European Medicines Agency
`
`London, 16 November 2006
`Doc. Ref. CPMP/EWP/561/98 Rev. 1
`
`COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
`(CHMP)
`
`GUIDELINE ON CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`
`DRAFT AGREED BY THE EFFICACY WORKING PARTY
`
`28 June 2005
`
`ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION
`
`15 September 2005
`
`END OF CONSULTATION (DEADLINE FOR COMMENTS)
`
`AGREED BY THE EFFICACY WORKING PARTY
`
`ADOPTION BY CHMP
`
`DATE FOR COMING INTO EFFECT
`
`31 March 2006
`
`4 October 2006
`
`16 November 2006
`
`1 June 2007
`
`This guideline replaces NfG on clinical investigation of medicinal products for the treatment of
`Multiple Sclerosis (CPMP/EWP/561/98)
`
`KEYWORDS
`
`Multiple sclerosis, guidance, neurological disease
`
`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 60
`E-mail: mail@emea.europa.eu http://www.emea.europa.eu
`©EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
`
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`Biogen Exhibit 2002
`Mylan v. Biogen
`IPR2018-01403
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`

`

`GUIDELINE ON CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY................................................................................................................... 3
`INTRODUCTION (BACKGROUND) ........................................................................................ 3
`
`1.
`
`2.
`
`5.
`
`SPECIFIC CONSIDERATIONS WHEN DEVELOPING PRODUCTS FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS ........................................................................... 4
`3. CRITERIA FOR ASSESSMENT OF EFFICACY IN CONFIRMATORY TRIALS ............ 7
`4. METHODS TO ASSESS EFFICACY......................................................................................... 8
`SELECTION OF PATIENTS ...................................................................................................... 9
`STRATEGY-AND DESIGN OF CLINICAL TRIALS............................................................ 10
`SAFETY ....................................................................................................................................... 11
`
`6.
`
`7.
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`EXECUTIVE SUMMARY
`This Guideline is intended to provide guidance for the evaluation of drugs for the treatment of
`multiple sclerosis. It should be read in conjunction with the Directive 75/318/EEC, as amended, and
`other current and future CHMP and ICH guidelines, in particular the guidelines on:
`•
`Statistical principles for clinical trials (ICH topic E9)
`• The extent of population exposure to assess clinical safety (ICH topic E1)
`•
`Pharmacokinetic studies in man
`• Dose response information to support drug registration (ICH topic E4)
`•
`Investigation of drug interactions
`• Choice of control group in clinical trials (ICH topic E 10)
`
`INTRODUCTION (background)
`1.
`Multiple Sclerosis (MS) is a common neurological disease affecting more than 1 million people
`worldwide. Its prevalence rate varies between races and geographical latitude, ranging from more than
`100 per 100,000 in Northern and Central Europe to 50 per 100,000 in Southern Europe.
`MS is an inflammatory condition that damages the myelin of the Central Nervous System and causes
`neurologic impairment and, frequently, severe disability. It is the commonest cause of neurological
`disability in young and middle-aged adults and has a major physical, psychological, social and
`financial impact on patients and their families, friends and bodies responsible for health care.
`The aetiology of MS remains unknown. It is generally assumed that MS is mediated by some kind of
`autoimmune process possibly triggered by infection and superimposed upon a genetic predisposition.
`As many as 80 to 85 % of all patients present with a form of disease known as relapsing-remitting MS
`(RRMS), which is characterised by unpredictable acute episodes of neurological dysfunction named
`clinical attacks or relapses, followed by variable recovery and periods of clinical stability. Within ten
`years more than 50% of patients who presented with a RR form eventually develop sustained
`deterioration with or without relapses superimposed; this form is called the secondary progressive
`variety of MS (SPMS). The term relapsing MS (RMS) applies to those patients either with a RRMS
`form or a SPMS form that are suffering relapses. Patients with RMS, in spite of suffering from
`different MS forms, constitute a common target for current treatments. Around 15% of patients
`develop a sustained deterioration of their neurological function from the beginning; this form is called
`primary progressive MS (PPMS). Some patients who begin with a progressive deterioration may
`experience relapses with time and this form is called progressive relapsing MS (PRMS). Besides these
`main types of disease, the benign variety of MS refers to a RRMS form with few relapses and no
`significant disability after several years of evolution. Conversely, the term malignant MS applies to a
`very aggressive variety leading to severe disability or death in a few years after the onset of the
`disease.
`Finally, the term clinically isolated syndrome (CIS) applies to those patients who have suffered a
`single clinical event but do not comply with the diagnostic criteria for definite MS.
`It is unclear whether the different courses of MS described are due to the same or to distinct
`pathophysiologic processes. Relapses are considered the clinical expression of acute inflammatory
`focal lesions whereas progression is considered to reflect the occurrence of demyelination, axonal loss
`and gliosis. Relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis are
`probably different stages of the same disease while primary progressive multiple sclerosis may imply
`different processes.
`In general, current therapeutic approaches include:
`Symptomatic treatment. This refers to all therapies applied to improve symptoms caused by the
`disease: fatigue, spasticity, ataxia, weakness, bladder and bowel disturbances, sexual dysfunction,
`pain, tremor, paroxysmal manifestations, visual impairment, psychological problems, cognitive
`dysfunction and other associated conditions that can improve with non specific treatments. Clinical
`development of these products is out of the scope of this guidance.
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`Treatment of acute relapses with corticosteroids
`Treatment aimed to modify the course of the disease. In this category there are therapies aimed to
`decrease the relapse rate or modify relapses; therapies aimed to diminish the accumulation of
`disability in time; and future therapies that pursue neuroprotection or intend to restore neurological
`function (e.g. by means of promotion of remyelination).
`Recent studies suggested that progression of lesions in MS might have, even in early clinical stages,
`two components: an active immunological aspect and a degenerative aspect; it is unknown to what
`extent these are causally interrelated. Currently approved therapies to modify the MS course target the
`immunological processes of the disease. Most of them are considered to act as immunomodulators but
`their mechanisms of action have not been completely elucidated: the relationships between changes of
`the immune response induced by these agents and the clinical efficacy in MS is far from settled.
`Immunosupressants or cytotoxic agents are also used in some patients after failure of conventional
`therapies.
`Based on the immunological nature of the disease, combination therapy targeting different parts of the
`immune processes may be reasonable and development of a new treatment as a combination therapy is
`a possible strategy.
`
`•
`
`2.
`
`SPECIFIC CONSIDERATIONS WHEN DEVELOPING PRODUCTS FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`2.1 Different goals of treatments
`Treatments of MS may have different goals that will lead to different clinical development plans and
`clinical trial designs:
`A)
`Treatment of acute relapses to shorten their duration and/or severity of symptoms and/or
`preventing their sequelae.
`B) Modification of the natural history of the disease. This includes:
`•
`Preventing or delaying the accumulation of disability. This may refer to the sustained
`accumulation of disability related with relapses or to the progression of disability either in
`the progressive phase of the disease (SPMS) or in PPMS. Those three situations demand
`a separate approach.
`Preventing or modifying relapses. It is not clear to what extent the effect on relapses is
`related to the prevention or delay in the long-term accumulation of disability, which is
`considered a more clinically relevant effect
`Improvement of an apparently stable residual disability
`C)
`2.2 Treatments for acute relapses
`Neurological impairment due to a relapse may improve spontaneously within weeks or few months.
`However, regarding a specific attack, prediction of the course and degree of later functional recovery
`is not possible. Therefore, parallel controlled clinical trials are mandatory to assess the benefit of any
`new therapy.
`Corticosteroids are the accepted treatment for acute relapses in MS. Plasmapheresis is used in severe
`relapses based on limited data. Corticosteroid therapy shortens the duration of the relapse and
`accelerates recovery, but there is no evidence that corticosteroid treatment improves the overall degree
`of recovery or alters the long-term course of the disease. These are relevant issues when investigating
`new treatments for relapses.
`As there is no agreement about the specific criteria of corticosteroid treatment (e.g. dosage, method of
`administration, tapering,..) the actually chosen regimen should be stated and justified in the protocol.
`If, for a test drug only an effect on the duration, severity and/or recovery from a relapse is claimed,
`this claim should be based on clinical trials with corticosteroid treatment as positive control and a
`placebo arm for the internal validation of the study. Even if only relapses with homogeneous signs or
`symptoms are considered, it is recognised that it is difficult to give a reliable assessment of the
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`severity of a relapse, either using clinical judgement or neurological scales. MRI with gadolinium may
`inform on the duration of the inflammatory activity.
`The trial should include escape conditions to allow switching to standard therapy when the patient
`fails to improve or even worsens. Patients should be followed for an appropriate time (e.g. at least
`6 months) after each relapse to be sure that the degree of recovery after the relapse is well assessed. It
`is recommended also to investigate the modification of the subsequent clinical course of the disease in
`terms of time free from subsequent relapse and progression of disability. The investigation of a
`modifying the effect on other products being used concomitantly as chronic treatments intended to
`modify the natural course of the disease, may be also valuable.
`If an effect is claimed with regard to the degree of recovery after a relapse and/or the long-term course
`of the disease, this should be demonstrated by means of placebo-controlled superiority trials.
`2.3 Treatments intended to modify the natural course of the disease
`It is important to differentiate between the clinical patterns of the disease: RRMS, SPMS with and
`without relapsing activity and PPMS (see 1.). Although these patterns are defined according to clinical
`features (occurrence of relapses, presence of gradual progression of disability) differences in
`histopathology and MRI (Magnetic Resonance Imaging) activity are also present.
`2.3.1 Relapsing multiple sclerosis
`The term relapsing MS includes 1) patients with RRMS, 2) patients with SPMS and superimposed
`relapses and 3) patients with a single demyelinating clinical event who show lesion dissemination on
`subsequent MRI scans according to McDonald’s criteria.
`Prevention and/or modification of relapse features as well as prevention or delay of the accumulation
`of disability as sequelae of acute relapses, are meaningful goals in the treatment of RMS
`Progression of disability, as a result of relapses from which patients do not fully recover take many
`years and, for the moment, there are no surrogate variables for evaluating progression of disability.
`Therefore large-scale long-term parallel group trials are required to establish clinically relevant
`treatment differences on disease progression.
`Relapse rate, relapse duration, recovery after relapses are all highly variable between patients and
`within one patient. Therefore, treatments intended to decrease the relapse rate or modify relapses
`should be evaluated in parallel trials sufficiently large and long to overcome this inter and intra-
`individual variability.
`Currently approved therapies have demonstrated a favourable effect on the rate and severity of
`relapses and some products also in the short-term (a few years) progression of disability. If a product
`demonstrates a benefit in relapse rate or severity without an accompanying effect on preventing or
`delaying disability, the clinical relevance of such benefit should be justified. For this reason studies
`aimed to evaluate an effect on relapse rate should also generate data with respect to disability.
`Although the effect on relapse rate may be investigated in patients with any form of relapsing MS, it is
`advisable to assess the effect on disability only in patients with relapsing remitting MS. It is therefore
`accepted that the indication in relapsing MS will mainly rely on the effects shown in patients with
`relapsing remitting MS and that an effect on relapses in relapsing remitting MS may be extrapolated to
`an effect on relapses in secondary progressive MS.
`Several major placebo-controlled clinical trials have provided evidence of an apparent short-term
`stabilisation in placebo-treated patients that could be explained, among others, by the regression to the
`mean phenomenon, and by a real placebo effect, as well as by the natural course of the disease.
`Approved therapies have been shown to favourably modify the short-term evolution of the disease
`although the benefit is modest, at the cost of significant inconveniences and side effects and it is not
`known whether the effect is maintained for years. Differences from placebo are not consistent across
`trials and the sensitivity of the available scales to measure progression of disability as well as other
`characteristics of clinical trials in this field do not assure the ability to detect clinically relevant
`differences.
`Therefore, equivalence (non-inferiority) trials are insufficient, as the only proof of efficacy and
`demonstration of superiority against placebo or active comparator should be provided.
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`Since it is anticipated that placebo-controlled clinical trials may raise problems of feasibility and even
`some ethical concerns, different approaches and alternative designs may be explored in order to
`circumvent these constraints. Although a three-arm trial including a placebo and an active control is a
`preferred design, it is recognised that it would be very difficult to undertake unless modifications to
`the design were introduced (e.g. a short duration three-arm trial, one-year placebo or placebo until
`patients have a new relapse, after which these patients will be drop out and subsequent parallel trial
`with only the two active arms). The proportion of subjects with no relapses over two years of
`follow-up then may be the primary endpoint. Other options may include add-on designs,
`placebo-controlled clinical trials in selected populations such as those refusing treatment after being
`well informed of available therapies or those where the benefits of current therapies are less clear.
`2.3.1.1 Clinically Isolated Syndrome (CIS)
`Patients with CIS are not considered an appropriate target for pivotal clinical trials aimed to
`demonstrate efficacy of products in MS.
`When a population in early stages of the disease and at high risk for further relapses is selected, it is
`expected that effects of treatments preventing further relapses may be of a greater magnitude. At the
`same time, however, the clinical relevance of the effect (with respect to long-term benefit) is less
`clear.
`Therefore it is difficult to extrapolate positive results in CIS patients to relapsing remitting MS.
`However, they may constitute either supportive evidence of efficacy in MS or an additional claim for a
`product with a demonstrated efficacy in relapsing remitting MS.
`In CIS, the delay of the occurrence of a second clinical attack, although relevant from a mechanistic
`perspective, is of limited clinical relevance. It is needed to demonstrate efficacy by means of a
`meaningful and sustained decrease in relapse rate over 2-3 year time and it is recommended to assess
`the decrease of the accumulation of disability.
`2.3.2 Secondary progressive multiple sclerosis (SPMS)
`Patients with SPMS suffer from steady progression of disability with or without additional
`deterioration as a result of acute relapses superimposed. Prevention or delaying the accumulation of
`disability should be the goal of the treatment.
`In trials conducted in patients with SPMS it is important to differentiate those patients with relapses
`from those without relapses, as some medications might favourably alter disability due to sequelae
`from acute attacks with no detectable effect on pure progression and, therefore, generalisation of the
`effect to patients without relapses would not be possible.
`2.3.2.1 SPMS with superimposed relapses
`Treatments focused on modifying relapses may be useful in patients still suffering relapses. This
`situation is covered under the indication of treatment for relapsing MS. However, it must be taken into
`account that some effect on relapses without an accompanying effect on disability may be considered,
`in these patients, less important than in RRMS. Therefore, the benefit-risk assessment of a new
`therapy might need to be done separately for those patients.
`2.3.2.2 SPMS without superimposed relapses
`To evaluate the efficacy of a product against disability progression in SPMS it is recommended to
`target only SPMS patients without relapses in order to exclude possible effects on disability related to
`effects on relapse activity.
`take years. Consequently,
`In SPMS, progression
`to disability may
`placebo-controlled parallel group trials are required.
`2.3.3 Primary progressive multiple sclerosis (PPMS)
`So far, clinical trials have not shown efficacy in this type of patients. Randomised, double-blind
`placebo-controlled clinical trials are necessary in order to assess the efficacy of any new treatment in
`PPMS.
`
`large-scale,
`
`long-term,
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`2.4 Treatments intended to improve apparently stable residual impairment
`Improvement of a fixed neurological impairment is a worthwhile treatment goal on its own in MS.
`Some products that potentially facilitate remyelination or improve nerve conduction are being
`developed. As the clinical experience with this new type of products is very limited, specific
`recommendations cannot be made.
`2.5. Combination therapy
`The limited efficacy observed with the authorised medicines and the possible intervention in several
`steps of
`the
`immune response or even
`in other pathological features of
`the disease
`(e.g. neuroprotection,...) suggests the possibility of combination therapies as a suitable approach.
`When combining therapies, in addition to general safety concerns, several aspects should be
`considered. First, it is possible that combination of useful immunomodulators does not improve
`efficacy or even may show less efficacy due to some antagonisms in their complex respective actions.
`Second, the possible risk of a too potent suppression of the immune response should be considered
`with respect to, e.g. infectious processes at the Central Nervous System and inhibition of existing
`remyelinisation.
`
`CRITERIA FOR ASSESSMENT OF EFFICACY IN CONFIRMATORY TRIALS
`3.
`3.1 Treatment of acute relapses
`Duration and severity of relapses and overall recovery or prevention of sequelae are relevant
`parameters. The duration of the gadolinium enhancement of T1 lesions is indicative of inflammatory
`activity and may be included as a secondary variable.
`The impact of those acute treatments on the subsequent course of the disease (rate and severity of
`further relapses, progression of disability, even change from relapsing remitting into SPMS) is also
`relevant. Therefore, long-term trials are also recommended to evaluate the benefit-risk ratio of a new
`treatment for acute relapses.
`3.2 Treatments aiming to modify the natural history of the disease
`3.2.1 Primary efficacy parameters
`The most relevant parameter in MS is the accumulation of disability usually takes place over many
`years. Changes in progression of disability in a few years, which can be shown in clinical trials, could
`be accepted as a proof of efficacy, although it would be highly desirable to evaluate if the effect is
`maintained on a long-term basis.
`It should be distinguished between accumulation of disability in relation to relapses in RRMS and
`progression of disability in SPMS or in PPMS.
`The primary efficacy parameter in confirmatory trials in SPMS and in PPMS should be a clinically
`measured prevention or delay of the disability progression.
`In patients with RRMS or SPMS with superimposed relapses (RMS), the primary efficacy parameter
`may also be the relapse rate although the number, duration or severity of relapses cannot be taken as a
`surrogate for disease progression and this would be expressed accordingly in the SPC. Moreover,
`progression of disability should be evaluated and worsening of disability should be reasonably
`excluded by means of adequately powered long-term studies.
`In patients with CIS the relapse rate and the percentage of patients with no further relapses are
`preferred efficacy variables instead of the time to the second clinical event. As in other MS forms,
`accumulation of disability is considered a relevant efficacy parameter that should be evaluated.
`3.2.2 Secondary efficacy endpoints
`• Disability. In studies where it is not the primary variable, it is a very important secondary
`endpoint that should be evaluated.
`• Relapses. Recommended parameters are the rate of relapses (in studies where it is not the
`primary efficacy parameter), frequency of moderate/severe relapses, proportion of patients
`free from relapses at a given time.
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`• MRI derived parameters.
`• Other measures related to progression of disability supplementary to the measure chosen such
`as the primary variable (e.g. neurological rating scales, measures of cognitive impairment,
`fatigue scales, ambulatory index,...).
`
`4. METHODS TO ASSESS EFFICACY
`4.1 Progression of disability
`Progression of disability should be assessed by means of valid, sensitive and reliable scales. Intra- and
`inter-observer reliability should be known or assessed.
`The Kurtzke’s Expanded Disability Status Scale (EDSS) is the most widely used and known scale to
`assess changes in disability in MS.
`The disadvantages and advantages of the EDSS in assessing disability in MS are well known.
`Therefore, on the one hand the development of alternative scales for assessing disability in MS is
`advocated since these scales, if validated and justified, may be more appropriate than the EDSS. On
`the other hand, the EDSS should still be used in order to facilitate comparisons with other studies.
`As the EDSS has a limited inter and intra-observer reliability, all possible actions intended to increase
`reliability of the scale should be adopted: training of observers, same physician evaluating the patient
`throughout the trial, standardised times and schedules for assessments, standardised protocols for
`neurological examination, measured distances for assessments of mobility and definitions of all the
`terms used. The mean change in score from the baseline is not an appropriate efficacy parameter.
`Based on EDSS scores, treatment failure or progression should be predefined e.g. as the achievement
`of a specified degree of disability or of a sustained worsening of relevant magnitude (1 point when
`EDSS scores ≤ 5.5; 0.5 points if baseline score is > 5.5). Acceptable efficacy parameters endpoints are
`the time to reach progression or the proportion of individuals who have shown progression at a
`pre-specified time.
`Accurate and reliable definition of sustained worsening is important and should include two
`consecutive examinations carried out by the same physician at least 6 months apart.
`As a supportive parameter, disability can also be expressed by summary measures obtained from serial
`measures at scheduled visits, indicating the degree of disability experienced by the patient during a
`period of time, disregarding whether it is in relation to relapses or not.
`It is recognised that the EDSS does not adequately assess upper limb function and cognitive
`impairment and the use of specific methods could be useful. In this context, additional neurological
`rating scales, quantitative neuro-performance tests (e.g. MSFC) or patient and neurologist global
`opinion may be used as secondary measurements of disability.
`4.2 Relapses
`Identification of a relapse may be difficult as patients frequently suffer from pseudo-exacerbations
`caused by infection, heat, or stress. An accurate definition of relapse (their occurrence, time of
`beginning, time of ending, minimum duration to qualify as a relapse, maximum time elapsed between
`two symptoms to qualify as a single relapse, severity) should be included in clinical trials.
`The use of corticosteroids (or other concomitant therapies) for the treatment of acute relapses that may
`occur throughout the trial should be carefully standardised.
`Even if an effect on relapses may be shown within one year, a maintained effect on relapses should be
`demonstrated at least during two years. Time to next (second relapse) may be difficult to interpret in
`terms of clinical relevance and it is not considered a good primary endpoint in confirmatory trials
`The annualised relapse rate is an acceptable parameter to assess relapses. The definition a priori of
`responders in terms of relapses (e.g. patients with ≤ 1 relapse) may be a useful variable.
`4.3 Magnetic resonance imaging
`Magnetic resonance imaging (MRI) is a useful tool for monitoring CNS lesions in MS.
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`Different MRI derived parameters have been related to clinical activity. For example, the appearance
`of gadolinium-enhancing lesions or new/enlarging T2 lesions have been related to relapses. The
`possible correlation between MRI parameters and long-term clinical outcomes is of utmost importance
`and several measures have been studied such as total lesion load (on T2 weighted images), chronic T1
`weighted hypointensity (chronic “black holes”) or several brain atrophy measures that have been
`related to tissue loss. In non-relapsing SPMS and PPMS, measures of CNS atrophy including grey and
`white matter volumes, and new MRI techniques (vide infra) may be particularly useful.
`So far, the correlation between Magnetic Resonance Imaging and clinical outcomes has not proved to
`be strong enough as to accept it as a validated surrogate endpoint in pivotal studies. In exploratory
`trials, however, changes in MRI findings may be used as a first indication of dealing with a potentially
`clinically effective product.
`New MRI techniques such as spectroscopy, magnetisation transfer or diffusion tensor have been
`developed. These neuroimaging procedures, as well as other new techniques, could be studied in
`future trials in order to increase the knowledge and try to validate them as a possible surrogate
`parameters for clinical outcome.
`All possible actions should be taken to ensure high quality MRI data and maximum reliability of
`measurements. Updated recommendations on appropriate technical facilities and standardised
`procedures and training should be followed.
`Reading of MRI images should be central and blinded.
`4.4 Health-related Quality of life (HRQoL)
`Few data are available on validation of specific instruments for HRQoL in patients suffering MS. If a
`claim with respect to HRQoL in MS is considered, reliable and validated scales should be used.
`
`SELECTION OF PATIENTS
`5.
`5.1 Diagnostic criteria
`Nowadays, the revised McDonald’s criteria (2005), which incorporate MRI are widely accepted.
`It is also possible to use the classical Poser’s diagnostic criteria for MS, based on patient history,
`clinical examination, CSF studies, evoked potentials, and exclusion of alternative diseases.
`5.2 Type of patients
`Depending on the purpose of the trial, different subgroups of patients should be selected a priori.
`Within each clinical form of the disease, relapse activity and severity of disability (e.g. defined
`according to EDSS score of < 3.5, 4-6 and > 6.5) as well as identifiable risk factors for high rate of
`relapses are important characteristics to define a priori subgroups of patients.
`Extrapolation from one subgroup of patients to others may not be possible.
`Patients in trials may be treatment naïve patients, patients who switch for reasons other than lack of
`efficacy, patients with suboptimal response to previous treatment. However, inclusion of therapy
`resistant patients should be avoided as they form a separate subgroup. Exclusively selection of therapy
`resistant patients is possible when the product is intended for this clinical setting, and a restricted
`indication will probably be obtained in this case. Appropriate definitions of non-response or
`suboptimal response should be verifiable and prospectively defined.
`In trials intended to evaluate relapse rate it is recommended not to include subjects with SPMS and
`superimposed relapses as this might complicate trial design and hamper the interpretation of the effect
`on relapses and disability.
`5.3 Special populations
`Currently available data of MS below the age of 16 years are limited. Therefore, a formal
`recommendation for this population can not been given. Generation of paediatric data is encouraged in
`order to support such recommendation.
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`STRATEGY-AND DESIGN OF CLINICAL TRIALS
`6.
`6.1 Pharmacodynamics
`The proposed mechanism of action should be described and discussed in relation to data obtained in
`relevant animal models (e.g. experimental autoimmune encephalomyelitis) and to changes in
`biological parameters seen in patients or healthy volunteers.
`When a combination therapy is pursued, hypothesis on synergism and lack of antagonism should be
`described and evaluated in relevant models whenever possible.
`Study of changes in biological parameters and occurrence of side effects in patients or healthy
`volunteers, if available and pertinent, may guide the dosage and dose regimen in later studies as well
`as support hypothesis about useful combination therapy.
`6.2 Pharmacokinetics
`Pharmacokinetics of the drug should be thoroughly investigated in accordance with relevant
`guidelines.
`6.3
`Interactions
`Data on pharmacodynamic interactions with other treatments of the disease are important. The
`possible interaction with the courses of corticosteroids to treat relapses should be addressed. Human
`studies of pharmacodynamic interaction between putative combinations are necessary prior to conduct
`clinical investigation of such combinations.
`Pharmacokinetic interactions should be investigated in accordance with relevant guidelines.
`6.4 Exploratory trials
`Characteristics of patients to be included may vary according to the proposed mechanism of action and
`goal of the treatment. However, to maximise possible treatment contrast, it seems reasonable to choose
`patients with predictors of high clinical activity and with only mild/moderate disability.
`In exploratory trials in RMS, the use of MRI derived parameters, as the main endpoint, is acceptable
`(see 4.3). Usually, studies will have a parallel double blind design and duration of 6 month may be
`adequate. Relapses and other clinically meaningful outcomes should also be evaluated.
`I