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Organisation of assay services
CHAPTER 13
Organisation of assay services
Binding assays, and in particular radioimmunoassays, have long since passed the stage at which they might be regarded as research procedures. There are now several important branches of clinical medicine which could not be actively pursued if these techniques were not available. This being the case an important consideration is the question of how to deliver the best possible service to the patient at the lowest possible price. The subject of this last chapter is, therefore, the organisation of assay services - who should do them and how they should be done. Although the discussion will centre around radioimmunoassay, it should be emphasised again that the isotopic label is not a defining feature of these techniques: however, the existence of alternative but equivalent systems would not alter the observations presented here.
13.1. Who should perform radioimmunoassay ? The practice of medicine and pathology is highly structured on a departmental basis and when a new subject emerges there may be a long period of years or even decades before it is formally recognised and established as a series of independent units. The specialised branches of surgery provide an excellent example of this. Until a new subject comes of age it will usually be practised under the aegis of an existing department and the final separation of the fledgling speciality is frequently a painful process at both the personal and administrative level. Radioimmunoassay presents an extreme example of the difficulties of this process. The sheer breadth of its application 510
Ch. 13
ORGANISATION OF ASSAY SERVICES
511
has led to its emergence from departments as disparate as endocrinology, obstetrics/gynaecology, clinical chemistry, nuclear medicine, anatomy and physiology. The only notable absence from this list is immunology - a subject which in its more traditional reaches has completely ignored one of its most important potential fields of activity. It may be most difficult to predict within any one hospital complex where one will find the radioimmunoassay laboratory; commonly there are several. This may be satisfactory, indeed inevitable, at the research level. It is highly unsatisfactory when the demand is for a routine service to patients. With only few exceptions, the best place for routine radioimmunoassays to be carried out is in a radioimmunoassay laboratory managed and staffL by people who are experts in radioimmunoassay. Whether this laboratory operates under the auspices of a department of clinical chemistry, or of nuclear medicine, or any other, is immaterial - the principle point to recognise is that no existing department has any prior claim to house it in the absence of experienced personnel. Radioimmunoassay is a sufficiently large subject and sufficiently different from any other to merit full-time staff who, whatever their previous background, are dedicated to this subject alone. A busy centre should have full-time personnel at all levels who are not expected to have a substantial and simultaneous commitment to routine clinical chemistry, to in vivo isotopic methods, or to a clinical discipline. Exceptions must, of course, be made for those situations in which the result is always required urgently, such as measurement of drug levels.
13.2. Organisation of an assay laboratory Although most present radioimmunoassay (RIA) laboratories have arisen on an ad hoc basis in existing departments, it is possible to make certain generalisations on the requirements of a new laboratory: (1) Stufr: the number of staff required can be judged from the total throughput of assays intended. As a rule of thumb it may be assumed that one technician can process 10,000 samples per year, or 250 per Subjecr i n d u p 531
512
RADIOIMMUNOASSAY A N D RELATED TECHNIQUES
working week. There are, of course, exceptions to this: for assays with tedious extraction steps the throughput will be very much reduced; for those which are automated it may be substantially greater. Similarly, the output of a technician who is responsible for several differenttypes of assay will be less than that of one responsible for only a single assay. For every 3-4 technicians actively engaged in RIA procedures, the unit will require one well-trained graduate. Regardless of the total number of staff involved, the unit will also require a full or part-time director who may be a medical or nonmedical graduate with an extensive background in radioimmunoassay. There are many situations in which a laboratory will be required to perform RIA procedures at throughputs considerably less than those suggested above (i.e. fewer than 250 samples per week). Examples would include the smaller district laboratory responsible for a small number of urgent determinations such as those required in the assessment of drug levels or of fetoplacental dysfunction. In these circumstances, 2 or 3 members of the general laboratory staff should be deputed to become familiar with the use of reagent kits (see below), so that any one of them is able to meet demand on an ad hoc basis. (2) Stajftraining: it is impossible at the present time to lay down any specific course of training for those involved in the management of a RIA laboratory other than that they should have a period of not less than 1 year in a recognised and active unit carrying out this type of work. The subject has not crystallised to the extent that any formal training scheme can substitute for experience, and the typical educational course now available can only provide a theoretical background to what is essentially a practical subject. Similarly, and for the reasons already noted above, it is impossible to be specific about the type of person who should be trained - a graduate in almost any scientific discipline would be appropriate, with perhaps a slight edge towards the biochemist. At the technical level the training problem is simpler. In essence, any reasonably intelligent person with a secondary education in
Ch. 13
OR(iANISA1 ION OF ASSAY S E R V I C E S
513
science subjects is suitable and can be introduced immediately to RIA techniques. No amount of previous experience and training in nonRIA subjects (e.g. medical physics, clinical chemistry) will qualify them any better. A young man or woman taken direct from school to work in a busy unit should be capable of independent running of an assay within 3 months and of several assays, if necessary, within a year. If well supervised and provided with a reasonable background of principle and practice such people will be as competent and effective - often more so - than those with a long list of irrelevant qualifications. (3) Space: the space requirements for a RIA laboratory do not differ significantly from those of any general analytical laboratory. A provision of 3-5 m of bench should be made for each person involved in the day-to-day handling of specimens together with additional areas for counters, centrifuges, automated equipment, sample reception and offices. A substantial unit with 12 staff and an annual throughput of 50,OOO-I 00,000 samples would be wellhoused in a total area of 300 m2. Currently, of course, many units fall substantially below this optimum. A specific requirement of the larger unit (i.e. those performing their own iodinations) is a completely separate area reserved exclusively for the handling of high levels of radioactivity; the design of this area should conform to national and international requirements for the amounts of activity likely to be handled. (4)Equipmerit: apart from the general equipment to be found in any biochemical laboratory, the only specific requirements of a RIA laboratory are for centrifuges capable of handling large numbers of tubes (100 plus) at the same time, and nuclear counters. The latter have already been described (# 3.3). In general, the laboratory processing less than 100 specimens per week for any one assay will be best served by a simple instrument with manual sample changing. If the numbers for any one assay are greater than this, or if the number of different assays performed is large, then a counter with automatic sample changing becomes necessary. One automatic machine with a single detector head should suffice for a throughput of up to 20,000 Suhlrcr im/c\ 11 531
514
RADIOIMMUNOASSAY A N D RELATED TECHNIQUES
samples per annum; above this number additional machines will be required pro rata. These figures are likely to vary with the introduction of multi-detector counters and fully automated systems with integral detectors (see 4 3.3 and Ch. 12). ( 5 ) Reagenfs: the source of the reagents used by any one laboratory will vary greatly with the size and type of unit concerned. At one extreme will be the very large group with international status who will probably prepare the majority of their own reagents and, indeed, be responsible for distributing these to other laboratories. At the other extreme will be the very small group who use nothing but ‘kits’ of reagents from outside suppliers. Between the two, every possible combination of local and outside supply will be encountered. For laboratories performing RIA (the majority of current techniques) a key point is whether or not they have facilities for radioiodination. In the absence of these, the unit is likely to be a predominantly kit user since there are few prime suppliers, either in the public or the private sector, who are prepared to deliver tracer on its own. By contrast, the other reagents for RIA can be prepared relatively easily from bulk materials with a long or almost indefinite half-life. Whether such materials will be subjected to adequate quality control by the small user is, of course, another matter. The primary aim of many laboratories, certainly in the public sector in the U.K., has always been to prepare as many reagents as possible on site. While admirable in principle this approach can suffer from 2 serious disadvantages. First, it has been repeatedly emphasised that no two sets of reagents, however apparently identical, will ever give exactly the same result. For this reason the onus of preparing both normal and clinical ranges, and the transmission of these to the physician, must rest on the individual unit. This type of discrepancy is minimised, and the value of the test in the smaller laboratory correspondingly enhanced, if completely common sets of reagents and a common methodology are distributed from a central source. Second, it is all too frequently overlooked that the preparation of primary reagents is time-consuming and expensive. Over-simplified costings are often presented which ignore labour and general over-
Ch. 13
ORCiANISAl ION OF ASSAY SERVICES
515
heads - yet for most materials these are by far the largest proportion of the real costs. As a rule of thumb it may be taken that a throughput of less than 50 samples per week for a given assay does not merit local preparation of reagents -a kit will be more cost-effective and probably give better results. Kits may be prepared either by public organisations or private firms, usually the latter. Commercial kits are often disparaged because of the high profit margins involved. This is a historic concept: over the last few years prices have not proved sensitive to inflation and margins are now comparable to those on most high-grade chemical reagents. However the increasing and highly desirable control over the quality of kits by Government bodies will inevitably, as it already has with drugs, curb competition and thus lead to an increase in prices in real terms.
13.3. Organisation o f assay services Development in the practical application of RIA demands that the services be organised to serve the best interests of the patient and that careful consideration should be given to the organisation of these services at the hospital, regional and national level. The primary criteria for such services are availability, efficiency, and cost, the 3 factors being closely related. Availability implies that an assay of clinical value, however recondite, should nevertheless be accessible to every clinician. Efficiency implies that the result should be available in the shortest possible time and should have accuracy and precision such that it confers maximum clinical benefit. Finally, the cost should be as low as is compatible with the maintenance of an effective service. The emergence of RIA techniques from the research field, with widely scattered units, many of which have little or no clinical commitment, has led to a situation which in most countries can only be described as chaotic. There can be little doubt that the best approach for future organisation will be on the basis of a national or even a supranational plan. An excellent example of what can or might be Suhjccr index p. 5 3 /
516
KADIOIMMUNOASSAY A N D KELA-TED TECHNIQUES
achieved is provided by current developments in the United Kingdom. Although these have been devised within the context of a socialised system of medical care, there is little reason why they should not be applicable within any other system. The basic design is that of a 3-tier system. At the district level (2-3 small hospitals or one large hospital) there will be a laboratory for assays which are either verycommon (e.g. thyroxine) or very urgent (e.g. digoxin). This laboratory will probably have part-time staff, and will not be responsible for the production of reagents. At the regional level there will be a larger laboratory responsible for a wide spectrum of the commoner assays, and for the production and distribution of reagents including radioactive tracer to the district laboratories. This laboratory will have full-time staff. At the national level there are 14 or more supraregional laboratories which have some functions comparable to those of the regional laboratories but which are also responsible for unusual and difficult assays which it would be uneconomic to set up everywhere (a good example is ACTH, for which there are 2 centres in the U.K.). A specific function of the supraregional centres is to institute and manage quality-control systems which apply to all assays wherever performed. The system described above has many advantages. Equally it has several disadvantages or at least drawbacks when it is run in practice. First, it is important that the organisation be established as a whole and not piecemeal. There is a strong tendency to set up the prestigious supraregional centres and then to ignore the remaining tiers. As a result the large centres are swamped with common assays to the detriment of their proper reference functions. Second, it has to be recognised that the distribution of reagents is often far more demanding of time, space, and personnel than is the preparation of these reagents. Simply because the large group has substantial stocks of materials it should not be assumed that these can be dispersed without some further investment. The apparent inability of many sophisticated assays to ‘travel’ serves to underline this point. Finally, it must be recognised that any degree of centralisation is bound to impose delays in results because of the logistic problems involved.
Ch. 13
ORGANISATION OF ASSAY SERVICES
517
For many assays already available such delays can negate the clinical value of any result. For many assays currently under development, such as those for enzymes and drugs, the same limitations will apply. Total centralisation, however superficially attractive and cost-effective, will not always provide the best service to the patient.
Organisation of assay services
Binding assays, and in particular radioimmunoassays, have long since passed the stage at which they might be regarded as research procedures. There are now several important branches of clinical medicine which could not be actively pursued if these techniques were not available. This being the case an important consideration is the question of how to deliver the best possible service to the patient at the lowest possible price. The subject of this last chapter is, therefore, the organisation of assay services - who should do them and how they should be done. Although the discussion will centre around radioimmunoassay, it should be emphasised again that the isotopic label is not a defining feature of these techniques: however, the existence of alternative but equivalent systems would not alter the observations presented here.
13.1. Who should perform radioimmunoassay ? The practice of medicine and pathology is highly structured on a departmental basis and when a new subject emerges there may be a long period of years or even decades before it is formally recognised and established as a series of independent units. The specialised branches of surgery provide an excellent example of this. Until a new subject comes of age it will usually be practised under the aegis of an existing department and the final separation of the fledgling speciality is frequently a painful process at both the personal and administrative level. Radioimmunoassay presents an extreme example of the difficulties of this process. The sheer breadth of its application 510
Ch. 13
ORGANISATION OF ASSAY SERVICES
511
has led to its emergence from departments as disparate as endocrinology, obstetrics/gynaecology, clinical chemistry, nuclear medicine, anatomy and physiology. The only notable absence from this list is immunology - a subject which in its more traditional reaches has completely ignored one of its most important potential fields of activity. It may be most difficult to predict within any one hospital complex where one will find the radioimmunoassay laboratory; commonly there are several. This may be satisfactory, indeed inevitable, at the research level. It is highly unsatisfactory when the demand is for a routine service to patients. With only few exceptions, the best place for routine radioimmunoassays to be carried out is in a radioimmunoassay laboratory managed and staffL by people who are experts in radioimmunoassay. Whether this laboratory operates under the auspices of a department of clinical chemistry, or of nuclear medicine, or any other, is immaterial - the principle point to recognise is that no existing department has any prior claim to house it in the absence of experienced personnel. Radioimmunoassay is a sufficiently large subject and sufficiently different from any other to merit full-time staff who, whatever their previous background, are dedicated to this subject alone. A busy centre should have full-time personnel at all levels who are not expected to have a substantial and simultaneous commitment to routine clinical chemistry, to in vivo isotopic methods, or to a clinical discipline. Exceptions must, of course, be made for those situations in which the result is always required urgently, such as measurement of drug levels.
13.2. Organisation of an assay laboratory Although most present radioimmunoassay (RIA) laboratories have arisen on an ad hoc basis in existing departments, it is possible to make certain generalisations on the requirements of a new laboratory: (1) Stufr: the number of staff required can be judged from the total throughput of assays intended. As a rule of thumb it may be assumed that one technician can process 10,000 samples per year, or 250 per Subjecr i n d u p 531
512
RADIOIMMUNOASSAY A N D RELATED TECHNIQUES
working week. There are, of course, exceptions to this: for assays with tedious extraction steps the throughput will be very much reduced; for those which are automated it may be substantially greater. Similarly, the output of a technician who is responsible for several differenttypes of assay will be less than that of one responsible for only a single assay. For every 3-4 technicians actively engaged in RIA procedures, the unit will require one well-trained graduate. Regardless of the total number of staff involved, the unit will also require a full or part-time director who may be a medical or nonmedical graduate with an extensive background in radioimmunoassay. There are many situations in which a laboratory will be required to perform RIA procedures at throughputs considerably less than those suggested above (i.e. fewer than 250 samples per week). Examples would include the smaller district laboratory responsible for a small number of urgent determinations such as those required in the assessment of drug levels or of fetoplacental dysfunction. In these circumstances, 2 or 3 members of the general laboratory staff should be deputed to become familiar with the use of reagent kits (see below), so that any one of them is able to meet demand on an ad hoc basis. (2) Stajftraining: it is impossible at the present time to lay down any specific course of training for those involved in the management of a RIA laboratory other than that they should have a period of not less than 1 year in a recognised and active unit carrying out this type of work. The subject has not crystallised to the extent that any formal training scheme can substitute for experience, and the typical educational course now available can only provide a theoretical background to what is essentially a practical subject. Similarly, and for the reasons already noted above, it is impossible to be specific about the type of person who should be trained - a graduate in almost any scientific discipline would be appropriate, with perhaps a slight edge towards the biochemist. At the technical level the training problem is simpler. In essence, any reasonably intelligent person with a secondary education in
Ch. 13
OR(iANISA1 ION OF ASSAY S E R V I C E S
513
science subjects is suitable and can be introduced immediately to RIA techniques. No amount of previous experience and training in nonRIA subjects (e.g. medical physics, clinical chemistry) will qualify them any better. A young man or woman taken direct from school to work in a busy unit should be capable of independent running of an assay within 3 months and of several assays, if necessary, within a year. If well supervised and provided with a reasonable background of principle and practice such people will be as competent and effective - often more so - than those with a long list of irrelevant qualifications. (3) Space: the space requirements for a RIA laboratory do not differ significantly from those of any general analytical laboratory. A provision of 3-5 m of bench should be made for each person involved in the day-to-day handling of specimens together with additional areas for counters, centrifuges, automated equipment, sample reception and offices. A substantial unit with 12 staff and an annual throughput of 50,OOO-I 00,000 samples would be wellhoused in a total area of 300 m2. Currently, of course, many units fall substantially below this optimum. A specific requirement of the larger unit (i.e. those performing their own iodinations) is a completely separate area reserved exclusively for the handling of high levels of radioactivity; the design of this area should conform to national and international requirements for the amounts of activity likely to be handled. (4)Equipmerit: apart from the general equipment to be found in any biochemical laboratory, the only specific requirements of a RIA laboratory are for centrifuges capable of handling large numbers of tubes (100 plus) at the same time, and nuclear counters. The latter have already been described (# 3.3). In general, the laboratory processing less than 100 specimens per week for any one assay will be best served by a simple instrument with manual sample changing. If the numbers for any one assay are greater than this, or if the number of different assays performed is large, then a counter with automatic sample changing becomes necessary. One automatic machine with a single detector head should suffice for a throughput of up to 20,000 Suhlrcr im/c\ 11 531
514
RADIOIMMUNOASSAY A N D RELATED TECHNIQUES
samples per annum; above this number additional machines will be required pro rata. These figures are likely to vary with the introduction of multi-detector counters and fully automated systems with integral detectors (see 4 3.3 and Ch. 12). ( 5 ) Reagenfs: the source of the reagents used by any one laboratory will vary greatly with the size and type of unit concerned. At one extreme will be the very large group with international status who will probably prepare the majority of their own reagents and, indeed, be responsible for distributing these to other laboratories. At the other extreme will be the very small group who use nothing but ‘kits’ of reagents from outside suppliers. Between the two, every possible combination of local and outside supply will be encountered. For laboratories performing RIA (the majority of current techniques) a key point is whether or not they have facilities for radioiodination. In the absence of these, the unit is likely to be a predominantly kit user since there are few prime suppliers, either in the public or the private sector, who are prepared to deliver tracer on its own. By contrast, the other reagents for RIA can be prepared relatively easily from bulk materials with a long or almost indefinite half-life. Whether such materials will be subjected to adequate quality control by the small user is, of course, another matter. The primary aim of many laboratories, certainly in the public sector in the U.K., has always been to prepare as many reagents as possible on site. While admirable in principle this approach can suffer from 2 serious disadvantages. First, it has been repeatedly emphasised that no two sets of reagents, however apparently identical, will ever give exactly the same result. For this reason the onus of preparing both normal and clinical ranges, and the transmission of these to the physician, must rest on the individual unit. This type of discrepancy is minimised, and the value of the test in the smaller laboratory correspondingly enhanced, if completely common sets of reagents and a common methodology are distributed from a central source. Second, it is all too frequently overlooked that the preparation of primary reagents is time-consuming and expensive. Over-simplified costings are often presented which ignore labour and general over-
Ch. 13
ORCiANISAl ION OF ASSAY SERVICES
515
heads - yet for most materials these are by far the largest proportion of the real costs. As a rule of thumb it may be taken that a throughput of less than 50 samples per week for a given assay does not merit local preparation of reagents -a kit will be more cost-effective and probably give better results. Kits may be prepared either by public organisations or private firms, usually the latter. Commercial kits are often disparaged because of the high profit margins involved. This is a historic concept: over the last few years prices have not proved sensitive to inflation and margins are now comparable to those on most high-grade chemical reagents. However the increasing and highly desirable control over the quality of kits by Government bodies will inevitably, as it already has with drugs, curb competition and thus lead to an increase in prices in real terms.
13.3. Organisation o f assay services Development in the practical application of RIA demands that the services be organised to serve the best interests of the patient and that careful consideration should be given to the organisation of these services at the hospital, regional and national level. The primary criteria for such services are availability, efficiency, and cost, the 3 factors being closely related. Availability implies that an assay of clinical value, however recondite, should nevertheless be accessible to every clinician. Efficiency implies that the result should be available in the shortest possible time and should have accuracy and precision such that it confers maximum clinical benefit. Finally, the cost should be as low as is compatible with the maintenance of an effective service. The emergence of RIA techniques from the research field, with widely scattered units, many of which have little or no clinical commitment, has led to a situation which in most countries can only be described as chaotic. There can be little doubt that the best approach for future organisation will be on the basis of a national or even a supranational plan. An excellent example of what can or might be Suhjccr index p. 5 3 /
516
KADIOIMMUNOASSAY A N D KELA-TED TECHNIQUES
achieved is provided by current developments in the United Kingdom. Although these have been devised within the context of a socialised system of medical care, there is little reason why they should not be applicable within any other system. The basic design is that of a 3-tier system. At the district level (2-3 small hospitals or one large hospital) there will be a laboratory for assays which are either verycommon (e.g. thyroxine) or very urgent (e.g. digoxin). This laboratory will probably have part-time staff, and will not be responsible for the production of reagents. At the regional level there will be a larger laboratory responsible for a wide spectrum of the commoner assays, and for the production and distribution of reagents including radioactive tracer to the district laboratories. This laboratory will have full-time staff. At the national level there are 14 or more supraregional laboratories which have some functions comparable to those of the regional laboratories but which are also responsible for unusual and difficult assays which it would be uneconomic to set up everywhere (a good example is ACTH, for which there are 2 centres in the U.K.). A specific function of the supraregional centres is to institute and manage quality-control systems which apply to all assays wherever performed. The system described above has many advantages. Equally it has several disadvantages or at least drawbacks when it is run in practice. First, it is important that the organisation be established as a whole and not piecemeal. There is a strong tendency to set up the prestigious supraregional centres and then to ignore the remaining tiers. As a result the large centres are swamped with common assays to the detriment of their proper reference functions. Second, it has to be recognised that the distribution of reagents is often far more demanding of time, space, and personnel than is the preparation of these reagents. Simply because the large group has substantial stocks of materials it should not be assumed that these can be dispersed without some further investment. The apparent inability of many sophisticated assays to ‘travel’ serves to underline this point. Finally, it must be recognised that any degree of centralisation is bound to impose delays in results because of the logistic problems involved.
Ch. 13
ORGANISATION OF ASSAY SERVICES
517
For many assays already available such delays can negate the clinical value of any result. For many assays currently under development, such as those for enzymes and drugs, the same limitations will apply. Total centralisation, however superficially attractive and cost-effective, will not always provide the best service to the patient.