Original Article

Cephalalgia 32(13) 953962 ! International Headache Society 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102412452047 cep.sagepub.com

Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache
Bernhard Aicher1, Hubertus Peil1, Barbara Peil2 and Hans-Christoph Diener3

Abstract Aim: To quantify and compare the responsiveness within the meaning of clinical relevance of efficacy endpoints in a clinical trial with over the counter (OTC) analgesics for headache. Efficacy endpoints and observed differences in clinical trials need to be clinically meaningful and mirror the change in the clinical status of a patient. This must be demonstrated for the specific disease indication and the particular patient population based on the application of treatments with proven efficacy. Methods: Patients global efficacy assessment during two study phases (pre-phase and treatment phase) was used to classify patients as satisfied or non-satisfied with the efficacy of their medication. The analysis is based on 1734 patients included in the efficacy analysis of a randomized, placebo-controlled, double-blind, multi-centre parallel group trial with six treatment arms. Based on this classification and the pain intensity recorded by the patients on a 100 mm visual analogue scale, group differences by assessment categories and receiver operating characteristic (ROC) curve methods were used to quantify responsiveness of the efficacy endpoints time to 50% pain relief, time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), pain intensity difference (PID) relative to baseline at 2 hours, and pain-free at 2 hours. Results: Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed for all efficacy endpoints. Patients with the highest rating of efficacy had the fastest and strongest pain relief. In comparison, patients assessing efficacy as less good reached a 50% pain relief on average nearly an hour later than those scoring efficacy as at least good. Simultaneously, their extent of pain relief was only half as great 2 hours after medication intake. Patients scoring efficacy as poor experienced practically no pain relief within the 4 hour observation interval. ROC curve calculations confirmed an adequate responsiveness for all continuous endpoints. The following cut-off points for differentiating between satisfied and non-satisfied patients were deduced from the data in the pre- and treatment phase, respectively: time to 50% pain relief 1:10 and 1:31 h:min, time until reduction of pain intensity to 10 mm 2:40 and 3:00 h:min, %SPIDweighted 68 and 64%, PID at 2 hours 35 and 35 mm. The sensitivity and specificity based on these cut-off points ranged from 70 to 79%. The binary endpoint pain-free at 2 hours showed a clearly higher specificity (80 and 87%) than sensitivity (65 and 61%) in the pre- and treatment phase, respectively. Conclusions: When global assessment of efficacy by the patient was used as external criterion, ROC curve calculations confirmed a high responsiveness for all efficacy endpoints included in this study. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed. The endpoint %SPIDweighted proved slightly but consistently superior to the other endpoints. SPID and %SPIDweighted are not easy to interpret and the time course of pain reduction is of high importance for the patients in the treatment of acute pain, including headache. The endpoint pain-free at 2 hours showed the expected high specificity, but at the cost of a concurrently low sensitivity and clearly makes less use of the available information than the endpoint time to 50% pain reduction, which combines the highly relevant aspects of time course and extent of pain reduction. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specific condition of a patient, should be added in future revisions of IHS guidelines for clinical trials in headache disorders.

Boehringer Ingelheim Pharma GmbH & Co. KG, Germany 2 Institute of Medical Biometry and Informatics Heidelberg, Germany 3 University Duisburg-Essen, Germany

Corresponding author: Hans-Christoph Diener, Department of Neurology and Headache Centre, University Hospital Essen, Hufelandstrasse 55, 45147 Essen. Email: hans.diener@uni-duisburg-essen.de

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Cephalalgia 32(13)

Keywords Responsiveness of efficacy endpoints, clinical relevance, over the counter analgesics, headache, ROC curve calculations, randomized clinical trials
Date received: 13 March 2012; revised: 15 May 2012; accepted: 27 May 2012

Introduction
Headache pain is dicult to dene and quantify. Consequently, quantication of analgesic ecacy is also dicult, in particular in clinical trials (1). The selection of primary ecacy endpoints in headache studies is a critical factor (2). In the 1970s and 1980s attention was focused on the benets and drawbacks of the various methods for measuring pain, ranging from yes/no responses through graded scales with variable numbers of categories to the continuous visual analogue scale (36), but the debate has since come to centre on the question of adequate primary ecacy endpoints or outcome measures (2,710). During this period the discussion on headache study methodology concentrated on the methods used in the clinical development programme of sumatriptan, including the 4-stage Likert scale used as a method of measurement and the ecacy endpoint selected (percentage of patients with a reduction in headache severity from moderate or severe to none or mild) (1113). The Committee on Clinical Trials in Migraine of the International Headache Society suggested as the primary ecacy parameter in acute treatment trials in migraine the number of migraine attacks resolved within 2 hours (14), although this suggestion has received some criticism in comparison with the response criterion referred to above (15). It has been noted out on several occasions, however, that little research has been conducted to determine which of these endpoints are considered by headache suerers themselves to be most important (16,17), and it has also been commented that new ecacy endpoints need to be dened for certain patients (18). The issue of which endpoint to use is still vexing (7). There is no consensus regarding how an endpoint translates into patient acceptability, or about the relative importance of each attribute in determining this acceptability (19). It is, however, universally accepted that in the context of clinical trials, outcome variables and observed dierences need to be clinically meaningful (20) and mirror the change in the clinical status of a patient. We used methods described for the assessment of outcome measures (21) to quantify and compare the performance of ecacy endpoints in clinical trials with OTC analgesics in headache. In general, outcome

measures have to be reliable, valid and responsive. In a previous paper (22) we reported some results on the validity of various ecacy endpoints in OTC headache trials. In this paper we focus on the responsiveness of these ecacy endpoints. Responsiveness is dened as the ability of an outcome measure to detect clinically important changes in a specic condition of a patient (21,23,24). An outcome measure with high responsiveness should be able to discriminate between the true condition states of the patient. If we restrict to two states of a condition (present or absent), this allows evaluation of responsiveness with methods originally used to assess the performance of diagnostic tests. The condition to be diagnosed (25) could be, for example, whether the clinical status was improved or non-improved or whether the patient was satised or non-satised with their treatment. The quantication and comparison of responsiveness of various outcome measures necessitates the denition of an external criterion for the differentiation between patients with the condition present or not. There is currently no gold standard for an external criterion in pain outcome measures. Examples of external criteria used comprise pain assessment and disability rating (23), return to full activities (25), use of additional rescue medication (26), global perceived eect assessed by the patient (24), standardized eect size (27), power of a test or sample size needed to detect a clinically important dierence (21) or patients global impression of change (28). We used the patients global assessment of ecacy as an external criterion to compare the responsiveness of common ecacy endpoints in headache trials.

Methods Patients, study design and treatments

The data for this analysis were collected as part of a randomized, placebo-controlled, double-blind, multicentre parallel group trial with six treatment arms, conducted between September 1998 and January 2003 (29). The primary objective of the study was to investigate the ecacy, safety and tolerability of the xed combination of acetylsalicylic acid paracetamol caeine in comparison with the combination without caeine, the single preparations, and placebo in patients who were

Aicher et al. used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics. The patients were enrolled by practitioners and specialists in general and internal medicine throughout Germany. Male or female patients (1865 years) who were not consulting for headache were asked whether they had headaches that they treated with non-prescription analgesics. Usual headaches had to meet International Headache Society criteria (30) for episodic tension-type headache (2.1) and/or migraine with or without aura (1.1, 1.2.1). They must have experienced these headaches for at least 12 months with a minimum of two headache episodes within the previous 3 months. Patients were excluded if previous or concomitant diseases or medication could interfere with one of the study drugs or inuence headache symptoms. Drug overuse connected with the headache and alcohol or drug abuse was also an exclusion criterion, as was pregnancy, lactation or participation in another clinical trial within 4 weeks of entering this study. Before enrolment the patients gave their written informed consent according to paragraphs 40 and 41 of the German Drug Law (AMG) and International Conference on Harmonisation, Guidance for Good Clinical Practice, E6 (ICH GCP) standards. Patients were allowed to terminate participation in the trial at any time, without giving reasons. The study was conducted in accordance with the Declaration of Helsinki, the AMG and ICH GCP standards and did not start before independent ethics committee approval was obtained. Patients randomly allocated to one of the six treatment groups treated their headache attack with a single dose of the allocated study medication. Before the randomized treatment phase a headache episode treated with the patients usual non-prescription medication was recorded (open pre-phase).

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. percentage of patients pain-free, dened as patients with reduction of pain intensity to at least 10 mm on the VAS, after 30 min, 1, 2, 3 and 4 hours . pain intensity dierence after 30 min, 1, 2, 3 and 4 hours (evaluated on the VAS) . weighted sum of pain intensity dierence (SPID) expressed as a percentage of the maximum achievable SPID (%SPIDweighted) . extent of impairment of daily activities before and after 30 min, 1, 2, 3 and 4 hours of drug administration (4-point verbal rating scale (VRS): 0 not impaired, 1 somewhat impaired, 2 greatly impaired, 3 usual daily activities impossible) . global assessment of ecacy by the patient (4-point VRS: 1 very good, 2 good, 3 less good, 4 poor) within 12 hours after administration of the trial medication based on the question How do you assess the ecacy of your tablets? . global assessment of tolerability by the patient and investigator (4-point VRS: 1 very good, 2 good, 3 less good, 4 poor) . safety assessment: recording of adverse events (time of onset, duration and intensity of adverse events; relationship between the drug treatment and adverse event determined by the investigator) Ecacy and safety endpoints were calculated twice, for the assessments at the end of the open pre-phase and for the assessments at the end of the randomized treatment phase.

Statistical analysis
The ecacy endpoints were compared by means of descriptive statistics sorted by the categories of the patients global assessment of ecacy. The performance of the endpoints in discriminating between patients satised and patients non-satised with the ecacy was further evaluated using receiver operating characteristic (ROC) methodology (31). Patients assessing ecacy as very good or good were classied as satised, patients scoring ecacy less good or poor as non-satised. Subsequently and for each continuous endpoint separately, cut-o points on the measurement scale for the endpoint were deduced from ROC curves using logistic regression analysis. If the patient was classied as satised with the ecacy and the endpoint measurement was above the cut-o point, the outcome was called true positive (Figure 1A). If the patient was classied as non-satised and the endpoint measurement was below the cut-o point, the outcome was called true negative. The ROC curve displays the true positive (sensitivity) versus the false positive (one minus specicity) rates for the range of possible cut-o points for predicting

Endpoints
Patients recorded pain intensity on a 100 mm visual analogue scale (VAS) before and then 30 min and 1, 2, 3 and 4 hours after drug intake in the patient diary. The calculated time to 50% pain relief was chosen as primary endpoint based on the pain intensity recorded on the VAS. The secondary endpoints of this study, which comprise both ecacy and tolerability parameters, were: . calculated time until reduction of pain intensity to 10 mm on the VAS . percentage of patients with at least 50% pain relief after 30 min, 1, 2, 3 and 4 hours (evaluated on the VAS)

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the global assessment of ecacy by the patient (Figure 1B and C). The area under the ROC curve (AUC) was calculated as a summary measure of its discriminatory ability. The cut-o point was chosen where the sensitivity and specicity were equal assuming equal importance of sensitivity and specicity. As the endpoint pain-free at a pre-specied time point is a binary variable a ROC curve cannot be calculated. There is only one pair of sensitivity and specicity. All calculations were performed twice based on the data of the pre-phase and the data of the randomized treatment phase.

Cephalalgia 32(13) patients recorded poor ecacy in the randomized treatment phase. All ecacy endpoints improved in parallel to the increase of the patients ecacy assessment (Table 1). Patients with the highest rating of ecacy had the fastest and strongest pain relief. In comparison, patients assessing ecacy as less good reached a 50% pain relief on average nearly an hour later (median time to 50% pain relief 1:45 h:min) compared with those scoring ecacy as at least good (median time to 50% pain relief 0:51 h:min) in the pre-phase. Simultaneously, the extent of pain relief was only half as great 2 hours after medication intake (mean PID 25.8 mm versus 46.2 mm as assessed on the VAS). Patients scoring ecacy as poor experienced almost no pain relief within the 4 hour observation period (median time to 50% pain relief > 4 hours and mean PID 7.5 mm). The corresponding values in the randomized treatment phase were overall slightly worse regarding the time to pain relief and slightly better with respect to the extent of pain relief (Table 1). The dierences between the categories of the patients global assessment of ecacy were qualitatively and quantitatively well comparable to those in the pre-phase.

Results Patient characteristics

The full analysis set comprised 1743 patients recruited in 133 centres (29). Of these, 15 patients in the pre-phase and nine patients in the randomized treatment phase did not assess the global ecacy at the end of the respective study phase. The remaining 1728 patients in the prephase and 1734 patients in the randomized treatment phase were included in the evaluation (76% women, 24% men; median age: 38 years; range 1672 years). Without treatment, the usual pain intensity was severe or very severe in 62% and moderate in 37% of patients. The severity of pain was associated with disability of performing usual daily activities. The mean SD pain intensity at baseline was 59.1 20.6 mm in the open prephase and 64.3 20.3 mm in the randomized treatment phase.

ROC curves and cut-off points

The ROC curves of all continuous ecacy endpoints were very close together and partly crossing (Figure 2). The ROC curves, the sensitivity and specicity, and consistently the AUC were more similar for the data from the randomized treatment phase than those from the pre-phase for all endpoints (Table 2). The AUC in the pre-phase ranged from 0.77 to 0.86 and that in the treatment phase from 0.84 to 0.89. The endpoint %SPIDweighted was slightly but consistently superior to the other endpoints. The optimal cut-o points for dierentiating between satised and non-satised patients were lower in the pre-phase than in the randomized treatment phase for the majority of endpoints. The following cut-o points were deduced from the ROC curves for the pre-phase and treatment phase, respectively: time to 50% pain relief 1:10 and1:31 h:min, time until reduction of pain intensity to 10 mm 2:40 and 3:00 h:min, %SPIDweighted 68 and 64%, PID at 2 hours 35 and 35 mm. Based on these cut-o points the sensitivity and specicity ranged from 70 to 77% in the pre-phase and 76 to 79% in the treatment phase. The binary endpoint pain-free at 2 hours showed a clearly higher specicity of correctly predicting a nonsatised patient (80 and 87% for the pre-phase and treatment phase, respectively) than the sensitivity of correctly predicting a satised patient (65 and 61%).

Major efficacy results

The superior ecacy of the triple combination containing acetylsalicylic acid, paracetamol and caeine could be shown for all ecacy endpoints such as the time to 50% pain relief (primary endpoint), time until reduction of pain intensity to 10 mm, pain intensity dierence, %SPIDweighted, extent of impairment of daily activities, and patients global ecacy assessment (29).

Group differences sorted by the assessment of efficacy

The majority of patients assessed ecacy as very good or good in both study phases (68% in the pre-phase, 64% in the randomized treatment phase, Table 1). Whereas the number of patients scoring ecacy as less good was nearly equal in both study phases (25% and 24% in the pre-phase and treatment phase, respectively), a slightly higher percentage (7% versus 12%) of

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Table 1. Summary of descriptive statistics for primary and secondary efficacy endpoints grouped by patients global efficacy assessment. Assessment of efficacy Very good n 255 Pre-phase Time to 50% pain relief [h:min] Median 0:33 Interquartile range 0:19 to 1:00 Time until reduction of pain intensity to 10 mm [h:min] Median 0:53 Interquartile range 0:28 to 1:49 %SPIDweighted [%] Mean (SD) 85.3 (16.4) PID at 2 hours [mm] Mean (SD) 50.9 (21.1) Pain-free at 2 hours [%] Percentage 78.4 Very good n 353 Randomized treatment phase Time to 50% pain relief [h:min] Median 0:38 Interquartile range 0:22 to 1:02 Time until reduction of pain intensity to 10 mm [h:min] Median 0:59 Interquartile range 0:44 to 1:52 %SPIDweighted [%] Mean(SD) 85.5 (13.2) PID at 2 hours [mm] Mean(SD) 56.7 (21.5) Pain-free at 2 hours [%] Percentage 78.4 Good n 923 Less good n 424 Poor n 126

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0:51 0:34 to 1:25 1:44 0:56 to 2:48 75.3 (20.1) 46.2 (20.5) 61.5 Good n 759

1:45 0:50 to >4:00 >4:00 2:13 to >4:00 40.2 (43.9) 25.8 (24.6) 23.2 Less good n 412

>4:00 3:28 to >4:00 >4:00 >4:00 to >4:00 5.0 (42.4) 7.5 (22.5) 7.1 Poor n 210

1:00 0:38 to 1:40 1:56 1:05 to 3:18 73.7 (18.9) 49.6 (21.4) 53.2

2:19 1:16 to >4:00 >4:00 2:37 to >4:00 43.7 (32.8) 27.2 (21.9) 18.2

>4:00 >4:00 to >4:00 >4:00 >4:00 to >4:00 8.5 (27.2) 6.5 (18.1) 2.4

Discussion
Responsiveness must be demonstrated for the specic disease indication and the particular patient population based on the application of treatments of proven ecacy (32). The data used was taken from a clinical study that showed the superior ecacy of the xed combination containing acetylsalicylic acid, paracetamol and caeine over the combination without caeine, the single preparations, and placebo in the treatment of headache for all ecacy endpoints, such as the time to 50% pain relief (primary endpoint), time until reduction of pain intensity to 10 mm, pain intensity dierence, %SPIDweighted, extent of impairment of daily activities, and patients global ecacy assessment (29). The quantication of the responsiveness always necessitates the choice of a reference criterion that

describes the status or change in a status of a patients condition. There is currently no gold standard for this criterion in pain outcome measures. The choice of the criterion is always problematic (24). It should be specic to the disease and the patient population studied. In self-medication, the patients choice of a particular therapy, which they take for their headache, depends on the subjective perception of ecacy and tolerability of the drug without consulting a doctor. As the global assessment of overall ecacy by the patient aims to summarize the patients overall impression about their state or change in their state (33), it is of particular importance in clinical trials with OTC medications for self-medication of headaches and qualies as a criterion with which to quantify and compare the performance of ecacy endpoints in these trials. It is relevant and sensible to ask the patient to assess their perceived benet (24) and to use their decision as a reference.

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Cephalalgia 32(13)

(A)

Classification due to cut-off for the endpoint non-improved improved Assessment of efficacy by patient non-satisfied satisfied true negative false negative Sens (x) 100 (C) Sensitivity (true positive) [%] false positive true positive

(B)

0 0 100-Spec (x)

50

cut-off x

50

100

100-Specificity (false positive) [%]

Figure 1. ROC method. (A) Decision table with possible outcomes. (B) Distribution of data of the efficacy endpoint for the two groups of patients with efficacy assessment as non-satisfied or satisfied including a possible cut-off point. (C) ROC curve for all possible cut-off points.

Pre-phase 1.0 1.0

Randomized treatment phase

0.8

0.8

Sensitivity

Sensitivity

0.6

0.6

0.4

0.4

0.2

0.0 0.0 0.2 0.4

Time to 50% pain relief Time to pain intensity of 10 mm % SPIDweighted Pain intensity difference at 2 hours Pain-free at 2 hours

0.2

Time to 50% pain relief Time to pain intensity of 10 mm % SPIDweighted Pain intensity difference at 2 hours Pain-free at 2 hours

0.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity

0.6

0.8

1.0

1-Specificity

Figure 2. Receiver operating characteristic (ROC) curves for primary and secondary efficacy endpoints based on patients global efficacy assessment as external criterion.

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Table 2. Area under the receiver operating characteristic (ROC) curve and sensitivity and specificity of cut-off points for primary and secondary efficacy endpoint based on patients global efficacy assessment as external criterion. AUC Pre-phase Time to 50% pain relief [h:min] Time until reduction of pain intensity to 10 mm [h:min] %SPIDweighted [%] PID at 2 hours [mm] Pain-free at 2 hours [%] Randomized treatment phase Time to 50% pain relief [h:min] Time until reduction of pain intensity to 10 mm [h:min] %SPIDweighted [%] PID at 2 hours [mm] Pain-free at 2 hours [%] 0.77 0.81 0.86 0.78 0.85 0.84 0.89 0.84 Cut-off point 1:10 2:40 68 35 1:31 3:00 64 35 Sensitivity [%] 70 75 77 71 65 76 77 79 76 61 Specificity [%] 70 75 77 71 80 76 77 79 76 87

The global assessment of ecacy in clinical trials reects these perceptions best. However, as we do not postulate global assessment of ecacy as the gold standard, further comparisons of ecacy endpoints against other reference criteria may be helpful. When global assessment of ecacy by the patient was used as external criterion, we have shown clinically relevant dierences between patients satised and nonsatised with the treatment for all ecacy endpoints included in the analysis. Patients satised with their medication reported a 50% pain relief approximately within 11.5 hours. A pain-free state should be reached by at least 3 hours after intake of the medication for patients to be satised with their medication. The reduction in pain intensity 2 hours after medication intake needed to be greater than 35 mm for these patients assessed on the 100 mm VAS. The cut-os for dierentiating between patients satised and non-satised with their treatment were determined assuming equal sensitivity and specicity. This was possible for all continuous endpoints. The binary endpoint pain-free at 2 hours used an a priori xed cut-o point with clearly higher specicity of correctly classifying non-satised patients compared with the sensitivity of correctly classifying satised patients. Nearly balanced sensitivity and specicity would result in the binary outcome pain-free at 3 hours. Higher specicity than sensitivity could be reached for the other endpoints if more stringent cut-o points were chosen. Outweighing specicity or sensitivity might be meaningful for specic study objectives. Without any restrictions it is reasonable to balance both. Lipton stated The assessment of migraine pain, associated symptoms, and disability is subjective, in that clinicians rely on patient rating of the severity of migraine symptoms. Patient assessment and corresponding physician evaluation form the basis for

treatment decisions and assessment of the ecacy of a migraine therapy (34). The FDA added, For some treatment eects, the patient is the only source of data. For example, pain intensity and pain relief are the fundamental measures used in the development of analgesic products. Many patient-reported outcome instruments are able to detect mean changes that are very small; accordingly it is important to consider whether such changes are meaningful (35). Although there are some surveys that judge and rank the relevance of possible endpoints from the perspective of the patients (3639), there is no clinical trial in headache to our knowledge in which the specicity and the sensitivity of the primary endpoint were analysed quantitatively with the global assessment of ecacy of the patients as reference criteria. This obvious question remained unanswered. Corresponding analyses would be helpful, but needs access to individual patientrelated information. With migraine and tension-type headache pain intensity increases over a certain period of time until fully developed. If the medication is taken very early, endpoints related to the baseline value are not very useful. This can be a problem in early intervention studies. The patients in the Thomapyrin study (29), however, were not instructed to take their study medication at any certain time point and the baseline values and the development of pain intensity show that in most patients the headache pain was fully developed. The ROC curve calculations conrmed a high responsiveness for all ecacy endpoints included in this study. The observed dierences between endpoints are, in general, small. Therefore the ROC curves for all endpoints were very close and partly crossing, although the endpoint %SPIDweighted proved slightly but consistently superior to the other endpoints.

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As recommended in the 2nd edition of the Guidelines for controlled trials of drugs in migraine the percentage of patients pain-free at 2 h, before any rescue medication, should usually be the primary measure of ecacy (40). According to the authors of the comments on this recommendation, this endpoint has the advantage that it reects patients expectations, is simple and not aected by rescue medication (40). The value of the 2-hour pain-free measure cannot be overemphasized, according to Ramadan (41). Although migraine patients stated incomplete or inconsistent pain relief as important issues for their assessment of a treatment in a telephone survey (36), the Thomapyrin study (29) showed that at least for analgesics used for the self-medication of headaches the patients weighted time to 50% pain reduction much higher than time to pain-free for their global evaluation of ecacy (22). Goadsby stated as a disadvantage that for patients with slowly settling headache the transition to no pain is dicult to discern and for some patients the reduction in headache pain to mild is a substantial and very benecial result (7). Tfelt-Hansen and coauthors say in the guideline that resolution, not alleviation, within 2 h might seem unrealistic with some drugs (40). The endpoint pain-free at 2 hours showed the expected high specicity, but at the cost of a concurrently low sensitivity. It clearly makes less use of the available information than, for example, the endpoint time to 50% pain reduction and copes less well with the objective to choose appropriate endpoints that reect realistic treatment goals for individual patients (42). It was recommended in the 2nd edition of the Guidelines for controlled trials of drugs in tensiontype headache again that pain-free rate at 2 h should be the primary ecacy measure (43). However, other possible endpoints were also discussed: Sum of pain intensity dierences (SPID) could theoretically be useful because it has the advantage of summarizing the benets of treatment over a clinically relevant period, e.g. 2 h (43). Ramadan pointed to the common use of endpoints such as SPID in pain studies (41). The version of SPID weighted according to the time points of pain intensity assessment proved to be the endpoint with the highest responsiveness in the present study. However, SPID and %SPIDweighted are not easy to interpret. The time course of pain reduction is of higher importance for the patients in the treatment of acute pain, including headache, than for example in the treatment of chronic pain under steady state conditions of the treatment. Tfelt-Hansen et al., in their review of single attack data, found that SPID did not appear to add anything and assumed that SPID usually gives similar results to other headache relief measures (44). Our analysis using the ROC method supports this assumption. The ROC method allows the quantication and

Cephalalgia 32(13) comparison of the responsiveness between clinical endpoints of very dierent types as the ROC curve depends only on the ranks of the observations and is independent of the scale used to measure the endpoint. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specic condition of a patient, is not yet suciently considered in the discussion of possible endpoints in both IHS guidelines, even though it is an aspect of great relevance in clinical trials. This should be added in future revisions of these guidelines. Funding
This work was supported by Boehringer Ingelheim Pharma GmbH & Co.KG Germany.

Conflict of interests
BA and HP are employees of Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. BP declares no conicts of interest. HCD received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer Vital, Berlin Chemie, Coherex, CoLucid, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Gru nenthal, Janssen-Cilag, Lilly, La Roche, 3M Medica, Medtronic, Menerini, Minster, MSD, Novartis, Johnson & Johnson, Pierre Fabre, Pzer, Schaper and Bru mmer, SanoAventis, and Weber & Weber. HCD has no ownership interest and does not own stocks of any pharmaceutical company.

References
1. Wallenstein SL and Houde RW. The clinical evaluation of analgesic effectiveness. In: Ehrenpreis S, Neidle A (eds) Methods in narcotics research. New York: Marcel Dekker, 1975, pp.127145. 2. Lipton RB. Methodologic issues in acute migraine clinical trials. Neurology 2000; 55: 5397. 3. Huskisson EC. Measurement of pain. Lancet 1974; 2: 11271131. 4. Kremer E, Atkinson JH and Ignelzi RJ. Measurement of pain: patient preference does not confound pain measurement. Pain 1981; 10: 241248. 5. Jensen MP, Karoly P and Braver S. The measurement of clinical pain intensity: a comparison of six methods. Pain 1986; 27: 117126. 6. Skovlund E and Flaten O. Response measures in the acute treatment of migraine. Cephalalgia 1995; 15: 519522. 7. Goadsby PJ. The scientific basis of medication choice in symptomatic migraine treatment. Can J Neurol Sci 1999; 26(Suppl. 3): S20S26. 8. Salonen R. Drug comparisons: why are they so difficult? Cephalalgia 2000; 20(Suppl. 2): 2532. 9. Sheftell FD and Fox AW. Acute migraine treatment outcome measures: a clinicians view. Cephalalgia 2000; 20(Suppl. 2): 1424.

Aicher et al.
10. McCrory DC, Gray RN, Tfelt-Hansen P, Steiner TJ and Taylor FR. Methodological issues in systematic reviews of headache trials: adapting historical diagnostic classifications and outcome measures to present-day standards. Headache 2005; 45: 459465. 11. Pilgrim AJ. Methodology of clinical trials of sumatriptan in migraine and cluster headache. Eur Neurol 1991; 31: 295299. 12. Pilgrim AJ. Early-phase clinical trials in migraine: efficacy, safety and dose-finding. Cephalalgia 1995; (Suppl. 15): 1013. 13. Pilgrim AJ. Lessons learned from the clinical development of sumatriptan. In: Olesen J, Tfelt-Hansen P (eds) Headache treatment: trial methodology and new drugs. Philadelphia: Lippincott-Raven Publishers, 1997, pp.119124. 14. IHS Committee on Clinical Trials in Migraine: Guidelines for controlled trials of drugs in migraine (first edition). Cephalalgia 1991; 11: 112. 15. Tfelt-Hansen P. Complete relief (HIS criterion) or no or mild pain (Glaxo criterion)? In: Olesen J, Tfelt-Hansen P (eds) Headache treatment: trial methodology and new drugs. Philadelphia: Lippincott-Raven Publishers, 1997, pp.157160. 16. Pietrini U, De Luca M and Del Bene E. Endpoints to evaluate efficacy of symptomatic drugs in migraine: what do patients want? Headache 2002; 42: 948949. 17. Coeytaux RR, Frasier PY and Reid A. Patient-centered outcomes for frequent headaches. Headache 2007; 47: 480485. 18. Landy SH, McGinnis JE and McDonald SA. Pilot study evaluating preference for 3-mg versus 6-mg subcutaneous sumatriptan. Headache 2005; 45: 346349. 19. Bigal M, Rapoport A, Aurora S, Sheftell F, Tepper S and Dahlof C. Satisfaction with current migraine therapy: experience from 3 centers in US and Sweden. Headache 2007; 47: 475479. 20. Friedman LM, Furberg CD and DeMets DL. Fundamentals of clinical trials. Boston: John Wright PSG Inc, 1982, pp.1224. 21. Kirshner B and Guyatt GH. A methodological framework for assessing health indices. J Chron Dis 1985; 38: 2736. 22. Pageler L, Diener HC, Pfaffenrath V, Peil H and Aicher B. Clinical relevance of efficacy endpoints in OTC headache trials. Headache 2009; 49: 646654. 23. Bronfort G and Bouter LM. Responsiveness of general health status in chronic low back pain: a comparison of the COOP Charts and the SF-36. Pain 1999; 83: 201209. 24. Beurskens AJHM, de Vet HCW and Ko ke AJA. Responsiveness of functional status in low back pain: a comparison of different instruments. Pain 1996; 65: 7176. 25. Deyo RA and Centor RM. Assessing the responsiveness of functional scales to clinical change: an analogy to diagnostic test performance. J Chron Dis 1986; 39: 897906. 26. Farrar JT, Portenoy RK, Berlin JA, Kinman JL and Strom BL. Defining the clinically important difference in pain outcome measures. Pain 2000; 88: 287294.

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27. Buchbinder R, Bombardier C, Yeung M and Tugwell P. Which outcome measures should be used in rheumatoid arthritis clinical trials? Arthritis Rheum 1995; 38: 15681580. 28. Farrar JT, Young Jr JP, LaMoreaux L, Werth JL and Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94: 149158. 29. Diener HC, Pfaffenrath V, Pageler L, Peil H and Aicher B. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single dose, placebo-controlled parallel group study. Cephalalgia 2005; 25: 776787. 30. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1998; 8(Suppl. 7): 196. 31. Pepe MS. The statistical evaluation of medical tests for classification and prediction. Oxford: Oxford University Press, 2003. 32. Revicki DA, Cella D, Hays RD, Sloan JA, Lenderking WR and Aaronson NK. Responsiveness and minimal important differences for patient reported outcomes. Health Qual Life Outcomes 2006; 4: 7074. 33. ICH Harmonised Tripartite Guideline E9. Statistical principles for clinical trials. CPMP/ICH/363/96, 1998: 137. 34. Lipton RB. Methodologic issues in acute migraine clinical trials. Neurology 2000; 55(Suppl. 2): S3S7. 35. U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health. Guidance for industry: patientreported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes 2006; 4: 79. 36. Lipton RB and Stewart WF. Migraine therapy: do doctors understand what patients with migraine want from therapy? Headache 1999; 39(Suppl. 2): S20S26. 37. Colman SS, Brod MI, Krishnamurthy A, Rowland CR, Jirgens KJ and Gomez-Mancilla B. Treatment satisfaction, functional status, and health-related quality of life of migraine patients treated with almotriptan or sumatriptan. Clin Ther 2001; 23: 127145. 38. Dodick D. Patient perceptions and treatment preferences in migraine management. CNS Drugs 2002; 16(Suppl. 1): 1924. 39. Lipton RB, Hamelsky SW and Dayno JM. What do patients with migraine want from acute migraine treatment? Headache 2002; 42(Suppl. 1): 39. 40. Tfelt-Hansen P, Block G, Dahlo f C, Diener HC, Ferrari MD, Goadsby PJ, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000; 20: 765786. 41. Ramadan NM. Assessing the efficacy of drugs for the acute treatment of migraine: issues in clinical trial design. CNS Drugs 2002; 16: 181196.

962
42. Antonaci F, Sances G, Guaschino E, De Cillis I, Bono G and Nappi G. Meeting patient expectations in migraine treatment: what are the key endpoints? J Headache Pain 2008; 9: 207213. 43. Bendtsen L, Bigal ME, Cerbo R, Diener HC, Holroyd K, Lampl C, et al. Guidelines for controlled trials of drugs in

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tension-type headache: second edition. Cephalalgia 2010; 30: 116. 44. Tfelt-Hansen P, McCaroll K and Lines C. Sum of pain intensity differences (SPID) in migraine trials. A comment based on four rizatriptan trials. Cephalalgia 2002; 22: 664666.