An introduction to the Essential Medicines concept

An introduction to the

Essential Medicines concept: balancing innovation with public health priorities

WHO HQ, Geneva

11 October 2017

Nicola Magrini Secretary,

WHO Expert Committee on the Selection and Use of Essential Medicines, Essential Medicines Department, WHO

Séminare sur les poliitiques pharmaceutiques, Sept 2015

EML 2017: 40th anniversary

Nicola Magrini Secretary

WHO Expert Committee on the Selection and Use of Essential Medicines Essential Medicines Department

Essential Medicines List: Concept and Procedures 3 |

20th EML & 6th EMLc - 2017

20th EML: 433 medicines

– 6th EMLc (children): 314 medicines

602 pages, >800 references


Contents of the presentation

1. EML a successful evidence-based idea: guiding

principles

2. Essential medicines … or why some drugs are

more important than others

3. Last update (2015): an important one

4. Next update 2017 or what’s next

2. Essential medicines … why some drugs are more important than other

EML 1977: early evidence-based adopter

No medicines for: • Memory loss and dementia

• Hepatoprotectants

• Immunostimulants

• Osteoporosis

• Medicines for dubious conditions (disease mongering)

• No medicines listed subsequently withdrawn for unexpected risks (e.g., cox-2 inhibitors)

• Important medicines for: – Antibiotics

– Neglected diseases

– Pain

– Mental health

– Chronic diseases

– Cancer

• Concise and clear

• Promoting uptake of best research findings on medicines into healthcare and national policies


Essential Medicines

Guiding principle: A limited range of carefully selected

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


EML criteria (EB 109/8, 2001)

Disease burden and public health need/relevance

Sound and adequate data on the efficacy (on relevant outcomes),

safety and comparative cost-effectiveness

– “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”

– “Affordability changed from a precondition into a consequence of the selection”

(Hogerzeil, BMJ, 2004)

WHO responsible management and oversight of CoIs

2008 WHO new Guideline Manual, adopting GRADE

Other considerations: regulatory status (off-label), availability,

guidelines


Lancet editorial October 24, 2015

3. EML rules and procedures

The WHO EB resolution 2001 EB109/8


EML: why it is a 'model List'

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


The EML reform in 2002:

more explicit criteria


WHO EB 109/8 - Medicines strategy


A more transparent and

evidence-based process (EB109/8 2001)








EML criteria (EB 109/8, 2001)

Essential medicines are those that satisfy the priority

health care needs of the population (it was deleted the majority of

the population)

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”


3. EML 2017: what has changed

The format for the final report


TRS TEMPLATE 2017


3. EML 2017: what will be available

An electronic version of the EML and

An EML database

ELECTRONIC DATABASE

ONLINE SEARCH ENGINE

LINK TO WHO GUIDELINES

TEMPLATE EVIDENCE SYNTHESIS

eEML: database & formats


eEML

The new

EML 2017


EML 2017 – major CHANGES/UPDATES

• Antibiotic comprehensive review

• 3 tiered categorisation: ACCESS, WATCH and RESERVE

• 23 syndromes reviewed: first and second choice

• Cancer: 8 medicines, 2 approvals

• HIV: dolutegravir, PreP

• HepC: sofosbuvir + velpatasivir (pangenotypic)

• Contraception: ulipristal and MPA

• …



Applications not endorsed (n=20)

COBI+ELV+FTC+TAF Gatifloxacin Polypill

Bevacizumab (del) Hypoclorous acid RUTF

Elabasvir+grazoprevir Insulin analogues Tenofovir alafenamide

(TAF)

FTC+RLP+TAF Lisinopril + HCTZ Tramadol

FTC + TAF Misoprostol (del) Trastuzumab emtansine

Enzalutamide NSCLC (TKIs, crizotinib) T2D 2nd line medicines

Gabapentin Oseltamivir (del)

EML 2017 Cancer & cancer pain

Recommendations

• Dasatinib (CML) • Nilotinib (CML) • Zoledronic acid (bone

metatsteses)

• Fentanyl (transdermal) • Methadone (already listed

for substitution treatment)

Rejections/standby • Enzalutamide (prostate) • Trastuzumab emtansine

(breast)

• TKIs, crizotinib (NSCLC)

• Tramadol (cancer pain)

Low Medium High

INCIDENCE OF DISEASE

TREATMENT

GOAL

Cure or “near

cure”

Significant

prolongation of

survival

Palliation of

symptoms with

small benefit in

survival

Leukemia and

Lymphomas in

Children and Adults

Early-Stage

Breast Cancer

CML Early-Stage Colon

Cancer

Testicular and ovarian

germ cell tumors

Stage III Ovarian

Cancer

Metastatic Breast

Cancer

HIGH

PRIORITY

Metastatic

Pancreatic Cancer

Metastatic

Lung Cancer

LOWEST

PRIORITY

GIST

Metastatic Prostate

Cancer

Metastatic

Bladder Cancer

LOW PRIORITY

Slide credit: Dr. Gilberto Lopes

Methodology to Develop Proposal for Revisions

GTN

21st EML (*6th EMLc) 2017 8.2 Cytotoxic and adjuvant medicines

All-trans retinoid acid (ATRA)

Cytarabine* Gemcitabine Procarbazine

Allopurinol* Dacarbazine* Hydroxycarbamide Rituximab

Asparaginase* Dactinomycin* Ifosfamide* Tioguanine*

Bendamustine Dasatinib Imatinib Trastuzumab

Bleomycin* Daunorubicin* Irinotecan Vinblastine*

Calcium folinate* Docetaxel Mercaptopurine* Vincristine*

Capecitabine Doxorubicin* Mesna* Vinorelbine

Carboplatin* Etoposide* Methotrexate* Zoledronic acid

Chlorambucil Filgrastim* Nilotinib

Cisplatin* Fludarabine Oxaliplatin*

Cyclophosphamide* Fluorouracil Paclitaxel*

21st EML (*6th EMLc) 2017

8.2 Cytotoxic and adjuvant medicines

All-trans retinoid acid (ATRA)

Cytarabine* Gemcitabine Procarbazine

Allopurinol* Dacarbazine* Hydroxycarbamide Rituximab

Asparaginase* Dactinomycin* Ifosfamide* Tioguanine*

Bendamustine Dasatinib Imatinib Trastuzumab

Bleomycin* Daunorubicin* Irinotecan Vinblastine*

Calcium folinate* Docetaxel Mercaptopurine* Vincristine*

Capecitabine Doxorubicin* Mesna* Vinorelbine

Carboplatin* Etoposide* Methotrexate* Zoledronic acid

Chlorambucil Filgrastim* Nilotinib

Cisplatin* Fludarabine Oxaliplatin

Cyclophosphamide* Fluorouracil Paclitaxel*

BLUE: added in 2015 GREEN: added in 2017


8.3 Hormones and antihormones

Anastrazole Hydrocortisone*

Bicalutamide Methylprednisolone*

Dexamethasone* Prednisolone*

Leuprorelin Tamoxifen


8.3 Hormones and antihormones

Anastrozole Hydrocortisone*

Bicalutamide Methylprednisolone*

Dexamethasone* Prednisolone*

Leuprorelin Tamoxifen

BLUE: added in 2015 GREEN: added in 2017

Indication Medicines

Acute lymphoblastic

leukaemia

(EML and EMLc)

Asparaginase

Cyclophosphamide

Cytarabine

Daunorubicin

Doxorubicin

Etoposide

Mercaptopurine

Methotrexate

Tioguanine

Vincristine

Dexamethasone

Hydrocortisone

Methylprednisolone

Prednisolone

Acute myelogenous leukaemia

(EML)

Cytarabine

Daunorubicin

Acute promyelocytic

leukaemia)

(EML)

All-trans retinoic acid

Cytarabine

Daunorubicin

Mercaptopurine

Methotrexate

Burkitt lymphoma

(EML and EMLc)

Calcium folinate

Cyclophosphamide

Cytarabine

Doxorubicin

Etoposide

Vincristine

Prednisolone

Chronic lymphocytic

leukaemia

(EML)

Bendamustine

Chlorambucil

Cyclophosphamide

Cyclophosphamide

Fludarabine

Rituximab

Prednisolone

Chronic myeloid leukaemia

(EML)

Hydroxycarbamide

Imatinib

Chronic myeloid leukaemia

IMATINIB RESISTANT

(EML)

Dasatinib

Nilotinib

Diffuse large B-cell lymphoma

(EML)

Cyclophosphamide

Doxorubicin

Rituximab

Vincristine

Prednisolone

EML 2017: medicines (by 32) cancers


Head and neck cancer

(EML)

Cisplatin

Early-stage breast cancer

(EML)

Carboplatin

Cyclophosphamid

e

Docetaxel

Doxorubicin

Fluorouracil

Methotrexate

Paclitaxel

Trastuzumab

Anastrozole

Leuprorelin

Tamoxifen

Early-stage cervical cancer

(EML)

Cisplatin

Early-stage colon cancer

(EML)

Calcium folinate

Capecitabine

Fluorouracil

Oxaliplatin

Early-stage rectal cancer

(EML)

Calcium folinate

Capecitabine

Fluorouracil

Epithelial ovarian cancer

(EML)

Carboplatin

Gemcitabine

Paclitaxel

Ewing sarcoma

(EML and EMLc)

Cyclophosphamid

e

Doxorubicin

Etoposide

Ifosfamide

Mesna

Vincristine

Follicular lymphoma

(EML)

Bendamustine

Cyclophosphamid

e

Doxorubicin

Rituximab

Vincristine

Prednisolone



Gastrointestinal stromal tumour

(EML)

Imatinib

Gestational trophoblastic

neoplasia

(EML)

Calcium folinate

Cyclophosphamide

Dactinomycin

Etoposide

Methotrexat

e

Vincristine

Hodgkin lymphoma

– adults* and paediatric

(EML and EMLc)

Bleomycin*

Cyclophosphamide

Dacarbazine*

Doxorubicin*

Etoposide

Vinblastine*

Vincristine

Prednisolone

Kaposi sarcoma

(EML)

Bleomycin

Doxorubicin

Paclitaxel

Vinblastine

Vincristine

Malignancy related bone disease

(EML)

Zoledronic acid

Metastatic breast cancer

(EML)

Capecitabine

Cyclophosphamide

Docetaxel

Doxorubicin

Paclitaxel

Trastuzumab

Vinorelbine

Anastrozole

Tamoxifen

Metastatic colorectal cancer

(EML)

Calcium folinate

Capecitabine

Fluorouracil

Irinotecan

Oxaliplatin

Metastatic prostate cancer

(EML)

Docetaxel

Bicalutamide

Leuprorelin

Nasopharyngeal cancer

(EML)

Carboplatin

Cisplatin

Fluorouracil

Paclitaxel



Non-small cell lung cancer

(EML)

Carboplatin

Cisplatin

Etoposide

Gemcitabine

Paclitaxel

Vinorelbine

Osteosarcoma

(EML and EMLc)

Calcium folinate

Carboplatin

Cisplatin

Doxorubicin

Ifosfamide

Mesna

Methotrexate

Ovarian germ cell tumours

(EML and EMLc)

Bleomycin

Cisplatin

Etoposide

Ifosfamide

Mesna

Paclitaxel

Vinblastine

Retinoblastoma

(EML and EMLc)

Carboplatin

Etoposide

Vincristine

Rhabdomyosarcoma

(EML and EMLc)

Cyclophosphamide

Dactinomycin

Ifosfamide

Mesna

Vincristine

Testicular germ cell

tumours

(EML and EMLc)

Bleomycin

Cisplatin

Etoposide

Ifosfamide

Mesna

Vinblastine

Wilms tumour

(EML and EMLc)

Dactinomycin

Doxorubicin

Vincristine


EML 2017 HIV & Hepatitis B/C

Recommendations

• Atazanavir + ritonavir

• Dolutegravir

• Raltegravir

• EFV400 + 3TC + TDF

• INH + B6 + CTX

• PrEP: TDF, TDF + FTC/3TC

• Sofosbuvir + velpatasvir

Rejections

• COBI + ELV + FTC + TAF

• FTC + RLP + TAF

• FTC + TAF

• Tenofovir alafenamide

• Elbasvir + grazoprevir

EML 2017 Malaria & TB

Recommendations

• Artesunate+pyronaridine

• DHA + PQP

• Delamanid (paediatrics)

• Ofloxacin (deletion)

• Isoniazid (+pyrazinamide) + rifampicin FDC (paediatrics)

Rejections

• Gatifloxacin

EML 2017 Reproductive health

Recommendations

• Ulipristal (emergency contraception)

• Medroxyprogesterone acetate (new SC formulation)

Rejections

• Misoprostol (deletion) – prevention PPH - unchanged in EML

Rejections

EML: why so many contraceptives

• To increase women choice

• To consider patients’ preferences

• To incorporate values

EML 2017 Non-communicable diseases

Recommendations

• Erythropoiesis-stimulating agents






Recommendations


• Budesonide + formoterol

• Lamotrigine - epilepsy

• Losartan

Rejections

• Bevacizumab (deletion)

– unchanged in EML

• Gabapentin

• Insulin analogues

• T2D 2nd line medicines

• Lisinopril + HCTZ

• Polypill


Oseltamivir

• Deletion NOT recommended

• Restricted use: moved to the Complementary List – critically hill patients with

influenza with a positive influenza test

• Access to all clinical data led to revision of the magnitude of benefit associated

with treatment

• WHO guidelines expected in 2018

• Review of clinical data in 2019: flagged for deletion

BMJ Tamiflu timeline


Recommendations




• Losartan

Rejections



• Gabapentin




• Polypill


Gabapentin

• NOT recommended for neuropathic pain

• Uncertainty in reported efficacy estimates related to publication and outcome

reporting biases


Gabapentin

• “Reporting bias occurs when the

dissemination of research findings is

influenced by the nature and direction

of the results. There is extensive,

even shocking, evidence of reporting

biases in the studies of Neurontin that

I reviewed for this report.”

• Studies were biased in their design

• Ghost authors

• Hiding of negative results

• Patients inappropriately excluded

from or included in the analyses

EML: why NOT gabapentin




Recommendations




• Losartan

Rejections



• Gabapentin




• Polypill

EML 2017: insulins analogues


EML 2017: diabetes second line





5. EML and pharmacological classes

Listing: one drug only per pharmacological class … implications for selection and procurement


EML and therapeutic equivalency 1/3




Example 1


Example 2 : limited square boxing


Example 3: limited square boxing



WHO supports pooled procurement mechanisms that

can increase competition among available

alternatives/options

Generic substitution and biosimilars role


Example 4: Erythropoetins

and respective biosimilars

Documents

An introduction to the Essential Medicines concept