Suggested use of terms, requirements and preferences for labelling and instructions for use

Malaria rapid diagnostic test products

Global Malaria Programme

© World Health Organization 2017

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WHO/HTM/GMP/2017.16

Table of contents

Introduction 1

Suggested use of terms 2

WHO requirements and preferences for the labelling of malaria RDT kit components: box, cassette packaging, cassette, buffer bottle and accessories 8

Labelling of the RDT box 9

Labelling of kit contents 12

Labelling of the cassette 14

Labelling of the buffer bottle 16

Labelling of accessories 17

WHO suggested generic template for Instructions for Use (IFU) 19

Annexes 32

2

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

1

InTRODUcTIOn

Rapid diagnostic tests (RDTs) largely account for the scale-up of malaria diagnosis in endemic settings. However, diversity in terminology, labelling and the instructions for use (IFU) limits their interchangeability and userfriendliness. Uniform, easy to follow and consistent terminology and labelling, aligned with international standards and appropriate for the level of the end user’s education and training, is crucial. This document is intended as a reference for malaria RDT manufacturers and follows on from the consensus building efforts of a 2014 Roll Back Malaria Partnership stakeholder consultation and special taskforce to harmonize terms and abbreviations as well as specifications for labelling of box, device packaging, cassettes, buffer bottle and accessories.1 Specifically, this reference indicates if WHO considers these specifications are requirements based on international standards or preferences based on the outcome of consultations with country programme implementers, experts in RDT implementation, IVD regulatory experts and manufacturers. These requirements and preferences are aligned with those of the WHO Prequalification (PQ) of IVDs programme and compliance will be monitored through the dossier and laboratory evaluation components of the WHO PQ process.2

1 Jacobs et al. Malaria Journal 2014, 13:505.2 http://www.who.int/malaria/publications/atoz/978924151268/en/

2

Suggested use of terms

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

3

PReF

eRRe

D T

eRm

Ab

bRev

.D

eSc

RIPT

IOn

SynO

nym

(N

OT

SUG

GES

TED

TER

M)

cO

mm

enTS

cAT

egO

Ry

Acce

ssor

ies

Artic

les

inte

nded

and

val

idat

ed b

y th

e RD

T m

anuf

actu

rer

to b

e us

ed w

ith th

e RD

T in

ord

er to

ach

ieve

its

inte

nded

pu

rpos

e (i.

e. s

peci

men

tran

sfer

dev

ice,

lanc

et, a

lcoh

ol

swab

)

Anc

illar

y ite

ms

The

acce

ssor

ies

prov

ided

mig

ht b

e re

plac

ed b

y ot

her i

tem

s with

out c

ompr

omisi

ng s

afe,

acc

urat

e pe

rfor

man

ce o

f the

test

, e.g

. diff

eren

t lan

cets

This

poss

ibili

ty o

f sub

stitu

tion

diffe

rent

iate

s “a

cces

sorie

s”

from

“com

pone

nts”

(see

‘Com

pone

nt’).

Alco

hol s

wab

A pa

d sa

tura

ted

with

alc

ohol

that

is u

sed

to c

lean

and

/or

disin

fect

ski

nAl

coho

l pad

, alc

ohol

w

ipe,

alc

ohol

pre

-pad

Ther

e w

as c

onse

nsus

that

“alc

ohol

sw

ab” i

s th

e te

rm in

br

oade

st u

se, b

oth

in s

poke

n la

ngua

ge a

nd in

labe

lling

.

Buff

erA

buffe

red

solu

tion

to e

nabl

e sp

ecim

en fl

ow a

nd

cond

ition

ing

of s

peci

men

s, to

opt

imiz

e se

nsiti

vity

and

m

inim

ize

non-

spec

ific

reac

tions

.

Man

y sy

nony

ms

are

in u

se, e

.g. “

bloo

d ly

sis

buffe

r”, “c

lear

ing

buffe

r”,

“ass

ay d

iluen

t”, “s

ampl

e di

luen

t”, “r

eage

nt”

Buff

er b

ottle

Plas

tic b

ottle

, ofte

n w

ith c

ap a

nd n

ozzl

e, c

onta

inin

g th

e bu

ffer,

inte

nded

to b

e us

ed in

mul

tiple

test

s

Buff

er v

ial

Smal

l via

l con

tain

ing

a su

ffici

ent v

olum

e of

buff

er to

pe

rfor

m a

sin

gle

RDT

test

. See

“prim

ary

pack

agin

g”

“Buff

er a

mpu

lla”

Buff

er w

ell

Phys

ical

pla

ce in

the

test

dev

ice

in w

hich

the

buffe

r is

appl

ied.

Som

e RD

Ts h

ave

a sin

gle

wel

l for

bot

h bu

ffer a

nd s

peci

men

.

Cas

sett

eTh

is is

the

test

form

at in

whi

ch th

e ni

troce

llulo

se s

trip

is

enca

sed

in a

pla

stic

hou

sing,

pre

sent

ing

open

ings

for t

he

resu

lt w

indo

w, f

or th

e sp

ecim

en a

nd b

uffer

wel

l(s) a

nd in

so

me

case

s fo

r eva

pora

tion.

Com

mon

ly re

ferr

ed to

as

the

“dev

ice”

Com

bina

tion

rapi

d di

agno

stic

test

Test

for d

etec

ting

mul

tiple

mal

aria

spe

cies

and

whi

ch

dist

ingu

ishes

P. f

alci

paru

m fr

om o

ther

mal

aria

spe

cies

Com

mon

ly re

ferr

ed to

as

a “c

ombo

test

”

Com

pone

ntD

edic

ated

par

ts o

f a fi

nish

ed, p

acka

ged,

labe

lled

RDT

kit t

hat a

re s

peci

fic to

and

nec

essa

ry fo

r per

form

ing

the

RDT.

The

se in

clud

e th

e te

st d

evic

e, b

uffer

bot

tle/v

ial a

nd

inst

ruct

ions

for u

se.

Not

e: T

here

can

be

no s

ubst

itutio

n fo

r a k

it co

mpo

nent

, w

here

as a

cces

sorie

s su

ch a

s a

lanc

et o

r alc

ohol

sw

ab

may

be

repl

aced

by

item

s th

at p

erfo

rm th

e sa

me

func

tion

or a

re p

urch

ased

sep

arat

ely.

Con

trol

line

Visib

le li

ne o

n th

e ni

troce

llulo

se s

trip

that

gen

eral

ly o

nly,

in

dica

tes

satis

fact

ory

mig

ratio

n of

buff

er a

Des

icca

ntD

ryin

g ag

ent u

sed

to p

rote

ct th

e te

st d

evic

e fr

om

hum

idity

. The

se m

ay c

hang

e co

lour

(sel

f-in

dica

ting)

to

indi

cate

hum

idity

sat

urat

ion.

The

bea

ds a

re c

onta

ined

in

a tra

nspa

rent

, par

tially

tran

spar

ent o

r non

-tra

nspa

rent

fib

er p

ouch

.

Silic

a ge

l is

the

mos

t co

mm

only

use

d de

sicca

nt fo

r RD

T pr

oduc

ts.

4

PReF

eRRe

D T

eRm

Ab

bRev

.D

eSc

RIPT

IOn

SynO

nym

(N

OT

SUG

GES

TED

TER

M)

cO

mm

enTS

cAT

egO

Ry

In v

itro

diag

nost

ic

med

ical

dev

ice

A de

vice

, use

d al

one

or in

com

bina

tion,

inte

nded

by

the

man

ufac

ture

r for

in v

itro

exam

inat

ion

of s

peci

men

s de

rived

from

the

hum

an b

ody,

sol

ely

or p

rinci

pally

to

pro

vide

info

rmat

ion

for d

iagn

osis,

mon

itorin

g or

co

mpa

tibili

ty. T

hey

incl

ude

reag

ents

, cal

ibra

tors

, con

trol

mat

eria

ls, s

peci

men

rece

ptac

les,

softw

are,

rela

ted

inst

rum

ents

or a

ppar

atus

or o

ther

art

icle

s (In

tern

atio

nal

Med

ical

Dev

ices

Reg

ulat

ors

foru

m)

http

://w

ww

.imdr

f.org

/do

cs/g

htf/

arch

ived

/sg

1/te

chni

cal-

docs

/gh

tf-sg

1-n0

45r1

2-in

-vitr

o-di

agno

stic

-cl

assifi

catio

n-07

0209

.pd

f

Requ

ired

Inst

ruct

ions

for u

se

IFU

Info

rmat

ion

prov

ided

by

the

man

ufac

ture

r to

the

user

ab

out t

he in

tend

ed p

urpo

se a

nd p

rope

r use

of i

n vi

tro

diag

nost

ics

and

any

prec

autio

ns to

be

take

n (G

HTF

/SG

1/n7

0:20

11)

“Pac

kage

inse

rt”,

“inst

ruct

ions

leafl

et”

Requ

ired

Job

aid(

s)D

ocum

ent d

escr

ibin

g th

e es

sent

ial m

ater

ials

to p

erfo

rm

an R

DT

(i.e.

pro

cedu

re o

r int

erpr

etat

ion)

pro

vide

d ap

art

from

the

IFU,

eith

er a

s a

sepa

rate

leafl

et a

nd/o

r prin

ted

on th

e de

vice

pac

kagi

ng o

r in/

on th

e RD

T bo

x

“Qui

ck g

uide

”, “p

icto

gram

test

ing

proc

edur

e”

Refe

r to

the

“WH

O g

ener

ic jo

b ai

ds” f

or a

n ex

ampl

e.

Kit

Set o

f com

pone

nts

and

acce

ssor

ies

pack

ed to

geth

er

and

inte

nded

for u

sing

a sp

ecifi

c RD

T (te

st d

evic

e, b

uffer

bo

ttle,

spe

cim

en tr

ansf

er d

evic

e, la

ncet

, alc

ohol

sw

ab,

inst

ruct

ions

for u

se) (

defin

ition

ada

pted

from

ISO

18113

-1:2

009)

Requ

ired

Lanc

etSh

arp,

nee

dle-

like,

ste

rile

med

ical

dev

ice

used

to

punc

ture

ski

n to

obt

ain

bloo

d (C

LSI H

04-A

6)Th

ey in

clud

e:

•pl

ain

met

al la

ncet

s (p

acke

d in

a s

ingl

e pa

ckag

es fo

r st

erili

ty)

•sa

fety

-sea

l lan

cets

(in

plas

tic h

ousin

g w

ith a

pla

stic

cap

)•

auto

-lan

cing

lanc

ets

(mou

nted

in p

last

ic h

ousin

g th

at is

ej

ecte

d au

tom

atic

ally

whe

n th

e pl

unge

r is

pres

sed)

•au

to-r

etra

ctab

le la

ncet

s (m

ount

ed in

pla

stic

hou

sing

that

is re

tract

ed a

utom

atic

ally

afte

r pun

ctur

e)

Lot

Defi

ned

amou

nt o

f mat

eria

l with

uni

form

pro

pert

ies

that

ha

s be

en p

rodu

ced

in o

ne p

roce

ss o

r ser

ies

of p

roce

sses

so

that

it c

an b

e ex

pect

ed to

be

hom

ogen

eous

(ISO

18113

-1:2

009)

“Bat

ch”

Requ

ired

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

5

PReF

eRRe

D T

eRm

Ab

bRev

.D

eSc

RIPT

IOn

SynO

nym

(N

OT

SUG

GES

TED

TER

M)

cO

mm

enTS

cAT

egO

Ry

Lot n

umbe

rD

istin

ctiv

e se

t of n

umbe

rs a

nd/o

r let

ters

for a

kit

or

com

pone

nt th

at s

peci

fical

ly id

entifi

es a

lot a

nd p

erm

its

traci

ng o

f its

man

ufac

ture

, pac

kagi

ng, l

abel

ling

and

dist

ribut

ion

hist

ory

(ISO

18113

-1:2

009)

“Bat

ch n

umbe

r”, “b

atch

co

de”

Requ

ired

Mal

aria

rapi

d di

agno

stic

test

RD

TA

colle

ctio

n of

reag

ents

and

oth

er a

ssoc

iate

d m

ater

ials

for

in v

itro

diag

nost

ics,

inte

nded

to b

e us

ed fo

r the

qua

litat

ive

and/

or q

uant

itativ

e de

tect

ion

of a

ntig

ens

from

one

or

mor

e sp

ecie

s of

Pla

smod

ium

in a

clin

ical

spe

cim

en w

ithin

a

shor

t per

iod,

rela

tive

to s

tand

ard

labo

rato

ry te

stin

g pr

oced

ures

, typ

ical

ly b

y an

imm

unoc

hrom

atog

raph

ic te

st

met

hod

This

test

is c

omm

only

use

d in

the

labo

rato

ry o

r in

poin

t-of

-car

e an

alys

es.

Man

ufac

ture

rAn

y na

tura

l or l

egal

per

son

with

resp

onsib

ility

for d

esig

n an

d/or

man

ufac

ture

of a

med

ical

dev

ice

with

the

inte

ntio

n of

mak

ing

the

med

ical

dev

ice

avai

labl

e fo

r use

, und

er

his

or h

er n

ame,

whe

ther

the

med

ical

dev

ice

is de

signe

d an

d/or

man

ufac

ture

d by

that

per

son

him

- or

her

self

or o

n hi

s or

her

beh

alf b

y an

othe

r per

son(

s) (G

HTF

/SG

1/N

055:

20

09 D

efini

tions

of t

he te

rms

“man

ufac

ture

r”, “a

utho

rized

re

pres

enta

tive”

, “di

strib

utor

” and

“im

port

er”)

Plas

mod

ium

an

tigen

Antig

en b

pro

duce

d by

mal

aria

par

asite

s an

d de

tect

ed

with

RD

TsTa

rget

, mar

ker,

anal

yte

Plas

mod

ium

P

“P” i

s to

be

used

onl

y as

the

abbr

evia

tion

of th

e ge

nus

and

in c

ombi

natio

n w

ith th

e sp

ecie

s na

me

(e.g

. P.

oval

e) o

r as

part

of th

e ab

brev

iatio

ns “P

m, P

o, P

v, P

f an

d Pv

om”;

it sh

ould

not

be

used

alo

ne.

pan-

A gr

oup

of h

uman

Pla

smod

ium

spe

cies

: Pf,

Pv, P

o an

d Pm

Plas

mod

ium

fa

lcip

arum

PfPl

asm

odiu

m fa

lcip

arum

Plas

mod

ium

(or

para

site)

lact

ate

dehy

drog

enas

e

pLD

H

Plas

mod

ium

(or p

aras

ite) l

acta

te d

ehyd

roge

nase

In p

aper

s an

d do

cum

ents

, bot

h “p

aras

ite” a

nd

“Pla

smod

ium

” lac

tate

deh

ydro

gena

se a

re u

sed.

In th

e pr

esen

t con

text

and

doc

umen

ts (s

uch

as IF

U).

it w

ould

be

bet

ter t

o m

aint

ain

“Pla

smod

ium

”

Plas

mod

ium

m

alar

iae

PmPl

asm

odiu

m m

alar

iae

Plas

mod

ium

ova

lePo

Plas

mod

ium

ova

le

Plas

mod

ium

viv

axPv

Pl

asm

odiu

m v

ivax

6

PReF

eRRe

D T

eRm

Ab

bRev

.D

eSc

RIPT

IOn

SynO

nym

(N

OT

SUG

GES

TED

TER

M)

cO

mm

enTS

cAT

egO

Ry

Plas

mod

ium

viv

ax,

oval

e, m

alar

iae

Pvom

Plas

mod

ium

viv

ax, o

vale

, mal

aria

e

Poin

t-of

-car

e te

stin

g PO

CTTe

stin

g us

ed a

t or n

ear t

he s

ite o

f pat

ient

car

e, le

adin

g to

a

poss

ible

cha

nge

in th

e ca

re o

f the

pat

ient

(ISO

228

70

2006

)

Prim

ary

pack

agin

g of

alc

ohol

sw

abs,

lanc

ets,

desic

cant

an

d ca

sset

tes

Laye

r of p

acka

ging

in im

med

iate

con

tact

with

the

item

Al

coho

l sw

ab, l

ance

t, de

sicca

nt o

r cas

sette

pa

ckag

ing

Pack

agin

g of

alc

ohol

sw

ab, l

ance

t, de

sicca

nt

or c

asse

tte

Pouc

h, s

ache

t

Use

“prim

ary

pack

agin

g” in

tech

nica

l com

men

ts

for m

anuf

actu

rers

(for

inst

ance

whe

n de

scrib

ing

requ

irem

ents

for l

abel

ling)

, and

use

“pac

kagi

ng

of th

e al

coho

l sw

ab” o

r “al

coho

l sw

ab p

acka

ging

” w

hen

addr

essin

g us

ers

durin

g tra

inin

g an

d in

IFU

(for

in

stan

ce: “

open

the

cass

ette

pac

kagi

ng”)

.

Prod

uct

RDT

as c

urre

ntly

mar

kete

d an

d id

entifi

ed, w

ith a

ssig

ned

nam

e, p

rodu

ct c

ode

and

regu

lato

ry v

ersio

n

Prod

uct c

ode

Uniq

ue c

ode

iden

tifyi

ng o

ne p

rodu

ct (o

r pro

duct

var

iant

) w

ith a

n as

signe

d na

me

and

a re

gula

tory

ver

sion

Cata

logu

e nu

mbe

r, pr

oduc

t num

ber,

refe

renc

e nu

mbe

r

RDT

box

or B

oxPh

ysic

al b

ox, u

sual

ly m

ade

of c

ardb

oard

, in

whi

ch th

e ki

t co

nten

ts (c

ompo

nent

s an

d ac

cess

orie

s) a

re p

acke

dSe

cond

ary

pack

agin

g,

kit b

ox

Read

ing

lege

ndAc

rony

ms

or c

hara

cter

s in

the

resu

lt w

indo

w, r

efer

ring

to th

e co

ntro

l and

test

line

s. T

he c

hara

cter

s m

ay b

e em

boss

ed in

the

plas

tic h

ousin

g or

prin

ted

on it

. The

re

adin

g le

gend

can

be

on e

ither

sid

e of

the

resu

lt w

indo

w.

Read

ing

scal

e

(Min

imum

and

m

axim

um) r

eadi

ng

time

Inte

rval

dur

ing

whi

ch v

alid

resu

lts c

an b

e ob

tain

ed

Resu

lt w

indo

wO

peni

ng in

the

test

cas

sette

sho

win

g th

e ar

ea o

f the

str

ip

cont

aini

ng th

e co

ntro

l and

test

line

(s)

Read

ing

win

dow

Revi

sion

hist

ory

A ta

ble

in w

hich

am

endm

ents

are

reco

rded

eac

h tim

e a

new

ver

sion

of th

e IF

U is

issu

ed

Sing

le p

ack

Kit i

ndiv

idua

lly p

acke

d w

ith a

ll th

e co

nten

t req

uire

d fo

r the

pe

rfor

man

ce o

f one

test

Si

ngle

test

pac

k,

singl

e te

st, i

ndiv

idua

lly

pack

aged

test

Spec

ies

spp.

Spec

ies

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

7

PReF

eRRe

D T

eRm

Ab

bRev

.D

eSc

RIPT

IOn

SynO

nym

(N

OT

SUG

GES

TED

TER

M)

cO

mm

enTS

cAT

egO

Ry

Spec

imen

wel

lPh

ysic

al p

lace

in th

e te

st c

asse

tte o

r dip

stic

k to

whi

ch th

e sp

ecim

en is

app

lied

Som

e m

alar

ia R

DTs

ha

ve a

sin

gle

wel

l for

bo

th s

peci

men

and

bu

ffer.

Spec

imen

tran

sfer

de

vice

D

evic

e us

ed to

tran

sfer

blo

od (o

r pla

sma

or s

erum

) to

the

test

dev

ice.

Thi

s in

clud

es: i

nver

ted

cup,

loop

, (gl

ass)

ca

pilla

ry tu

be, (

plas

tic) s

traw

, pip

ette

.

Sam

plin

g de

vice

The

term

“spe

cim

en tr

ansf

er d

evic

e” m

ay b

e sh

orte

ned

to “t

rans

fer d

evic

e”.

Sym

bol k

eyLi

st o

f sym

bols

with

writ

ten

expl

anat

ion

(“le

gend

”)Ke

y to

sym

bols

Test

line

Line

on

the

nitro

cellu

lose

str

ip th

at is

inte

nded

to d

ispla

y th

e re

actio

n w

ith a

spe

cific

targ

et a

ntig

en (H

RP2,

pLD

H,

aldo

lase

)

The

term

“ban

d” c

an

be u

sed

depe

ndin

g on

th

e RD

T de

sign

(two-

, th

ree-

and

four

-ban

d RD

T pr

oduc

ts)

Test

str

ipTh

e ph

ysic

al m

ediu

m, e

.g. n

itroc

ellu

lose

, in

whi

ch th

e m

igra

tion

and

reac

tion

take

pla

ce

“Tes

t mem

bran

e”

Two-

, thr

ee-

and

four

-ban

d RD

TsRD

Ts w

ith tw

o, th

ree

or fo

ur li

nes,

incl

udin

g th

e m

igra

tion

cont

rol l

ine,

and

one

, tw

o or

thre

e te

st li

nes

User

A

train

ed o

r ski

lled

pers

on, w

ho is

com

pete

nt a

nd w

ho

uses

the

RDT

Ope

rato

r, en

d-us

er

Vers

ion

num

ber

Num

ber g

iven

to a

ny la

belli

ng, i

nclu

ding

labe

ls,

inst

ruct

ions

for u

se (o

r job

aid

s) o

r any

oth

er m

ater

ials

dist

ribut

ed w

ith th

e pr

oduc

t, to

allo

w tr

acki

ng o

f cha

nges

.

a . I

n th

e ca

se o

f mal

aria

RD

Ts, t

he c

ontro

l lin

e be

com

es v

isibl

e if

suffi

cien

t dye

-lab

elle

d an

tibod

y (c

arrie

d in

the

buffe

r) a

ccum

ulat

es o

n th

e te

st s

trip

line

con

tain

ing

suffi

cien

t, in

tact

bou

nd

capt

ure

antib

ody.

b . A

ntig

ens

are

not r

ecom

bina

nt.

8

GeneRAL nOTe On LABeLLInG LeGIBILITy

There are no international guidelines on font sizes for labels of in-vitro diagnostics.

• According to the Guideline on the readability of the labelling and package leaflet of medicinal products for human use, revision 1, 12 January 2009, characters of at least 7 points (or of a size in which the lower case “x” is at least 1.4 mm in height) with a space between the lines of at least 3 mm are recommended.*

• The US Food and Drug Administration document Guidance on medical device patient labelling; final guidance for industry and FDA reviewers (2001), for patients and lay caregivers, recommends use of at least 12-point type whenever possible and a serif font for text.

* http://ec.europa.eu/health/files/eudralex/vol2/c/2009_01_12_readability_guideline_final_en.pdf

WHO requirements and preferences for the labelling of malaria RDT kit components

bOx, cASSeTTe PAckAgIng, cASSeTTe, bUFFeR bOTTle AnD AcceSSORIeS

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

9

labelling of the RDT box

Orientation

FIGURE 1. convention of terms for the front view of a malaria RDT box

labelling of the RDT box

• Left (lateral) • Front• Top • Right (lateral)• Back • Bottom

LefT (LATeRAL)

TOP

fROnT

RIGHT (LATeRAL)

BOTTOm

BACK

GeneRAL RequIRemenTS AnD PRefeRReD OPTIOnS fOR LABeLLInG mALARIA RDT BOxeS cATegORy

1. Labels should be printed on the cardboard as permanent printing or applied as water-resistant labels (applied with water-resistant glue). Printing should be indelible and should last the life span of the RDT product.

Preferred

2. use only internationally recognized symbols (ISO 15223–2012 or, if applicable, the Globally harmonized system of classification and labelling of chemicals.1

Required

3. Labelling must be legible, for instance in open letter type and font size equivalent to Miriad bold 10.

Required

4. The official language(s) in which the intended use is displayed should be relevant to the region in which the RDT product will be used. In Figure 2, English, French, Spanish and Portuguese are displayed.

Preferred

5. Display the essential information on the top (see Figure 2), front and at least one lateral side of the RDT box (left or right) (see Figure 3). The label contains all the relevant information required for stock management (e.g. product identity, storage conditions and material provided). An exception can be made for custom or variable prints, such as lot number and expiration date, and, in case of use, also production date. These can be printed on only one side of the box.

Preferred

1. http://www.hse.gov.uk/chemical-classification/labelling-packaging/hazard-symbols-hazard-pictograms.htm

10

What should be displayed: cATegORy

1. Product name with sufficient detail for the user to uniquely identify the device and its intended use, e.g.

• commercial name of the RDT product

• “malaria”

• targeted species and antigen(s)

• “antigen” or “Ag”

Required

2. Product code (and symbol) Required

3. Intended use (to be included if the product name does not include sufficiently specific information). If there is insufficient space on the label, this statement can be included on the IFU: diagnosis of malaria, in vitro diagnostic, professional use.

Required

4. number of tests provided in the kit box Required

5. In vitro diagnostic (symbol) Required

6. Name and physical address of the legal manufacturerTelephone and/or fax number and/or website

Required

7. Lot number (and symbol) Required

8. expiration date (and symbol)

Preferred format: YYYY-MM

Required

9.

9a.

9b.

materials (content) and quantities

• Materials provided, and quantities of each

• Items required but not provided, i.e. those items required for safe, accurate use of the test, such as a lancet (with symbol)

Required

Preferred

10. Storage conditions (symbols) Required

11. Warnings or precautions (symbols)

For instance: - do not use if package is damaged (symbol)

• read instructions before use (symbol)

• biohazard (symbol), if applicable i.e. desiccant containing cobalt chloride; buffer with sodium azide concentration (≥0.1%)

Required

12. Additional easily visible warning in case the procedure or Ifu has changed substantially

Information about the change and effective date should be included as a separate note in the box or in the IFU

Preferred

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

11

FIGURE 2. example label on the top of the RDT box. blue indicates specific RDT product items

4°C

30°C

commercial name, malaria Antigen Pf/Pan (HRP2/ pLDH) RDT

xxxxxxxxxx Σ

xx

Rapid test for the antigen detection of malaria (Plasmodium x)

Test rapide de détection d’antigène du paludisme (Plasmodium x)

Prueba rápida para detección de antígeno de malaria (Plasmodium x)

Teste rápido para detecção de antígeno da malária (Plasmodium x)

Professional use only

xxxxxxx

yyyy-mm

name, physical address of legal manufacturer, website, telephone and/or fax number

FIGURE 3. example labelling of one lateral side and the front of an RDT box. blue indicates specific RDT product items

commercial name, malaria Antigen Pf/Pan (HRP2/pLDH) RDT

xxxxxxxxxxx

Content: XX indicates quantities. Could state number of pouches and what each pouch contains

•Cassettes (xx)•Specimen•Transfer devices (xx)•Alcohol swabs (xx)•Lancets (xx)•Buffer bottle (xx)•Instructions for use (x)

Σxx

xxxxxxx

Indicate symbol for method of sterilization

Required but not provided

•Gloves•Biosafety sharps container•Biohazard waste container•Timer•Pencil/pen

yyyy-mm

4°C

30°C

12

labelling of kit contents

LABeLLInG Of CASSeTTe PRImARy PACKAGInG

What should be displayed: CATeGORy

1. Product name with sufficient detail for the user to uniquely identify the product and its intended use, e.g.

• commercial name of the RDT product

• “malaria”

• targeted species and antigen(s)

• “antigen” or “Ag”

Example: Commercial name, Malaria Pf/Pv (HRP2/pLDH) Antigen (RDT)

Required

2. for product code (or symbol) Preferred

3. Intended use (to be included if the product name does not include sufficiently specific information): If there is insufficient space on the label, this statement can be included on the IFU: diagnosis of malaria, in vitro diagnostic, professional use only, point-of-care.

Required

4. In vitro diagnostic (symbol) Required

5. name (or logo) of the legal manufacturer Required

6a.

6b.

Lot number (and symbol)

The lot number is preferably identical to the one on the RDT box.

Required

Preferred

7a.

7b.

expiration date (and symbol)

Preferred format: YYYY-MM

The expiration date is preferably identical to that on the RDT box. The expiration date must not be earlier than the expiration date on the RDT box.

Required

Preferred

8. quantity of tests per packaging (if more than one test) Preferred

9. unless there is no space, list contents of packaging and quantities, including desiccant

Preferred

10. Storage conditions (symbols) Required

11. Warnings or precautions (symbols)

For instance:

• do not use if package is damaged (symbol)

• read instructions before use (symbol)

• single use (symbol)

Required

GeneRAL nOTe

According to ISO 18113-2:2009, in the case of a kit, each component shall be identified by name, letter, number, symbol, colour or graphics in the same manner on all labels and in the instructions for use.

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

13

Where labels should be put:

Display all standard generic information on one side of the packaging and the custom or variable information (expiration date, lot number) on the opposite side. Preferred

FIGURE 4.example labelling of cassette primary packaging. blue indicates specific RDT product items

4°C

30°C

Commercial name, malaria Antigen Pf/Pan (HRP2/ pLDH) RDT

for product code: xxxxxxx

Σ xx

Content:• 1 cassette• 1 desiccant • 1 specimen transfer device

manufacturer name or logo

xxxxxxx

yyyy-mm

14

LefT

DISTAL

RIGHT

PROxImAL

Long

axi

s

Short axis

labelling of the cassette

convention of terms used to describe the orientation of the cassette

Figure 5 shows the most common RDT, a three-band RDT targeting two antigens (P. falciparum and pan-Plasmodium antigens) in a two-step procedure (add specimen, next add buffer), with a cassette containing individual specimen and buffer wells. The following convention of terms is used: proximal (closest to the specimen and buffer wells) and distal (at the end of the migration [absorption] pad). A vertical view of the cassette (with the direction of the specimen and buffer flow “upwards”) shows a right- and a left-hand side.

FIGURE 5.conventions for terms to describe the cassette

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

15

LABeLLInG: CATeGORy

1. Printing in indelible ink is recommended instead of characters embossed in the cassette housing. The test and control line legends and the actual test lines should be well aligned.

Preferred

2. All printing should be along the short axis. Preferred

3. A single, unequivocal reading legend should be present on the right-hand side of the results window.

Preferred

4. All abbreviations comply with those listed in document “Abbreviations”. In addition, “1” for the sample well, “2” for the buffer well (chronological order)

Preferred

5. Labelling must be legible: for instance, open letter type, clear print Required

note: The cassette surface should be of a material (and profile) on which it is possible to write (with a standard ink pen or pencil). Space should be left for writing patient identification. Preferred

What should be displayed: cATegORy

1. Product name (with indication of “Malaria”, antigen-based “Ag”, the Plasmodium species and the antigens detected) or logical abbreviation (referenced in the IFU)

Required

2. Labelled specimen and buffer wells (see above) e.g. “1” for the sample well, “2” for the buffer well (chronological order) – Preferred

Required

3. Reading legend with Plasmodium species detected (see abbreviations: Pf, pan, Pv)

Preferred

16

labelling of the buffer bottle

geneRAl ReqUIRemenTS AnD OUTlIneS FOR lAbellIng RDT bUFFeR bOTTleS: cATegORy

1. Labels: Well-fixed water-resistant label (applied with water-resistant glue) or permanent printing, indelible ink lasting the life span of the RDT product.

Preferred

2. use only internationally recognized symbols (ISO 15223–2012). Required

3. The official language(s) displayed should be relevant to the region in which the RDT product will be used.

Preferred

What should be displayed: cATegORy

1. Product name, with sufficient detail for the user to uniquely identify the product and its intended use, e.g.

• commercial name of the RDT product

• “malaria”

• targeted species and antigen(s)

• “antigen” or “Ag”

Example: Commercial name, Malaria Pf/Pv (HRP2/pLDH) Antigen(RDT)

(preferred option)

or with sufficient detail for the user to identify the type of product with which to use the buffer, e.g. Malaria RDT

(acceptable option)

Preferred

2. Contents: Buffer Required

3a.

3b.

For product code (symbol)

(preferred option)

or a reference code that is also written on the RDT packaging and/or in the instructions for use

(acceptable option)

Preferred

Required

4. In vitro diagnostic (symbol) Required

5. name (or logo) of the legal manufacturer Required

6. Lot number (and symbol) Required

7. Volume of contents or number of examinations that can be performed Required

8. expiration date (and symbol)

Preferred format: YYYY-MM

The expiration date must not be earlier than the expiration date on the RDT box and test packaging.

Required

Required

9. Storage conditions (symbols) Required

10. Warnings or precautions (symbols)

At least :do not use if package is damaged (symbol); hazard symbol, if sodium azide concentration is ≥ 0.1% (symbol); read instructions before use (symbol)

Required

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

17

FIGURE 6.Proposal for printing relevant information on the buffer bottle

4°C

30°C

Commercial name, malaria Antigen Pf/Pan (HRP2/ pLDH) RDT

for product code: xxxxxx

Contents : Buffer

xxxxxxx

yyyy-mm

manufacturer name (or logo)

xx ml or number of examinations

labelling of accessories

Definitions

Accessories of in vitro diagnostics are articles specifically and explicitly intended by the manufacturer to be used with a device to enable that device to be used in accordance with the intended purpose (ISO 18113-1, CE Directive 98/79). Specimen transfer devices, lancets, alcohol swabs and desiccant are included.

geneRAl ReqUIRemenTS AnD OUTlIneS: cATegORy

1. Labels should be printed on the device or packaging as permanent printing or applied as water-resistant labels (with water-resistant glue). The ink should be indelible and should last the life span of the product. If it is not practicable to display the information on the device itself (e.g. lancets, specimen transfer devices), some or all of the information may appear on the packaging of multiple items (if used) (GHTF/SG1/N70/2011:5.0 and Annex 1.8.8.1 of EU Directive 98/79).

Required

2. use of symbols, when adequate, is encouraged instead of text. Only Internationally recognized symbols (ISO 15223-2012) should be used.

Required

3. The language(s) used should be relevant to the region in which the RDT product will be used.

Preferred

4. The table below lists the information to be displayed on different accessories or on their packaging.

18

lAbel InFORmATIOn TRAnSFeR DevIce

lAnceT AlcOHOl SWAb

DeSIccAnT cATegORy

Name of accessory X X X X Required

Intended use if name of accessory does not indicate it (sufficient to identify the device and its intended use: e.g. transfer device, antiseptic, desiccant)

X X X X Required

Name of the legal manufacturer of the accessory (preferred to RDT manufacturer)

X X X X Preferred

For alcohol swab: antiseptic, product and concentration (e.g. isopropyl alcohol70%)

X Required

Product code of the accessory X X Preferred

For a transfer device other than inverted cup and loop: permanent volume mark

X Preferred

Lot number X X X Required

X Preferred

Indicate “in vitro diagnostic” use X

Expiration date (preferred format: YYYY-MM)

X Preferred

X X Required

Quantity of items, indicated on the outer packaging (if applicable) (symbol)

X X X Required

Specimen volume transferred X Preferred

Single use (symbol) X X X Required

Sterile (and by what method), if applicable

X Required

X Preferred

Do not use if package is damaged (symbol)

X X Required

Warning: “Do not swallow or eat” and “harmful” (text or symbols) in relevant language(s)

X Preferred

X Required

Interpretation of colour change, if applicable

X Required, if

applicable

Mal

aria

rap

id d

iag

nost

ic t

est

pro

duc

ts

sug

ges

ted

use

of

term

s, r

equ

irem

ents

an

d p

refe

ren

ces

for

labe

llin

g a

nd

inst

ruct

ion

s fo

r u

se

19

The present document is a template for generic IFU of malaria rapid diagnostic tests.

It must be adapted to the specific product.

Words or terms that are definitely product-related and variable are in blue. This template can be adapted according to present or future characteristics of the concrete product. Instructions for the designer are printed in italics and put into text boxes.

The present document uses the safety-seal lancet and inverted cup as an example. Other combinations are possible.

general suggestions

• Provide IFU version number including indication of language and date.

• Highlight changes (shaded in grey) with regard to the previous version.

• Text: ensure that the IFU is easily readable (e.g. Flesch-Kincaid grade < 6)

• use type size of at least 9 points, as measured in font ‘Times New Roman’, not narrowed, with a space between lines of at least 3 mm and an open letter type;

• use short sentences and terms that are easy to understand;

• use consistent terms and words throughout the IFU (see the section on Suggested use of terms);

• use active verb (imperative) rather than passive voice/”should”;

• stress important information (capitals, italics, underline);

• turn any list into a bulleted or numbered list;

• put “when” and “if” before “what” (“If the color indicator is red, discard the test”);

• put the warning before the action step in the procedure;

• make sure warnings are clearly indicated;

• use one line per action.

References on readability and a readability calculator are included in Annex 1.

• Figures:

• use figures that are large enough so that they are easily visible;

• drawings may be more informative than photographs;

WHO suggested generic template for Instructions for Use (IFU)

20

• Generic job aids for malaria RDTs published by WHO-FIND provide clear drawings (see http://www.who.int/malaria/areas/diagnosis/rapid-diagnostic-tests/job-aids/en/);

• put figures on the left side, text on the right side;

• refer to each figure in the text;

• check that the figures match the real-life situation (device, transfer device, gloves, right-handed operator).

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TAble OF cOnTenTS

Product

• Product name

• Product code

• Number of tests provided in the kit

Intended use

• Test principle

• Intended user

• Required specimen

Warnings and precautions

materials

• Materials provided

• Materials required but not provided

Storage and stability

Procedure

• Before testing

• Sample preparation

• Test procedure

• Capillary whole blood from finger prick

• Venous whole blood from venipuncture

• Interpretation of the test result

limitations of the test, causes of false-negative and false-positive results

• Limitations of Malaria RDTs

• False negative results

• False positive results

• Invalid tests and problems of background clearing

Performance specifications

bibliography

manufacturer contact information

IFU version number and date of issue of the instructions for use

Symbol key

Product specific and other variables printed in blue

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Product

• Commercial name, Malaria Antigen Pf/Pan (HRP2/ pLDH) Rapid Diagnostic Test (RDT)

• Product code xxxxxx and presentation (number of tests per kit)

Intended use

This XXX test kit is an in-vitro diagnostic immunochromatographic assay for the qualitative detection of infection with Plasmodium parasites causing malaria in human whole blood specimens. It does not assess parasite densities.

It assists trained competent users and is not intended for lay users:

• in detecting Plasmodium infections

• to differentiate infection by Plasmodium falciparum from the non-P. falciparum species (Plasmodium vivax, Plasmodium malariae, Plasmodium ovale).

note: Malaria RDTs can give positive results after successful anti-malarial treatment. Therefore, the XXX test kit is not recommended for monitoring response to anti-malarial treatment.

Test principle

The following Plasmodium antigens are detected in this test:

• Histidine rich protein 2 specific for P. falciparum (Pf-HRP2)

• Plasmodium lactate dehydrogenase specific for P. falciparum (Pf-pLDH)

• Plasmodium lactate dehydrogenase specific for P. vivax (Pv-pLDH)

• Plasmodium lactate dehydrogenase common to all human Plasmodium species (pan-pLDH)

• Aldolase common to all human Plasmodium species

The cassette contains a test strip pre-coated with capture antibodies.

The sequence of events is as follows:

1. Whole blood is applied to the specimen well (labelled well 1).

2. Next, buffer is applied to the buffer well (labelled well 2).

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3. Migration of the specimen/buffer mixture starts, towards the other end of the cassette.

4. The specimen-buffer mixture passes the conjugate pad, which contains detection antibodies targeting Pf-HRP2, Pf-pLDH, Pv-pLDH, pan-pLDH and/or aldolase antigens. These detection antibodies are conjugated to colloidal gold. If present in the specimen, Plasmodium target antigens bind to this detection antibody-conjugate.

5. The antigen-antibody-conjugate complex migrates further and binds to the capture Plasmodium-specific antibodies present on the test line. These capture antibodies bind to another site (epitope) of the Plasmodium target antigens.

6. The capture antibodies are applied on a narrow section of the test strip: as a result, the antibody-conjugate with the colloidal gold will be concentrated and become visible as a red colored line.

7. The excess of the detection antibody-conjugate that was not bound by the Plasmodium target antigens and the capture antibodies moves further until it binds to a goat anti-mouse control antibody. There, the colloidal gold will create a red colored control line. The visualization of the control line indicates that the migration was successful. It does not confirm the presence of specimen.

The main components of the test are:

• Test strip:

• Detection antibodies conjugated to colloidal gold (in the conjugate pad):

– Mouse monoclonal antibodies (IgG) specific to Pf-HRP2-gold colloid

– Mouse monoclonal antibodies (IgG) specific to pan-pLDH-gold colloid

– (any other combination)

• Capture antibodies (on the nitrocellulose membrane):

– Plasmodium falciparum line: Mouse monoclonal antibodies (IgG) specific to Pf-HRP2

– Plasmodium species (pan) line: Mouse monoclonal antibodies (IgG) specific to pan-pLDH

• Control line (on the nitrocellulose membrane) : Goat anti-mouse polyclonal antibodies (IgG)

• Buffer vial:

• Bovine serum albumin, Triton X-100, Sodium azide (0.095 %)

Intended user

• The test is intended to be performed by a trained user.

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Specimen required

• Capillary whole blood or venous whole blood with the following anticoagulant: EDTA, heparin, oxalate or citrate.

• Time between specimen collection and specimen testing:

• Capillary: immediately

• Venous: immediately. If immediate testing is not possible, store the whole blood specimen at X-X °C for maximum XX hours.

Warnings and precautions

• For in vitro diagnostic use only.

• Read the instructions carefully before performing the test.

• Apply standard biosafety precautions for handling and disposal of potentially infective material.

• Handle all specimens as potentially infectious.

• Wear gloves while handling specimens and performing the test.

• Avoid splashing and aerosol formation.

• Clean up spills thoroughly using an appropriate disinfectant.

• The buffer contains 0.095% sodium azide as a preservative which may be toxic if ingested. When disposed of through a sink, flush with large quantities of water.

• Do not use any other buffer than the buffer supplied within this kit.

• Do not use the kit beyond the expiration date.

• Do not use if the packaging is damaged.

• Do not use any other specimen than whole blood.

• Do not use if the product has been exposed to excessive heat or humidity.

• Perform the test immediately after opening of the cassette packaging.

• Do not re-use the test.

materials

materials provided

• XX cassette package, each containing:

• 1 test device

• 1 packet of desiccant

• X buffer bottle(s) – XX ml

Do not use any other specimen than whole blood

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• XX specimen transfer devices (inverted cup) – x µl

• XX single-use safety-seal lancets

• XX alcohol swabs

• 1 instructions for use

materials required but not provided

• New pair of disposable gloves

• Pen/pencil

• Timer

• Extra lancets and alcohol swabs, if needed (lancet misfires, lancet does not produce sufficient blood volume, alcohol swab is dried out, etc.)

• Biosafety sharps container

• Biohazard waste container (for potentially infectious waste)

• If whole blood is collected by venipuncture, venipuncture blood collection materials and precision pipette, plus tips

Test kit storage and stability

• Store the kit between X–XX °C.

• Do not store the kit in the freezer.

• Protect the kit from humidity.

• The kit has a shelf life of XX months from the date of manufacture. The kit is stable until the expiration date marked on the RDT box and/or the packaging of individual components when stored as specified.

• The buffer is stable for XX months (or until the expiry date) even after opening.

Procedure

before testing

1. Prepare all necessary materials :

• When stored in the refrigerator, bring the kit to room temperature (XX-XX°C) minimum xx minutes before use.

• Prepare the materials (refer to the section on Materials).

2. Check the expiration date of the kit (including buffer).

If expired, do not use but take another unexpired kit.

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3. Check that the cassette packaging is not damaged.

If damaged, discard the test and use another test.

4. Open the cassette packaging and check the desiccant (if provided).

If there is a humidity indicator and it shows saturation (color changed from orange to green), throw away the cassette and take another cassette packaging.

If the color of the desiccant does not show a change, you can use the test.

Throw away the desiccant in the non-sharps (non-infectious) disposal container.

5. Take the cassette and place it on a flat surface, horizontally.

You see:

• a result window (marked with C, pan, Pf )

• a circle well marked “1” (for specimen)

• a square well “2” (for buffer)

6. Write the patient name or identifier on the cassette.

7. Put on gloves. Use new gloves for each patient.

8. Add if needed additional instructions on how to open the buffer bottle correctly – for instance, how to pierce the nozzle.

Test procedure (see reference Generic RDT training manual in Annex 2)

Capillary whole blood from finger prick

1. Wear gloves.

2. Choose a finger for the finger prick:

• Do not choose a finger that is swollen, bruised or scarred.

• Preferably choose the 3rd or 4th finger of the hand the patient does not use to write. Alternatively choose the heel or the earlobe for neonates.

3. Open the packaging of the alcohol swab. Take out the alcohol swab. Do not throw away the empty packaging (wrapper) but keep it aside.

4. Wipe the complete fingertip with the alcohol swab.

Wait until the finger has completely dried (minimum 30 seconds).

5. Place the alcohol swab in the wrapper and set it aside (you will use it again to stop the bleeding after you collected the patient’s blood).

6. Take the safety-seal lancet.

7. Detach the cap of the lancet.

Perform the test immediately after opening of the cassette packaging.

Do not re-use the test.

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Puncture the side of the pulp (ball) of the finger with the lancet, perpendicular to the lines of the fingerprint.

Dispose the lancet immediately into the sharps box.

8. Make sure a well-formed drop of blood is present.

9. If there is no well-formed drop of blood, repeat the finger prick using a new lancet and choose a different puncture site.

10. Take the inverted cup and collect 5 µl of blood by dipping the circular end of the inverted cup into the whole blood drop.

11. Place the circular end of the inverted cup in the circle well (marked “1”) so that it touches the strip (pad at the bottom of the well).

Press down lightly to transfer all the blood to the strip.

Put the used inverted cup into the non-sharps disposal container for potentially infectious waste.

12. Take the alcohol swab you put aside (step 5).

Ask the patient to press it to the finger prick to stop the bleeding.

After use, put the alcohol swab into the non-sharps disposal container for potentially infectious waste.

13. Take the buffer bottle.

Hold the open buffer bottle vertically above the square well (marked “2”).

In a vertical position, squeeze the buffer bottle gently and apply exactly X drops into the square well (marked “2”).

14. Remove your gloves and discard them into the non-sharps disposal container for potentially infectious waste.

15. Write the time on the cassette or set a countdown timer to the required reading time.

16. Read test results after a minimum of xx minutes but no later than xx minutes. Use a good light source when reading the test results.

Venous whole blood from venipuncture

1. Wear gloves.

2. Collect blood by standard venipuncture procedure into a tube containing the correct anticoagulant (EDTA, heparin, oxalate or citrate).

3. Mix the tube gently.

Avoid the tip or center of the finger.

Do not use water or any other buffer than the buffer supplied within this kit.

Hold the buffer bottle vertically – this ensures that the drops contain the correct volume of buffer.

Do not read results after xx minutes

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4. Transfer 5 µl of whole blood in the circle well (marked “1”) of the cassette using a precision pipette.

5. Perform steps 12–16 of the previous section (“Capillary whole blood from finger prick”).

Interpretation of the test result

1. After xx but no later than xx minutes: compare the test lines with the presentation in the table below.

2. Where possible, have the results confirmed by a second reader within this time frame.

3. Line intensities may vary from faint to strong intensity.

Consider also a faint test line as a positive result.

4. Record the test results as noted in the table below.

5. Consult the national guidelines for malaria case management to complement the table below.

lIneS THAT yOU See PIcTURe/DRAWIng RecORD THe FOllOWIng ReSUlT TAke THe FOllOWIng AcTIOn

nO line at ‘C’ (= control)

Put figures of all possible line combinations

Invalid

Take a new cassette packaging and repeat the test

Line at ‘C’ and nO other line

Put figures of all possible line combinations

Negative

Line at ‘C’ AND at ‘Pf’

Put figures of all possible line combinations

Positive for Plasmodium falciparum

Line at ‘C’, at ‘Pf’ AND at ‘pan’

Put figures of all possible line combinations

Positive for Plasmodium falciparum (or rarely, a mixed infection with P. vivax, P. ovale and/or P. malariae)

Line at ‘C’ AND at ‘pan’

Put figures of all possible line combinations

Positive for non-falciparum malaria: P. vivax, P. ovale or P. malariae (or, rarely, a mixed infection with these species)

Other line combinations

Put figures of all possible line combinations

Write down the result

Note: the XXX test kit does not differentiate between P. vivax, P. ovale and P. malariae

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limitations of the product, causes of false-negative and false-positive results

ALL mALARIA RDTS HAVe LImITATIOnS In COmmOn

They may occur despite correct storage and test procedure and are related to:

• the general design of the RDT (detection limit, prozone, no quantification)

• the antigen (HRP-2 deletions, HRP-2 persistence after treatment)

• the operator (overlooking faint test lines)

• the species (in general: sensitivity for P. falciparum > P. vivax > P. ovale/malariae).

Other limitations related to the end-user and the conditions during transport and storage. Some limitations are listed below – unless they do not apply for the RDT product under consideration, they should be mentioned.

See also reference “Universal access to malaria diagnostic testing: an operational manual. World Health Organization 2011

malaria RDT have limitations

They may be the cause of:

• false-negative results (no test lines but the patient has malaria)

• false-positive results (test lines visible but the patient does not have malaria)

• invalid test result (no control line and/or incomplete clearing of background)

Sensitivity for detecting malaria is lower in the case of P. ovale and P. malariae.

False-negative results can occur in the following conditions:

• very low antigen concentrations/parasite densities, for instance < 100 parasites/µl. Note that most clinical cases have higher parasite densities.

• very high parasite densities (very exceptional, prozone or high-hook effect) for the HRP-2 antigen

• deletions in the HRP-2 gene resulting in no production of the HRP-2 antigen (of relevance only for mRDTs that detect this antigen, and only significantly present in the Peruvian Amazon)

• high fraction of insterstitial fluid due to “milking” of fingertip

False-positive results can occur – amongst others – in the following conditions:

• rheumatoid factors, antinuclear antibodies, human anti-mouse antibodies

• viral infection (such as hepatitis B or hepatitis C, dengue)

• parasitic infection (such as schistosomiasis and trypanosomiasis)

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Invalid tests and problems of background clearing may occur:

• In lipaemic and icteric specimens

Note: The presence of the control line only means that migration of added liquid occurred. It does not guarantee that:

• the correct specimen has been used

• the specimen has been applied correctly

• the specimen and test have been correctly stored

• the test procedure was followed correctly

Performance specifications

ReCOmmenDATIOnS fOR DIAGnOSTIC PeRfORmAnCe SPeCIfICATIOnS

• State at least the following specifications and information:

1. Analytical sensitivity (detection limit)

2. Analytical specificity (rheumatoid factor, antinuclear antibody, other infections and influence of lipemic/icteric/hemolyzed specimens)

3. Diagnostic sensitivity

4. Diagnostic specificity

5. Repeatability (test-related, laboratory conditions)

6. Reproducibility (operator-related, field conditions)

• Give enough detail and oversight:

• the numbers of specimens used (and if applicable, confidence intervals)

• the different specifications for P. falciparum, P. vivax, P. ovale and P. malariae

• type of study and setting, geographic place, study period and population

(e.g. laboratory study on stored specimens, clinical study, field study)

• parasite densities and reference methods when appropriate

• present results in a clear way (e.g. table)

• refer to type of study (in-house study, external study, study report or published in scientific literature)/include a bibliography/reference list

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Product-related publications

• Test kit evaluations (product related studies)

general publications

• Biosafety and sampling

• WHO reference documents

• Description of problems on RDT implementation, end-user errors

contact of manufacturer

Name of the legal manufacturer

Full physical address of the manufacturing site (street, city, zip code, country)

Contact for technical assistance ( telephone/fax number, email address)

version number of IFU and date of issue

XXXXX – Language (En, Esp, Fr, etc.) – YYYY/MM/DD

Symbol key

ReCOmmenDATIOnS fOR BIBLIOGRAPHy

• Select relevant publications in a practical and product-oriented way.

• In Annex 3, some references for relevant topics are provided.

bibliogaphy

ReCOmmenDATIOnS fOR SymBOL Key

• Only use internationally recognized symbols.

• In Annex 4, an example of a symbol key is provided.

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Annex 1: ReFeRenceS FOR ReADAbIlITy

The following websites explain how to assess and calculate readability – the tool is primarily developed for English texts.

• http://www.online-utility.org/english/readability_test_and_improve.jsp

• http://www.mang.canterbury.ac.nz/writing_guide/writing/flesch.shtml

Readility can also be assessed in a Microscoft Word document:

1. Click the File tab, and then click Options

2. Click Proofing

3. Under “When correcting spelling and grammar in Word”, make sure the “Check grammar with spelling check” box is selected

4. Select “Show readability statistics” and click on “OK”

After you enable this feature, open a file that you want to check, and check the spelling. When Outlook or Word finishes checking the spelling and grammar, it displays information about the reading level of the document.

Annex 2: ReSOURceS

generic and product specific job aids for Pf –only and combination RDT

Refer to the following websites:

• Generic: http://who.int/malaria/areas/diagnosis/rapid-diagnostic-tests/job-aids/

• Product specific: https://www.finddx.org/implementation-resources/

generic RDT training manual

How to use a rapid diagnostic test (RDT): a guide for training at a village and clinic level 2009.

Universal access to malaria diagnostic testing: an operational manual. World Health Organization 2011

• http://www.who.int/malaria/publications/atoz/9789241502092/en/

Annexes

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Annex 3: exAmPle OF bIblIOgAPHy

Product-related publications

• Test evaluations (product related study)

general publications

• Biosafety and sampling

1. Clinical and Laboratory Standards Institute. Procedures and devices for the collection of diagnostic capillary blood specimens; approved standard, fifth edition. CLSI H04-A6, Vol. 28, No. 25, 2008.

2. Clinical and Laboratory Standards Institute. Procedures for the collection of diagnostic blood specimens by venipuncture; approved standard, sixth edition. CLSI H03-A6, Vol. 27, No. 26, 2007

3. World Health Organization: Laboratory biosafety manual, third edition. Geneva: WHO; 2004. http://www.who.int/csr/resources/publications/biosafety/Biosafety7.pdf

• WHO reference documents

1. World Health Organization: Good practices for selecting and procuring rapid diagnostic tests for malaria. Geneva: WHO; 2011. http://www.who.int/malaria/publications/atoz/9789241501125/en/

2. World Health Organization: Guidelines for the treatment of malaria. Third edition. Geneva: WHO; 2015. http://www.who.int/malaria/publications/atoz/9789241549127/en/

3. World Health Organization: Malaria Rapid Diagnostic Test Performance; Results of WHO product testing of malaria RDTs: Rounds 1–7 (2008–2016). Geneva: WHO; 2017. http://apps.who.int/iris/bitstream/10665/258597/1/9789241512916-eng.pdf

4. World Health Organization: Malaria RDT job-aids and training manuals. http://www.who.int/malaria/areas/diagnosis/rapid-diagnostic-tests/job-aids/en/

5. World Health Organization: Management of severe malaria – A practical handbook. Third edition. Geneva: WHO; 2013. http://www.who.int/malaria/publications/atoz/9789241548526/en/

6. World Health Organization: Transporting, storing and handling malaria rapid diagnostic tests at central and peripheral storage facilities. Geneva: WHO; 2009. http://www.who.int/malaria/publications/atoz/malaria_rdt_central_2009.pdf

7. World Health Organization: Universal access to malaria diagnostic testing. An operational manual. Geneva: WHO; 2011. http://www.who.int/malaria/publications/atoz/9789241502092/en/

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• Description of problems on RDT implementation, end-user errors (included prozone, buffer substitution, false positive,…)

1. Gamboa D, Ho M, Bendezu J, Torres K, Chiodini P, Barnwell J, Incardona S, Perkins M, Bell D, McCarthy J, Cheng Q: A large proportion of P. falciparum isolates in the Amazon region of Peru lack pfhrp2 and pfhrp3: implications for malaria rapid diagnostic tests. PLoS One 2010, 5:e8091. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008091

2. Gillet P, Scheirlinck A, Stokx J, De Weggeleire A, Chauque H, Canhanga O, Tadeu B, Mosse C, Tiago A, Mabunda S, Bruggeman C, Bottieau E, Jacobs J: Prozone in malaria rapid diagnostics tests: how many cases are missed? Malar J 2011, 10:166. http://www.malariajournal.com/content/10/1/166

3. Gillet P, Mori M, Van Den Ende J, Jacobs J: Buffer substitution in malaria rapid diagnostic tests causes false-positive results. Malar J 2010, 9:215 http://www.malariajournal.com/content/9/1/215

4. Maltha J, Gillet P, Cnops L, Van Den Ende J, Van Esbroeck M, Jacobs J: Malaria rapid diagnostic tests: Plasmodium falciparum infections with high parasite densities may generate false positive Plasmodium vivax pLDH lines. Malar J 2010, 9:198. http://www.malariajournal.com/content/9/1/198

5. Maltha J., Gillet P., Jacobs J. Review: Malaria rapid diagnostic tests in endemic settings. Clin Microbiol Infect 2013; 19: 399–407. http://onlinelibrary.wiley.com/doi/10.1111/1469-0691.12151/pdf

6. Maltha J., Gillet P., Jacobs J. Review: Malaria rapid diagnostic tests in travel medicine. Clin Microbiol Infect 2013; 19: 408–415. http://onlinelibrary.wiley.com/doi/10.1111/1469-0691.12152/pdf

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Annex 4: exAmPle OF SymbOl legenD

SymbOl exPlAnATIOn SymbOl exPlAnATIOn

In vitro diagnostic medical device Product code

Σ Content sufficient for < n > tests

Consult instructions for use

Lot number Use by YYYY-MM-(DD)

Date of manufacture YYYY-MM-(DD) Manufacturer

Do not reuse Do not use if packaging is damaged

Temperature limitation Lower limit of temperature

Sterile Upper limit of temperature

Irritant Biological risk

Keep away from sunlight Keep dry