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Vaccine quality—can a single standard be defined?
Vaccine 20 (2002) 1000–1003
Short communication
Vaccine quality—can a single standard be defined? Julie Milstien∗ , Nora Dellepiane, Scott Lambert, Lahouari Belgharbi, Chris Rolls1 , Ivana Knezevic, Jacqueline Fournier-Caruana, David Wood, Elwyn Griffiths Department of Vaccines and Biologicals, World Health Organization, Geneva, Switzerland Received 6 September 2001; accepted 17 September 2001
Abstract To analyze the current global situation with respect to vaccine quality and to monitor progress in attaining it, it is first necessary to define what this means. While acknowledging that manufacturers are responsible for the quality of the vaccines they produce, World Health Organization (WHO) proposes a definition for “vaccines of assured quality” which depends on the existence of a competent and fully functional regulatory authority as assessed by an external expert team using widely agreed indicators to regulate the product. A vaccine of assured quality is defined as one that consistently meets appropriate levels of purity, potency, safety and efficacy as judged through an independent review system competent to take an evidence-based decision on the product for a specified population in a specific context. Such a review system would make use of all available information, such as licensing dossiers, surveillance of field performance, lot-by-lot scrutiny, appropriate laboratory testing, cGMP inspection of manufacturers, and evaluation of clinical trials, generally assumed by a fully functional regulatory authority. This definition implies that, faced with the same risk/benefit, any competent group would come to the same decision. The definition also indicates clear pathways to improve vaccine quality by strengthening national regulatory authorities and WHO is actively engaged in this task. By insisting on competent regulatory oversight, while recognizing the role of risk analysis in the selection of vaccines for use, WHO strongly reiterates the need for a single standard of quality. Only vaccine of assured quality should be considered for use in national immunization programs on the basis of the risk/benefit ratio for the particular population. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Vaccine development; Vaccine quality; World Health Organization; Risk/benefit; Vaccine regulation
1. Introduction
2. Definition: vaccine of assured quality
As part of its mandate to assure the quality of vaccines used in national immunization programs, the World Health Organization (WHO) has a multi-pronged approach of interventions—directed at manufacturers, national and regional regulatory agencies and researchers—to ensure vaccine quality. To analyze the current global situation with respect to vaccine quality and to monitor progress in attaining it, it is first necessary to define what this means. Once this is done, discussion can begin on whether there can be, are, or should be different standards of vaccine quality. It has historically been difficult to arrive at a single definition of vaccine quality as needs and thus, the risk/benefit ratio may differ in different situations. However, it is important to arrive at a definition that is reasonable and consistent.
Most authorities agree on the concepts of safety, efficacy and purity in a definition of vaccine quality. In addition, lot-to-lot consistency in the manufacturing process should be demonstrated. The international standards for these parameters are defined for individual vaccines by the WHO Expert Committee on Biological Standardization in WHO requirements, recommendations or guidelines for production and control of vaccines (see, e.g. [1]). While acknowledging that manufacturers are responsible for the quality of the vaccines they produce, WHO has defined compliance with vaccine quality specifications in terms of the active functioning of a competent regulatory body [2]. This paper proposes the following definition for a vaccine of assured quality:
∗
Corresponding author. Tel.: +41-22-791-3564; fax: +41-22-791-4384. E-mail address: [email protected] (J. Milstien). 1 Present address: Therapeutic Goods Administration, Canbera, Australia.
A vaccine product that, on a lot-to-lot basis, consistently meets appropriate levels of purity, potency, safety and efficacy as judged through an independent review system competent to take an evidence-based decision
0264-410X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 1 ) 0 0 4 2 2 - 4
J. Milstien et al. / Vaccine 20 (2002) 1000–1003
on the product for a specified population in a specific context. Implicit in the definition is that, faced with the same risk/benefit, any competent group would come to the same decision. Vaccines of assured quality are thus defined in terms of the national regulatory authority or equivalent body responsible for regulatory oversight. WHO has provided guidelines on what constitutes an appropriate regulatory body [3,4], the nature of the functions they should have legally enforceable powers to perform (licensing, surveillance of field performance, lot-by-lot scrutiny, appropriate laboratory testing, cGMP inspection of manufacturers and evaluation of clinical trials), and has defined through wide consultation indicators to assess national regulatory performance at the global level [5].
3. Implications of the definition The definition above has several key implications that must be recognized. First of all, the definition gives the national (or regional for Europe) regulatory body the major role in impacting vaccine quality, and in addition defines the need for activities based on assuring the functioning of national regulatory authorities as a major way to improve vaccine quality. This approach has been employed by WHO in recent years and has allowed a documentation of the functioning of the national regulatory authority in 31 of 50 vaccine producing countries to date. With this system, WHO can now say, for example, that virtually 100% of Hemophilus influenzae type b vaccine used in the world is of assured quality, while for BCG vaccine, that figure is closer to 50%. A second implication is that risk perception and the risk/benefit ratio will have a strong impact on the acceptability of the products. This does not mean that a product is of intrinsically lower quality if it is acceptable in one country and not another. For example, vaccines for most public sector immunization programs are required to meet certain standards of thermostability and so, for example, all measles containing vaccines sold to United Nations agencies must meet the WHO recommendation for thermostability at 37 ◦ C for 7 days in the lyophilized form. Measles-containing vaccines for use in several industrialized countries do not need to meet this criterion as it is judged that the risk of heat damage through the distribution system is low. This does not mean that the vaccine not confirmed as thermostable is of lower quality. Another example of the suitability of vaccine in a particular population based on risk/benefit ratio could be a candidate HIV-1 vaccine. HIV-1 vaccine with about 50% efficacy could have positive effect if used in populations with high HIV-1 incidence, but might not be suitable for the population in countries with a low incidence of HIV infection. Also, the efficacy and safety of an HIV vaccine tested in a US population might not be suitable for an African population because
1001
of differences in laboratory values and confounding epidemiological parameters in the local population (e.g. higher eosinophil counts because of intestinal helminths which is common in some countries) which could have an impact on the immune response as well as on safety evaluation. A third example has to do with the use of thiomersal as a preservative in vaccines. In monodose vaccine presentations steps are being taken to limit the use of thiomersal because of the perceived risk of exposure of infants to mercury through multiple immunizations. Because of cost and capacity constraints, single dose presentations are not available to the developing world. Faced with the choice of no vaccine or vaccines containing sufficient thiomersal to protect against the real risk of contamination in field use, WHO and many countries have opted to continue use of multi-dose vaccines containing thiomersal. This does not mean that vaccines preserved with thiomersal are of lower quality. Indeed, a thiomersal-free inactivated tick-borne encephalitis vaccine was recently withdrawn from the market because of adverse events not seen with the thiomersal-containing product. On the other hand, authorization of marketing of a less effective vaccine to ensure absence of adverse events when safe alternatives exist might be seen as allowing the use of a lower quality vaccine. This charge has been directed at several regulatory authorities authorizing the marketing of some acellular pertussis vaccines. The importance is that the risk decision must be evidencebased. There is scope for different decisions confronted with the same set of vaccine characteristics in different situations. Both of the implications discussed above, the role of the national regulatory authority and the impact of national risk assessment in acceptability, are in line with current interpretations of the technical barriers to trade provisions of the World Trade Organization [6] as they impact vaccine quality.
4. Testing the definition 4.1. Is this definition useful? Consider the case of combination vaccines based on DTwP (whole cell pertussis). This is a fairly new product line now being incorporated into many developing countries immunization schedules. At the same time, a parallel product line, based on DTaP (acellular pertussis) is being used in many industrialized countries. In fact, these DTwP-based combination vaccines are currently licensed in Europe, on the understanding that they will not be marketed within Europe. Yet they are manufactured by well-known vaccine manufacturing firms to the highest standards, have received rigorous review in terms of appropriateness of clinical data through the European centralized procedure, meet WHO requirements and the conditions of United Nations agencies tenders. Moreover, they are subject to continuing regulatory oversight deemed by both WHO and most countries to be
1002
J. Milstien et al. / Vaccine 20 (2002) 1000–1003
fully functional and competent. This situation may present a dilemma for those countries and there are many that define use in the country of manufacture as an essential criterion of vaccine quality. These vaccine do not meet this criterion, yet it is doubtful that they would be excluded in definitions of quality vaccines. The proposed WHO definition can resolve this dilemma. 4.2. Are there circumstances where a vaccine might be felt to be of assured quality in one situation and not in another? An example of this is a product, say oral polio vaccine, for which the working seed may have been grown using bovine serum sourced from countries with reported cases of bovine spongiform encephalopathy (BSE). Until the recognition a few years ago of the epidemiological link between consumption of beef from certain areas and a variant of Creuzfeld-Jacob disease, bovine sera sourced from Europe and products produced using it were considered totally acceptable. Despite the fact that there has been no evidence that sera could transmit BSE and that the dilution factor of residual sera from working seed to final product is many orders of magnitude, most national regulatory authorities now choose to disqualify products where there is any association with European-sourced sera. The product is the same—and yet by many definitions it is no longer of good quality. The definition of assured quality allows a systematic and transparent way to resolve this contradiction.
regulate products that are being purchased by United Nations agencies, such as the US, France, India, Japan and Korea, have been evaluated by the same criteria. Experts from many countries, including for example Australia, Belgium, Brazil, Egypt, Indonesia, Poland, South Africa, and Tunisia, have been trained in the methodology and made up the assessment teams along with WHO staff. In some cases, joint assessment teams have evaluated regulatory authorities for their capacity to oversee both pharmaceutical products and vaccines, thus expanding the impact of the strategy. The process has resulted in a quantifiable improvement in the way regulatory authorities perform their mission, and WHO maintains records, function by function, of this progress. This process will continue for the foreseeable future. 5.2. Networking among regulatory authorities National regulatory authorities should share information that will allow other authorities know that they have reviewed the data submitted for licensing, and to notify them of observations during the course of product marketing. This information sharing will strengthen all regulatory authorities in the performance of their missions. WHO is supporting this effort by:
It is our position that what we are defining is one standard of compliance to the basic elements that impact quality, recognizing that the ratio between risks and benefits will change depending on the context in which the product is used.
• The Global Training Network for Vaccine Quality, a group of selected training institutions offering training and follow-up activities in topics related to vaccine regulation according to standardized curricula. • Promoting networking among national regulatory authorities for vaccines both through existing structures, such as the regional conferences of drug regulatory authorities and the drug monitoring centers, and through the follow-up workshops of the Global Training Network. • Developing new curricula relating to licensing and regulation of vaccines that emphasize the need for communication among regulatory authorities.
5. Future activities
5.3. Strengthen the capacity of countries to carry out risk analyses and weigh these against potential benefit
4.3. Does this necessarily mean two or more standards of quality?
The definition is also useful in that it mandates clear activities that should proceed both at the national and the international levels to improve vaccine quality and its perception. 5.1. Strengthen national regulatory authorities using harmonized criteria As mentioned, many countries and regulatory experts have already been involved in development and application of the criteria for assessing national regulatory authorities. Input was solicited from 38 countries in developing the indicators and a meeting of recognized experts was held at WHO to finalize them. Since that time, they have been tested in almost 50 countries. National regulatory authorities who
Risk/benefit analysis capacity needs to be promoted. At present it is not an integral part of vaccine utilization decisions in countries. The recent case of rotavirus vaccine is a case in point. The product, produced in the US and licensed by the US Food and Drug Administration, was reported to be associated with cases of intussusception during a large phase-IV post marketing study. The product is still licensed in the US, but the manufacturer has withdrawn it from the market following withdrawal of recommendations for its use by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics [7]. This decision was followed by several meetings discussing the potential use of the product in developing countries. In this case the possibilities for the use of this particular vaccine do not
J. Milstien et al. / Vaccine 20 (2002) 1000–1003
exist as the manufacturer has confirmed that it will not be available. However, the scenario might have been different had risk analysis capacity in countries that could have strongly benefited from use of this product been stronger. 5.4. Advocacy In a less than perfect world, whenever there is the possibility of more than one alternative, people are bound to think that one alternative might be “better” or “worse” than the other. What WHO is trying to emphasize in this approach to vaccine quality is that there is only one standard of quality—and that standard will be enforced by a competent regulatory authority. However, there may be a different selection of products appropriate to different epidemiological situations. To get this message across will need a strong advocacy message on the part of the public sector.
1003
References [1] WHO Technical Report Series 897, In: Proceedings of the 49th Meeting of this Committee, Geneva, 1998. [2] Statement on vaccine quality, WHO/VSQ/GEN/96.02 Rev, available from Document Center, Department of Vaccines and Biologicals, WHO, Geneva, http://www.who.int/vaccines-documents. [3] WHO Technical Report Series, 822, Annex 2. Guidelines for national authorities on quality assurance for biological products, 1992. [4] WHO Technical Report Series, 858, Annex 1. Regulation and licensing of biological products in countries with newly developing regulatory authorities, 1995. [5] Regulation of vaccines: building on existing drug regulatory authorities, WHO/V&B/99.10, available from Document Center, Department of Vaccines and Biologicals, WHO, Geneva, http://www.who.int/vaccines-documents. [6] Technical Barriers to Trade, Article 2.5. [7] Centers for Disease Control and Prevention: Withdrawal of rotavirus vaccine recommendation. MMWR Morb Mortal Wkly Rep 1999;48(43):1007.
Short communication
Vaccine quality—can a single standard be defined? Julie Milstien∗ , Nora Dellepiane, Scott Lambert, Lahouari Belgharbi, Chris Rolls1 , Ivana Knezevic, Jacqueline Fournier-Caruana, David Wood, Elwyn Griffiths Department of Vaccines and Biologicals, World Health Organization, Geneva, Switzerland Received 6 September 2001; accepted 17 September 2001
Abstract To analyze the current global situation with respect to vaccine quality and to monitor progress in attaining it, it is first necessary to define what this means. While acknowledging that manufacturers are responsible for the quality of the vaccines they produce, World Health Organization (WHO) proposes a definition for “vaccines of assured quality” which depends on the existence of a competent and fully functional regulatory authority as assessed by an external expert team using widely agreed indicators to regulate the product. A vaccine of assured quality is defined as one that consistently meets appropriate levels of purity, potency, safety and efficacy as judged through an independent review system competent to take an evidence-based decision on the product for a specified population in a specific context. Such a review system would make use of all available information, such as licensing dossiers, surveillance of field performance, lot-by-lot scrutiny, appropriate laboratory testing, cGMP inspection of manufacturers, and evaluation of clinical trials, generally assumed by a fully functional regulatory authority. This definition implies that, faced with the same risk/benefit, any competent group would come to the same decision. The definition also indicates clear pathways to improve vaccine quality by strengthening national regulatory authorities and WHO is actively engaged in this task. By insisting on competent regulatory oversight, while recognizing the role of risk analysis in the selection of vaccines for use, WHO strongly reiterates the need for a single standard of quality. Only vaccine of assured quality should be considered for use in national immunization programs on the basis of the risk/benefit ratio for the particular population. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Vaccine development; Vaccine quality; World Health Organization; Risk/benefit; Vaccine regulation
1. Introduction
2. Definition: vaccine of assured quality
As part of its mandate to assure the quality of vaccines used in national immunization programs, the World Health Organization (WHO) has a multi-pronged approach of interventions—directed at manufacturers, national and regional regulatory agencies and researchers—to ensure vaccine quality. To analyze the current global situation with respect to vaccine quality and to monitor progress in attaining it, it is first necessary to define what this means. Once this is done, discussion can begin on whether there can be, are, or should be different standards of vaccine quality. It has historically been difficult to arrive at a single definition of vaccine quality as needs and thus, the risk/benefit ratio may differ in different situations. However, it is important to arrive at a definition that is reasonable and consistent.
Most authorities agree on the concepts of safety, efficacy and purity in a definition of vaccine quality. In addition, lot-to-lot consistency in the manufacturing process should be demonstrated. The international standards for these parameters are defined for individual vaccines by the WHO Expert Committee on Biological Standardization in WHO requirements, recommendations or guidelines for production and control of vaccines (see, e.g. [1]). While acknowledging that manufacturers are responsible for the quality of the vaccines they produce, WHO has defined compliance with vaccine quality specifications in terms of the active functioning of a competent regulatory body [2]. This paper proposes the following definition for a vaccine of assured quality:
∗
Corresponding author. Tel.: +41-22-791-3564; fax: +41-22-791-4384. E-mail address: [email protected] (J. Milstien). 1 Present address: Therapeutic Goods Administration, Canbera, Australia.
A vaccine product that, on a lot-to-lot basis, consistently meets appropriate levels of purity, potency, safety and efficacy as judged through an independent review system competent to take an evidence-based decision
0264-410X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 1 ) 0 0 4 2 2 - 4
J. Milstien et al. / Vaccine 20 (2002) 1000–1003
on the product for a specified population in a specific context. Implicit in the definition is that, faced with the same risk/benefit, any competent group would come to the same decision. Vaccines of assured quality are thus defined in terms of the national regulatory authority or equivalent body responsible for regulatory oversight. WHO has provided guidelines on what constitutes an appropriate regulatory body [3,4], the nature of the functions they should have legally enforceable powers to perform (licensing, surveillance of field performance, lot-by-lot scrutiny, appropriate laboratory testing, cGMP inspection of manufacturers and evaluation of clinical trials), and has defined through wide consultation indicators to assess national regulatory performance at the global level [5].
3. Implications of the definition The definition above has several key implications that must be recognized. First of all, the definition gives the national (or regional for Europe) regulatory body the major role in impacting vaccine quality, and in addition defines the need for activities based on assuring the functioning of national regulatory authorities as a major way to improve vaccine quality. This approach has been employed by WHO in recent years and has allowed a documentation of the functioning of the national regulatory authority in 31 of 50 vaccine producing countries to date. With this system, WHO can now say, for example, that virtually 100% of Hemophilus influenzae type b vaccine used in the world is of assured quality, while for BCG vaccine, that figure is closer to 50%. A second implication is that risk perception and the risk/benefit ratio will have a strong impact on the acceptability of the products. This does not mean that a product is of intrinsically lower quality if it is acceptable in one country and not another. For example, vaccines for most public sector immunization programs are required to meet certain standards of thermostability and so, for example, all measles containing vaccines sold to United Nations agencies must meet the WHO recommendation for thermostability at 37 ◦ C for 7 days in the lyophilized form. Measles-containing vaccines for use in several industrialized countries do not need to meet this criterion as it is judged that the risk of heat damage through the distribution system is low. This does not mean that the vaccine not confirmed as thermostable is of lower quality. Another example of the suitability of vaccine in a particular population based on risk/benefit ratio could be a candidate HIV-1 vaccine. HIV-1 vaccine with about 50% efficacy could have positive effect if used in populations with high HIV-1 incidence, but might not be suitable for the population in countries with a low incidence of HIV infection. Also, the efficacy and safety of an HIV vaccine tested in a US population might not be suitable for an African population because
1001
of differences in laboratory values and confounding epidemiological parameters in the local population (e.g. higher eosinophil counts because of intestinal helminths which is common in some countries) which could have an impact on the immune response as well as on safety evaluation. A third example has to do with the use of thiomersal as a preservative in vaccines. In monodose vaccine presentations steps are being taken to limit the use of thiomersal because of the perceived risk of exposure of infants to mercury through multiple immunizations. Because of cost and capacity constraints, single dose presentations are not available to the developing world. Faced with the choice of no vaccine or vaccines containing sufficient thiomersal to protect against the real risk of contamination in field use, WHO and many countries have opted to continue use of multi-dose vaccines containing thiomersal. This does not mean that vaccines preserved with thiomersal are of lower quality. Indeed, a thiomersal-free inactivated tick-borne encephalitis vaccine was recently withdrawn from the market because of adverse events not seen with the thiomersal-containing product. On the other hand, authorization of marketing of a less effective vaccine to ensure absence of adverse events when safe alternatives exist might be seen as allowing the use of a lower quality vaccine. This charge has been directed at several regulatory authorities authorizing the marketing of some acellular pertussis vaccines. The importance is that the risk decision must be evidencebased. There is scope for different decisions confronted with the same set of vaccine characteristics in different situations. Both of the implications discussed above, the role of the national regulatory authority and the impact of national risk assessment in acceptability, are in line with current interpretations of the technical barriers to trade provisions of the World Trade Organization [6] as they impact vaccine quality.
4. Testing the definition 4.1. Is this definition useful? Consider the case of combination vaccines based on DTwP (whole cell pertussis). This is a fairly new product line now being incorporated into many developing countries immunization schedules. At the same time, a parallel product line, based on DTaP (acellular pertussis) is being used in many industrialized countries. In fact, these DTwP-based combination vaccines are currently licensed in Europe, on the understanding that they will not be marketed within Europe. Yet they are manufactured by well-known vaccine manufacturing firms to the highest standards, have received rigorous review in terms of appropriateness of clinical data through the European centralized procedure, meet WHO requirements and the conditions of United Nations agencies tenders. Moreover, they are subject to continuing regulatory oversight deemed by both WHO and most countries to be
1002
J. Milstien et al. / Vaccine 20 (2002) 1000–1003
fully functional and competent. This situation may present a dilemma for those countries and there are many that define use in the country of manufacture as an essential criterion of vaccine quality. These vaccine do not meet this criterion, yet it is doubtful that they would be excluded in definitions of quality vaccines. The proposed WHO definition can resolve this dilemma. 4.2. Are there circumstances where a vaccine might be felt to be of assured quality in one situation and not in another? An example of this is a product, say oral polio vaccine, for which the working seed may have been grown using bovine serum sourced from countries with reported cases of bovine spongiform encephalopathy (BSE). Until the recognition a few years ago of the epidemiological link between consumption of beef from certain areas and a variant of Creuzfeld-Jacob disease, bovine sera sourced from Europe and products produced using it were considered totally acceptable. Despite the fact that there has been no evidence that sera could transmit BSE and that the dilution factor of residual sera from working seed to final product is many orders of magnitude, most national regulatory authorities now choose to disqualify products where there is any association with European-sourced sera. The product is the same—and yet by many definitions it is no longer of good quality. The definition of assured quality allows a systematic and transparent way to resolve this contradiction.
regulate products that are being purchased by United Nations agencies, such as the US, France, India, Japan and Korea, have been evaluated by the same criteria. Experts from many countries, including for example Australia, Belgium, Brazil, Egypt, Indonesia, Poland, South Africa, and Tunisia, have been trained in the methodology and made up the assessment teams along with WHO staff. In some cases, joint assessment teams have evaluated regulatory authorities for their capacity to oversee both pharmaceutical products and vaccines, thus expanding the impact of the strategy. The process has resulted in a quantifiable improvement in the way regulatory authorities perform their mission, and WHO maintains records, function by function, of this progress. This process will continue for the foreseeable future. 5.2. Networking among regulatory authorities National regulatory authorities should share information that will allow other authorities know that they have reviewed the data submitted for licensing, and to notify them of observations during the course of product marketing. This information sharing will strengthen all regulatory authorities in the performance of their missions. WHO is supporting this effort by:
It is our position that what we are defining is one standard of compliance to the basic elements that impact quality, recognizing that the ratio between risks and benefits will change depending on the context in which the product is used.
• The Global Training Network for Vaccine Quality, a group of selected training institutions offering training and follow-up activities in topics related to vaccine regulation according to standardized curricula. • Promoting networking among national regulatory authorities for vaccines both through existing structures, such as the regional conferences of drug regulatory authorities and the drug monitoring centers, and through the follow-up workshops of the Global Training Network. • Developing new curricula relating to licensing and regulation of vaccines that emphasize the need for communication among regulatory authorities.
5. Future activities
5.3. Strengthen the capacity of countries to carry out risk analyses and weigh these against potential benefit
4.3. Does this necessarily mean two or more standards of quality?
The definition is also useful in that it mandates clear activities that should proceed both at the national and the international levels to improve vaccine quality and its perception. 5.1. Strengthen national regulatory authorities using harmonized criteria As mentioned, many countries and regulatory experts have already been involved in development and application of the criteria for assessing national regulatory authorities. Input was solicited from 38 countries in developing the indicators and a meeting of recognized experts was held at WHO to finalize them. Since that time, they have been tested in almost 50 countries. National regulatory authorities who
Risk/benefit analysis capacity needs to be promoted. At present it is not an integral part of vaccine utilization decisions in countries. The recent case of rotavirus vaccine is a case in point. The product, produced in the US and licensed by the US Food and Drug Administration, was reported to be associated with cases of intussusception during a large phase-IV post marketing study. The product is still licensed in the US, but the manufacturer has withdrawn it from the market following withdrawal of recommendations for its use by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics [7]. This decision was followed by several meetings discussing the potential use of the product in developing countries. In this case the possibilities for the use of this particular vaccine do not
J. Milstien et al. / Vaccine 20 (2002) 1000–1003
exist as the manufacturer has confirmed that it will not be available. However, the scenario might have been different had risk analysis capacity in countries that could have strongly benefited from use of this product been stronger. 5.4. Advocacy In a less than perfect world, whenever there is the possibility of more than one alternative, people are bound to think that one alternative might be “better” or “worse” than the other. What WHO is trying to emphasize in this approach to vaccine quality is that there is only one standard of quality—and that standard will be enforced by a competent regulatory authority. However, there may be a different selection of products appropriate to different epidemiological situations. To get this message across will need a strong advocacy message on the part of the public sector.
1003
References [1] WHO Technical Report Series 897, In: Proceedings of the 49th Meeting of this Committee, Geneva, 1998. [2] Statement on vaccine quality, WHO/VSQ/GEN/96.02 Rev, available from Document Center, Department of Vaccines and Biologicals, WHO, Geneva, http://www.who.int/vaccines-documents. [3] WHO Technical Report Series, 822, Annex 2. Guidelines for national authorities on quality assurance for biological products, 1992. [4] WHO Technical Report Series, 858, Annex 1. Regulation and licensing of biological products in countries with newly developing regulatory authorities, 1995. [5] Regulation of vaccines: building on existing drug regulatory authorities, WHO/V&B/99.10, available from Document Center, Department of Vaccines and Biologicals, WHO, Geneva, http://www.who.int/vaccines-documents. [6] Technical Barriers to Trade, Article 2.5. [7] Centers for Disease Control and Prevention: Withdrawal of rotavirus vaccine recommendation. MMWR Morb Mortal Wkly Rep 1999;48(43):1007.