WHO/BS/2013.2230 ENGLISH ONLY EXPERT … · They play a vital role in facilitating the transfer of...

WHO/BS/2013.2230

ENGLISH ONLY

EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION

Geneva, 21 to 25 October 2013

New projects requests and updates for development of WHO reference

preparations for blood products and in vitro diagnostic devices

Document prepared by the WHO Secretariat, based on inputs from WHO

Collaborating Centres supporting biological standardization activities

NOTE:

This document has been prepared for the purpose of inviting comments and suggestions on the

proposals contained therein, which will then be considered by the Expert Committee on Biological

Standardization (ECBS). Comments should be submitted electronically to the Responsible Officer:

Dr Ana Padilla at email: [email protected], with a copy to Dr David Wood at

email: [email protected]

The outcome of the deliberations of the Expert Committee will be published in the WHO

Technical Report Series.

© World Health Organization 2013

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WHO/BS/2013.2230

Introduction

The provision of global measurement standards is an important normative activity of WHO.

Biological reference preparations that are accepted internationally enable the efficacy, quality, purity

and safety of very many biological medicines, used in the prevention, treatment or diagnosis of

disease or conditions, to be stated in a common language worldwide. International biological

reference standards support the use of many biological and immunological assays for the quality

control of a wide range of biologicals including vaccines and blood-derived products of traditional

types as well as those derived from modern biotechnological approaches. They also have important

applications in the standardization of materials and approaches used in medical diagnostics such as

diagnosing disease, monitoring therapy, blood safety, and public health applications (e.g. monitoring

immune status, screening for disease or susceptibility) or otherwise characterizing biological

material from individuals.

WHO biological reference standards are widely used in the development, evaluation,

standardization and control of products by manufacturers, blood establishments, regulatory

authorities and in biological research. They play a vital role in facilitating the transfer of laboratory

science into worldwide clinical practice and the development of safe and effective biologicals.

The timely development of new reference standards and reference panels is critically

important to harness scientific developments for new biologicals. At the same time, the active

management of the existing inventory of reference preparations requires a carefully planned

programme of work to replace established materials before the stock of containers, which comprises

the standard, is exhausted.

Considerations for assignment of priorities to development of WHO International Biological

Measurement Standards or Reference Reagents have been published (WHO TRS 932, Annex 2,

Appendix 1, 2005). These considerations are used as guiding principles by the Secretariat and the

WHO Collaborating Centres to develop a proposed programme of future work. To facilitate and to

improve transparency in the priority setting process, a simple tool has been developed which

describes the salient features of each new project proposal.

This document provides a means for the Committee and other stakeholders to review and

comment on new proposals that are under consideration. The proposals in this document cover

requests to initiate new projects in the area of blood products and related biologicals, including in

vitro diagnostic devices.

WHO/BS/2013.2230

Blood products and in vitro diagnostic devices

Proposed projects for endorsement Proposed WHO 5th International Standard for Hepatitis C Virus RNA

for NAT assays ……………………………………………………………………… ........... 4

Proposed WHO 1st International Standard for Anti-Cytomegalovirus IgG …… ............. 6

Malaria Antibody reference panel………………………………………………………… .... 8

Review of the WHO Catalogue: Proposals for discontinuation or replacement………. 10

Sensitivity standards for cancer gene mutation detection assays ………………………15

Proposed WHO 1st Reference Reagent for High and low titre anti-A and anti-B

in serum/plasma ....................................................................................................... 19

Update on WHO 1st IS for Rubella Immunoglobulin ……………………………………. . 21

Proposed WHO 2nd International Standard for Anti-tetanus Immunoglobulin………. .. 23

Assignment of a FIX antigen value to the WHO 4th IS for FII, VII, IX, X plasma

and to the proposed WHO 5th IS for FIX concentrate ……………………………… ... 25

Proposed WHO 1st International Standard for Activated

Coagulation Factor XI (FXIa)…………………………………………………………...... 27

Proposed WHO 2nd International Standard for Ancrod ……………………………… .... 29

Proposed WHO 4th International Standard for Streptokinase ……………………… ..... 31

Addendum 1 : Meeting report on WHO Consultation on Commutability of WHO Biological Reference Preparations for In Vitro Detection of Infectious Markers, WHO Headquarters, Geneva, 18-19 April, 2013 Addendum 2: Final report on the evaluation of the WHO Reference Reagent for Activated Blood Coagulation Factor XI (FXIa), Human

WHO/BS/2013.2230

Proposal (title) Proposed 5th WHO International Standard for Hepatitis C Virus RNA for Nucleic Acid Amplification Techniques

Proposer (name of Institution)

NIBSC Principal contact Jacqueline Fryer

Rationale The WHO International Standard for HCV RNA is used in the calibration of secondary reference materials and in the validation of HCV NAT assays used in the safety testing of blood and blood products. HCV NAT is also widely used in the management of HCV infection, particularly in the diagnosis of disease and monitoring the response to antiviral therapies. Despite there being sufficient stock of the 4th HCV IS (06/102) for 5 years, there have been some concerns over the stability of the material at elevated temperatures (WHO/BS/2011.2173). It was decided at the XXIII meeting of SoGAT Blood Virology group (April 2012) to bring forward the replacement of the HCV WHO International Standard. Further freeze drying trials are required to determine the stability of HCV antibody-positive vs. antibody-negative preparations, prior to replacement.

Anticipated uses and users

Used to calibrate secondary reference materials and in the validation of HCV NAT assays. Anticipated users are; blood transfusion centres, clinical laboratories, control authorities, and IVD manufacturers.

Source/type of materials Candidate materials will comprise a genotype 1a, HCV RNA positive plasma sample. This will be diluted in pooled human plasma to a concentration of 105 IU/mL and filled in 0.5 mL volumes. Freeze drying trials will be performed in order to investigate the relative stability of HCV antibody-positive vs. HCV antibody-negative preparations. The 1st and 2nd HCV International Standards comprised HCV antibody-positive plasma, meanwhile, the 3rd and 4th HCV International Standards comprised HCV antibody-positive plasma. Issues with stability of the 3rd and 4th HCV International Standards at elevated temperatures were noted recently (WHO/BS/2011.2173). Meanwhile, the 1st and 2nd HCV International Standards demonstrated long-term stability.

Outline of proposed collaborative study

The collaborative study will involve 15-20 laboratories worldwide (incl. laboratories outside Europe and the US), performing a range of HCV NAT-based methods, and representing IVD manufacturers, blood product manufacturers, blood transfusion centres, clinical and reference laboratories, and control authorities.

Study samples; candidate replacement standard, 4th HCV International Standard, 1st or 2nd HCV International Standard

Issues raised by the proposal

None

Action required

ECBS to endorse proposal

WHO/BS/2013.2230

Proposer's project reference

VIR00026 Date proposed: October 2013

CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)

Approval status of medicine or in vitro diagnostic method

NAT is the recommended method for the detection of HCV RNA in human plasma.

Number of products or methods

A range of NAT-based methods are available for the detection and quantification of HCV RNA, including both commercial and laboratory-developed assays.

Public health importance

The need to standardize NAT-based assays for HCV is ongoing. NAT is routinely used to manage HCV infections and there remains a major risk of transfusion-transmitted infection due window-period donations.

Global importance

Over 200 million people are infected with HCV worldwide with an overall incidence of around 3.3% of the world's population.

Global need from regulatory & scientific considerations

NAT testing of blood and blood products for HCV RNA is mandated in many parts of the world.

ECBS outcome

WHO/BS/2013.2230

Proposal: Proposed 1st International anti-HCMV IgG Standard

Proposer: PEI Principal Contact Nina Wissel

Dr. Heinrich Scheiblauer, Dr. Sigrid Nick

Rationale: Human Cytomegalovirus (HCMV) is spread worldwide with a prevalence of

40 to 100%. The virus causes relatively mild and asymptomatic infections

in immunocompetent persons, but can cause congenital disease and

severe complications with immunodeficiency, e.g. immunological

immaturity, acquired immunodeficiency or immunosuppression. In addition,

avoidance of blood products from primarily seropositive HCMV donors is

especially helpful to avoid transfusion transmitted HCMV. Therefore

diagnostics of HCMV-specific IgG and IgM antibodies and IgG avidity play

a major role in prenatal care, blood transfusions and especially

transplantation medicine.

Current diagnostic HCMV assays differ considerably in their sensitivity and

there is no international reference material available.

The project was presented in the Collaborating Center´s meeting 2013.

Anticipated Uses

and Users:

If possible a unitage will be assigned to the material. Therefore the

analytical sensitivity of anti-HCMV IgG assays can be determined. It may

also serve for calibration of secondary standards by manufacturers of

diagnostic kits, for quality control by competent authorities and by users. A

standard may also aid to assess anti-HCMV weak positive in the

seroconversion phase of primary and reactivated HCMV infection.

Source/Type of

Materials:

Three anti-HCMV-IgG positive human plasma specimens (each 700ml) out

of 53 specimens in total were selected by a feasibility study at PEI. The

specimens were tested with 5 different anti-HCMV IgG test kits and 5

different anti-HCMV IgM tests comprising various methods and test formats

(ELISA, ChLIA, MEIA, ECLIA and immunoblot; qualitative and quantitative;

coated with virus lysate or recombinant protein/peptides; sandwich and

indirect format). The following results were obtained:

Positive for anti-HCMV-IgG in dilution with an endpoint titer up to

1:1024 in the most sensitive assays.

High avidity for anti-HCMV-IgG

In the immunoblot the IgG samples reacted with IE1, p150, CM2,

p65, gB1 and gB2

All three samples were anti-HCMV IgM negative to avoid interference

with IgG.

After pooling of the three samples 2000 mL will be available.

Outline of

proposed

collaborative

study

Suitability and commutability of the material will be assessed in an

international collaborative study involving a range of anti-HCMV IgG and

IgM positive samples and a variety of different anti-HCMV IgG test kits and

test formats.

WHO/BS/2013.2230

Issues raised by

the proposal:

none

Actions required: Once the proposal is accepted by the ECBS a collaborative study will be

initiated to demonstrate suitability of the preparation.

Ref: Date proposed: 30/06/2013

ECBS Outcome: N/A

WHO/BS/2013.2230

Proposal Malaria Antibody Reference Panel

Priority High: 1. There is no FDA-approved antibody detection test for malaria. 2. Malaria Antibody Reference panel is required to support the

development of antibody/antigen test kits for malaria and bring uniformity in antibody assays used for donor screening for malaria and epidemiology and vaccine studies.

WHO CC Principal Contact Sanjai Kumar

Date proposed ECBS

Rationale Currently no Malaria Antibody Reference panel is available for use by researchers or test kit developers. This has hampered the efforts to harmonize the antibody assays for laboratories across the world and development of commercially available antibody based test kits for malaria. In particular, there is an urgent need for antibody-based assays for use in blood donor screening. Transfusion-transmitted malaria (TTM) is a serious risk of blood transfusion around the world. In the absence of a licensed blood-screening test in the U.S., each year approximately 1 case of TTM is reported and around 150,000 donors are deferred based on their history of travel or prior residence in the malaria endemic regions. Only a very small fraction of these deferred donors have actually been exposed to malaria parasites. An antibody-based donor screening test for malaria has the prospect to further reduce the number of TTM cases and allow the donor reentry after a significantly shortened deferral period. Specifically, availability of a Malaria Antibody Reference panel will be of great benefit in evaluating the efficacy of antibody based tests under development and as lot-release panel for future licensed tests. In addition, Malaria Antibody panel will bring uniformity in determining antibody responses in multicenter vaccine studies and in measuring malaria transmission in endemic areas.


1. The biggest users of a Malaria Antibody Reference Panel will be the kit manufacturers of diagnostics and blood donor screening tests for malaria.

2. Lot-release testing for licensed tests for malaria diagnosis and donor screening.

3. Additional uses of Malaria Antibody Reference panel include the development of validated enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent antibody (IFAT) to measure vaccine-induced responses in multi-center malaria vaccine trials and in epidemiological studies to measure the intensity of malaria transmission.

Source/type of materials

Individual or pooled serum/plasma samples from humans infected with Plasmodium falciparum parasites.

WHO/BS/2013.2230

Stability Liquid or lyophilized serum/plasma samples should be stable under refrigeration for several years.


1. Collection of serum samples from adults infected with Plasmodium falciparum parasites from malaria endemic areas.

2. Confirm the Plasmodium species-specificity and antibody levels in IFAT against asexual stage P. falciparum parasites.

3. Selection of serum samples possessing the highest levels of antibodies against P. falciparum malaria.

4. Generation of at least five panel members that incorporate the high, medium, low and non-reactive antibody levels and serum sample from malaria negative individual in IFAT.

5. Testing of Malaria Antibody Reference panel by participating laboratories.

6. Testing of pooled samples under different storage (temperature and duration) and shipping conditions.

Issues raised by proposal

1. Use of recombinant P. falciparum antigens in reference panel. The availability and cost of recombinant proteins is an issue but deserves further discussion.

2. Participation of international laboratories with expertise in malaria serology.

Action required ECBS to endorse proposal

WHO/BS/2013.2230

Proposals for discontinuation or replacement of Biological Reference

Preparations for Blood Products and related Biologicals.

Report of the 4

th Meeting of WHO Collaborating Centres to support the development of Biological

Reference Preparations for blood products and in vitro diagnostic devices

16-17 April 2013

The current list of WHO biological reference preparations comprises a total of 126 blood products

and related biologicals, including international standards, reference panels and reference reagents.

These products are grouped below into five major categories according to the area in which they are

used and the type of source material (Figure 1).

The majority of these 126 preparations (~70%) were established in the past 12 years (Figure 2) and

include 60% new standards and 40% replacements. A remarkable increase in the number of

standards has been observed during this period of time within the categories of blood safety,

infectious markers and hemostasis/thrombosis, which is likely to reflect the improved regulation on

quality and safety of blood products.

Blood Products and related Biologicals

Figure 2. Overall information of the WHO biological reference preparations (international standards,

reference panels and reference reagents) established by the Expert Committee on Biological

Standardization for blood products and in vitro diagnostics within three different time periods.

The current list also includes a number of standards (n=19) that have been established before the

1990’s and never replaced since then (Table 1). Around 50% of these preparations are still in

relatively high demand (≥50 requests/year), while ten preparations have been identified as materials

WHO/BS/2013.2230

of low interest or limited information available. A review of the latter preparations has been carried

out in order to evaluate the potential need for their discontinuation or replacement with a new

standard.

The following criteria have been considered for this evaluation: i) scientific information available

about the nature of the standard and the need for international harmonization of assays; ii) impact of

the standard on public health and in particular on clinical management and on evaluation of products

activity; and iii) use of the standard in terms of potential impact if discontinued or replaced.

In the following paragraphs a general overview of these 10 preparations is provided with the

purpose to support further discussions on their potential discontinuation and, whether considered

appropriate, replacement with a new standard.

Table 1 List of WHO reference preparations established before the ‘90s.

*Data provided by NIBSC

Anti-c incomplete, anti-E complete and anti-C complete blood typing sera. Anti-c incomplete, anti-E complete and anti-C complete blood typing sera were established in 1976,

1983 and 1984 respectively as first WHO International Standards for the detection of the relative Rh

antigens in red blood cells (WHO/BS/83.1424). Antibodies against these antigens are responsible

for most of the haemolytic transfusion reactions as well as for the haemolytic disease of the newborn

[1]. It should be noted that current commercial test reagents for Rh phenotype detection are

monoclonal preparations, which may partially explain why these WHO standards are in relatively

low demand. Due to their clinical significance in the blood safety area worldwide, it is considered

appropriate to discuss whether a discontinuation and possibly a replacement with minimum potency

reagents as it was done for anti-A, anti-B and anti-D (anti-Rho) blood grouping reagents would be

required.

WHO/BS/2013.2230

Anti-nuclear factor (homogenous) serum, Anti-nuclear ribonucleoprotein serum, Anti-smooth

muscle (anti-actin) serum

Generally, high titres of anti-nuclear factor, anti-nuclear ribonucleoprotein and anti-smooth muscle

antibodies have been associated with a number of autoimmune conditions, including systemic lupus

erythematosus (SLE), mixed connective tissue disorders (MCTD) (e.g. rheumatoid arthritis and SLE)

and autoimmune liver diseases (AiLD), respectively. However it is widely recognized that test

results for these autoantibodies alone are insufficient to establish the diagnosis of the disease and

should be interpreted in the clinical context. A brief overview of these three preparations is

presented below, however it should be referred to the relevant references for further information

about these autoantibodies and their utility in disease clinical management.

The first WHO International Preparation for Anti-nuclear factor (ANF) was established in 1970 and

it was prepared from a pool of sera obtained from 6 patients with SLE (WHO/BS/70.1005). In

particular, ANF are autoantibodies directed against self-antigens of the cell nucleus which are

developed in patients with systemic autoimmune rheumatic diseases (SARD). Common detection

methods for these antinuclear antibodies (ANA) are based on indirect immunofluorescence

techniques (results reported in titers and patterns of immunofluorescent staining) or enzyme linked

immunosorbent assays (ELISA). In general, a positive ANA result has a poor predictive value

because antinuclear antibodies can be also developed in patients with non-rheumatic diseases as well

as in normal, healthy people [2, 3]. Conversely, the high negative predictive value of this test is

useful to exclude the presence of an ANA-associated disease.

The first WHO international reference reagent for Anti-nuclear ribonucleoprotein (Anti-RNP),

established in 1983, was prepared from a pool of sera from a patient with Raynaud’s disease

(WHO/BS/83.1390). In particular, anti-RNP are a subtype of ANA that have been associated with

MCTD, with a greater prevalence observed in patients with Raynaud’s phenomenon. Anti-RNP

antibodies can be detected using different assays, including counter-immunoelectrophoresis (CIE),

indirect immunofluorescence, blotting, commercial ELISA kits and line immunoassays [4]. As for

anti-nuclear factor antibodies, anti-RNP antibodies are consistently detected in MCTD but they have

a low diagnostic value since patients with high levels of these autoantibodies may show no clinical

manifestations of an autoimmune disease.

Established in 1983, the first WHO International Reference Reagent for Anti-smooth muscle was

prepared from the serum of a healthy donor in whom there was no clinical evidence for the presence

of the antibody (WHO/BS/83.1390). This material was proposed as specificity control for pattern

recognition of these autoantibodies by indirect immunofluorescence. Generally, the presence of high

titres of anti-smooth muscle antibodies (anti-SMA) is indicative of AiLD (e.g. autoimmune hepatitis

type 1 and 2, and primary biliary cirrhosis) [5]. However, as for the other autoantibodies, detection

of high titers in the absence of any other clinical and laboratory feature is insufficient to make a

definitive diagnosis. In 2004, the Committee for Autoimmune Serology of the International

Autoimmune Hepatitis Group (IAIHG) defined their own guidelines for serology testing of

autoimmune hepatitis-associated antibodies, including recommendations for substrate preparation,

optimal sample dilution, selection of controls etc. [6].

In conclusion, it is recommended to consider proposals for the discontinuation or further testing of

these three preparations because of: i) very limited information provided in WHO documents on

WHO/BS/2013.2230

these materials as well as at the WHO Collaborating Centre; ii) methods for autoantibodies testing

seem to have evolved considerably since the establishment of these standards more than 30 years

ago and iii) the limited clinical decision making impact of autoantibodies tests.

Human serum complement components C1q, C4, C5 factor B and total complement CH50

The first WHO International Reference Preparation for these four complement components was

established in 1980 from a pool of 82 plasma samples (WHO/BS/80.1281) [7]. In the collaborative

study, antigenic (for C1q, C4, C5 and factor B) and functional (for CH50) activities were measured

using single radial immunodiffusion and nephelometry assays, and haemolytic, respectively. In

general, complement activity of individual component levels are measured in patients with

suspected or established clinical conditions characterized by increased or decreased complement

activation, including a number of immunodeficiency, inflammatory or autoimmune diseases [8]. At

ECBS in 2007, it was suggested to monitor usage of this preparation before making a final decision

on its discontinuation. It was also reported that there is limited available information on this

standard. It is therefore suggested to consider a proposal for the discontinuation of this preparation.

β-thromboglobulin (β-TG) and Platelet factor 4 (PF4)

Established in 1984, the first WHO International Standards for β-TG and PF4 were prepared from

purified plasma proteins (WHO/BS/84.1455). These platelet-specific proteins are stored in the

alpha-granules and secreted in the plasma upon platelet activation. Hence, increased plasma levels

of β-TG and PF4 have been used as a marker of abnormal platelet activation, which plays an

important role in a number of thrombotic disorders [9]. Common techniques for serological

measurement of β-TG and PF4 include radioimmunoassay (as described in the original collaborative

study) and ELISA. Nevertheless, some issues related to the measurement of these proteins should be

considered, including the unavailability of their true normal values, which can vary considerably and

independently under different conditions. It should also be noted that commercial ELISA kits for β-

TG and PF4 are currently available which provide protein standards containing recombinant forms

(e.g. human PF4/CXCL4 ELISA kit from Sigma).

It is, therefore, proposed to review the utility of these standards and consider whether a proposal for

their replacement may be required. NIBSC has been requested to provide further information about

these standards.

Anti-echinococcus serum

The first WHO International Reference Reagent for Anti-Echinococcus was established in 1975

(WHO/BS/75.1106). This preparation, which is a pool of four sera obtained from confirmed cases of

Echinococcosis, was intended to be used in the serological detection of this parasitic infection,

which is caused by the larval stages of the dog tapeworm E. granulosus and characterized by growth

of fluid-filled cysts mainly in lungs and liver [10]. The disease is endemic in many rural areas

worldwide, where it is transmitted in a cycle between dogs (definitive host) and livestock (mainly

sheep, intermediate host). Disease diagnosis is based primarily on imaging techniques; in addition

serological testing for detection of specific IgG antibodies can be performed to confirm clinical

diagnosis results, in suspect cases or in people enrolled in screening programmes. Test methods

described in the original collaborative study include latex agglutination, indirect haemagglutination,

WHO/BS/2013.2230

complement fixation, bentonite flocculation, and immunoelectophoresis. Yet, most of these methods

have been largely superseded by more specific and sensitive techniques such as ELISA and

immunoblotting.

Dr Simone Magnino, WHO Control of Neglected Tropical Diseases (NTD), has provided the

following information from experts in this field:

Serodiagnostics has moved on greatly since this standard was produced, and today a standard

reference serum needs to be qualitatively characterized with regard to species- and also genotype-

specificity. In short, experts are of the opinion that this reagent is of no use due to its poor

characterization. It is considered not useful for standardization purposes.

Request to the Committee: Based on the above information, the Committee is requested to provide advice in relation to the

proposals for review, discontinuation or replacement when appropriate.

References

1. RhD haemolytic disease of the fetus and the newborn. Blood Rev. 2000 Mar; 14(1):44-61.

Urbaniak SJ, Greiss MA.

2. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies

to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med. 2000 Jan;

124(1):71-81. Kavanaugh A at al.

3. The clinical utility of a positive antinuclear antibody test result. Am J Med. 2013 Apr;

126(4):342-8. doi: 10.1016/j.amjmed.2012.09.014. Epub 2013 Feb 8. Abeles AM, Abeles M.

4. Anti-Sm and anti-RNP antibodies. Autoimmunity. 2005 Feb; 38(1):47-54. Migliorini P. et al.

5. Autoimmune liver serology: current diagnostic and clinical challenges.World J Gastroenterol.

2008 Jun 7;14(21):3374-87. Bogdanos DP at al.

6. Liver autoimmune serology: a consensus statement from the committee for autoimmune

serology of the International Autoimmune Hepatitis Group. J Hepatol. 2004 Oct; 41(4):677-83.

Vergani D at al.

7. Progress towards international reference standards for human serum proteins. J Biol Stand.

1978; 6(2):133-58. Reimer CB at al.

8. Complement in health and disease. Adv Drug Deliv Rev. 2011 Sep 16; 63(12):965-75. doi:

10.1016/j.addr.2011.06.005. Epub 2011 Jun 16. Carroll MV, Sim RB.

9. Platelet activation: assessment and quantification. Eur Heart J. 2001 Sep; 22(17):1561-71.

Kamath S at al.

10. Prevention and control of cystic echinococcosis. Lancet Infect Dis. 2007 Jun; 7(6):385-94. Craig

PS at al.

WHO/BS/2013.2230

Proposal (title) Sensitivity standards for cancer gene mutation detection assays


NIBSC Principal contact Ross Hawkins

[email protected]

Rationale Cancer is a worldwide problem: ~40% of all new cancer cases arise in Asia. As stated in the WHO Guide for Effective Programmes “Cancer Control: Diagnosis and Treatment” (See: http://www.who.int/cancer/modules/FINAL_Module_4.pdf) more than 70% of all cancer deaths occur in low- and middle-income countries, and it is a WHO objective to “To reduce by 50% the mortality from all cancers that are amenable to early diagnosis and treatment.” The document also states “For a diagnosis and treatment programme to be effective, it should target people with curable cancers, and it should deliver good quality services (early detection, diagnosis, treatment and follow-up)…” The ability to identify the key ‘driver’ mutation in a tumour together with the existence of new drugs which target particular cancer mutations means that cancers are increasingly being treated in a specific and targeted manner. This increases survival and reduces the wastage of inappropriate drug treatments. A generic proposal is being made for standards for cancer diagnostics as this area is new to standardisation. Endorsement by ECBS is sought for the production of reference panels to standardise bioassays for cancer diagnostics. Panels for several gene mutations are proposed for production over the next 3 years:

Cancer type Gene Mutation(s)

Leukemia JAK2 V617F

Melanoma BRAF V600E

Colon KRAS G12D; G12A; G12V; G12S; G12R; G12C; G13D

Breast/Lung PIK3CA H1047R; H1047L;E542K; E545D; E545K

Breast ERBB2 (HER2)

Gene amplification

The list above is based upon the most frequent tests performed for which drugs are available but which only are effective on tumours carrying these mutations. Each panel would consist of a range of dilutions of mutant DNA in wild-type DNA extracted from cell lines. The actual levels in each panel would be set by the clinically relevant threshold for diagnosis and treatment. It is important that these panels are introduced rapidly before conflicting local practices are adopted which would increase the likelihood of wrong diagnoses.

http://www.who.int/cancer/modules/FINAL_Module_4.pdf

WHO/BS/2013.2230

If ECBS is supportive of the programme, we would like the committee to specifically consider the endorsement of the JAK2/Leukemia project. The JAK2 V617F mutation is frequently found in Chronic Myelogenous Leukemia patients negative for the BCR-ABL translocation. The V617F mutation results in constitutive activation of the JAK2 tyrosine kinase, but renders the cancer cells susceptible to tyrosine kinase inhibitor drugs resulting in effective treatments for patients carrying this mutation.


Manufacturers of assays & companion diagnostics. Diagnostic laboratories.

Laboratories will use these materials to determine that their assays are sufficiently sensitive, and also to ensure method validity after changing reagents or personnel.

Source/type of materials

Cell lines


Pilot and collaborative studies are intended to assess the suitability of the reference materials using different assays


Non-freeze drying to be considered

Action required ECBS to endorse proposal.


TDI-00003 TDI-00004 TDI-00005 TDI-00006

Date proposed: January 2013



In vitro diagnostic assays – CE-marked, FDA-approved, CLIA or ISO15189 certified.


Various, all PCR-based


High. These specific cancers are common and there is no assay standardisation

Global importance High.


The availability of validated reference reagents should help harmonize the sensitivity & quality of cancer diagnostic testing.

WHO/BS/2013.2230

Proposal: Standardisation of cancer clone mutation-detection assays Running title: Cancer and leukemia diagnostic reference panels Proposer: Ross Hawkins (NIBSC) As stated in the WHO Guide for Effective Programmes “Cancer Control: Diagnosis and Treatment” more than 70% of all cancer deaths occur in low- and middle-income countries, and it is a WHO objective to “To reduce by 50% the mortality from all cancers that are amenable to early diagnosis and treatment.” The use of recombinant DNA techniques and DNA sequencing over the last 20 years has led to a genomic characterisation of cancer cells, in which key chromosomal translocations and sequence mutations may drive tumour development. Characterisation of these mutations not only helps characterise the cancer type, but also identifies potential ‘Achilles heels’ which drugs can be developed to act upon. There is a rapidly growing list of new drugs developed to specifically inhibit aberrantly activated mutant cancer proteins. An early example of a drug developed to specifically act upon a mutated oncoprotein is Imatinib which blocks the ATP binding domain of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. A high level of inter-laboratory variability in CML clone quantitation assays required each lab to derive a conversion factor by sending sample materials to labs in Germany or Australia. The establishment of conversion factors is time consuming, complex, expensive and only open to a limited number of laboratories at any given time. Therefore a WHO International Standard calibrated to the pre-existing international scale was developed to provide a more accessible mechanism of assay standardisation and enable the production of commercial secondary standards. The problem of inter-laboratory assay sensitivity and variability is repeating with other cancer nucleic acid-based diagnostics. The early introduction of international reference materials is necessary to avoid wide performance variation between laboratories and the subsequent need to develop a variety of mutation-specific conversion factors. The effectiveness of Imatinib is indicated by the graph below based upon CML cases in the USA (from Sellers [2011], Cell 147: 26-31 )

WHO/BS/2013.2230

DNA sequence mutations which cause constitutative activation of other kinases are a common feature of other types of cancer and can also be exploited to develop targeted therapies. The most pressing examples are those which have entered clinical practice include: JAK2, BRAF, PIK3CA, EGFR and KRAS (linked with resistance to anti-EGFR therapy). As oncogene mutations are acquired during life, samples for diagnostics are a mixture containing a small percentage of mutant cancer cells in a background of wild-type cells. Thus diagnostic tests must be sufficiently sensitive to detect mutant cells at a low and defined percentage. Reference panels of mixed mutant/wild-type DNA at different dilutions will be required to act as assay sensitivity standards. Secondary standards or in-house control materials may then be calibrated against these standards. The panels will differ from Genetic Reference Materials previously produced at NIBSC which have mostly been aimed at aiding the detection of in-born (i.e. constitutional) mutations requiring complex and difficult detection assays. JAK2 A common mutation (V617F) in the JAK2 gene is frequently found in patients suffering from myeloproliferative neoplasms (MPNs). Less commonly, mutations are found in the thrombopoietin receptor gene (MPL). A survey of British leukemia diagnostic laboratories overwhelmingly expressed an interest in JAK2 V617F diagnostic reference materials. As testing for this mutation and subsequent drug treatment tailored to it has entered clinical practice, a reference panel for this mutation is considered to have high priority. The WHO classification of neoplasms of the haematopoietic and lymphoid tissues, published in 2001 and updated in 2008 represents a worldwide consensus on the diagnosis of these tumors (Swerdlow et al 2008). Its worldwide acceptance stems from biologically sound underlying principles, and its clinical relevance, practicality and reproducibility in diverse international settings. The demonstration of an acquired mutation within JAK2 and/or MPL now forms part of the World Health Organisation criteria for the diagnosis of MPN. Patients presenting with erythrocytosis should be assessed for the presence of a JAK2 mutation. All materials will be derived from cell lines as these allow for consistent genotype replacement upon exhaustion of DNA stocks. Product Presentation It is proposed to discontinue the use of freeze drying in ampoules for these cancer reference panels, as the minimum DNA input is sufficient for several hundred assays, which encourages users to store the reconstituted DNA for long periods which may cause erroneous data through degradation and contamination. Freeze drying in small plastic tubes or air-drying in the presence of a stabilizing matrix offer lower-volume alternative to ampoules offering potential single-use, lower unit cost and potential avoidance of refrigeration. The demonstration of user-approval and stability of air-dried DNA is being explored now by the CE-marking of such materials at NIBSC. Reference Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008.

WHO/BS/2013.2230

Proposal (title) Reference Reagent for high and low titre Anti-A and anti-B in serum/plasma


NIBSC Principal contact Susan Thorpe

Rationale Mismatched kidney transplants can be performed successfully if the recipient has sufficiently low levels of anti-A and anti-B. Patients may be considered for a mismatched transplant if anti-A/anti-B titres are 128 or below, in which case plasmapheresis is performed to reduce titres to 16 or below. However, anti-A and anti-B titrations are not consistent across laboratories. Reference preparations with nominal anti-A and anti-B titres are necessary to ensure greater standardisation of methodology and results, with a later possibility of defining cut-off limits when these become clearer.


Transfusion centres and serology labs

Source/type of materials Human plasma


A pilot study will be conducted in the first instance to determine whether the reference preparations should be plasma- or serum-based and whether titrations across labs are likely to be tight enough to enable identification of nominal titres.

Definitive fill preparations will be evaluated by labs (using the same methods) in order to determine nominal titres for assignment. High titre and low titre preparations will be prepared and evaluated.




BIO-00003 Date proposed: February 2013



Haemagglutination titrations using gel cards


2 preparations

WHO/BS/2013.2230

Proposal title Reference Reagent for high and low titre Anti-A and anti-B in serum/plasma


Very important if you need a kidney transplant and a matched donor is not available (approx. 1500-1700 transplants carried out per year in the UK)

Global importance

Over 80 countries routinely perform kidney transplants


~65,000-70,000 kidney transplants worldwide annually, use of mismatched donations facilitates process

ECBS outcome

WHO/BS/2013.2230

Proposal (title) Standardisation of rubella antibody testing


NIBSC Principal contact Silke Schepelmann

Rationale Rubella virus infection during pregnancy can cause birth defects (CRS, congenital rubella syndrome) and serological testing for antibodies against rubella is important for pregnant women as up to 50% of rubella infections are estimated to be asymptomatic. The recommended cut-off for positive IgG levels of rubella antibodies is 10 IU/ml. However, a number of different instruments and assays to measure rubella antibodies are commercially available, which are based on different methods, resulting in test results that can vary greatly between different laboratories, and it has been questioned how meaningful the cut-off value really is.

There is a need to improve the standardisation of rubella assays.

It is proposed to get involved with a WHO collaborative study involving several different rubella kit manufacturers. Two reference materials will be included in this study as a standard and as a sample, respectively; the 2nd British rubella antiserum standard and the 3rd International rubella reference standard.


The study will assess the possibility of calibrating different kits and assays so that they produce comparable test results that can be interpreted using a universal cut-off threshold. All laboratories that perform rubella antibody testing worldwide will benefit from the outcome of this study.

Source/type of materials WHO Third International Standard for Anti-Rubella Immunoglobulin, Human (RUBI-1-94). This was prepared from human normal immunoglobulin from the Statens Serum Institute in Denmark. NIBSC currently hold 1350 ampoules of this material (minimum stock level 700 ampoules).

Second British Standard Anti-Rubella Serum, Human (67/182). This material has been prepared from human hyperimmune sera from the UK National Blood transfusion Service. There are currently 1790 ampoules available at NIBSC (250 minimum stock level).

Confirmed seronegative blood samples from blood banks.


The collaborative study will involve 5-10 manufacturers worldwide, performing standard in-house rubella antibody tests which have been established in their laboratories. NIBSC will also participate. The assays will be calibrated against the Third International Standard for Anti-Rubella Immunoglobulin, Human (RUBI-1-94). The panel of study samples will include the Second British Standard Anti-Rubella Serum, Human (67/182).


None


WHO/BS/2013.2230


VIR-00034 Date proposed: September 2013

CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES


Rubella serology is a widely used diagnostic method.


At least nine different kits and instruments are commercially available.


Rubella virus infection in pregnant women can cause CRS, and many countries vaccinate adolescent females and/or children against rubella, preventing the transmission of rubella virus and providing indirect protection against CRS. Pregnant women and women of childbearing age are screened for rubella antibodies using a variety of different kits, assays and instrumentation from different manufacturers. The test results determine whether the women are offered rubella vaccine or not. A pregnant woman may also wrongly decide on an elective termination if her antibody titer was incorrectly found to be low.

Global importance

WHO has set targets for the elimination of rubella and the prevention of CRS in the WHO European Region. Rubella virus circulation and CRS will increase if vaccination programmes do not achieve the required herd immunity threshold of 80%. Serological surveillance is vital to support immunisation strategies and to monitor progress towards international disease control targets. Serological surveillance avoids many of the limitations of passive disease reporting systems for rubella, in which many infections are either mild or asymptomatic, and congenital rubella syndrome, in which there are few cases reported due to poor surveillance systems. Furthermore, the effectiveness of a rubella vaccination programme can be evaluated by the identification of susceptible cohorts among women of childbearing age (Nardone et al., Bulletin of the WHO, Volume 91, July 2013). Subsequent vaccination of these women further increases the effectiveness of rubella immunisation programmes.


Rubella serology is carried out throughout the world. Control laboratories such as NIBSC also apply the test to characterise immunoglobulin preparations.

ECBS outcome [BLANK]

WHO/BS/2013.2230

Proposal (title) The 2nd International Standard for Anti-tetanus Immunoglobulin, Human


NIBSC Principal contact Dr Paul Stickings

Rationale Clinical management of suspected (e.g. wounds in high risk individuals) and confirmed cases of tetanus involves the use of tetanus antitoxin. Although equine preparations are still in use in some regions, the use of human tetanus immune globulin (TIG) is recommended and has totally replaced equine products in many countries. The antitoxin potency for most TIG preparations is labeled in IU/ml. WHO established the 1st IS for Anti-tetanus Immunoglobulin, Human in 1992 for the purpose of calibrating therapeutic human TIG preparations. This standard has also been used for calibration of diagnostic kits used to determine anti-tetanus antibody levels in human serum. As of June 2013, there are <1000 ampoules remaining and a replacement standard is therefore needed.


Primary intended use is for the calibration of human TIG preparations. Secondary use is for calibration of assays used to measure tetanus antibody levels in human serum. Recommendation for this purpose will be subject to satisfactory demonstration of commutability.

Primary users will be manufacturers of TIG; if recommended for diagnostic use, the standard will also be used by manufacturers of diagnostic kits, tetanus vaccine manufacturers (for clinical trials), public health and other clinical laboratories.

Source/type of materials Purified human tetanus immunoglobulin (source yet to be identified and agreed). Note that comparable material was used as the source material for production of the 1st IS (TE-3)


Aim of the collaborative study will be to assign value (tetanus antitoxin potency) to the candidate material. It is proposed that only one candidate is included in the study because this is a replacement standard and the source material used will be comparable to that used for production of the 1st IS. Calibration will be done by functional toxin neutralization test in vivo. Where possible, participants will be asked to perform in vitro immunoassays that are used in routine control of TIG products. Potency will be determined relative to TE-3.


The source material will be bulk material used for production of a therapeutic preparation of TIG. This material is highly purified and has a high tetanus antitoxin potency (usually >>100 IU/ml). Although suitable for the primary intended use, an assessment of commutability will be needed to determine whether such material can also be used for calibration of diagnostic kits and other immunoassays used for measuring tetanus antibody levels in human serum. TE-3 is currently used for this purpose, although an assessment of commutability was not done.

WHO/BS/2013.2230

If the proposed replacement standard is shown to be non-commutable with human serum an additional IS will need to be established for the purpose of human diagnostic use.

Action required ECBS to endorse proposal to replace the 1st IS (TE-3)


BAC00046 Date proposed: 11 June 2013



Human TIG is licensed for prophylaxis against tetanus, and therapy.

Commercial diagnostic kits for human serology are available.


There are more than 10 manufacturers of human TIG globally.

Approximately 6 CE marked diagnostic kits are available in Europe

In addition to commercial diagnostic kits for tetanus antibody, there are a number of in-house immunoassays in use as well as a mouse bioassay.


Tetanus remains a significant health problem in many developing countries and use of TIG is essential for prophylaxis against tetanus and in some cases for treatment of active disease. Although tetanus disease is rare in developed countries, stockpiles of TIG are maintained for emergency use and TIG is also used for clinical management of high risk wounds.

Global importance

Tetanus remains a significant cause of mortality in developing countries. TIG is produced and used globally.


Monographs for tetanus antitoxin include a requirement for a minimum potency of the product. Dosing of most TIG products is done in IU and an International Standard is essential for accurate and standardized labeling of these products.

ECBS outcome

WHO/BS/2013.2230

Proposal (title) IS for Blood Coagulation Factor IX, Antigen The 5th International Standard for Blood Coagulation Factor IX, concentrate The 4th International Standard for Blood Coagulation Factor II, VII, IX and X, Plasma


NIBSC Principal contact Elaine Gray

Rationale While potencies have been assigned to both the plasma and concentrate

international standards for FIX, there are no antigen values for these

standards. FIX antigen values have now become important:

1. Patients with congenital FIX deficiency can have high/normal antigen but low functional activity, so antigen measurement helps to define the phenotype of the disease

2. With recombinant and new generation therapeutics, antigen values that help to define the specific activity of the products would be valuable for characterisation of these products.

3. A number of gene therapies for FIX is now in advance clinical trials. It would be important to have antigen reference standard to support the measurement of the level of FIX antigen expression.

The proposal is to value assign the current 4th IS for FII, VII and X, plasma

and the proposed 5th IS for FIX Concentrate with FIX antigen against local

normal pooled plasma. This will be carried out in the same collaborative

study (due to submit to ECBS in 2015) that will value assign the functional

activity of the proposed 5th IS for FIX Concentrate


Approximately 600 ampoules of IS for FIX are dispatched each year. With the new products in the pipeline, there have been an increase in the demand of this IS by the OMCLs and manufacturers.

Source/type of materials Candidates for concentrate standard will be procured from FIX manufacturers. The Plasma IS will be one of the test samples in the study.


Plasma derived and possibly recombinant candidates and the Plasma IS

will be assayed against the local normal plasma pool in an international

collaborative study involving at least 20 laboratories, using their routine

clotting and chromogenic methods.


None



Date proposed:

WHO/BS/2013.2230



Globally, at least 10 manufacturers producing approximately 30 licensed products. The Plasma IS is used by clinical laboratories as well as assay kit manufacturers to calibrate their calibrators


Approximately 30 products. Two assay methods: Clotting and chromogenic assays.


Haemophilia B is a congenital deficiency that affects mostly male from all

geographic locations.

Global importance

Accurate potency labeling is of paramount importance to the efficacy of the

replacement therapy of haemophilia B patients.


It is important that the international standard provides the continuity of the unit to ensure the good intra- and inter-laboratory agreement as this will influence treatment of the patients and the efficacy and safety of the products.

ECBS outcome [BLANK]

WHO/BS/2013.2230

In 2012, a preliminary report on the collaborative study to evaluate the WHO Reference Reagent for Activated Blood Coagulation Factor XI (FXIa), Human, 11/236 was presented to the ECBS. ECBS established this preparation as the WHO Reference Reagent for FXIa and requested further information on on-bench stability data to be presented at the next ECBS meeting. The final report containing on-bench stability data together with full analysis of data for the collaborative study is attached to this proposal for a new international standard for FXIa. Since its establishment, over 1000 ampoules of the Reference Reagent have been issues and the end-users have found this material useful in development of assays for procoagulant activity in immunoglobulin products. In the 2013 Official Medicine Control Laboratory (OMCL) meeting in Helsinki, the OMCLs reported that the Reference Reagent for FXIa has been instrumental in harmonisation of results. Due to the huge demand on the Reference Reagent for FXIa, there is only sufficient stock for another year. The following is a proposal to establish an International Standard for FXIa, with a view to replace the Reference Reagent.

Proposal The 1st WHO International Standard for Activated Coagulation Factor XI (FXIa)

Proposer Elaine Gray, NIBSC

Principal contact Elaine Gray

Rationale Following the reports of thromboembolic events associated with the clinical use of IVIG, investigation by OMCLs, US FDA and manufacturers indicated that the procoagulant component could be FXIa. Currently reference material is not available to aid development of assay methods and intra- and inter-laboratory agreement on the measurement of FXIa. A reference standard for FXIa is urgently needed to ensure harmonisation of measurement of FXIa in IVIG products. In 2012, the ECBS established an interim reference reagent to cover the immediate need. Over 1000 ampoules of this reagent have been issues and the end-users have found this material helpful in development of assays and harmonisation of results. An international standard for FXIa is now needed to replace the Reference Reagent for FXIa. A purified preparation of human FXIa has been sourced, filled and ampouled and the collaborative study will be initiated in Q4, 2013, with projected timeline for submission to ECBS in 2014. This international standard, when established, will supersede the reference reagent for FXIa.


High demand, at least 500 ampoules per year as this will be used by all OMCLs and manufacturers of immunoglobulins and FXI therapeutic concentrates.

Source/type of materials Purified human FXIa purchased from a commercial source.


The final product will be compared with the reference reagent for FXIa in a large international collaborative study for assignment in international unit. The bulk material will be physico-chemically characterized and calibrated by active site titration. The molar concentration of the final products will be estimated by comparison with the active site titrated bulk. This will be carried out at NIBSC or a limited number of laboratories. Through this

WHO/BS/2013.2230

exercise, the relationship between molar concentration and international unit for FXIa could be established. The IS will be labeled in IU, with molar concentration stated in IFU.


The international unit assigned to this IS will need to be reconciled with the unit assigned to the Reference Reagent for FXIa.



NIBSC BIO-00057

Date proposed: 06/01/2012



Approximately 10 manufacturers of IVIG products with more than 50 licensed products. Two manufacturers of factor XI concentrates.


See above


A reference material would provide laboratories with a much needed standard to measure the amount of thrombogenic FXIa in both IgGs and FXI concentrates. Without a reference standard, it would not be possible to set specification for limit of FXIa in IVIG products.

Global importance

IVIG is a highly used product for primary and secondary immunodeficiencies. There is always a global shortage of products. The provision of the FXIa reference material will help to improve the safety of the products.


This reference material was requested by the OMCLs, EDQM, EMA and the US FDA (WHO collaborating centres).

ECBS outcome

Please refer to WHO/BS/2013.2230 Addendum 2

WHO/BS/2013.2230

Proposal (title) The 2nd International Standard for Ancrod


NIBSC Principal contact Craig Thelwell

Rationale The 1st International Reference Reagent for Ancrod (74/581) was established in 1977 and stocks are now low. Ancrod is a thrombin-like serine protease, however unlike thrombin ancrod cleaves fibrinogen to form an unstable fibrin that is rapidly cleared from circulation. This has an anticoagulant effect, by reducing circulating fibrinogen levels, and also a pro-fibrinolytic effect. Ancrod has been implicated primarily for treatment of ischemic stroke, however clinical trials over several decades have shown mixed results, with the last clinical trial for stroke ending 2008. Ancrod is not currently licensed in any country, since the therapeutic product (Arwin/Arvin) was withdrawn in the 1980s. Ancrod has other indications and is currently in clinical trials for treatment of sudden sensorineural hearing loss (SSHL). The proposed mechanism of action is by reducing circulating fibrinogen, and therefore blood viscosity, oxygen is more effectively delivered to the inner ear. Because of its anticoagulant and pro-fibrinolytic properties there is still interest in the clinical applications of ancrod, including for stroke treatment where a positive effect has been shown in some patient groups. Because of this interest the standard remains popular (Average 110 ampoules per year 2008-2012).


Potency assignment for therapeutic Ancrod by product manufacturer. Calibration of Ancrod potency used in research and development by industry and academia. The ancrod IS is supplied to labs in more than 10 different countries, including several in Europe, USA, China, Japan and Russia.

Source/type of materials One product manufacturer identified. Ancrod is purified from the venom of the Malayan pit viper (Calloselasma rhodostoma)


One candidate material calibrated relative to the 1st IS using clotting methods in a multicenter study.


Recruiting participants could be difficult and the study may be small. No stability data on 1st IS beyond initial study. Intended use has changed since 1st IS was established.

Action required ECBS to evaluate proposal


Date proposed: March 2013

WHO/BS/2013.2230



Clinical trial phase 1/2 for SSHL. No current license for ischemic stroke treatment.


One commercial product ‘Viprinex’ , manufactured in Germany by Nordmark GmbH.


Ancrod is implicated for treatment of a number of indications however its significance has not yet been established in clinical trials.

Global importance If licensed Ancrod could be of global importance.


Viprinex has US orphan designation to establish and maintain anticoagulation in heparin-intolerant patients undergoing cardiopulmonary bypass, however this was assigned in 1989 and is not FDA approved for this orphan indication.

ECBS outcome

WHO/BS/2013.2230

Proposal (title) The 4th International Standard for Streptokinase

Proposer (Institution) NIBSC Principal contact Craig Thelwell

Rationale The 3rd International Standard for Streptokinase (00/464) was established in 2001 and stocks are now low. Streptokinase is a bacterial plasminogen activator used as a thrombolytic drug in the treatment of acute myocardial infarction (AMI). Streptokinase remains the most widely used thrombolytic worldwide, especially in developing countries. This is reflected in the sales of the 3rd IS which is the most popular thrombolytic standard, and sales have increased annually over the past four years (283 in 2012).


Potency assignment for therapeutic streptokinase by product manufacturers.

Source/type of materials Therapeutic native streptokinase preparation, purified from culture filtrates of Group C Streptococcus equisimilis H46A.


One candidate material calibrated relative to the 1st IS using chromogenic and fibrin based methods in a multicenter study. Recombinant products may also be sought for comparative analysis in different assay systems, which for some products are known to give different responses relative to the native IS preparation.


Action required ECBS to evaluate proposal


Date proposed: May 2013



Licensed worldwide.

No. of products >10 licensed products worldwide


Streptokinase has a history of effective treatment for AMI, and ischemic heart disease is one of the leading causes of death worldwide.

Global importance Streptokinase is the most widely used thrombolytic agent worldwide, especially in developing countries.


There is a narrow “therapeutic window” for fibrinolytic-antithrombotic regimens and the potential for adverse outcomes is high if incorrect doses are administered.

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