The Need for International Surveillance of Biologicals: Distribution, Use, and Efficacy

The Need for International Surveillance of Biologicals: Distribution, Use, and Efficacy Unfficia translation from the orinalFrench. S. HALTERa AND A. LaFONTAINEb INTRODUCTION In recent decades biomedical research has provided a large number of new materials for use in health activities. The number of biological products used in curative, preventive, or restorative medicine has become considerable. A large variety of these products have become of decisive importance for establishing correct diagnoses or for thera- peutic or prophylactic measures. Many of them are formulated, manufactured, and distributed by official institutions, but others have entered the private commercial sector. The significant effect these products can have on individual or community health implies that due attention must be given to the safety and guarantees which one has the right to ex- pect of them or of the new procedures which they make possible. Many biologicals display particular sensi- tivity or fragiibty when exposed to such exter- nal factors as temperature, humidity, and light. The properties of others may be modified as a result of changes dunng manufacture or stor- age. Some strains from which biologicals are produced may become attenuated or modified, thus creating a potentially dangerous situation if the persons applying these products continue to believe in their effectiveness after it has be- come inadequate or non-existent. Numerous instances could be cited in which the quality of biologicals has decisively affected the health and even the life of the individuals concerned. These considerations provide abun- dant justification for the need for permanent suTveillance and control of such products. It must be added that a large number of dis- coveries in the biologicals field are made in one country, which then becomes the manufac- turer-sometimes the exclusive producer-of these substances, although they are exported and used in a constantly growing number of other countries. It would be neither useful nor desirable for each country itself to manufacture and distribute the very large number of pro- ducts involved. International collaboration or even international solidarity is, therefore, es- sential in connection with their production and distribution. The question immediately arises as to what guarantees of conformity, quality, safety, and efficacy should be given to the users and reci- pients. Although some countries can, if neces- sary, establish surveillance and control facilities, most cannot. Indeed, it might be more worth- while to deliberately seek approaches to inter- national collaboration so that the field of appli- cation, quality, and efficacy of the products can be studied and developed both carefully and successfully. The matters to be dealt with at the inter- national level will necessarily include the fol- lowing AIMS OF SURVEILLANCE AND DEFINITION OF BIOLOGICALS AiMs It is necessary in the first place to make sure that the products to be used by, or d Seaetary General, Ministrv ofPublic Health and Family Affairs, Belgium b Director, Institute ofHygiene and Epidemiology, Belgium. 157 158 S. Halter and A. LaFontaine made available to, the authorities, the medical profession, or the public, are identified and identifiable (dvrif chemical means are quite often inadeqra e), are measurable to a certain degree using standards or reference substances; are of acceptable safety for patients, users, the public, and basic resources;a and are of demon- strable efflcacy, whether intended for preven- tive, diagnostic, or therapeutic use. Once the priductWhas been accepted, it must be kept under surveillance so as to examine its initial results, detect any side-effects, prevent improper use, and make sure that it remains effective. Moreover, the value of using a biologi- cal product must be regularly assessed by drawing up an asement of the advantages and disadvantages of theproduct in relation both to other products AXd other possible methods. The trend in its effitacy with the passage of time must be evaluated, without forgetting the pos- sibility of delayed siae-effects, unfavourable or otherwise. Definition. The definition of biologicals is very flexible. Initially the term was applied mainly to vaccines, antigens, antibodies, and, in general, to microbiological substances, or sub- stances of micrbbfological origin, and to sub- stances produced by the reactions of the or- ganism to such" products. Biologicals can be used in man or in animals for prophylactic, therapeutic, or diagnostic purposes. (The veteri- nary aspects cannot be separated from the medical aspects proper, particularly as biologi- cals are used in connection with quite a large number of anthropozoonoses.) Subsequently, the term was extended to cover a series of similar substances of biological origin (such as therapeutic substances of human origin) and a sedeg of pharmaceutical sub- stances of biological origin. One of the common features of these substances was that they were often difficulf tWdefine or measure chemically (such as certiPa tltbiotics, initially at least) and that theyw generally assayed by biologi- cal techniques so that some products of purely chemical origin were for some time included in 8Especially for substances intended for veterinary use. the list of biologicals (e.g., arsphenamine). Gradually, with advances in chemistry, anti- biotics such as ristocetin and chleramphenicol, and vitamins such as axerophthol acetate, were removed from this group. Finally, a series of microbiological sub- stances derived trorn the tissues or blood, or that may occur in animal or human antibodies, were included among the biologicals. Among them are the specific and nonspecific globulins and the anti-insulins. Generally speaking, the broad sense of the term biologicals can be described, on the basis of the WHO definition, as "the establishment of international biological standards and inter- national biological reference preparations for the main purpose of providing a uniform and world-wide definition of the potency of pre- parations which are used in the prevenition, treatment, or diagnosis of human and animal diseases, and which cannot be suitably charac- terized by chemical or physical procedures." The second aim of establishing standards and preparations of this kind is to facilitate research that is likely to be applied in clinical practice. Nature of Surveillance. In view of the aims of surveillance, there is no doubt that the char- acteristics of biologicals are such as to require international surveillance. It would be unthinkable, for example, for a country exposed to cholera to use an atten- uated mutant under different geographic condi- tions where it could acquire an unacceptable degree of pathogenicity. It is important that the measurement units and techniques be com- parable, since no chemical reference is possible. Moreover, international trade needs to be faci- litated so that these products, on which the lives of millions of people may depend, can be transferred readily from one country to another. Finally, international surveillance must provide for the essential epidemiological assess- ments (as with smallpox), the communication of observations on efficacy and side.effects, the identification of new needs, and the develop- ment of decision-making procedures. The Need for International Surveilbnce of Bioogials: Distribution, Use, and Efficacy SURVEILLANCE OF THE RULES GOVERNING MANUFACTURE, EXPERIMENTAL STUDIES AND CLINICAL TRIALS, AND THE DISTRIBUTION OF THE SUBSTANCES Clinical trials, to which further reference will be made later, cannot be embarked upon until all the preliminary development work and the experimental studies have been completed and evaluated.' The rules governing development cover the manufacturing standards with which a prepara- tion must comply if it is to be active, reliable, and safe. The international adoption of these rules would facilitate the exchange of products between countries and would provide guidelines for the authorities responsible for national pro- duction, who might otherwise experience dif- ficulty in selecting appropriate methods for testing and control. Most biological substances can be effectively controlled only during their processing; in this respect they differ fundamentally from conven- tional medicines, where control is concerned mainly with the finished product. For example, how can the presence of adventitious virus be determined in a Salk vaccine during prepara- tion? How can the clharacternstics of the vaccine antigen be ascertained? How can the quality of tissue cultures be established? Problems of this kind call for the establishment of international rules of 'production that each manufacturing country will adopt and will guarantee to have applied to any product exported to another country. In general, these standards apply to the producers and to control laboratories. The standards concerning manufacturers deal with the qualifications of technical personnel and with the authority they must be able to exercise over manufacture; with the premises and equipment they must have at their disposal: with the administrative and technical checks to be conducted during production: with the efficacy, safety, and stability tests; with the packaging of the products; with the arrange- ments for sampling and labeling; with storage and distribution; and with recordkeeping. The general standards concerning control laboratories also deal with the qualifications and authority of the staff, with the premises and equipment, and with the method of work. The most effective method, in our view, is the granting of manufacturing licenses, the organi- zation of inspections, and the performance of the necessary control tests on the strains, on the intermediate stages of manufacture (with the development of effective measures for inter- mediate control that permit an objective inter- pretation of the tests and an assessment of their reliability), and on the finished products. This control laboratory, backed up by a competent scientific council, should issue the general per- mit, followed by an individual permit for each batch released, and should draw up a control certificate for products manufactured and con- trolled within the country for the benefit of importing countries. Admittedly the standards and conditions will vary according to the type of substance: those described below apply mainly to vaccines, but they can also be extended, often in a more flexible form, to other biotogicals for which the control of the finished product may be easier. However this may be, there is a public health danger that biologicals may be incautiously lumped together with pharmaceutical products, as was certainly the conviction ofWHO when it organized this meeting. If these standards are to be put into effect it is also essential, even starting from international units and reference standards, to have interna- tional reference preparations that permit effec- tive comparison. The changeover from experimental lab- oratory studies and tests on laboratory animals to practical utilization is a delicate matter. It presupposes, firstly, the strict application of the medical (or veterinary) ethics goveming any new method of prophylaxis, therapy, or diag- nosis. I stress the aspect of diagnosis, since the 159 160 ' S EHalter snd A.LaFoutslne marketing of a bad tuberculin or a bad melitin may have disastw8 consequences both for the individual and for the epidemiology of infec- tious diseases. Secondly, it presupposes an ob- jective evaluation of the results (which should be regularly checked after the introduction of the product, whwr appropnrate) and of any concurrent or oonoomtant factors, whether medical or othervite (e.g., in cholera control, is it preferable to vncdcte, to undertake sanita- tion measures, or to apply chemoprophylaxis?). This delicate point deserves the special atten- tion of the Conference. There are twol other basic aspects that should be considered, particularly for live vac- cines. 1. The stabiy -of the attenuation char- acistics oihe strins used (neither too much nor too little): This leads to the virtal necemsty for seed lots. 2. The dm a of the cells or cell lines used or of the hum or animal sub- jts, paric in the ese of imnmuno- logical product, therapeutic substances, or tisue pepwations. SURVEILLANCE OF USE The fundamental rules set out in the section on surveillance duxing developmenta apply to the regular manufacture and distribution of biological substanom. Among the problems raised by distribution, attention is drawn to the need to abide by the prescribed conditions (physical condition, temperature, conditions of transport and distri- bution, and so on) and to observe the expira- tion dates. In many cases special distribution networks are needed to ensure stability and be- cause the authorities need to check on the ap- plication of a given prophylactic, diagnostic, or even therapeutic measure. A further requirement may be that adminis- tration of the substances be restricted to specially trained persons, able to keep a register and a geographical area of the admnistration of the products or of the results of tests, both in groups and in individuals. This is because it is important to know when and how children were vaccinated, whether they were given sera or serum fractions, whether their skin reaction underwent conversion, or whether their serolo- gical tests were positive for syphilis or yaws. Moreover, the authorities should organize sentinel groupsb.as a check on the efficiency of prevention (e.g., vaccines) or treatment (e.g., anti-Rh globulins) and it would be valuable to consider the use of control groups. In addition, however, It must be possible to assess the dura- tion of immunization (or sensitization) and the sentinel groups must enable the investigator to follow, for example, the duration of the pre- scribed level of safety for poliomyelitis or rubella vaccine. However, surveillance of use must also cover more subtle factors, such as the persistence of the characteristics and effects of a vaccine, the detection of side-effects, im- mediate or otherwise, the possible importance of revaccinations, and so on. SURVEILLANCE OF EFFICACY In the light of the defmition of biologicals, we must clearly distinguish between: 1. Biologicals with a specific therapeutic action (specific sera, certaIn antibiotics, certain hormones, allerges) or with more general action (ganma globulins); 2. Bioloials used for diagnos In v*io (tuberculin, Frei antie, melitin, sler- Sens) or for diagnos in vitro (antigens for the detection of antibodies, anti- bodies for the identification of nAcro- organisms or biological subdances, and so on);ad 3. Biologicals with a prophylactic action (especially vaccines and antigens, some substances derived from blood, globulins for the prevention of hepatitis). aSoc WHO Technica Report Series No. 323: Requirements for Biological Substances (19661 bA sentinel group could consist, for example, of vaccinated subjects kept under careful surveillance. It differs from the control group, which b often difficult to accept from the ethical point of view. The Need for International Surveillance of Bioiopcals: Distribution, Use, and Efficacy In the first two cases, the surveillance of ef- ficacy is mainly concerned with the quality control carried out by the control laboratory and with the skdll of the user. In the third case, other factors such as the conditions governing the onset of the disease may be involved, or there may be concurrent or concomitant factors at either the individual or group level. The public health services have a major part to play in controlling these factors; hence, such biologicals should remain under the permanent supervision of these authorities. As regards the conditions goveming the on- set of a disease, there is the example of in- fluenza, for which any preventive activity must be backed up by active epidemiological and nosological surveillance. The safeguarding of smallpox eradication necessarily entails careful surveillance of any potential reservoirs in pri- mates. The appearance of rabies among rodents in Westem Europe is an unexpected occurrence that could revive the whole rabies problem. And as for poliomyelitis vaccination, it must be accompanied by checks on the virological situa- tion and on the immunity status of the vac- cinated subjects and poputations and by identi- fication of all cases of clinically similar neuro- logical conditions. Concurrent factors involve the synergistic (or anergic!) effect of other conditions. In diag- nosis, this effect may take the form of trouble- some interferences, such as yaws in association with syphilis. The conconitant factors may be of a dif- ferent kind. For example, the immunological defense of a child with kwashiorkor is very dif- ferent from that of the normal child. As for cholera, it is valid to compare the effects of vaccine in an affected area and in a neigh- bouring area with similar sanitation; but it is absurd to compare the effect of vaccine on well-fed white people who observe the basic rules of hygiene with the effect of the vaccine on starving populations incapable of applying any elementary rules of hygiene. rhese investigations make it necessary to make certain decisions, such as whether to re- place an inactivated vaccine with a live vaccine (poliomyelitis) or to replace a parenteral vac- cine with one administered by a different route (rubella or influenza). These considerations show the complexity and subtlety of the necessary investigations and of the resulting conclusions. The varied nature of some decisions based on the observed facts makes it practicalUy es- sential for an international agency to intervene, since few countries could undertake all the in- vestigations and research needed by themselves; it is not easy for each and every public health authority to decide independently on the policy to follow. CONCLUSIONS The above elements-which in any case do not claim to cover all aspects-are so complex and numerous and involve such a variety of pos- sible situations that they call for intemational collaboration. The experience of recent years, and the work ofWHO in particular, offers clear proof of this. Another proof of the effectiveness of in- ternational collaboration can be found in the work that the Center for Disease Control, Atlanta, an agency of the U.S. Public Health Service, has been doing for many years, parti- cularly with respect to laboratory reagents used for the activities mentioned in this paper. There are many other initiatives in the form of bilateral or multilateral collaboration be- tween countries in certain regions. 161