Concept paper on the need for revision of the guideline on clinical investigation of medicinal products in the treatment of depression

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Derick Lucas
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1 2 3 10 Nvember 2016 EMA/CHMP/183826/2016 Cmmittee fr Medicinal Prducts fr Human Use (CHMP) 4 5 6 7 Cncept paper n the need fr revisin f the guideline n clinical investigatin f medicinal prducts in

1 Nvember 2016 EMA/CHMP/183826/2016 Cmmittee fr Medicinal Prducts fr Human Use (CHMP) Cncept paper n the need fr revisin f the guideline n clinical investigatin f medicinal prducts in the treatment f depressin 8 Agreed by Central Nervus System Wrking Party Octber 2016 Adpted by CHMP fr release fr cnsultatin 10 Nvember 2016 Start f public cnsultatin 18 Nvember 2016 End f cnsultatin (deadline fr cmments) 28 February The prpsed guideline will replace 'Guideline n clinical investigatin f medicinal prducts in the treatment f depressin' (CPMP/EWP/518/97, Rev. 2) Cmments shuld be prvided using this template. The cmpleted cmments frm shuld be sent t CNSWPsecretariat@ema.eurpa.eu Keywrds Majr Depressin, Treatment Resistant Depressin, Partial Respnse, Antidepressants, Augmentatin Strategies, Cgnitive Dysfunctin Churchill Place Canary Wharf Lndn E14 5EU United Kingdm Telephne +44 (0) Facsimile +44 (0) Send a questin via ur website An agency f the Eurpean Unin Eurpean Medicines Agency, Reprductin is authrised prvided the surce is acknwledged.

2 Intrductin Majr Depressive Disrder (MDD) is ne f the mst cmmn psychiatric disrders, which is the furth leading cause f glbal disease burden and affects abut 15 % f the general ppulatin. As utlined in the guidance dcument MDD is nt a benign disrder and risk f suicide is cnsiderable. Althugh a brad therapeutic armamentarium fr treatment f majr depressive episdes (MDE) is available, still abut ne-third f patients treated fr the cnditin d nt respnd satisfactrily t the first antidepressant prescribed 1-4. Incmplete treatment respnse r treatment resistance have been described cmmnly in up t 50 % f the treated patient ppulatin 3,5,6. The current guideline distinguishes between requirements fr trials t study mntherapy in treatment resistant depressin (TRD) and trials t study augmentatin/add-n treatment in case f insufficient respnse t mntherapy. Hwever, in light f the mst up t date evidence generated, the definitin and identificatin f partial respnders needs t be revisited. In clinical practice, mrever, augmentatin and cmbinatin strategies in TRD appear valid appraches 7. Several aspects fr different trial designs in these difficult patients (TRD and partial respnders) therefre require recnsideratin 8. A paradigm shift is taking place in psychiatry where increasingly separate dmains in the brader cntext f a categrical disrder are studied separately 9 and may becme the target f drug develpment if sufficient ratinale exists in supprt. The treatment f specific symptms within the disrder is als reflected in the Diagnstic and Statistical Manual f Mental Disrders, Fifth Editin (DSM 5). As e.g. cgnitive disturbances are paramunt acrss CNS disrders and may warrant a distinct apprach, this will challenge new drug develpment in the cming years T supprt a separate claim fr efficacy n cgnitive aspects in patients with MDD, specific studies shuld be perfrmed 13. It depends n the rbustness f the results whether a separate indicatin can be pursued r whether the data shuld rather be mentined in sectin 5.1. Fr applicatin f an indicatin n cgnitive aspects in patients with MDD a specific effect n cgnitive functin needs t be shwn that culd clearly be disentangled frm the verall depressive symptms. The current guidance lacks recmmendatins with respect t cgnitive functin in MDD. In additin, a number f methdlgical issues in the way clinical trials in depressin are cnducted are nw being discussed in the scientific cmmunity including the reasns fr increasing placeb respnse and the adequateness f the measures f utcme These issues, tgether with the need t accunt fr ppulatin differences in terms f gender and drug metablism might need regulatry guidance. Altgether, the apparent changes in the cnceptual framewrk f psychiatric diseases expressed in the DSM 5, the unmet medical need in TRD and insufficient treatment respnders, and the recgnitin f specific treatment targets acrss disrders, warrant recnsideratin f strategies in clinical trial design, recruitment f patient ppulatins and definitins f endpints. Hence, several amendments f the depressin guideline as well a recnsideratin/recnfirmatin f existing principles need discussin. 2. Prblem statement The current guideline needs revisin cvering the latest develpments with regard t requirements fr clinical trials in partial and nn-respnders with MDD and ptins f targeting new functinal dmains. In additin, it may include requirements t increase depressin clinical trials efficiency. Cncept paper n the need fr revisin f the guideline n clinical investigatin f medicinal prducts in the treatment f depressin EMA/CHMP/183826/2016 Page 2/5

3 Discussin (n the prblem statement) In the prpsed update f the guidance dcument, the fllwing issues will be discussed: Definitin f target ppulatin: general MDD ppulatin, treatment resistant depressin and partial respnders: Diagnstic criteria Age and gender sensitivity Presence f c-mrbidities Crss cultural differences, e.g. nn-eu (e.g. US) data t EU ppulatins 65 Design strategies: Chice f cmparatr Apprpriate endpints Usefulness f cmbinatin therapies and crrespnding study designs, e.g. add-n and augmentatin Placeb effect 71 Cgnitive deficit as a separate dmain in depressin: Definitin f cgnitive disturbances in depressin Trial design strategies Recmmendatin In cnclusin, it is recmmended t update the current Guideline n clinical investigatin f medicinal prducts in the treatment f depressin. Althugh sme f the key issues f guidance have nt changed, mre elabrate recmmendatins culd be given t increase clinical trial efficiency maintaining the validity f the cnclusins. Updated recmmendatins are especially needed n the cnduct f trials in TRD and partial respnders. New guidance n the requirements t supprt specific separate claims, e.g. n cgnitin, shuld als be included. The anticipated changes are cnsidered substantial enugh t recmmend a public cnsultatin. T ensure unifrmity f clinical studies and t set standards, the CNS Wrking Party (CNSWP) recmmends revising the guideline. 5. Prpsed timetable It is planned t release fr cnsultatin a draft CHMP guidance dcument nt later than Sep Resurce requirements fr preparatin The preparatin f this guideline will invlve the CNSWP. Drafts f the dcument will be discussed with Bistatistics Wrking Party (BSWP), Scientific Advice Wrking Party (SAWP) and ther relevant WPs and cmmittees. 90 Cncept paper n the need fr revisin f the guideline n clinical investigatin f medicinal prducts in the treatment f depressin EMA/CHMP/183826/2016 Page 3/5

4 Impact assessment (anticipated) It is expected that the update f the Guideline will be helpful t achieve cnsensus in the evaluatin f medicinal prducts fr the treatment f MDD by regulatry authrities in the Eurpean Cmmunity. Furthermre, it is expected, that such guideline will prvide guidance with respect t methdlgy, assessment tls and clinically relevant utcmes in a) Majr Depressive Disrder (MDD) b) Partial respnders with MDD c) Treatment Resistant Depressin (TRD) d) Cgnitive disturbances in depressin and thus wuld imprve quality and cmparability f develpment prgrams fr these specific indicatins by pharmaceutical cmpanies. 8. Interested parties The interested parties in the guidance dcument include learned scieties and academia (e.g. Eurpean Cllege f Neurpsychpharmaclgy (ECNP) and thers), pharmaceutical industry (e.g. EFPIA and thers) and ther regulatry agencies. 9. References t literature, guidelines, etc. 1 Brent, D.A. & Birmaher, B. Treatment-resistant depressin in adlescents: recgnitin and management. Child Adlesc Psychiatr Clin N Am 15, , x (2006). 2 Keller, M.B. Issues in treatment-resistant depressin. J Clin Psychiatry 66 Suppl 8, 5-12 (2005). 3 Thase, M.E. & Rush, A.J. When at first yu dn't succeed: sequential strategies fr antidepressant nnrespnders. J Clin Psychiatry 58 Suppl 13, 23-9 (1997) 4Rush AJ, et al. Sequenced treatment alternatives t relieve depressin (STAR*D): ratinale and design. Cntrl Clin Trials 2004;25: Suery, D., Papakstas, G.I. & Trivedi, M.H. Treatment-resistant depressin. J ClinPsychiatry 67 Suppl 6, (2006). 6 Fava, M. Diagnsis and definitin f treatment-resistant depressin. Bil Psychiatry 53, (2003). 7 McIntyre RS et al. Treatment resistant depressin: definitins, review f the evidence, and algrithmic apprach. J Affect Disrd 2014; 156:1-7 8Iven N et al. Des the presence f an pen-label antidepressant treatment perid influence study utcme in clinical trial examining augmetnatin/cmbiantin strategies in treatment partial respnders/nnrespnders with majr depressive disrder? J Clin Psychiatry 2012; 73 (5): Williams LM et al. Develping a clinical translatinal neurscience taxnmy fr anxiety and md disrder: prtcl fr the baseline-fllw up Research dmain criteria Anxiety and Depressin ( RAD ) prject. BMC Psychiatry Mar 15;16(1):68 10 Papakstas GI Antidepressants and their effect n cgnitin in majr depressive disrder. J Clin Psychiatry Aug; 76(8) Cncept paper n the need fr revisin f the guideline n clinical investigatin f medicinal prducts in the treatment f depressin EMA/CHMP/183826/2016 Page 4/5

5 McIntyre RS et al. The Prevalence, Measurement, and Treatment f the Cgnitive Dimensin/Dmain in Majr Depressive Disrder. CNS Drugs : Malhi GS et al. Md disrders: neurcgnitive mdels. Biplar Disrd Dec;17 Suppl 2: Trivedi MH et Greer TL Cgnitive dysfunctin in uniplar depressin: implicatins fr treatment. J Affect Disrd Jan; : Ivien N et Papakstas GI Crrelatin between different levels f placeb respnse rate and clinical trial utcme in majr depressive disrder: a meta-analysis. J Clin Psychiatry 2012 Oct;73(10) 15 Leuchter AF et al. Rle f pill-taking, expecatin and therapeutic alliance in the placeb respnse in clinical trials fr majr depressin. Br J Psychiatry 2014;205: Pecina M et al. Placeb-activated neural systems are linked t antidepressant respnses: Neurchemistry f placeb effects in majr depressin. JAMA Psychiatry 2015 Nv;72(11): Rse SP et al. Practising evidence-based medicine in an era f high placeb respnse: number needed t treat recnsidered. Br J Psychiatry 2016 May;208(5): Cncept paper n the need fr revisin f the guideline n clinical investigatin f medicinal prducts in the treatment f depressin EMA/CHMP/183826/2016 Page 5/5

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