phase illness,late-phase illness, refractory patients).

Dose-finding tolerability studies involving antipsychoticmedications generally call for involvement of target patientpopulations earlier in the process than with other classes ofdrugs because it is difficult to ethically justify administering


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Neuropsychopharmacology: The Fifth Generation of Progress538

these drugs to healthy volunteers for more than a week ortwo, and patterns of tolerance may be quite different inpatients versus healthy volunteers.

It is not always possible to accurately predict clinicaldosage requirements from preclinical studies; therefore, itis important to establish a full range of tolerable dosages inorder to provide an appropriate range for efficacy studies.

Drug development programs have been delayed and at timesabandoned because of inadequate dose-finding efforts in theearly stages of development (1). In addition, it is not unusualfor dosage recommendations to change after a drug is mar-keted.

It is also important to have sufficient data on absorption,elimination, metabolism, and drugdrug interactions, toinform trial design.

Treatment trials generally fall into three broad categories:acute, continuation, and maintenance (or relapse preven-tion). Sometimes attempts are made to study two or eventhree phases in the same trial, but controversy surroundsthe need to rerandomize patients before drawing conclu-sions about relative efficacy in maintenance-phase treat-ment. Patient characteristics may vary somewhat in termsof desirability within specific trials, but overall the followingissues should be considered.

Patient Characteristics

It is important to be clear on whether or not patients arein a state of acute relapse or exacerbation as opposed topartial remission or a stable plateau of chronic symptom-atology. At times investigators will withdraw patients fromongoing treatment in order to transition them to a clinical

trial, resulting in some symptom exacerbation. The impor-tance of these different approaches is that they may result inpatients with very different degrees of drug responsiveness,different patterns of baseline symptomatology, and varyingdegrees of stability in baseline symptomatology.

The ideal sample of patients is probably those who havenot already been partially treated so that the full degree andtime course of response can be determined. However, giventhe way that subjects must be ascertained and recruited fortrials, it is likely that some treatment will have already beenadministered. The fact that participants have been partiallytreated or are in a chronic symptomatic state does not neces-sarily preclude the detection of a subsequent, clinically sig-

nificant drug effect, but it is likely that the nature and mag-nitude of the effect will be altered.

The subjectivity of many components of symptomatol-ogy in psychiatric disorders creates special challenges. Giventhe fact that many symptoms are subjective and cannot beconfirmed or quantified using objective measures, the as-sessment of baseline status can be difficult. Clinicians areparticularly familiar with patients suffering from psychoseswho are more open and explicit about pretreatment psycho-pathology once they begin to improve. Some patients may

not appear eligible for a trial or be willing or able to giveinformed consent until they are partially treated.

A variety of subject characteristics should be consideredin terms of inclusion and exclusion criteria. Specific deci-sions will be influenced by the nature and goals of the partic-ular trial.

Age is often a basis for exclusion (either too young or too

old). Age can certainly affect pharmacokinetics of particulardrugs. The elderly are more likely to have comorbid medicalconditions and be more sensitive to some adverse effects,and there are a variety of issues when young patients areincluded in trials. These and other factors have led to apaucity of subjects at the extreme age ranges in clinical trials.However, there has recently been increased recognition ofthe need for more early data on diverse age groups, andmechanisms are being implemented to encourage their in-clusion in clinical trials.

Gender can be an important variable, and women areoften underrepresented in clinical trials.

Ethnicity may have implications for drug metabolismand tolerance. In addition, as pharmacogenomic strategiesare developed to extend clinical trial data, more accuratedocumentation of race will be critical.

Marital status can be a proxy for psychosocial adjustmentand illness course, and may therefore be of prognostic signif-icance.

Weight and body mass index have become an increasingconcern from a public health standpoint and because of theconsiderable weight gain observed with some psychotropicdrugs and in particular several new-generation antipsychoticmedications (2).

Diagnostic subtype can be important in helping to char-

acterize those patients most likely to benefit from specifictreatments. Duration of illness and the duration of the cur-rent episode can be important in helping to define popula-tions in terms of drug responsivity as well as long-termcourse and outcome. A particular problem in many trialsis categorizing patients histories in terms of drug respon-siveness. A current episode duration of more than 2 or 3weeks could suggest that the patient is poorly or only par-tially responsive to the treatments that have already beenadministered, or, alternatively that some other factor is com-plicating treatment response (e.g., noncompliance, comor-bid conditions, etc.). It can often be difficult to time theonset of illness or of a specific episode. As putative novel

compounds are developed, it may become increasingly im-portant to test these agents in patients who have not alreadybeen chronically exposed to other medications.

The specific type and severity of signs and symptomsrequired for entry into a trial will vary depending on theoverall goals. Usually a minimal threshold of severity is es-tablished for core symptoms of interest. It is hoped thatstudies will also focus on patients selected on the basis ofsignificant residual or secondary symptoms if they are associ-ated with subjective distress and/or functional impairment.


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40: Issues in Clinical Trial Designs 539

If trials are designed to focus specifically on patients whowere nonresponders or intolerant to other treatments, ex-plicit criteria should be developed to identify such groups.There is debate as to whether or not a prospective trial isnecessary to confirm treatment refractoriness, but this iscertainly the most conservative approach because it also ad-dresses to some extent the potential change in treatment

milieu and attention resulting from participation in a re-search trial. In addition, there is enormous variability in thequality of retrospective assessment of treatment response.

Drug washout is a challenge in acutely ill patients. Ifsome exacerbation in symptoms occurs, this complicatesestablishment of a baseline as well as adding to ethical con-cerns and management issues. On the other hand, absenceof a washout means a true baseline is not achieved, assum-ing that there has been some degree of response and oradverse effects from the prior treatment. The use of a con-current placebo group in the treatment trial mitigates theseconcerns to some extent, but does not eliminate them en-tirely. The type, dosage, and half-life of prior treatmentswill influence how long a washout is necessary to preventpotential withdrawal effects from influencing baseline rat-ings. Whether or not a washout takes place (and how longit is) can have implications for assessing the effects of subse-quent treatment. The effects of withdrawal are neither con-sistent nor predictable, which complicates establishment ofan appropriate baseline.

Premorbid social adjustment is a variable that does haveprognostic significance, particularly in schizophrenia. Pooradjustment is associated with poorer outcome, and may bean indicator of those patients in whom early neurodevelop-mental abnormalities or prodromal symptoms were more

severe.Comorbid psychiatric disorders should be evaluated anddocumented. Though there are insufficient data to deter-mine what influence comorbid conditions are likely to haveon overall response to psychotropic medications, commoncomorbid conditions should be studied at some point tohelp assure generalizability and to inform clinical practice.In addition, some studies tentatively suggest that differentmedications may have more or less impact on measures of,for example, substance abuse, suggesting that this could alsobe an important outcome measure in appropriate popula-tions.

In studying antipsychotic medications it is important to

document the presence and severity of any preexistingmovement disorders in order to have an adequate baselineassessment and to ensure that a preexisting condition (orwithdrawal effect) is not attributed to subsequent treatment.

It is essential that patients be assessed for their capacityto give informed consent. It is beyond the scope of thischapter to discuss this in great detail, but patients shouldbe able to describe and explain in their own words the re-search in which they are agreeing to participate, its goals,its experimental aspects, and its potential risks and benefits.

They must understand that they have the right to withdrawat any time and that they will not be penalized in any wayif they choose to do so.

Trial Design

One of the most critical and difficult aspects of trial design

is weighing and balancing what is ideal and what is feasible.An ideal trial for which patients cannot be recruited or inwhich they cannot be retained will not achieve its goals.In addition, though many questions ultimately need to beaddressed, it is usually impossible to adequately addressmultiple questions in a single trial.

The duration of a trial will be influenced by whether ornot a placebo group is included. The longer the duration,the more difficult to justify the retention of patients onplacebo, and the higher the dropout rate, the less useful arethe data.

The time course of response to psychotropic medicationis generally variable. The modal time frame of response hasto be factored into trial design in order to allow estimatesof statistical power. In the acute treatment of schizophrenia,for example, most patients will experience at least half ofthe ultimate degree of improvement within the first 4 to 6weeks (assuming that there was not an inordinately longtitration phase). In many studies a significant drug effect isseen after only 1 to 2 weeks; however, different signs andsymptoms are likely to have a different time course of re-sponse. For example, agitation is likely to respond morerapidly than delusions or thought disorder. In addition,there may be a subgroup of patients who are slower to re-spond, and for such patients longer trials may be needed.

If a between-drug comparison of the full extent of responseis ultimately important, then much longer trials are needed(e.g., 6 months or longer), and this begins to encompassthe continuation phase of treatment. As more and moredomains of outcome are of interest in clinical trials (suchas primary negative symptoms or cognitive dysfunction inschizophrenia), it will be important to better characterizethe time course of response for these variables in order toestablish minimum and optimum durations of trials forthese purposes. Estimates of expected degrees of improve-ment in various domains will be critical for statistical powercalculations.

The Role Of Placebos

The decision as to whether or not to use a placebo in short-term, acute trials remains a topic of considerable contro-versy, and some dynamic tension continues to exist betweenregulatory requirements, investigators, institutional re-view boards, patients and families, and other interested par-ties. There are a number of important arguments that canbe made against the routine use of a placebo in clinicaltrials. Rothman and Michels (3) argue that when an effective


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treatment exists for a particular disease, the use of a placebois inappropriate on both logical and ethical bases. However,the argument suggests that the use of a placebo is appropri-ate in cases when an effective treatment is not available. Aproblem remains in how to define effectiveness. The use ofthe term effectivein this context is not necessarily identical tothe current use ofeffectivenessas differentiated from efficacy.

In a complex disease such as schizophrenia, we continueto struggle with establishing the most meaningful defini-tions of efficacy and effectiveness. If we define responsenarrowly in terms of positive symptoms, then certainly someresponse to conventional agents is expected. In the case ofsevere deficit symptoms or in patients who have provenrefractory to other drugs, the issue is less clear.

A particular problem arises when response to a proveneffective treatment (or so-called gold standard) can varyenormously from trial to trial and in some cases be ratherlow, or when response to a placebo is generally high (4).

The argument is often made that in developing newdrugs to treat a condition for which effective treatments arealready available, the question should not be is the new drugsuperior to placebo but rather is the new drug superior toan already available agent. Unfortunately, given the natureof the diseases and the adverse effects associated with somepsychotropic drugs, a new drug could be superior in onedomain and inferior in another, while being a very valuableaddition to the therapeutic armamentarium. The use of pla-cebo controls can still be important to determine whetheror not in some domains a drug is inferior, but still betterthan a placebo, or whether its inferiority in one domain issuch that it would change the overall effectiveness equation.

To provide an example, suppose drug A were somewhat

less effective than drug B in controlling acute symptoms,but some patients did quite well on drug A. At the sametime, drug B was associated with serious side effects thatmight result in a substantial number of patients discontinu-ing the medication within a short period of time. Wouldwe prefer to have drug A available to treat those patientswho benefited from it, while then giving drug B to thosewho dont. Before approving drug A, we would want to becertain that it was superior to a placebo, though inferior todrug B in the particular domain of acute response.

There are a host of issues relating to the use of placebosthat have been discussed in more detail elsewhere. As Lavori(5) has emphasized, the data sets available from current

placebo-controlled trials are usually heavily truncated, dif-ferentially by treatment groups, and certainly nonran-domly. He argues that most investigators use ad hoc sta-tistically unjustifiable maneuvers such as last observationcarried forward (LOCF) and that the interpretation ofpositive results in the context of badly truncated data re-quires unverifiable assumptions, external to the observeddata of the study.

Another important consideration in the use of a placebois the potential harm resulting from a delay in instituting

active treatment. This is a difficult question to adequatelyaddress; however, there have been some attempts to examinethe consequences, both short- and long-term, of receivinga placebo in the context of short-term trials. Overall, theredo not appear to be demonstratable deleterious effects ofparticipating in short-term trials (6,7). The issue of lengthydelays (i.e., 6 months or longer) in implementing treatment

has been a topic of discussion in first-episode schizophreniapatients, with some authors suggesting that the longer dura-tion of untreated psychosis is associated with poor outcome.In one patient cohort, this effect was reported in short-termoutcome (8), but the effect was no longer evident in long-term follow-up (9). Short-term clinical trials usually involvedurations of 4 to 8 weeks. Therefore, it is important torecognize potential differences in consequences betweenbrief delays and relatively long delays in treatment. Lavori(5) argues that because assessments in placebo-treated pa-tients are usually truncated because of high dropout rates,we do not know the full consequences of exposure to aplacebo. The field would certainly benefit from more intent-to-treat analyses as well as long-term follow-up of patientswho were involved in placebo-controlled trials.

Designs involving the treatment of patients who havefailed on other treatments are another challenge. One couldargue that placebo controls are more acceptable in this con-text because there is no effective treatment. However, it isusually the case that these patients have demonstrated somebenefit from standard, albeit inadequate, treatment. There-fore, the appropriate comparison would be the new treat-ment versus standard treatment, with the only outcome ofinterest being the superiority of the former.

The decision as to whether or not to use placebo or active

controls or both in a particular trial is not an easy one.There are complex issues that need to be considered, andit is hoped that further knowledge involving the determi-nants of heterogeneity in response will facilitate more ra-tional and acceptable trial designs (10).

A related problem is the use of rescue medication. Bal-ancing the desire to retain subjects and the desire to preventharm and not withhold effective treatment is a critical issue.To what extent should other medications be available forthose participants who would otherwise be dropped froma trial due to lack of efficacy and need for alternative treat-ment? Extensive use of rescue medication can make it diffi-cult to accurately assess the drug effect (even though use of

rescue medication can be a telling outcome in and of itself).The use of adjunctive medication to treat adverse effectsthat occur in the course of a trial can also be a concern(e.g., the use of antiparkinsonian medication). Here, too,rates of utilization can be an important outcome measure,yet at the same time the additional medication might haveother undesirable effects (e.g., cognitive impairment).

A number of novel designs have not been widely used,and to some extent there is a disincentive to utilize them,particularly in a regulatory context.


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Crossover designs have been suggested as one alternative,although some exposure to a placebo is still involved. Apatient receives a potentially active compound and if re-sponse occurs, crossover to a placebo takes place. If responsedoes not occur, the placebo phase is not required. The pla-cebo phase in this context helps to determine whether ornot the response to medication was a true drug effect or

not. It is argued that this design has the advantage of eachpatient serving as his or her own control, allowing all pa-tients to eventually receive active medication and increasingstatistical power.

The applicability of this design varies depending on thenature of the disorder being studied, the time course ofresponse, and the vulnerability to relapse or symptom exac-erbation once active treatment is replaced by a placebo. Forexample, this design may be more informative in rapid cy-cling bipolar patients (11) than in the context of an acutetreatment trial in other disorders. Also, this trial does noteliminate exposure to a placebo. From an ethical standpoint,how do we weigh the delay in providing active treatmentagainst the withdrawal of effective treatment once a responseoccurs, with the outcome of interest being an exacerbationof symptoms?

Other alternative designs include adaptive allocationstrategies. The intent of this approach is to reduce the num-ber of subjects exposed to placebo, ineffective, or toxic treat-ments. This is achieved by altering the probability of a par-ticipants receiving one treatment or another based on theprobability established to that point in the trial of whichtreatment is associated with the best outcome. These designsare difficult to conduct, and they require knowledge of theresults of completed subjects in order to allocate treatment

for the next subject. In addition, the response criteria haveto be clearly established a priori. The design becomes morecomplicated when three or more arms are included in atrial. Some studies have utilized such designs with success(12). The ultimate goal of reducing the number of subjectsexposed to inferior treatments can be achieved; ultimately,however, the number of subjects required will depend onthe effect size of interest. (For further discussion see ref.13.)

Active Controls

Comparisons between experimental treatments and active

controls require careful consideration in terms of specificdrugs, dosage, adverse effects profiles, titration require-ments, etc. If a dose of the comparator is too low, efficacycould be less than possible, and if the dosage is too high,then adverse effects may occur more often. This issue isoften a particular concern in industry-sponsored studies,where marketing issues often influence the choice of com-parator and even its dose. This highlights the potential valueof studying a range of doses of both the comparator andthe experimental drug. Though this is costly, the informa-

tion can be particularly valuable in informing clinical prac-tice. Unfortunately, this is rarely done (14). To some extent,this results from unfounded assumptions that we have gooddata on dose-response relationships with drugs that havebeen in widespread use. Often that is not the case. In addi-tion, dosage requirements will vary depending on the popu-lation. For example, in schizophrenia, first-episode patientsin general respond to lower doses than multiepisode pa-tients, and acute treatment usually requires higher dosesthan maintenance treatment.

Another design that is being increasingly utilized is theadjunctive or add-on strategy. This is particularly usefulwhen subjects with partial or inadequate response are thefocus of interest. Rather than switching participants fromthe unsatisfactory treatment to a new treatment, partici-pants are randomized to an added placebo or added experi-mental treatment. In this approach, no drug withdrawal isnecessary and the question of interest is whether or not thenew treatment provides additional benefit.

The potential disadvantages of such a design includedrugdrug interactions, particularly if a novel effect is antic-ipated from the adjunctive treatment. Will this be influ-enced by the original treatment (e.g., different receptorbinding profiles)? This approach is particularly relevantwhen monotherapy is the exception rather than the rule.This type of design has been employed in the developmentof anticonvulsant medications (15).

Continuation Treatment

After improvement in acute symptomatology, there is a pe-

riod of consolidation and stabilization often referred to asthe continuation phase. It is assumed that discontinuationof medication during this period would be associated witha higher risk of relapse than subsequent discontinuation. Itis difficult to specify when the transition from continuationtreatment to maintenance (or prophylactic) treatment oc-curs, but at least 6 months is a reasonably conservativethreshold. The question arises as to how to characterizethose patients who have experienced clinically significantimprovement, but continue to have more than mild symp-toms. In such patients, the continuation phase could be-come indefinite rather than transitioning to maintenance

treatment. This is a semantic distinction because the goalof maintenance treatment is to prevent a relapse or reexacer-bation of psychotic signs and symptoms.

A continuation versus discontinuation design can be asensitive test for drug effect. However, ethically, consentand protection issues are a major concern when any degreeof worsening becomes an outcome measure. If such designsare considered, strategies such as sequential analyses orplanned interim analysis would be important in terminatingthe study at the earliest appropriate time.


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Maintenance Treatment

In any potentially recurring or chronic illness, the issue oflong-term treatment is critical (15). Clearly, the more infor-mation on natural history and untreated course that is avail-able from whatever source, the better in helping to definethe goals and objectives of maintenance treatment. How-

ever, as is often the case, long-term outcome data in sucha context are likely to be unavailable, and when comparisonsare made with historical data there have often been changesin diagnostic criteria, ascertainment techniques, or otherfactors that would limit generalizability.

In considering the role of maintenance treatment, fre-quency, severity, and potential consequences of relapse arecritical. Is maintenance treatment justified if a relapse isunlikely to occur for several years? This will be influencednot only by the consequences of a potential relapse, but alsoby the potential consequences of the prophylactic treatmentitself.

In this context, the appropriateness both from a scientific

and ethical standpoint of including a placebo control is anenormous concern. The fact that relapse rates on activemedication and placebo can vary enormously from onestudy, one site, or one population to another is an importantconsideration. Some would argue that an active comparisoninvolving an experimental medication could result in asmany or more relapses than could occur in a placebo-con-trolled trial given the sample size needed to avoid a type IIerror. Concerns similar to those raised previously apply hereas well in terms of multiple domains of outcome and bene-fit-to-risk ratio. If drug A had a significantly higher relapserate than drug B but was much safer and more likely to betaken on an ongoing basis, would this drug be utilized if itwere shown to be superior to a placebo? How much worsethan standard treatment and how much better than placebowould a drug have to be in order to decide one way or theother? This is an unresolved issue in terms of regulatory,scientific, and ethical concerns.

Many of the issues raised previously in the discussion ofacute treatment apply here as well. Patient characteristics,age, sex, ethnicity, age at onset of illness, duration of currentor most recent episode, baseline psychopathology, comorbidconditions, etc. are all important issues. Even premorbidpsychosocial adjustment has been shown to have some pre-dictive power in relapse prevention studies in schizophrenia

(8,17).Issues such as reference comparator, dosage, route of ad-ministration, concomitant treatments (both pharmacologicand nonpharmacologic), a priori relapse or exacerbation cri-teria, duration, and strategies to enhance and measure com-pliance are all important in designing such studies.

The duration of such trials is critical in achieving overallgoals. Results can be quite different during the first year ofmaintenance treatment as compared to the second, withrelapse rates often being higher in the first year following

recovery from an acute episode as compared to the secondyear (18). At the same time, in some studies involving dos-age reduction, relapse rates were higher in the second yearthan in the first (19).

This discussion also relates to the issue of time courseof relapse in establishing appropriate durations for mainte-nance trials. In schizophrenia, for example, based on histori-

cal data most relapses do not occur for several months aftercomplete drug discontinuation in stable outpatients. Onecontext where time course of potential noncompliance andtime course of relapse was such that trial designs were proba-bly inadequate to find meaningful differences was in thecomparison of oral and depot medications. A number ofdouble-blind controlled trials were conducted in which pa-tients were randomly assigned to depot or oral medicationsand therefore had to receive both injections and tablets, oneof which was a placebo. The duration of all but one of thesetrials was 1 year. In general, they failed to find the significantdifferences that had been expected given high rates of non-compliance in schizophrenia and high rates of relapse fol-lowing drug discontinuation. However, meta-analysis ofthese studies supports the value of long-acting injectablepreparations (20).

It is likely that the less than expected effects were dueto an inadequate duration. Given the fact that subjectsagreeing to receive both injections and tablets in a double-blind design are on the more compliant end of the spectrum,one would not expect noncompliance to occur rapidly. Infact, it could take many weeks or months, particularly giventhe frequent assessments and the psychosocial support in-volved in being part of a research project. Because the relapsethat ensues after complete discontinuation of medications

is not likely to occur for several months, it would be unreal-istic to expect to observe a difference between depot andoral medication in such a study if the duration was only 1year (21). The only such study that lasted 2 years found nodifference between treatments in the first year, but evidenceof clear separation in the second (22). However, the samplesize was inadequate to have sufficient statistical power toestablish a significant difference, even in the second year.

The role of nonpharmacologic treatments and environ-mental factors in long-term studies is also important. Thereis clear evidence that application of nonsomatic interven-tions can have significant impact on relapse rates amongindividuals receiving pharmacotherapy. Although ideally

nonpharmacologic treatment should be controlled, if it isnot there should be documentation of availability and utili-zation so that potential confounds can be identified.

Another important issue in the design of maintenancetrials is whether or not rerandomization following recoveryfrom an acute episode is necessary to demonstrate efficacyin the maintenance phase. In some drug development pro-grams, those patients who respond in the context of anacute trial will be followed and relapse rates reported incomparison to a reference drug. This design provides data


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from only those patients who responded to each drugacutely. The argument is made that to demonstrate efficacyin relapse prevention, patients should be rerandomized orthe study should be started after patients have been stabi-lized on any drug. This then allows conclusions to be drawnregarding prophylactic efficacy among patients in general,not just those who responded to an acute trial of a particular

drug. (In addition, it is important to recognize high ratesof attrition for other causes in acute treatment trials.) Thisis not to say that there is no value in collecting long-termcontinuation data on a particular medication, because thesedata are important in setting the stage for subsequent evalua-tion and comparisons.

As more domains of interest are examined in schizophre-nia, it is necessary to consider the specific designs requiredto establish efficacy and particular outcome measures. Inrecent clinical trials, attempts have been made to collectdata on an array of measures when at times important con-founds can compromise interpretation. For example, inschizophrenia, primary negative symptoms are difficult tostudy in the context of an acute treatment trial that hasselected patients on the basis of having clinically significantpositive symptoms. Trials need to be conducted in patientsselected on the basis of having residual negative symptomsnot complicated by acute positive symptoms or significantextrapyramidal side effects. Remarkably few such studieshave been done.

Similar concerns surround the issue of cognitive dysfunc-tion. Newer antipsychotics show some promise in improv-ing measures of cognitive function (23). However, studyingthese measures requires designs specific to their optimumassessment. In addition, the ultimate question in measuring

cognitive performance will be what impact these changeshave on functioning, either psychosocial or vocational, levelof care, family burden, etc. To date, such studies have notbeen conducted, and it is premature to conclude that meas-urable differences on specific cognitive tests will translateinto meaningful differences in functioning.

SELECTION OF PARTICIPANTS IN CLINICALTRIALS

The issues discussed in the previous paragraph serve as ex-amples of how patient selection becomes a critical focus in

expanding our knowledge of specific drug effects.

Effectiveness Research

Increasing attention has been focused on the fact that tradi-tional randomized clinical trials often include highly se-lected patients who may not be representative of the popula-tion at large. As new medications are used in routine clinicalpractice, there is often a considerable gap in the knowledgebase needed to inform decision making. For example, many

patients with schizophrenia have comorbid conditions (e.g.,substance abuse) that could influence dosing patterns, ad-verse effects, overall response rates, compliance, drug inter-actions, etc. The pharmaceutical industry does not necessar-ily have an incentive to conduct effectiveness research, asthe narrowly defined clinical trial is the most useful andprobably cost-effective approach to the drug approval pro-

cess. In addition, including patients with comorbid psychi-atric and medical conditions can potentially increase ratesof apparent adverse effects where attribution can be difficult.

At the same time, mechanisms should be sought for con-ducting effectiveness trials, which are extremely importantin informing clinical practice and public policy decisions.

Approaches to Subject Selection

Diagnosis and PhenomenologicCharacterization

At present, diagnostic classification is an important element

in patient selection. Although nosology shifts over time, itis important to incorporate into the selection criteria theuse of an established diagnostic system with proven validityand established reliability. Ideally, research should involvea more systematic and formal diagnostic process than simplyrelying on a hospital chart diagnosis. Formal evaluation in-struments are available for specific diagnostic systems. Al-though the use of the complete interviews may be overlytime-consuming and not cost-effective for some types ofresearch, at minimum a checklist indicating how patientsmet specific diagnostic criteria should be completed.

As discussed previously, diagnostic subtype has not beena consistent predictor of drug response; however, as classifi-cation systems improve and, it is hoped, subtypes becomemore meaningful, this element will have increasing impor-tance in clinical trial design.

Because many psychotropic drugs are effective across arange of illnesses, a phenomenologic approach to character-izing pharmacologic effect could be reasonable. Althoughissues of reliability and generalizability would have to becarefully addressed, it is hoped that further research willlead to advances in this perspective.

Biological Classification

Although diseases such as schizophrenia have been charac-terized by a broad array of biologic abnormalities, there areas yet no well-validated biological classification systems thathave proven to be useful in clinical trials or in drug develop-ment. This may be largely due to lack of systematic effectsin this direction rather than an absence of potentially in-formative relationships. As further advances take place indiverse perspectives ranging from neuroimaging to pharma-cogenomics, it is just a matter of time before biologicalclassification becomes a critical ingredient in this context.


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At present, many of the findings are based on group differ-ences and are not necessarily appropriate as selection criteriafor clinical trials. In addition, a variety of concerns includingsensitivity and specificity will need to be addressed in furtherdeveloping this perspective.

PHARMACOKINETIC ISSUES

The more knowledge available about pharmacokinetics andmetabolism (including activity of metabolites) before large-scale clinical trials are designed, the better. Understandingpotential relationships between blood levels and therapeuticresponse as well as adverse effects can be very helpful inoptimizing treatment outcome. However, relevant data areoften inadequate before critical decisions about dose anddosing schedules are made. If more attention were given tothese issues earlier, clinicians would have to struggle lesswith establishing appropriate treatment strategies. Advancesin brain imaging have set the stage for useful investigationduring early stages of drug development; however, here, too,few systematic efforts have been made to take advantageof the potential of such studies to help establish optimumstrategies for clinical trials.

Clinicians value the availability of different deliverymethods for psychotropic medications, given the challengesof both acute and long-term treatment. Oral, liquid, intra-muscular, and long-acting forms should be developed andtested in clinical trials as early as possible. Different clinicaltrial designs may be necessary with different preparationsintended for different levels of acuity or phases of treatment.Here, too, the more information available about pharmaco-

kinetic and pharmacodynamic issues, the better.Given the heterogeneity of clinical response and theenormous variability in drug absorption and metabolism,randomly assigning patients to different plasma levels ofinterest can be a powerful tool in establishing dose-responserelationships and optimum dosing guidelines. Though moredifficult than the standard trial, such studies are feasible,but rarely done (24).

ASSESSMENT OF THERAPEUTIC EFFECTSAND CLINICAL CHANGE

There are many established instruments for the assessmentof psychopathology in clinical trials. In some cases, theseinstruments have been utilized for many years. However,there continues to be a dearth of new scale development.This is partially due to the tedious nature of the develop-ment process and the reluctance of many sponsors of clinicaltrials to utilize a new instrument. As new drugs are devel-oped with potentially different spectrums of activity, itwould be useful to have new scales designed to be sensitiveto specific therapeutic effects. This is particularly appropri-

ate since many of the original assessment scales were vali-dated by proving sensitive to the effects of specific classesof psychotropic medications. (For detailed discussions ofspecific instruments for clinical assessment see refs. 25 and26.)

As outcome measures of interest become more broad, anarray of separate supplemental instruments are being em-

ployed to measure quality of life, social and vocational ad-justment, cognitive functioning, and substance abuse. Indesigning assessment batteries, it is important to chooseinstruments with proven reliability and validity as well asinstruments that are likely to be sensitive to the kind oftreatment effect being measured. Meaningful clinical effectsshould be identified with specific measures of change inorder to ensure that the sample size provides adequate statis-tical power.

As increasing numbers of assessments are employed, itis also important to recognize the burden created for patientsand raters. Careful thought should go into selecting themost informative measures and planning a data analysis pro-gram with a priori primary and secondary hypotheses.

PROBLEMS IN ASSESSMENT

Because psychiatric disorders are often complex, multifa-ceted diseases and some key symptoms are purely subjective,the techniques used for assessment can be critical. Informa-tion regarding psychopathology is most frequently obtainedfrom direct patient interview and observation, though infor-mation from other sources (e.g., family, nurses) is some-times used. Patient report can be impeded by intentional

concealment, lack of insight, paranoid ideation, and theoverall acuity and severity of the illness. It is not uncommonfor psychiatric patients to reveal more psychopathology asthey begin to respond to treatment than they did prior toits initiation. The reliability and validity of different sourcesof information in assessing specific domains have not beenadequately studied. In many trials assessors who are notfamiliar with the patient on an ongoing basis are asked torate psychopathology. Although these ratings can be sensi-tive to treatment effects, it is likely that a person who hasongoing contact with the patient in a treatment contextwill provide a more accurate assessment. Here, too, researchcomparing different rater allocation strategies would be

helpful in determining which is most valid and cost-effec-tive. It is critical to have the same rater evaluating the patientthroughout the trial whenever possible. Despite establishinghigh degrees of interrater reliability, this kind of continuityis important.

The timing of assessments and the time frame chosenfor a given assessment should be determined by the goalsin the study. In general, when rating psychopathology, theprevious week is a reasonable time frame. Patients are lesslikely to accurately recall specific symptoms that are more


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remote in time. The time frame used for a particular assess-ment does not need to coincide with the interval betweenassessments. In a long-term trial it is not necessary to ratepatients weekly. But when they are assessed, the previousweek can be the focus of the assessment.

ASSESSMENT OF ADVERSE EXPERIENCES

The two major goals of drug developmentto enhancetherapeutic efficacy and to improve tolerabilitygo handin hand, particularly in the case of psychotropic medica-tions, where many side effects of psychotropic drugs overlapclinical signs and symptoms of psychiatric illnesses. Giventhe frequent long-term nature of psychotropic drug treat-ment, adverse effects become critical in influencing compli-ance and determining the overall benefit-to-risk ratio.

In general, the methods for detecting adverse events havebeen given far less attention than the methods for evaluatingefficacy. Controversy exists as to the most valid means ofaccurately estimating the incidence of adverse effects. Manyclinical trials rely on patient self-report, with some specificqueries or rating scales used to assess known adverse effects(e.g., extrapyramidal side effects or tardive dyskinesia) thatare outcomes of interest. Given the subjective nature ofmany adverse events, there is a concern that detailed, specificqueries across a broad range of possible symptoms will resultin the elicitation of far more symptoms than an unstruc-tured approach.

A methodologic comparison study (27) suggested thatthe general elicitation of adverse events is more practicaland appropriate for routine clinical trials than a comprehen-

sive and lengthy interview. At the same time the field needsto acknowledge the possibility of inordinate delays in recog-nizing the frequency of specific adverse events such as thesexual dysfunction associated with selective serotonin reup-take inhibitor (SSRI) antidepressants.

There is a strong argument for the use of data and safetymonitoring boards when large and/or long-term studies areinvolved or high-risk treatments are being studied.

CONCLUSION

The clinical trial remains the mainstay of treatment develop-

ment. It is always hoped that further advances will evolvemore rapidly than they do, but there is reason for considera-ble optimism that over the next decade there will be impor-tant advances in predicting and understanding psychotropicdrug response whether via functional neuroimaging, phar-macogenomics, or other potential developments. In addi-tion, it is hoped that increasing emphasis on studying abroader array of functionally meaningful outcome measuresin the context of better informed benefit-to-risk assessmentand documentation of cost-effectiveness will lead to clinical

trial designs to better address the full range of public healthissues.

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Análise de problemas e desafios em estudos psiquiátricos CH40_537-546

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