# Presentation: 461285

## Higher Order Reference Methods and Reference

** ****Materials for Clinical Diagnostics**** **

- Willie E. May
- Analytical Chemistry Division
- Chemical Science and Technology Laboratory

## Measurements and Standards for Clinical Diagnostics

_**Major NIST Deliverables**_

**Standards for the Clinical Diagnostic Community**
- “Higher Order” Reference Methods
- Standard Reference Materials
- Interactive Measurement QA Programs
**Biomarker Validation Program (**
**Micronutrients in Blood **
**To Facilitate:**
- Improved Measurement Accuracy and Medical Decision-Making
- Reduced Healthcare Costs
- International Trade Traceability to “standards of higher order”

## Measurements and Standards for Clinical Diagnostics

_**Major Deliverables**_

**Linkage to the International Community through:**
**  ****International Comparison Studies**
- Health Status Markers in Serum
- Optical Filter and pH Standards
- Approaches for Purity Assessment
**Joint Committee on Traceability in Laboratory Medicine (JCTLM)**
- Providing leadership in the identification of  reference  materials and reference methods appropriate to meet the “higher order” requirements of the EC IVD Directive
- Developing protocols for establishment of a worldwide network of clinical reference laboratories
**To Facilitate:**
** ****International Acceptance of NIST Standards**

## New International Regulatory Driver: EU IVD Directive

***Implementation begins in December, 2003***
**Worldwide *****in vitro***** diagnostic device market is ~$20B**
**> ****60% of European market is supplied by U.S.**** **

***Scheduled Implementation***
**First IVD product with CE Mark may be placed from June 2000 onwards**
**All *****new***** IVD products *****must *****have mark by December 2003 **
**Existing IVD products may be sold without the CE mark until December 2005**

***Stated Purpose of Directive***
**Eliminate trade barriers *****within Europe***** by ensuring access to the entire EU market with one single product approval (CE Mark)**

***Essential Requirements***
**IVD Calibrators and/or control materials must be traceable to *****“standards of a higher order”***
**nationally/internationally recognized *****certified reference materials***

## Slide 5

## “....  the traceability of values assigned to calibrators and control materials must be assured through available reference measurement procedures and/or reference materials of higher order ...” 

***“******....  the traceability of values assigned to calibrators and control materials must be assured through available reference measurement procedures and/or reference materials of higher order ...”***** **
**Annex 1 (3) 2****nd**** para**

**US IVD Manufacturers have requested **
**that NIST develop internationally recognized reference methods and SRMs **
**to meet the traceability requirement.**

## Attendees included:

**Attendees included:**
**IVD Manufacturers**
**Regulatory Agencies and Notified Bodies**
**Providers of Proficiency Testing Programs, Laboratory Accreditation, and  Measurement Quality assessment Materials**
**Laboratory professionals involved in standardization of laboratory methods**
**International Standards Laboratories**

## JOINT COMMITTEE on TRACEABILITY in LABORATORY MEDICINE

- JCTLM a global initiative,formedin Paris, June 12, 2002

## Creation of Joint Committee on Traceability in Laboratory Medicine (JCTLM)

**The aim of the Joint Committee is to meet the need for a worldwide platform to promote and give guidance on internationally recognized and accepted equivalence of measurements in Laboratory Medicine and traceability to appropriate measurement standards.**

## JCTLM Aim

- Promotion of the traceability concept
- Dissimination of information on certified Reference Materials and Reference Measurement Procedures
- Establish links between Reference Laboratories and Metrology Institutes
- Co-ordination/guideance in the establishment of Reference Measurement Systems
- Identification of clinically relevant projects conducted by appropriate professional organisations – encourage collaborations
- Encourage application of Reference Measurement Systems by the IVD Industry

## JCTLM  is  Composed of Four Principals  and Two Working Groups

**ISO**

**FDA**

**CEN**

**ANSI**
**(USA)**

**NCCLS**

**AACC**

**DGKC**

**IFCC**

**JCTLM**

**EDMA**

**Advamed**

**JCCLS**

**NMIs**

**EQAS**

**JCTLM  is  Composed of Four Principals  and Two Working Groups**

**Principals**
- NMIs via CIPM/BIPM
- IFCC
- ILAC

**Working Groups**
- Reference Materials and Reference Procedures
- Reference Laboratory Networks
*Implementation Protocols*

## JCTLM - Structure

- JCTLM – Governing Body
**Chair: J. Thijssen (IFCC)**
** ****Priority setting**
** ****Approval of WG’s results**
- JCTLM Working Groups: Task oriented
-    1. _Reference Materials and Reference Methods_
- 		**Chair:  W.May (NIST), H. Schimmel (IRMM) **
**	**
-    2. _Reference Laboratories - Networks_
- 		**Chair: L. Siekmann (IFCC), L. Thienpont (IFCC)****IFCC)**
- 		**Guidelines for reference laboratories**
**	****	****Identification of networks**

## Draft International Recognition Arrangement for Higher Order Reference Materials, Higher Order Reference Measurement Procedures and Reference Measurement Laboratories for Laboratory Medicine 

_**Preamble**_
- In response to an urgent need to establish internationally recognized lists of higher order reference materials, higher order reference measurement procedures and reference measurement laboratories for laboratory medicine, a **Joint Committee for Traceability in Laboratory Medicine (JCTLM)** has been formed.
- The **BIPM**, **IFCC** and** ILAC**, being parties to the JCTLM, have drawn up a International Recognition Arrangement (IRA) for higher order reference materials, higher order reference measurement procedures and reference measurement laboratories for laboratory medicine.

## International Recognition Arrangement for Higher Order Reference Materials, Higher Order Reference Measurement Procedures and Reference Measurement Laboratories for Laboratory Medicine 

_**The Arrangement**_
- The BIPM/IFCC/ILAC IRA lays down a process whereby reference materials, and reference measurement procedures are examined with respect to conformity with appropriate international documentary standards, and whereby reference material properties are verified by measurements made in institutes with demonstrated competence in the field.
**The output of the IRA is a provisional database of internationally recognized reference materials, reference measurement procedures and reference laboratories** that can be used by the IVD industry and other users to meet the requirements of national and international regulations.
- The proper use of the higher order reference materials and reference measurement procedures recognized by this Arrangement calls for the existence of networks of competent reference measurement laboratories for specified measurands. The IRA will provide a database of such reference measurement laboratories that have demonstrated their competence by fulfilling all of the following criteria:
- a)	operation of a reference measurement procedure of  higher order for a given measurand;
- b)	participation in relevant key comparisons, or reference measurement laboratory proficiency testing 	programmes, or other relevant international comparisons;
- c)	operation of a quality system (meeting the requirements of ISO 17025 or ISO 15195) for the reference 	measurement procedure;
- d)	demonstration of their compliance with the quality system via accreditation or documented peer review.

## International Recognition Arrangement for Higher Order Reference Materials, Higher Order Reference Measurement Procedures and Reference Measurement Laboratories for Laboratory Medicine 

_**Publication of the provisional database of higher order reference materials,  reference measurement procedures and reference laboratories**_
- The higher order reference materials, reference measurement procedures and reference laboratories that are endorsed by** **this process will be published in a database by the BIPM and the IFCC and will be publicly available on the BIPM and IFCC websites with links from other websites as necessary.
_**Signatories to the Arrangement**_
- The BIPM/IFCC/ILAC Arrangement is open for signature by all interested stakeholders, namely:
- -**	****NMIs and other producers of higher order reference material;**
- -	**Professional societies in the field of laboratory medicine;**
**-****	****Quality assurance organizations in the field of laboratory medicine;**
**-****	****Regulatory authorities;**
**-****	****International organizations.**

## Creation of Joint Committee on Traceability in Laboratory Medicine (JCTLM)

**The aim of the Joint Committee is to meet the need for a worldwide platform to promote and give guidance on internationally recognized and accepted equivalence of measurements in Laboratory Medicine and traceability to appropriate measurement standards.**

**Working Group 1 -  Reference Measurement Methods and Reference Materials ****	****	****chaired by NIST and IRMM**
**Purpose****: **to identify reference materials and reference procedures and
- endorse those appropriate to meet the requirements of the EC Directive
- regarding in-vitro diagnostic medical devices.

## JCTLM Working Group-IReference Materials and Reference Measurement Procedures

***Co-Chairs: Willie May (NIST), Manfred Grasserbauer (JRC-IRMM)***
- Wednesday, August 28, 2002
**JCTLM Working Group-I:  **
**Reference Materials and Reference Measurement Procedures**
- Co-Chairs: W. May (NIST), H. Schimmel  (JRC-IRMM)
- 19-20 March, 2003	IRMM, Geel, Belgium

## Joint Committee on Traceability in Laboratory Medicine

**JCTLM**

**Review Teams for Highest Priority Analyte Areas**
***Worldwide representation from Lab Accreditation Organizations,  NMIs, ***
***Professional Societies , and IVD Industry***
**	****Electrolytes****	****	****Enzymes**
**	****Metabolites and Substrates****	****	****Proteins**
**	****Nucleic Acids****	****	****Drugs**
**	****Hormones****	****	****Coagulation Factors**

## The Electrolytes Review Team:

**Dr. W. Külpmann, MH-Hannover (Germany)**
**Dr. S. Long, NIST (USA)**
**Dr. P. D’Orazio, IL (USA)**
**Dr H. Schimmel, IRMM (Belgium)**
**Dr. L. Penberthy, Flinders Med. Ctr. (Australia)**
**C. Jain, Beckman (USA)**
**Dr. K. Kuwa, Univ. Tskuba (Japan)**
**Dr. L. Ma, NRCCRM,  (China)**
**R. Miller Dade Behring (USA)**

## Nominated Reference Methods and Reference Materials

- 			**Reference Methods****	****	****Reference materials**
-    			            **79**			          **436**
- Blood Gases		              			            		 2
- Coagulation Factor						28
- Drugs				3				84
- Electrolytes			20				64
- Enzymes			  6				  8
- Hormones			21  				10
- Metab. & Substrates		22				62
- Non-Electrolyte Metals	 	 3				62
- Nucleic Acids						  	  4
- pH								  1
- Proteins			  	3				51
- Vitamins							  9
- Other								58

## International Recognition Arrangement for Higher Order Reference Materials, Higher Order Reference Measurement Procedures and Reference Measurement Laboratories for Laboratory Medicine 

_**The Process, Technical Basis and Procedures**_
- The technical basis of the process is:
- 	(a) the evaluation by Working Groups of the JCTLM of nominated reference materials and reference 	measurement procedures and their implementation in reference measurement laboratories against 	relevant ISO Standards **(15193, 15194, 15195, 17025, 17511 and 18153),** ISO Guides **(34 and 35),** 	and WHO Guidelines and,
- 	(b) measurements to demonstrate the comparability of reference materials, the properties of which are 	expressed in SI units or, if not yet possible, international units of the WHO or other internationally 	agreed units.
- Reference materials nominated for evaluation are examined by Working Groups of the JCTLM and, where required to demonstrate comparability, measurements to document the comparability of “higher order” materials for the same measurand will be carried out by laboratories with demonstrated competence in the field. Competence of these laboratories can be demonstrated by, either:
- a)	their performance in relevant CIPM-MRA comparisons. and their implementation of an appropriate 	quality system, which together  result in internationally validated measurement capabilities for 	specified measurands;
- b)	or by laboratories fulfilling the criteria for recognition as a reference measurement laboratory for a 	specified measurand, according to the requirements outlined in this arrangement;
- c)	or by achieving accreditation for the appropriate scope of measurements. Such accreditation shall be 	based on a laboratory’s implementation of an appropriate quality system, which includes regular 	participation in appropriate proficiency testing programmes, together with evidence of traceability of 	measurement results to the SI or international standards of the WHO or other internationally agreed 	references.

## International Recognition Arrangement for Higher Order Reference Materials, Higher Order Reference Measurement Procedures and Reference Measurement Laboratories for Laboratory Medicine 

_**Commitment of Signatories to the Arrangement**_
- Signatories to the IRA agree to the process and recognize the published provisional database of higher order reference materials and reference measurement procedures, and the database of reference measurement laboratories.
_**Responsibility**_
- That the materials listed in the database meet their stated specification and continue to be available remains wholly the responsibility of the producers of these materials and is not the responsibility of either the JCTLM or the BIPM, IFCC or ILAC.
- Responsibility for reference measurement procedures meeting their stated specification remains with the laboratory that performs the measurement, and is not the responsibility of either the JCTLM or the BIPM, IFCC or ILAC.

## CEN and ISO work related tometrological traceability of IVD MDs

- Presentation of **reference measurement procedures **(EN 12286:1998 + 12286/A1:2000; ISO/FDIS 15193)
- Description of **reference materials **(EN 12287:1999, ISO/FDIS 15194)
- Metrological **traceability** of values assigned to calibrators and control materials (prEN ISO/FDIS 17511)
- Metrological **traceability** of values for catalytic concentration of **enzymes** assigned to calibrators and control materials (prEN ISO/FDIS 18153)
- Laboratory medicine - Requirements for **reference measurement laboratories** (prEN ISO/FDIS 15195)
- [R.D. 2002-06-09]

## 2nd Meeting JCTLM 

** ****Sevres France,  20-21 June 2003**
**Review Teams  presented report categorizing all Nominated Reference Materials and Reference ****	****Methods based on their Assessment of Compliance with relevant ISO Standards/Guides (e.g., 15193, 15194,17511, 18153)**
- 	****** **list		**Fully Compliant**
** ******** **	list	**	****Provisionally Acceptable**
** ******** ****	**list	**	****	****Does Not Meet Requirements**
**  ****Coagulation Factors**
**  ****Drugs**
**  ****Electrolytes**
**  ****Enzymes**
**  ****Hormones****	**
**  ****Metabolites and Substrates****	**
** ****	****Nucleic Acids****	**
** ****	****Proteins**
**	**

## JCTLM Meeting

** ****Sevres France,  20-21 June 2003**
** ****Each Review Team to perform Gap Analysis and present list of Highest             ****	****	****	****Priority Needs**
**All ********- and ********- List  Reference Materials to be Tested using CCQM Key Comparison -Validated ****	****Methods**
-  to assess comparability
-  to assess veracity of the Normative Standards-Based Review Process

## Cholesterol in Human Serum

**Cholesterol in Human Serum**

## Slide 27

## Uc

**QUANTITY**

**SI-UNIT**

**PRIMARY REFERENCE MATERIAL**

**(Primary Calibrator)**

**Pure or Purified Analyte**

**SECONDARY REFERENCE MATERIAL**

**(Biological, matrixed Calibrator)**

**INTERNATIONAL CERTIFIED MATERIAL**

**INDUSTRIAL MASTER CALIBRATOR**

**WORKING CALIBRATOR**

**PRODUCT CALIBRATOR**

***Primary Measurement Procedure***

***International ***

***Reference Measurement Procedure***

***International ***

***Reference Measurement Procedure***

***Routine Measurement Procedure***

- Value Transfer

- Value Transfer

- Value Transfer

**T**

**R**

**A**

**C**

**E**

**A**

**B**

**L**

**E**

**to**

**S**

**I**

**PATIENT SAMPLE**

**U****c**

**VAL UE T R ANS F E R**

**International **
**Protocols **
**(Value Transfer,**
**Value Assignment)**

## Alpha List - Cholesterol in Serum  (none on Beta list recommendations)

**Alpha List - Cholesterol in Serum****  **(none on Beta list recommendations)

****	**JCCRM 211-1M, JCCRM 211-1H (2 different materials) *
*	**certificate designations used as identifier for this RM in following discussions*

## Example:    Results of two independent sets of analyses on all proposed 

- JCCRM 211-1H
- SRM 909b l-1
- SRM 909b l-2
- SRM 968c l-1
- SRM 968c l-2
- SRM 1589a
- SRM 1951a l-1
- SRM 1951a l-2
- SRM 1952a l-1
- SRM 1952a l-2
- SRM 1952a l-3

***Example:*****    ****Results of two independent sets of analyses on all proposed **
**JCTLM ********-List Serum Reference Materials for Cholesterol) by a SINGLE laboratory**

- 2 materials

- 2 materials (2 levels)

- 2 materials (2 levels)

- 2 materials (2 levels)

- 3 materials (3 levels)

- Laboratory:	NIST (one lab for all materials)
- Campaigns: 	2 independent sets of analyses
- 	1 sample of each material/set
- Methodology:  	ID/GC-MS
- Calibrant:  	SRM 911b, Cholesterol

**Protocol**

**RMs**

## JCTLM -List:  Cholesterol in Serum CRMs

**Recently, NIST performed two independent sets of analyses on all proposed JCTLM ********-List Serum CRMs for Cholesterol (Metabolites and Substrates category).**
**The ratio of the NIST measurements to the CRM certified values are shown below:  The error bars represent 95% confidence intervals (k=2)**

**NIST Analyses:**
- ID-MS
- Calibrant:	 NIST SRM 911b
- 		Cholesterol

**CRMs are all comparable within ~1 % ****relative**

**aging materials??**

**uncertainties need to be reevaluated**

## JCTLM -List :  Cholesterol in Serum CRMs

- The measured/certified ratios for this set of CRMs are:
- ~ normally distributed
- with a standard deviation of ~0.7%

**JCTLM ********-List :  Cholesterol in Serum CRMs**

##   Listed CRMs

**JCTLM ********-List:  Potassium in Serum CRMs**

- Recently, NIST performed two independent sets of analyses on all proposed JCTLM -List Serum Electrolyte CRMs for potassium.
- The ratio of the NIST measurements to the CRM certified values are shown below:  The error bars represent 95% confidence intervals (k=2)

**NIST Analyses:**
- ID-ICP-MS
- Calibrant:  NIST SRM 918a, Potassium Chloride (Clinical Standard)

******  ****Listed CRMs**
**are all comparable**

##   CRM comparability independent of analyte level

**JCTLM ********-List :  Potassium in Serum CRMs**

******  ****CRM comparability**** ****independent of analyte level**

- The measured/certified Ratios for this set of CRMs are:
- normally distributed
- centered on the certified values
- with a standard deviation of <0.5%

## Slide 35

##  Next Review Priorities

** ****Blood Grouping and Typing**
** ****Blood Gases**
** ****Infectious Diseases**
** ****Non-Electrolyte Metals**
** ****Vitamins**
** ****Microarrays ???**