Essential Medicines List: Concept and Procedures 1 |1 | WHO Essential Medicines List Concept/Process and Update on EML 2015 WHO Essential Medicines List Concept/Process and Update on EML 2015 WHO Technical Briefing Seminar Nicola Magrini – WHO, EMP November 4, 2014 – WHO Geneva

Essential Medicines List: Concept and Procedures 2 |2 | Essential Medicines Guiding principle: A limited range of carefully selected essential medicines leads to better health care, better medicines management, and lower costs Definition: Essential medicines are those that satisfy the priority health care needs of the population Selection: Selected with due regard to disease prevalence, evidence on efficacy and safety, and comparative cost- effectiveness.

Essential Medicines List: Concept and Procedures 3 |3 | … 38 years of EML st Model list published, 208 active substances - List is revised every two years by WHO Expert Committee Revised procedures approved by WHO (EB109/8) - Last revision EML (April 2013) contains 374 medicines The first list was a major breakthrough in the history of medicine, pharmacy and public health Médecins sans Frontières, 2000

Essential Medicines List: Concept and Procedures 4 |4 |

5 |5 | The Essential Medicines List and concept "The concept of essential medicines is one of the major public health achievements in the history of WHO. It is as relevant today as it was at it inception over 30 years ago." Dr Margaret Chan — Director-General, WHO

Essential Medicines List: Concept and Procedures 6 |6 | Why is it 'model' Model for its selection process (“one medicine per class” approach unless clinically relevant differences demonstrated ) Model to facilitate efforts to 'improve health' of population Regulation Quality (Rational) Responsible and evidence-based use Procurement and Supply Access : Availability, Affordability, Accessibility and Acceptability

Essential Medicines List: Concept and Procedures 7 |7 | 18th WHO Model List of Essential Medicines Report of the WHO Expert Committee, 2013 N. = 208 N. = 374

Essential Medicines List: Concept and Procedures 8 |8 | EML 2013 in numbers 374 – total number of drugs/medicines –Core list: 282 (FDC: 23) –Complementary list: 68 (FDC: 1)

Essential Medicines List: Concept and Procedures 9 |9 | EML 2013 in numbers Adult List 374 – total number of drugs/medicines –Core list: 282 (FDC: 23) –Complementary list: 68 (FDC: 1) Pediatric List 278 in total –Core list: 206 (FDC: 11) –Complementary list: 60 (FDC: 1)

Essential Medicines List: Concept and Procedures 10 | Process Evidence Based and Transparent Applications invited - addition/deletion/modification –Format proposed (see Applications) and WHO technical Dpt involved –Deadlines: a semester the year before next EC (…, 2013, 2015, … yearly?) –All applications go online Applications peer reviewed by experts –Peer reviews go online Comments invited from any one interested (WHO Depts., Professional Societies, International agencies, Academia) –Comments go on line Expert Committee makes final decisions –Report goes on line

Essential Medicines List: Concept and Procedures 11 | EML criteria (EB 109/8, 2001) Disease burden and public health need Sound and adequate data on the efficacy, safety and comparative cost-effectiveness of available treatments –Need for special diagnostic or treatment facilities considered “Absolute cost of the treatment will not constitute a reason to exclude a medicine from the Model List that otherwise meets the stated selected criteria”

Essential Medicines List: Concept and Procedures 12 | Application period for EML 2015 (Expert Committee April 2015) Open for 6 months: 15 June 2014 – 30 November 2014 Applications evaluated for methodology: systematic review, evidence appraisal and synthesis (when needed, changes and new application requested) Application can be rejected (by EML secretariat) for lack of sufficient rigour in reporting available evidence Application sent to 2 or 3 Panel members (acting indipendently as blinded referees)

Essential Medicines List: Concept and Procedures 13 | EML: applications, referees and EC The opinions and evaluations expressed by the 2 (or 3) referees are brought to the attention of WHO Expert Committee (EC) EC has a plenary discussion and takes a decision Usually without voting

Essential Medicines List: Concept and Procedures 14 | A walk through the process A walk through the process

Essential Medicines List: Concept and Procedures 15 | The application form/template

Essential Medicines List: Concept and Procedures 16 | EML Application: additional info posted on how to prepare an applicatio

Essential Medicines List: Concept and Procedures 17 | EML criteria and GRADE … the basics A systematic review of the best available evidence A systematic review (synthesis and appraisal) is more important than a metanalysis (pooled estimate) Importance of summary evidence table … with appraisal of risk of bias (study defect/reliability) to evaluate confidence in estimates (for both outcomes of efficacy and safety) … this was once called quality of evidence

Essential Medicines List: Concept and Procedures 18 | EML and evidence table for benefits and harms GRADE … example 1

Essential Medicines List: Concept and Procedures 19 | EML and evidence table for benefits and harms GRADE … example 2

Essential Medicines List: Concept and Procedures 20 | EML and evidence table for benefits and harms GRADE … example 2

Essential Medicines List: Concept and Procedures 21 | EML and evidence table for benefits and harms GRADE … example 2

Essential Medicines List: Concept and Procedures 22 | EML and evidence table for benefits and harms GRADE … example 2

Essential Medicines List: Concept and Procedures 23 | EML and evidence table for benefits and harms GRADE … example 3

Essential Medicines List: Concept and Procedures 24 | EML and evidence table for benefits and harms … example 4

Essential Medicines List: Concept and Procedures 25 | The application review process (EB109/8)

Essential Medicines List: Concept and Procedures 26 | EML: transparency and dialogue All applications - public Expert reviews – public Comments and clarifications letters – public Technical Report (summarising all the discussion) - public

Essential Medicines List: Concept and Procedures 27 | EML transparency: web applications

Essential Medicines List: Concept and Procedures 28 | EML transparency: Expert Reviews

Essential Medicines List: Concept and Procedures 29 | EML transparency: Comments

Essential Medicines List: Concept and Procedures 30 | EML criteria (EB 109/8, 2001) Disease burden and public health need Sound and adequate data on the efficacy, safety and comparative cost-effectiveness of available treatments –Need for special diagnostic or treatment facilities considered “Absolute cost of the treatment will not constitute a reason to exclude a medicine from the Model List that otherwise meets the stated selected criteria”

Essential Medicines List: Concept and Procedures 31 | EML 2015 A few big challenges

Essential Medicines List: Concept and Procedures 32 | Opportunity to improve EML updating When highly effective drugs are available Cancer drugs: how to choose the few highly effective (patented, high cost) medicines (2 discussed in EML 2013: trastuzumab in breast cancer and imatinib in chronic myeloid leukemia). Other medicines: see next table, … New HCV drugs (new direct antiviral, single agents and combinations, IFN free regimens) TB large update New anticoagulants: oral (NAC) and surely LMWH

Essential Medicines List: Concept and Procedures 33 | Opportunity to improve EML updating When highly effective drugs are available Cancer drugs: how to choose the few highly effective (patented, high cost) medicines (2 discussed in EML 2013: trastuzumab in breast cancer and imatinib in chronic myeloid leukemia). Other medicines: see next table, … New HCV drugs (new direct antiviral, single agents and combinations, IFN free regimens) TB large update New anticoagulants: oral (NAC) and surely LMWH

Essential Medicines List: Concept and Procedures 34 | EML cancer update: first line treatment

Essential Medicines List: Concept and Procedures 35 | EML cancer drugs: candidates (15-20)

Essential Medicines List: Concept and Procedures 36 | Opportunity to improve EML updating When highly effective drugs are available Cancer drugs: how to choose the few highly effective (patented, high cost) medicines (2 discussed in EML 2013: trastuzumab in breast cancer and imatinib in chronic myeloid leukemia). Other medicines: see next table, … New HCV drugs (new direct antiviral, single agents and combinations, IFN free regimens) TB large update New anticoagulants: oral (NAC) and surely LMWH

Essential Medicines List: Concept and Procedures 37 | EML and New HepC drugs Very effective oral drugs (IFN free regimens) A WHO GL with a strong recommendation Sofosbuvir and Ledipasvit/sofosbuvir combination (already IN the applications) What to di with financial implications What to do with new drugs in the pipeline

Essential Medicines List: Concept and Procedures 38 | Opportunity to improve EML updating When highly effective drugs are available Cancer drugs: how to choose the few highly effective (patented, high cost) medicines (2 discussed in EML 2013: trastuzumab in breast cancer and imatinib in chronic myeloid leukemia). Other medicines: see next table, … New highly HCV drugs (new direct antiviral, single agents and combinations, IFN free regimens) TB large update New anticoagulants: oral (NAC) and surely LMWH

WHO guidance on the management of drug-resistant TB,

The candidate drugs 1) New molecules Bedaquiline, Delamanid 2) Repurposed for TB, in EML Amoxicillin-clavulanate, Azithromycin, Clarithromycin, Clofazimine, Imipenem/cilastatin, Meropenem 3) Repurposed, not in EML Linezolid, Gatifloxacin, Terizidone

Essential Medicines List: Concept and Procedures 41 | Opportunity to improve EML updating When highly effective drugs are available Cancer drugs: how to choose the few highly effective (patented, high cost) medicines (2 discussed in EML 2013: trastuzumab in breast cancer and imatinib in chronic myeloid leukeima). New highly HCV drugs (new direct antiviral, single agents and combinations, IFN free regimens) TB drugs (12) WHO could have a leadership role in improving access to highly effective medicines (as was for HIV in 2002)

Essential Medicines List: Concept and Procedures 42 | EML timeline

Essential Medicines List: Concept and Procedures 43 | Apr 2014 EML TRS 2013 printed June-Dic 2014 Jan-March 2015 Apr 2015 Preparation of a 6 month application period (15 th June – 1 st December 2014) Contacts and exchanges with WHO technical Dpts and other UN agencies Reviewing application forms and criteria towards full systematic reviews and GRADE adoption EML timeline

Essential Medicines List: Concept and Procedures 44 | Apr 2014 Application period open June-Dic 2014 Jan-March 2015 Apr 2015 Commissioning and coordination of applications Alignment of WHO GL with EML timeline (HIV, TB, RH, MH Verify the full adoption of systematic reviews and GRADE approach Manage questions and feedbacks from countries on EML adoption and implementation December (10 th – 15 th ): web publication of all applications EML timeline

Essential Medicines List: Concept and Procedures 45 | Apr 2014 EML reviewing and EC referees, and comments June-Dic 2014 Jan-March 2015 Apr 2015 Verify applications (the early the better) for full adoption of systematic reviews and GRADE approach Answers to questions and feedbacks from Countries to be presented to Expert Committee (EC) Summarise a TRS text for EC and prepare the List Merging adult and pediatric Lists into one List to facilitate readability Increase usefulness of EML database EML timeline

Essential Medicines List: Concept and Procedures 46 | Apr 2014 EML web publication June-Dic 2014 Jan-March 2015 Apr 2015 EC meeting April 2015 EML published end of April and summary of decisions taken TRS finalisation for publication (…) TBC: Availability of a EML database of decisions taken and indications evaluated/approved/rejected EML timeline

Essential Medicines List: Concept and Procedures 47 | WHAT ABOUT DEVICES IN EML?

Essential Medicines List: Concept and Procedures 48 | Where do we start from

Essential Medicines List: Concept and Procedures 49 | Just few devices are in EML To strengthen a WHO policy (on contraception) To be consistent across various WHO GL/documents If apply, be supported by a WHO technical Dpt Suggestion: first be in a WHO policy document or GL and then apply to EML (rather than the other way round)

Essential Medicines List: Concept and Procedures 50 | Conclusions Application for EML will be opened soon and will remain open for 6 months It is strongly encouraged to make an application connected with a WHO technical department Frame your proposal within a WHO policy document/GL Send it early enough to be reviewed Expert Committee 2015 EML Meeting: April 2015

Essential Medicines List: Concept and Procedures 51 |

Essential Medicines List: Concept and Procedures 52 | Rational drug therapy (RDT) Quality use of medicines Appropriate use of medicines Responsible and evidence-based use Access to essential medicines and implementation at country level

Essential Medicines List: Concept and Procedures 53 | Selection process

Essential Medicines List: Concept and Procedures 54 | EML: why a model? A model for process and transparency Evidence-based rigorous process: high scrutiny on quality of evidence AND on its applicability at a global level Management of conflicts of interests Feed backs from country implementation

Essential Medicines List: Concept and Procedures 55 | Access and appropriate use of medicines: issues and challenges – PUSH MODE How to give access to the best available evidence –Full access to all available evidence –Understanding: critically appraised, highly scrutinised with multidisciplinary considerations –How? Are TRS report enough? Probably NOT … Connection and good alignment with WHO guidelines –Examples from: OC, TB, HIV, HepC, Mental Health, …

Essential Medicines List: Concept and Procedures 56 | Access and appropriate use of medicines: issues and challenges – PULL MODE New drugs are introduced different from EML EML in delay … important new drugs –LMWH –Cancer drugs –… Drugs lacking good enough supporting evidence –Drugs for memory –…

Essential Medicines List: Concept and Procedures 57 | How to support good prescribing

Essential Medicines List: Concept and Procedures 58 | Two different level of action: one supporting the other 1.Access to available evidence –Retrieval, systematic review, critical appraisal, synthesis and user-friendly presentation –Understanding, applicability and relevance, 2.Guidelines and recommendation –Standard and conditional recommendation and indicators of use

Essential Medicines List: Concept and Procedures 59 | The importance of the context Actual medicines use at local/national level Access to available evidence Guidelines and recommendations Drug utilization data: international comparison, small and large area variability, …

Essential Medicines List: Concept and Procedures 60 | The importance of the context Actual medicines use at local/national level Access to available evidence Guidelines and recommendations Drug utilization data: international comparison, small and large area variability, … The need for a comprehensive pharmaceutical policy:

Pharmaceutical policy By pharmaceutical policy we mean the conscious efforts of national governments to influence the pharmaceutical system

Pharmaceutical policy By pharmaceutical policy we mean the conscious efforts of national governments to influence the pharmaceutical system

… health system Equitable access Affordability Appropriate use

Functions of pharmaceutical sector Registration of medicines Licensing of pharmaceutical business Inspection of establishment Medicine promotion Clinical trials and independent confirmatory research Indipendent drug information Guidelines program and evidence-based recommendations Selection of essential medicines Procurement of medicines Distribution of medicines Drug utilization

There is a difference Independent drug bulletins Cochrane reviews Clinical Evidence Uptodate Guidelines Recommendations Consensus conferences Inappropriate uses