Licensing of Biological Products: A Survey of Practices

Licensing of Biological Products: A Survey of Practices F. T. PERKINS In some countries there has been control of biological products for over 50 years but the degree of control has varied from a "gentle- man's agreement" to strict control with mean- ingful inspection. It is interesting to observe that the controls of biological products as they exist today have been developed largely as a result of two major accidents. The Cutter incident in America in 1955,in which a batch of inactivated poliomyelitis vaccine containing live Mahoney type I poliomyelitis virus was inadver- tently released with devastating consequences, led to a most stringent enquiry into the production of vaccines and sera with a subse- quent penetrating review of the methods of the production and control of biological substances in general. In addition to this, the "thalidomide affair" showed that there was a need for the establishment of regulatory authorities with powers to inspect production and demand tests of new drugs on an unprecedented scale in an attempt to prevent any future smilar occur- rence of such an unfortunate episode. By some it may be argued that the pendulum has swung too far in the direction of control, and research thereby is being seriously hampered, but it is to be hoped that in order that progress may continue we may find a way to advance research for the benefit of mankind. In preparing for this presentation an enquiry was sent to 14 countries known to have different systems for the control of vaccines and sera. These ranged from countries in which it was difficult to determine the precise pro- cedure followed, because unique powers were in the hands of a small group of people in the Ministry of Health, to those countries in which all stages of the procedure were published in the most minute detail and neither producer nor controller was allowed flexibility in the interpretation of the law. There was a distiction between those coun- tries in which the vaccines and sera were produced by government laboratories, which merely satisfied the needs of the country and were not interested in exporting their products, and those countries in which there were many manufacturers selling their products at home and abroad and in which there was much importation. The attitude of the government laboratories naturally tended to be more paro- chial and much more flexible than those coun- tries needing to impose their laws stringently on an international level. Nevertheless, there was no evidence that either system of control was safer than the other because an adequate degree of safety had been built into both systems. In spite of these differences there was a common approach to the licensing of a new product which may be considered in 10 stages and the variations were in the emphasis placed on the importance of each stage. The stages were: 1. Starting materials. The manufacturer in- variably discussed with the control authority or safety committee the bacterial or virus strains to be used for vaccine production. Further- more, media used for the growth of the microorganisms were considered especially with respect to the excipients that may appear in the final product and which may give nrse to sensitization in man. Chief, Biological Standardization. WHO, Geneva 35 F. T. Perkins 2.- Production of seed materal. The produc- tion of the suspension of microorganisms (seed material) from which all batches of vaccine were to be produced was discussed. Special attention was paid to the data on (i) toxi- cology, including those of all excipients, (ii) pharmacology, again including the tests on excipients, (iii) tests for oncogenicity and teratogenicity where appropriate, and (iv) ex- tensive tests in animals. 3. Tests in man. At this stage in some countries tests were done in man and pernis- sdon for such teats may or may not have been required. In some countries the manufacturer carried out the tests on his own employees, accepting full responsibility for any untoward sequelae and makdng provision for compensa- tion. Such studies were carried out with ex- trene care and there were no reports of any consequence with respect to adverse reactions as a result of such pilot trials. Nevertheless, they provided valuable data for the subsequent decisions that were to be made before the approval of the first field trials im lager numbers of volunteers from the public sector. In other countries, where pilot studies on the seed material were carried out, perminsion from a review body was required. Such review bodies had a most diffcult task for there was little guidance to indicate what the outcome of vaccination in nn might be. Where an animal model for experimentation existed, then some guidance may hav been available but in many instances there was no guidance and the initial investigations had to be done in man after demonstrating only freedom from toxicity by al the available biological systems of animals and cell cultures. These tests ot seed material were not done in the majority of the countries. 4. Application for clinical trial. When the manufacturer had established a consistency record for production, an application for a clinical trial was made. The documentation required in such an application varied from country to country but in those countries in which there was a formal review body the documents required included: 4.1 all toxicology and pharmacology data 4.2 all animal data (including rodents and other mammals) 4.3 protocols of production and test data 4.4 results of tests in man (if any) 4.5 protocol of the proposed clinical trial including the names of centres, the investigators as well as the size of the trial. 5. Review of the clinical data. Where there may have been a particular risk the review body may have exercised the right to review the clinical data at several stages during the progress of the trial. This was done in very few countries. 6. Application for marketing. When the manufacturer had produced several batches of vaccine and shown that the strain from which the vaccine was made was safe and inuno- genic in man, then application for marketing was made. The data included in such an application were: 6.1 the production and test data on at least five consecutive batches of vac- cine 6.2 all data on toxicology and pharma- cology 6.3 all data on animal tests 6.4 studies for oncogenicity and tu- mourogenicity 6.5 aU clinical trial data 6.6 copies of the labels, leaflets, and packaging. 7. Granting of a license. In most countries the granting of a license permitted the manu- facturer to market the product without further formality. In some countries, however, there was a requirement, especially for new products, that each batch should be submitted for ex- ternal control, the results of which should be completed before the batch could be marketed. 8. Surveillance in man. Although most countries declared that there was a system of 36 licensing of Biological Produ: A Survey of Praticem 37 surveillance of vaccines, in operation this was mainly superficiaL On the other hand in some countries there was a requirement that the medical records of the first few thousand children receiving a new vaccine were registered in a computer programme and at intervals enquiries into their health were made. 9. Reporting of advrsve reactions Most countries relied upon the reporting of adverse reactions by physicianu as the only means of surveillance. Although in practice this should work, it was known that in all countries there was gross under-reporting. Nevertheless, a vac- cine giving rise to frequent adverse reactions would be brought to the attention of the authorities. 10. Changes in production methods. In countries in which there was a stringent review body system it was incumbent upon the manufacturer to report all changes in manufac- turing procedure. The possible outcome of such changes was reviewed before permission to make the changes was granted. Such a pro- cedure was in force in about half of the countries. Although there appears to be much variation in the enforoement of the review body pro- cedure amongst the countries, there was control in all countries. In the countries involved in the control of products from many manufacturers both at home and abroad there was a compre- hensive, meaningful and stringent control pro- cedure. In addition to the, controls exercised by review bodies, premises and staff of the manu- facturer were inspected and shown to comply with modem methods of good manufacturing practice. The World Health Organization docu- ments referring to such practices, as well as a list of requirements for the manufacture and control of biological substances which are adhered to by most countries are listed as sup- porting documents to this paper.a Over the last two decades hundreds of millions of doses of vaccines have been given with very few reactions. Furthermore each vaccine has been developed by a series of careful studies including those in man and such studies have anply demonstrated the care taken to ensure safety and efficacy. There remains much to be done in developing effective pro- phylactics against respiratory and possibly diarrhoeal diseases as well as against cancer. Man wfll always be required to play a part in the testing of such prophylactics during the stages of development and it is to be hoped that we are able to find a way to allow such progress to continue. Supporting Documents 1. WHO Technical Report Series, 1966, No. 323: Re- quirements fo( Biological Substances: Manufactur- ing Establisbments and Control Laboratories, pp. 11-22. 2. WHO rechnical Report Series, 1970, No. 444, An- nex 3: Development of a National Control Labora- tory for Biological Substaces. 3. WHO Technical Report Series, 1973, No. 530, An- nex 4: Genera Requirements for the Steriity of Biological Substace. 4. WHO Technical Report Serias, 1975, No. 563: Guidelines for Evaluation of Drugs for Use in Man. tAppendix I F. T. Perkins APPENDIX I COMPLETE LIST OF REQUIREMENTS FOR BIOLOGICAL SUBSTANCES No. Year 178 1959 Requirements for Biological Substances: t. General Requirements for Manufacturing Establishments and Control Laboratories 2. Requirements for Poliomyelitis Vaccine (Inactivated) 179.. 1959 Requirements for Biological Substances: 3. Requirements for Yellow Fever Vaccine 4. Requirements for Cholera Vaccine 180 1959 Requirements for Biological Substances: 5. Requirements for Smallpox Vaccine 200 1960 Requirements for Biologcal Substances: 6. General Requirements for the Sterility of Biological Substances 237 1962 Requirements for Biological Substances: 7. Requirements for Poliomyelitis Vaccine (Oral) 274 1964 WHO Expert Committee on Biological Standardization: 8; Requirements for Pertussis Vaccine 9. Requirements for Procaine Benzylpenicillin in Oil with Aluminum Monostearate 293 1964 WHO Expert Committee on Biological Standardization: 10. Requirements for Diphtheria Toxoid and Tetanus Toxiod 323 1966 WHO Expert Group: Requirements for Biological Substances (Revised 1965) 1. General Requirements for Manufacturing Establishments and Control Laboratories 2. Requirements for Poliomyelitis Vaccine (Inactivated) 5. Requirements for Smallpox Vaccme 7. Requirements for Poliomyelitis Vaccine (Oral) 329 1 966 WHO Expert Committee on Biological Standardization. I1. Requirements for Dried BCG Vaccine 12. Requirements for Measles Vaccine (live) and Measles Vaccine (Inactivated) 361 1967 WHO Expert Committee on Biological Standardization: 9. Requirements of Procaine Benzylpenicillin in Oil with Aluminum Monostearate (Revisions adopted 1966) 13. Requirements for Anthrax Spore Vaccine (Live-for Veterinary Use) 14. Requirements for Human Immunoglobulin 15. Requirements for Typhoid Vaccine 384 1968 WHO Expert Committee on Biological Standardization: 16. Requirements for Tuberculins 17. Requirements for Inactivated Influenza Vaccine 38 Licensing of Biological Products: A Survey of Practices No. Year 413 1969 WHO Expert Committee on Biological Standardization: 4. Requirements for Cholera Vaccine (Revised 1968) 18. Requirements for Immune Sera of Animal Origin 444 1970 WHO Expert Committee on Biological Standardization: 19. Requirements for Rinderpest Cell Culture Vaccine (Live) and Rinderpest Vaccine (Iive) 20. Requirements for Brucella abortus Strain 19 Vaccine (Live-for Veterinary Use) 444 1970 WHO Expert Committee on Biological Standardization: Development of a National Control Laboratory for Biological Substances (A guide to the provision of technical facilities) 463 1971 WHO Expert Committee on Biological Standardization: 21. Requirements for Snake Antivenins 486 1972 WHO Expert Committee on Biological Standardization: 7. Requirements for Poliomnyelitis Vaccine (Oral) (Revised 1971) 530 1973 WHO Expert Committee on Biological Standardization: 4. Requirements for Cholera Vaccine (Revised 1968) (Addendum 1973) 6. General Requirements for the Sterility of Biological Substances (Revised 1973) 17. Requirements for Inactivated Influenza Vaccine (Addendum 1973) 22. Requirements for Rabies Vaccine for Human Use 565 1975 WHO Expert Committee on Biological Standardization: Recommendations for the Assessment of Binding-Assay Systems (including Immunoassay and Receptor Assay Systems) for Human Hormones and their Binding Proteins (A guide to the formulation of requirements for reagents and assay kits for the above assays and notes on cytochemical bioassay systems) Development of national assay services for hormones and other substances in community health care xxx 1976 WHO Expert Committee on Biological Standardization: 3. Requirements for Yellow Fever Vaccine (Revised 1975) 20. Specifications of Tests Used in the Requirements for Brucella Abortus Strain 19 Vaccine (Live-for Veterinary Use) (Addendum 1975) 23. Requirements for Meningococcal Polysaccharide Vaccine 39