By J. Stejnar. Emmanuel College.

In (rather than cure) so that aspects of QoL may other situations order anafranil 75mg overnight delivery anxiety eyes, the successive values of DBP be the primary concerns for any comparison of themselves may be utilised in making the formal alternative approaches to management and care comparisons anafranil 75 mg with visa anxiety workbook pdf. If a single aspect of this QoL on each subject is the same, then the analysis measured at one time point is to be used for may be relatively straightforward, perhaps using comparison purposes, then no new principles are repeated measures analysis of variance. On the required either for trial design purposes or anal- other hand, if the numbers of observations ysis. On the other hand, and more usually, there recorded varies or if the intervals between may be several aspects of the QoL instrument successive observations vary from patient to that may need to be compared between treat- patient or if there is occasional missing data, then ment groups and these features will usually be the summary and analysis of such data may be assessed over time. One option is to calculate the area by often-unequal numbers of assessments avail- under the curve (AUC) and use this as a single able from each patient caused either by missing measure for each patient, thus avoiding the use assessments in the series for a variety of reasons of more complex analytical methods. Fayers superseded somewhat in Phase III trials by the and Machin42 and Fairclough43 discuss these fea- use of general estimating equations and multi- tures of QoL data in some detail. The technical details are beyond As we have discussed previously, there is the scope of this book but most good statistics also a problem associated with the numerous packages39 now include facilities for these types statistical tests of significance of the multiple of analyses. These pose problems of inter- yet had much impact on the reporting of clinical pretation which have also been addressed by trials, although a good example of their use has Fayers and Machin42 (Chapter 14). Please take the time to read and answer each question carefully by filling in the bubble that best represents your response. How strongly do you agree or disagree with each of the following statements? Strongly Agree Uncertain Disagree Strongly agree disagree a) I enjoy listening to music. In general, would you say your health is: Excellent Very good Good Fair Poor 2. Much better Somewhat better About the Somewhat Much worse now than one now than one same as one worse now than now than one year ago year ago year ago one year ago year ago Please turn the page and continue © Medical Outcomes Trust and John E. One way to overcome this problem is for pare costs associated with different treatments the clinical protocol to rank the domains of QoL we would follow the basic ideas of blinding and to be measured in terms of their relative impor- randomisation and then record subsequent costs tance and to confine the formal statistical tests incurred by the patient and the health provider. A very careful protocol would be necessary to define which costs are being considered so that this is measured consistently for all patients. ECONOMIC EVALUATION A treatment that is not very effective might, for example, result in the patient needing more Most trials are intended primarily to address frequent consultations. Safety is frequently an nurse and other paramedical personnel contact important (though secondary) objective. Health time would then be recorded as a cost but it economics is becoming increasingly important needs to be clear whether patient travel costs, and is often now evaluated as part of a ran- for example (still direct costs, but not to the domised controlled trial. However, There are four main types of cost analyses that most trials are aimed primarily at assessing effi- are usually considered: ciency and a limitation of investigating costs in a clinical trial is that the schedule of, and fre- • cost minimisation, simply to determine the best quency of, visits by the patient to the physician treatment to minimise the total cost of treating may be very different to what it would be in the disease; routine clinical practice. Typically patients are • cost effectiveness, a trade-off between the cost monitored more frequently and more intensely of caring for a patient and the level of efficacy in a trial setting than in routine clinical prac- offered by a treatment; tice. The costs recorded, therefore, in a clinical • cost benefit, a trade-off between the cost of trial may well be different (probably greater but caring for a patient and the overall benefit (not restricted to efficacy); possibly less) than in clinical practice. How- nomic evaluations is determining what indirect ever, if we keep in perspective that, in a clini- costs should be considered. Direct costs are usu- caltrial,itistherelative efficacy of one treat- ally easier: costs of medication, costs of those ment over another (even if one of them is a giving the care (doctors, nurses, health visitors) placebo) then this limitation, whilst still impor- and the basic costs of occupation of a hospi- tant, can be considered less of an overall objec- tal bed. The same argument should be applied in and productivity, loss of earnings and produc- pharmacoeconomic evaluations and the relative tivity of spouses or other family members who increase/decrease in costs of one treatment over may care for a sick relative and contribution to another can be reported. Because of the Recommendations on trials incorporating health ambiguity associated with these indirect costs, economics assessment have been given by the most pharmacoeconomic evaluations performed BMJ Economic Evaluation Working Party. GENERAL ISSUES 29 TRIAL SIZE these trials, some have an observed HR that is above the hatched horizontal line. This line When designing a new trial, a realistic assessment has been drawn at a level that is thought to of the potential benefit (the anticipated effect represent a clinically worthwhile advantage to the size) of the proposed test therapy must be made test treatment. The history of clinical trials research been outside the funnel had they been estimated suggests that, in certain circumstances, rather from more observed deaths. Thus we might ambitious or over-optimistic views of potential conclude from Figure 2. The benefit test of hypothesis implies no difference between observed, as expressed by the hazard ratio (HR) groups. Conversely, a statistically significant for the new treatment, is plotted against the result does not necessarily imply a clinically number of deaths reported in the trial publication.

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Because of the nature of AML and its treat- If an agent can be safely added to the ment purchase 50 mg anafranil with amex teenage depression definition, several statistical issues in the design and usual dose of conventional therapy buy generic anafranil 50mg online depression great, it might analysis of clinical trials need special attention. Possible study designs for trials of new post-remission therapies are shown in Table 9. The post-remission phase observation without treatment which produces is sometimes further divided into earlier consol- very few if any long-term disease-free survivors idation therapy and later maintenance therapy, and shorter CR durations. The choice among but for our purposes here, two phases are suf- the various randomised approaches might be ficient. It is natural to design studies to compare influenced by the unique features of the agent therapies in each of these two phases, leading to being tested. Also, given the very poor results factorial designs, in which patients are randomly observed with standard therapy, it could be assigned to one of two or more induction thera- argued that a straightforward Phase II trial in pies (the first factor) and then to one of two or which the new agent is evaluated alone could more maintenance therapies (the second factor). However, a number of anti-cancer agents and well-known statistical design. Much has been have been approved by the FDA in recent years written about this design applied in the clinical under an accelerated approval mechanism, based 16 trials setting. The twist in the current situation is that the second randomisation is applicable only for patients who respond to the induction ther- Table 9. As noted above, in the case of older AML agents in post-remission therapy patients, only about 50% of all patients entered Phase II studies on study may respond and, thus, be eligible and New agent alone medically suitable for the second randomisation. Randomised Phase III studies It is typical to separate the objectives of such Observation vs. For example, HAEMATOLOGIC CANCERS 145 CALGB 8923 was a randomised clinical trial attention is focused on identifying activity of of this type involving AML patients at least an agent, no matter how small. However, the CR rate etic growth factor, and placebo following initial is a very imperfect surrogate for more mean- chemotherapy. The hypothesis was that the GM- ingful clinical outcome measures described CSF would reduce infectious complications and below, and has been defined differently by dif- perhaps increase the response rate. Responding ferent leukaemia treatment groups, and should patients were to be randomised to receive one never be used as a substitute for them, espe- of two post-remission regimens, cytarabine alone cially in Phase III clinical trials. This outcome these designs is that there is no direct estimation measure is a good measure of the overall or testing of the four possible treatment poli- control of disease from the start of therapy cies implied in the design. The policies are and combines the effects of induction and defined by selecting one of two induction ther- post-remission therapies. In a Phase III trial, apies followed by one of two post-remission all randomised patients contribute to any therapies, if a response is obtained and the analysis of EFS under the usual intent-to- patient consents to continue. For • Disease-free [or relapse-free] survival (DFS) – example, if both randomisations are done at the this is a standard outcome measure in trials time of study entry with a planned intent to of adjuvant therapy for solid tumours, but in treat analysis, then the inevitable (and antici- AML trials, DFS refers to the survival time pated) large patient drop-out can substantially spent free of disease. Thus, DFS is applicable complicate evaluation of the second therapeutic only to patients who achieve a CR. Since patients OUTCOME MEASURES who fail to achieve a CR are excluded, this measure is unsuitable as an overall assessment There are various choices for outcome measures of therapy. However, it is useful for compar- in clinical trials involving AML patients. The ing two or more post-remission therapies as primary ones are: long as it is recognised that the distribution of DFS is not representative of the result to be • Response rate – the proportion of patients who expected for all patients. This measure suffers from the same are sometimes included in Phase II trials where problems as DFS and, in addition, the usual 146 TEXTBOOK OF CLINICAL TRIALS Kaplan–Meier estimation is no longer valid which treats other risks as independent censoring (see discussion below on competing risks). One way to • Overall survival (OS) – the time from the start properly account for the dependence is through of study to death is an obviously critical out- the use of the cumulative incidence curve, a come measure for any generally fatal disease topic that has been extensively explored in recent like AML in older adults. However, there STATISTICAL MODELS are often difficulties in interpretation, partic- ularly if multiple therapies are given, or if Statistical models are heavily used in AML patients cross over to the alternative therapy trials. Nevertheless, the importance of DFS, OS) are often handled non-parametrically overall survival is so fundamental that it should in the primary analysis (e. For example, the Q-TWiST fraction (c) of patients are cured (or at least method discounts survival time spent with an will have long-term control of disease) and unacceptable level of adverse symptoms due the rest (1 − c) are not. Improved quality of life is equally time-to-failure in the patients not cured. For some purposes in designing and analysing tri- als of therapy for older AML patients, it is infor- SUMMARY mative to use the techniques of competing risks analysis. There will be a large number of compounds inally arose in the context of analysing various available for evaluation in upcoming years and causes of death, but it is applicable more gener- it is desirable that such studies be conducted ally.

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The M-wave is the response to a supramax- Diagnostic reliability imal stimulus of the peripheral nerve purchase anafranil 10mg with amex anxiety used in a sentence, and therefore an electric measure of muscle size cheap anafranil 25 mg with amex depression symptoms medicine. It is used as a ref- EMG is important in the differential diagnosis of cervical erence signal with which post transcranial stimulation spondylosis. It shows degrees of denervation and the num- MEP amplitude and duration are compared, i. The increased CML can be found in not only degenerative but also inflammatory dis- eases of the central nervous system, such as multiple scle- F-wave rosis. Kameyama examined 67 patients with clinically rel- evant cervical myelopathy, and 24 patients with cervical F-wave recordings allow for the determination of a total canal stenosis without myelopathy. A positive corre- peripheral conduction time (peripheral latency: PL) from lation was found for the group of myelopathy patients. De the anterior horn cell to the muscle, which thus includes Mattei found sensitivity of MEPs in patients with cervical the conduction over the motor root to its exit from the in- compression myelopathy to be 70% for upper extremity tervertebral foramen. Distinct delay of the F-wave or a reduced number clinically relevant cervical myelopathy who underwent of clearly distinguishable F-waves after a given number of decompressive surgery. Patients who presented a CML supramaximal peripheral stimuli, in association with nor- longer than 15 ms and/or polyphasic wave pattern of the mal distal motor conduction, is a sign of a proximal le- potential had worse surgical results than the remaining pa- sion. The trophic lateral sclerosis, while in 19 out of 20 patients with authors of this excellent study, which is the only RCT to cervical myelopathy, a pathological finding was observed. The spondylotic cervical myelopathy has been prospectively problem is to find the predictive factors for a satisfac- examined by Bednarik et al. The group changes of tory outcome either for the surgical or the nonsurgical some SEP and MEP parameters correlated with the changes approach. It would be desirable to arrange a multicen- in clinical score, which means they could be used as an ter study aimed at addressing these questions, as has objective tool for the assessment of the results of therapy. First, however, it would In clinical silent cervical cord compression, abnormali- be necessary to validate the scoring systems carefully, ties were found in half the subjects (n=91) and predicted probably replacing those currently used to obtain more clinical manifestation of myelopathy in one-third of them reliable and reproducible data. The most promising candidates for highly predicted Guidelines for treatment procedures, either conservative good results from either conservative treatment or sur- or surgical, in patients with cervical myelopathy do not gery could be the transverse area of the stenotic cord, exist. The literature in this respect presents controversial duration of the disease, osseous or cartilaginous results. Increasing age, clinical, neurophysiological signs, compression, developmental diameter of the canal, pos- and the general health condition are relevant factors in the itivity of electrophysiologic findings, low-signal inten- decision-making process. Only 43 pa- As the indications for surgical decompression of cervi- tients (69%! Neither ISI nor spinal cord area was signifi- – Conduct a neurological assessment and diagnostic work cantly associated with outcome. The authors conclude out to exclude other systemic diseases that early decompression for mild cervical myelopathy is – If in doubt, wait and see, but carry out regular con- not warranted either by ISI or reduced spinal cord area. Factors that – Surgery is indicated in progressive and/or severe forms are unchangeable by nature, such as developmental steno- of cervical myelopathy sis or progressive degenerative changes of the cervical – Multimodal intraoperative monitoring (MIOM) is re- spine, are parameters to consider or indicate surgical de- quired for demanding decompressive surgery, to opti- compression. Negrin P, Lelli S, Fardin P (1991) M, Simonetti S, Spadavecchia L, Se- Dvorak J, Bock WJ (1994) The Euro- Contribution of electromyography to veri P, Andrioli GC, Favale E (1988) pean Myelopathy Score. In: Bauer BL, the diagnosis, treatment and prognosis Electrical stimulation of the motor Brock M, Klinger M (eds) Advances in of cervical disc disease: a study of tracts in cervical spondylosis. Electromyogr Clin Neu- Neurosurg Psychiatry 51:796–802 berg, pp 266–268 rophysiol 31:173–179 2. Neuhuber WL, Zenker W (1989) Cen- Merton PA, Morton HB (1985) Mag- Smrcka V, Krbec M, Stejskal L, tral distribution of cervical primary af- netic stimulation of the human brain. Chaloupka R, Surelova D, Novotny O, ferents in the rat, with emphasis on J Physiol 369:3 Urbanek I, Dusek L (2002) Approaches proprioceptive projections to vestibu- 3. Barker AT, Jalinous R, Freeston IL to spondylotic cervical myelopathy: lar, perihypoglossal, and upper thoracic (1985) Non-invasive magnetic stimula- conservative versus surgical results in spinal nuclei. Kameyama O, Shibano K, Kawakita H, (1990) Central projections of cervical Novotny O, Surelova D, Filipovicova Ogawa R (1995) Transcranial magnetic primary afferents in the rat. Some gen- D, Prokes B (1998) The value of so- stimulation of the motor cortex in cer- eral anatomical principles and their matosensory and motor evoked poten- vical spondylosis and spinal canal functional significance. Bischoff C, Meyer BU, Machetanz J, arthrosis and disc degeneration in an 28.

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