New EU Guidance on MDD Clinical Trials Luca Pani, Valentina Mantua Italian Medicines Agency (AIFA) l.pani@aifa.gov.it v.mantua@aifa.gov.it 1

Public Declaration of transparency/interests* Interests in pharmaceutical industry NO Currently Last 2 years More than 2 years but less than 5 years ago More than 5 years ago (optional) Direct interests: Employment with a company X Consultancy for a company Strategic advisory role for a company Financial interests Ownership of a patent Indirect interests: Principal investigator Investigator Individual’s Institution/Organisation receives a grant or other funding CME Courses *Luca Pani, in accordance with the Conflict of Interest Regulations approved by AIFA Board of Directors (26.01.2012) and published in the Italian Government Official Journal on 20.03.2012 according to 0044 EMA/513078/2010 on the handling of the conflicts of interest for scientific committee members and experts Note: For this presentation I am not receiving any compensation

Public Declaration of transparency/interests* Interests in pharmaceutical industry NO Currently Last 2 years More than 2 years but less than 5 years ago More than 5 years ago (optional) Direct interests: Employment with a company X Consultancy for a company Strategic advisory role for a company Financial interests Ownership of a patent Indirect interests: Principal investigator Investigator Individual’s Institution/Organisation receives a grant or other funding CME Courses *Valentina Mantua, in accordance with the Conflict of Interest Regulations approved by AIFA Board of Directors (26.01.2012) and published in the Italian Government Official Journal on 20.03.2012 according to 0044 EMA/513078/2010 on the handling of the conflicts of interest for scientific committee members and experts Note: For this presentation I am not receiving any compensation

The 21st century’s challenge! …the true size and burden of disorders of the brain in the EU was significantly underestimated in the past. Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for disorders of the brain as the core health challenge of the 21st century. H.U. Wittchen et Al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology (2011) 21, 655–679.

The model of care for brain disorders We feel that the level of civilization of a Country is measured by its care for patients affected by brain disorders, who need a level of assistance far more complex than many others. It is important for the National Health Service (NHS) to adequately support the treatment of brain disorders from an economic, physical, emotional and social fragility perspective. Policies and regulatory structures should be focused on patients’ needs.

Depression in the EU An estimated 5 million EU citizens aged 55-74 report having depression (corresponding to 30.3 million people aged 14 and over). Depression prevalence varies considerably among EU Member States and it is higher among women. Depression prevalence is underestimated because many people with depressive symptoms do not seek professional help. Depression is more prevalent among people aged 45 years and over (less pronounced for men). Depression prevalence is higher among less educated people. Dutch National Institute for Public Health and the Environment (RIVM). Europeans of retirement age: chronic diseases and economic activity. December 2012.

Major Depression Disorder (MDD) is… One of the most common psychiatric disorders (15% of the general population); The fourth leading cause of global burden of diseases; Associated with substantial psychosocial dysfunction and high individual mental strain as well as with excess morbidity and mortality; Associated with a considerable risk of suicide. MDD is not a benign disorder!

Is the current approach used in clinical trials adequate? Major Depression Disorder (MDD) Is the current approach used in clinical trials adequate?

From the old Guidance…

…to the new one Despite many approved antidepressants there is still a need for new medicinal products with better efficacy (e.g. faster onset of action, higher rates of response and remission) and improved safety profile in patients with MDD. The typical design to demonstrate efficacy and safety of an antidepressant remains a randomized, double-blind, placebo controlled, parallel group study comparing change in the primary endpoint. Inclusion of a well-accepted standard as an active control is strongly recommended. The update clarifies the requirements in clinical trials for special populations (children, adolescents, elderly, treatment resistant or partial responders). The need to monitor the degree of suicidal thoughts and behaviour and their change (improvement or worsening) with antidepressant therapy by use of validated instruments is confirmed.

Despite many approved antidepressants there is still a need for new medicinal products with better efficacy (e.g. faster onset of action, higher rates of response and remission) and improved safety profile in patients with MDD. Better efficacy: Should it target a selected subgroups with identifiable cluster symptoms? Faster onset of action: is it better or worse? Higher rates of response/remission: from secondary to primary endpoints?

Investigation of relapse and recurrence The 6 months cut-off point is not used for regulatory purposes. For authorisation it should be shown that a short-term effect can be maintained during the index episode. Randomised withdrawal study, allowing to study relapse prevention, is probably the best design.

The typical design to demonstrate efficacy and safety of an antidepressant remains a randomized, double-blind, placebo controlled, parallel group study comparing change in the primary endpoint. Inclusion of a well-accepted standard as an active control is strongly recommended. Active control: Should it be recommended or MANDATORY? A new treatment is INNOVATIVE if it provides patients with additional clinical benefits compared to currently available thrapeutic options.

Ethically, however, the use of a placebo is a controversial issue. Use of placebo In about one-third to two-third of the trials, in which an active control is used as a third arm, the effect of the active control could not be distinguished from that of placebo and a non-inferiority margin cannot be determined. Though showing superiority over an active comparator, to permit adequate evaluation of efficacy, randomised double blind comparisons versus placebo are needed. Ethically, however, the use of a placebo is a controversial issue.

Special populations or different illnesses? The update clarifies the requirements in clinical trials for special populations (children, adolescents, elderly, treatment resistant or partial responders). Special populations or different illnesses?

Special Populations Older people Known products: subgroup analysis. New products: specific trials. In both situations PK studies should be conducted. Children and adolescents After psychotherapeutic approaches. Specific studies are necessary. Duration: at least 8 weeks.

Depression in the elderly Unipolar Prodromal to neurodegenerative disorders PK/PD model needs to be adjusted to endogenous changes in neurotransmitter levels

Concept of Involution Melancholia Depressive States Constitutional (1st Episode < 40 y.) Periodical (Circular) Insanity Manic-Depression (in elaboration) Acquired (1st Episode > 40 y.) Involutional Melancholia More common in women (60%) Hereditary traits Anxiety and fear of danger of some kind Agitation and Insomnia No clouding of the consciousness Poverty of ideas but memory generally not impaired Somatic delusion of hypochondrial nature Retardation and psychomotor retardation are rare Progress toward deterioration E. Kraepelin., “Textbook of Psychiatry”, V Ed. 1896

but then he changed his mind... ”These results show that for most of these disorders which have been designated as melancholia there now exists no sufficient reason to separate them from manic-depressive insanity.” E. Kraepelin, Introduction to Dreyfus G.L.: Die Melancholia ein Zustanbild des Manisch-Depressiven. 1907 Melancholia Simplex States Stupor Melancholia Gravis * Paranoid Melancholia * Fantastic Melancholia * Delirious Melancholia * *Characterized by presence of delusions and /or hallucinations E. Kraepelin., “Textbook of Psychiatry”, VIII Ed. 1910

Treatment Resistant Depression (TRD) A relevant proportion of patients up to one third do not adequately respond to treatment and up to 20% are considered non-responders. No specific treatments (and no validated clinical criteria and thresholds to define TRD) have been approved for this condition: Re-evaluation of the initial diagnosis; Optimization of the initial regimen using switching to other antidepressants; Augmentation strategies; Monotherapy with second generation antipsychotics; Electroconvulsive therapy.

TRD and MDD are NOT the same depression! TRD is a life threatening disease with possibly a different underlying biology when compared to MDD. Companies are reluctant to develop new monotherapy treatments for Major Depression, which may not be competitive on the market. Industry is focusing on augmentation therapies and patients with TRD are systematically excluded from these trials. It is not usefull to grant extension of indication for TRD only to those products already approved for MDD because it may miss some interesting compounds which may fail to show efficacy in MDD but may well work on TRD.

Monotherapy in patients with TRD Monotherapy in patients with TRD could be a separate but additional claim. At least one additional short term trial should be performed. Subgroup analyses among treatment resistant patients in trials conducted in a general population with major depressive episodes are not sufficient to obtain the extended indication. The design of studies in TRD is essentially the same but the key differences are: the choice of control and the definition of the patient population. The primary objective would be to demonstrate superiority to the active comparator (which is expected to have insufficient effect in this patient population) but currently no medicinal product has been approved for TRD.

Augmentation/add-on treatment A specific claim with data demonstrating efficacy in short term (4-6 weeks) and long term trials is need. Patient population should consist only of “true” partial responders. Patients with TRD are not suitable candidates for augmentation. Patients are randomised to receive active augmentation treatment or placebo in addition to standard medication. Inclusion of a treatment arm as active comparator could be of interest for augmentation trials. Maintenance studies are necessary (randomised withdrawal studies)

Extrapolations Patients included in the trials will be diagnosed as having MDD using accepted diagnostic criteria (e.g. DSM 5). Depressive symptoms are also seen in other psychiatric disorders or other types of depression. If such specific claims are strived for, additional studies to the classical development program for major depression should be provided.

An example: depressive and anxious symptoms Anxiety symptoms may be a part of MDD due to a co-morbid disorder like GAD The antianxiety effect is therefore a part of the antidepressant effect and no additional claim can be granted. Registration clinical trials will usually recruit patients with moderately MDD episodes

An example: Bipolar Disorder (BD) Major depressive episode may also occur in the framework of a BD To obtain this claim a compound should show efficacy in BD. Results from studies with antidepressants in unipolar depression may be partly extrapolated to BD. However, results from studies in BD (e.g. atypical neuroleptics, mood stabilisers) cannot be extrapolated to the unipolar situation. Both bipolar I and bipolar II patients might be included and the possibility of further subgroup analysis might be allowed if justified in the protocol. Patients should be diagnosed as having Major Depressive episode as part of a BD as defined by usual criteria (e.g. DSM 5). Study drug may be used as monotherapy, or in combination. For a monotherapy claim, patients need to be off lithium or off any other mood stabilisers because of possible rebound phenomena and they should not be lithium resistant. Switching criteria and incidence of switching need to be established.

Assessment of Therapeutic Efficacy Results: discussed in terms of both clinical relevance and statistical significance. Methods and studies: should be agreed to with the regulatory Agency. Duration: short-term trials (6 weeks); long-term trials (randomised withdrawal trials). Efficacy: must be assessed by justified rating scales. Study population: homogenous; according to DSM 5. Study design: parallel, double blind, randomised placebo controlled trials. Comparison with a standard product. Clinical pharmacology studies: PK, PD, Interaction.

Specific adverse events (AE) to be monitored Psychiatric Cardiovascular Haematological Endocrinological Long-term safety Sexual dysfunction Overdose and suicide Metabolic risk factors AE on cognitive functioning AE in children and adolescence Extrapyramidal symptoms (EPS) Rebound/withdrawal phenomena/dependence Serotonin syndrome/Neuroleptic malignant syndrome

In Conclusion our Policy Recommendations Notwithstanding the availability of many compounds with established efficacy and safety there is a high need for innovative antidepressants. It has been shown that many patients without adequate treatment suffer from a tendency of higher frequency of major depressive episodes together with increased episode severity. The new guideline focuses on antidepressant products developed specifically for major depressive disorder in order to encourage pharmaceutical companies to foster development of new antidepressants. Pharmaceutical companies should not only restrict their development to a claim of acute treatment of major depressive episodes, but should also provide clinical trial data for additional claims (recurrence prevention and TRD).

In Conclusion our Policy Recommendations We must reposition treating physicians at the center of drug discovery programs, rethinking the support of CROs in this respect (the individuality of brain disorders must be recognized and accounted for in clinical trials). Sensitize public opinion on the need on investment in research and development in brain research also through patients organization to overcome the stigma and the prejudice towards brain disorders. Supporting continued innovation in the field of mental disorders shall be considered as an economic and cultural challenge that we all need to undertake for a better future in many patients’ lives and to tighten the gap between patients’ expectations and care needs on one side and the existing innovative therapies on the other.

THANK YOU FOR YOUR ATTENTION L.Pani@AIFA.GOV.IT V.Mantua@AIFA.GOV.IT