The continued recognition of the importance of

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1 Pediatric Combination Vaccines: Their Impact on Patients, Providers, Managed Care Organizations, and Manufacturers S. Michael Marcy, MD Objectives: To review the potential benefits of pediatric combination vaccines to children, parents, providers, managed care organizations, and manufacturers and to discuss the scientific, social, and economic issues that need to be addressed to provide optimum uptake of these vaccines. Results: Combination vaccines provide multiple advantages for children, parents, and providers; however, their development involves considerable research and expense to ensure efficacy and safety. As the complexity of these vaccines increases, more extensive laboratory and clinical trials will be needed to ensure antigen compatibility, immunogenicity, and acceptable reactogenicity. To accommodate the large numbers of subjects necessary to establish vaccine efficacy and the absence of rare severe adverse events, revision of future licensure requirements may be necessary. Cost-benefit studies will be helpful in guiding pricing levels for manufacturers, efficient purchase plans for providers, and appropriate reimbursement policies for managed care organizations. Conclusions: The continued development and introduction of new combination vaccines offers significant potential benefits. Optimal uptake will require careful review of their many advantages and attention to potential problems perceived by those who will be affected by their use: manufacturers, children, parents, providers, and payers. (Am J Manag Care 2003;9: ) The continued recognition of the importance of pediatric immunization to minimize and possibly eradicate serious viral and bacterial infections in childhood has led to a dramatic increase in the number of injections children receive in the first years of life. In 1990, 8 injections were required by age 15 to 18 months in the United States. 1 With the introduction of varicella vaccine in 1995 and pneumococcal conjugate vaccine in 2000 and the change to exclusive use of inactivated polio vaccine (IPV) in 1999, children now require 16 to 20 injections within the first 12 to 18 months of life to comply with current recommendations. 2 Although the benefits of these vaccine recommendations are well established, there is apprehension from parents and those administering the vaccines about the emotional and physical impact of the ever-increasing number of vaccine injections on the young child. The response to these concerns has been the development of combination vaccines. Vaccines containing antigens derived from multiple infectious agents or serotypes have been in use in the United States for more than 50 years, starting with the introduction in 1945 of multivalent influenza and pneumococcal vaccines for adults, and followed in 1949 by diphtheria-tetanus (DT) and diphtheriatetanus-pertussis (DTwP) vaccines for routine immunization of infants. 3 This trend continued during the next 4 decades, as additional combinations of live (trivalent oral polio and measles-mumpsrubella) and inactivated (trivalent inactivated polio, 23-valent pneumococcal, and quadrivalent meningococcal) antigens were developed and achieved widespread use. Now, vaccines conferring immunity against 6 distinct infectious conditions (eg, DT-acellular pertussis-ipv-b-haemophilus influenzae type b [DTaP-IPV-HepatitisB-Hib]) have been in use in Europe for several years. 4,5 Additional combinations, some directed against as many as 7 illnesses, are also in use in Europe and Canada or are under consideration for future development (Table). Their availability in the United States From the Department of Pediatrics, University of Southern California and University of California at Los Angeles Schools of Medicine, Los Angeles; and the Department of Pediatrics, Kaiser Foundation Hospital, Panorama City, Calif. Dr Marcy is also a consultant for GlaxoSmithKline and Abbott Pharmaceuticals. This study was funded by an unrestricted educational grant from GlaxoSmithKline, Philadelphia, Pa. Correspondence to: S. Michael Marcy, MD, UCLA Center for Vaccine Research, Harbor UCLA Medical Center, 1124 W Carson St, Torrance, CA mike.marcy@kp.org. 314 THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2003

2 Pediatric Combination Vaccines would go a long way toward reducing the number of injections required in infancy. The introduction of such vaccines into practice has become a priority for public health officials, healthcare providers, third-party payers, and parents. Potential difficulties associated with using combination vaccines are emerging and need to be addressed to ensure that their development and uptake continue. Providers and payers have concerns related to the economics of purchasing, storing, and administering multivalent vaccines and a range of monovalent vaccines for patients who change providers and whose previous immunizations are not synchronous with those in use by their new provider. There is also the uncertainty of efficacy after use of different vaccines from different manufacturers and the safety (and cost) of administration of superfluous extra antigens when components of a combination vaccine overlap with previous immunizations. Pharmaceutical manufacturers, uneasy over rising development costs, are concerned about the need for large and expensive phase 3 safety and efficacy trials for each new addition, or change in combination, of antigens in a multivalent vaccine. All of these issues need to be addressed if the availability of new combination vaccines is to continue. With the imminent licensure of several new combination vaccines, administrators and clinicians need to be informed about their benefits and drawbacks and about the process by which these products are conceived, developed, evaluated, and marketed. This article highlights the extensive research required for licensure of multivalent vaccines, their potential economic and societal benefits, and possible measures that can facilitate their continued availability and ensure their uptake by the medical community. 9 DEVELOPMENT OF COMBINATION VACCINES Table. Pediatric Combination Vaccines: New and Under Development* 5-8 HepB-HepA* DTaP-HepB* DTaP-HepB-Hib DTaP-IPV-Hib* DTaP-HepB-IPV DTaP-HepB-IPV-Hib* DTaP-HepB-IPV-Hib-HepA MMR-V PnC-MnC PnC-MnC-Hib HepB indicates hepatitis B vaccine; HepA, hepatitis A vaccine; DTaP, diphtheria-tetanus-acellular pertussis vaccine; Hib, Haemophilus influenzae type b vaccine; IPV, enhanced, inactivated trivalent polio vaccine; MMR-V, measles-mumps-rubellavaricella vaccine; PnC, pneumococcal conjugate vaccine; and MnC, meningococcal conjugate vaccine. *Licensed for use outside the United States. Previous combinations using licensed monovalent or trivalent vaccines were created by reconstituting a lyophilized vaccine with a liquid preparation (eg, DTwP/IPV + lyophilized HibPRP-T 10 and DTaP + HibPRP-T), 7 mixing liquid vaccines in the syringe (eg, DTwP and Hib), 11 or using a dual-chambered syringe that kept the components separated until the time of injection (eg, DTwP and IPV). 12 These were, however, temporizing measures awaiting the development of combination vaccines with individual components merged at the time of manufacture into a single multivalent unit. The ideal combination vaccine should contain multiple antigens that are heat stable, safe, and affordable. In addition, it should be effective when administered shortly after birth and should require only a single oral dose to confer lifetime immunity. Development of such a supervaccine has been a primary goal of the Children s Vaccine Initiative. 13 Intense efforts are now under way to provide combination vaccines with greater ease of use, using new technologies such as microencapsulation, liposome carriers, biologic vectors, naked DNA, and new mucosal and cutaneous delivery systems, including edible vaccines. 6,14 Current strategies for development of combination vaccines using inactivated antigens have been based mainly on the addition of various antigens to a DTaP spine. 14,15 In most cases, this process is complex, costly, and uncertain. Physicochemical interactions, immune (antigenic or epitopic) interference, and carrier-induced epitopic suppression are unpredictable consequences of mixing antigens and may reduce immunogenicity and efficacy For example, combinations of DTaP with Hib, although used successfully for several years in Germany and Canada, have not been approved for VOL. 9, NO. 4 THE AMERICAN JOURNAL OF MANAGED CARE 315

3 primary immunizations in the United States, largely because of concerns about lower Hib antibody titers generated by this combination. 20,21 Physicochemical interactions may be specific not only to the antigens but also to adjuvants, stabilizers, preservatives, buffers, and salts required to enhance and maintain efficacy. To add to the complexity, these interactions can vary according to when the components of multivalent vaccines are mixed (early vs late in the manufacturing process) and even with different lots of the same product. Development of a combination vaccine is a prolonged and unpredictable process with a high chance of failure, far more complex and detailed than the simple mixing of components. Once the initial development and manufacturing problems are overcome and a vaccine has undergone successful phase 1 and 2 trials, further testing is necessary to ensure its safety and efficacy. 17 Evaluations of antigenic consistency from lot to lot, confirming the reliability of the manufacturing process, are also required. 22 If the vaccine contains a new component (not previously licensed for monovalent use), fullfield phase 3 efficacy and safety trials will be prerequisite for Food and Drug Administration (FDA) approval and licensure. 23 Such randomized trials with case-controlled studies can be difficult to conduct if components of the vaccine under study are recommended in the immunization schedule and used routinely. Recently, it has been suggested that when a new combination vaccine is composed of previously licensed components, efficacy trials may not be required if the immunogenicity of these components when given in combination is comparable to that previously demonstrated for those products when used individually. 6,17,24 This surrogate for efficacy, however, can only apply to vaccines for which a serologic response has been shown to correlate with protection. For antigens such as pertussis for which no serologic correlates of immunity have been identified, protective efficacy is more difficult to assess and has proved to be a barrier to the development of combination vaccines involving this basic component. 25 Similarly, uncertainty over protective concentrations of antibodies necessary for prevention of pneumococcal and meningococcal disease 25 may delay development and licensure of a childhood meningitis vaccine composed of these antigens combined with Hib conjugate vaccine. Increasing public uncertainty over vaccine safety requires ever greater scrutiny for rare serious adverse events, which may be beyond numerical (or economic) achievability. 26 This uncertainty has been heightened recently by awareness that the risk of vaccine adverse events (eg, vaccine-associated paralytic polio) may be greater than that of natural disease in a highly immunized population. Although prelicensure trials including a few thousand individuals are generally adequate to identify common, mild local and systemic reactions, rare severe reactions may not be recognized until distribution of millions of doses of the vaccine, as was the experience with intussusception associated with use of rotavirus vaccine. 27 To compare the reaction rate for a combination vaccine with that of each component administered separately, achieving any degree of certainty over the likelihood of rare serious reactions will require enrollment of patients in numbers far too great to make development of such a vaccine economically feasible. For example, to rule out a 10% increase in the frequency of a reaction that occurs in 1 of every 1000 injections of the individual components will require enrollment of >2 million patients. Excluding even an unlikely 30% increased reaction rate will require patients. 23 To overcome this problem, it has been suggested that provisional licensure be granted after phase 2 trials, proceeding straight to enhanced postmarketing phase 4 surveillance, where rare adverse events could be detected by closer monitoring. 28 This process could be facilitated by use of an increased number of sentinel sites using large linked databases such as the Vaccine Safety Datalink Project sponsored by the Centers for Disease Control and Prevention. 29,30 Despite its practical appeal, ethical concerns over attempting to demonstrate vaccine safety in individuals who have not provided their consent or assent to participate in a safety trial, albeit large scale and nationwide, make this suggestion controversial. It recently has been suggested by FDA staff that phase 3 prelicensure studies, rather than being curtailed or eliminated, be expanded to ensure detection of adverse events that might go undetected under current programs. 7 Once a combination vaccine is conceived, developed, field tested, licensed, and manufactured in quantity a process taking up to 10 years in a highly competitive industry focused on the development of bigger and better vaccines there exists the possibility of it being superceded relatively quickly. The Table illustrates how a pentavalent vaccine not yet licensed in the United States could be threatened with replacement by a hexavalent vaccine currently licensed in Europe while it, in turn, might one day be superseded by a heptavalent combination already 316 THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2003

4 Pediatric Combination Vaccines under evaluation. Unless the experience in other countries documenting the safety and effectiveness of these vaccines can be used to justify their licensure in the United States, the rigors of the FDA approval process may well preclude the further development of either for use in the United States. The difficulties inherent in the development of combination vaccines have important implications for the continued commitment of pharmaceutical firms to their development and for their uptake by the medical community. The expense of bringing out a new combination vaccine is necessarily reflected in its pricing. If the cost of the combination product considerably exceeds the cost of the individual components, providers may not be adequately reimbursed for administration of the combination vaccine by their payers and so may be unable to provide it for their patients. It remains to be seen whether public preference for combination vaccines, their heightened utilization, and competitive bidding by large HMOs for identical or similar products will be adequate to mitigate prices for purchasers while still providing manufacturers with a fair return on their development costs. IMPACT OF COMBINATION VACCINES ON PARENTS AND PATIENTS The major benefit of combination vaccines to children and parents or caregivers is clearly the reduced number of injections required to achieve full immunization. Although current vaccination programs require infants to receive 16 to 20 injections by age 18 months, the use of combination vaccines currently licensed elsewhere or under development (eg, DTaP-IPV-HepB-Hib and measlesmumps-rubella-varicella), given together with pneumococcal conjugate vaccine, could reduce this to a more manageable 9 injections, with most visits requiring only 2 injections. Physicians seem to be more concerned than parents about the number of injections given at a single visit Several studies have indicated, however, that parents are also reluctant to subject their children to multiple injections simultaneously and would, in many cases, accept extra charges 35,36 or extra clinic visits to avoid this problem. For example, Madlon-Kay and Harper 37 found that for a 2-month-old infant needing 3 injections, approximately 40% of parents would prefer they be given at 2 visits; when 4 injections were required, almost 60% of parents would prefer to make 2 visits. These findings were confirmed by Woodin et al. 31 Among parents who objected to what they perceived as an excessive number of injections, none would have refused 3 shots for their infant if their physician recommended they be given. In the same study, 60% and 80% of physicians (vs 40% of parents) were concerned about giving 3 and 4 injections, respectively, indicating that the likelihood of parents receiving such a recommendation was fairly small. IMPACT OF COMBINATION VACCINES ON PROVIDERS Cost-benefit and cost-effectiveness analyses of immunization have, with few exceptions (eg, 7- valent pneumococcal conjugate vaccine), 38,39 shown that childhood vaccines, in particular combination vaccines, are highly cost effective and, in most instances, cost-saving. 40,41 The benefits for providers in particular can be significant. In addition to reduced concerns over generating pain and anxiety in their patients and parents, reductions in supply and administration costs, immunization and nursing errors, and inventory and wastage are also potential advantages. Not included in the economic analyses is the benefit derived from reduced nursing time and faster patient turnaround time with use of multivalent combination vaccines vs individual components. Studies 42,43 performed in a managed care environment have demonstrated that the time savings associated with vaccine preparation, injection, and documentation can be significant: 4 to 5 minutes total per immunized child 42 or approximately 2 minutes per injection, 43 depending on the total number of immunizations and the setting (examination room or injection room). A peripheral advantage from the parental perspective was a reduction in crying time of approximately 1 minute, 43 a factor that could affect immunization compliance, particularly when it is recognized that parents would be willing to pay a median of $25 (range, $0-$1000) or to come back another day to eliminate the perceived trauma to their children of even 1 extra injection per visit. 35 However, a variety of issues could potentially adversely affect acceptance and utilization of these vaccines: the uncertain interchangeability of vaccine products from different manufacturers, the unnecessary administration of superfluous extra antigens, and the reimbursement policies of payers. VOL. 9, NO. 4 THE AMERICAN JOURNAL OF MANAGED CARE 317

5 Approval of a combination vaccine by the FDA generally indicates its interchangeability with monovalent formulations and other combination products with similar component antigens produced by the same manufacturer; however, the same assurance cannot always be given for products from other manufacturers. 6 This problem is highlighted when patients change providers and immunization records indicate only the antigens given without specifying combinations, manufacturer, or lot number. Accumulating data suggest that most vaccines with similar antigens will prove to be interchangeable. Although it is recommended that vaccines from the same manufacturer be used for all doses of a vaccination series whenever possible, 2 results of studies 2,6 of serologic responses to tetanus-diphtheria toxoids (pediatric and adult types), oral and IPV, rabies, HepA, HepB, and Hib vaccines used in the United States indicate that these products from different manufacturers can be used interchangeably. Limited data 2 for acellular pertussis vaccines indicate that products from different manufacturers may be used for the fourth and fifth doses and even for the second and third doses if the manufacturer of a DTaP given earlier is not known or readily available. Although comparable data for other pediatric vaccines are not yet available, these observations suggest that manufacturer continuity may not be a critical factor in ensuring vaccine immunogenicity, making the use of combination products an attractive option. Another factor reducing the number of vaccines a provider needs to stock is the evidence suggesting that administration of extra, unneeded antigens in a combination vaccine (ie, when the subject has already received the recommended number of doses of 1, but not all, antigens in the vaccine) is an acceptable practice. The Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians recommend that combination vaccines are preferred 2 and should be used 6 whenever any component of the combination is indicated and its other components are not contraindicated. Except for giving extra doses of tetanus toxoid containing vaccines, which can increase the likelihood of hypersensitivity reactions, there is little risk of significant heightened reactogenicity after administration of extra doses of inactivated or subunit vaccines in current use, including HepB, Hib, or IPV. 2,6 A more immediate consideration for providers regarding the use of combination vaccines relates to economic and reimbursement policies enacted by health insurers and managed care systems. Although multivalent vaccines may, in some circumstances, reduce costs through the advantages noted previously, they may, conversely, introduce new expenses in other situations. If practice patterns compel the need to stock a larger inventory of vaccines, thereby increasing administrative costs relating to purchase, storage, and recording of immunizations, expenses will rise. Although extra vaccination is an acceptable practice and one that should be reimbursed by indemnity health insurance and managed care systems, 6 if third-party payers determine that they will limit reimbursement of combination vaccines based on the sum cost of antigens delivered rather than on the actual cost of the vaccine and refuse to cover the cost engendered by giving extra antigens, the difference will have to be borne by the providers. In addition, for providers on a fee-for-service contract, replacing 3 or 4 vaccine injections with a single injection could significantly reduce billing and income. Finally, increased use of combination vaccines will require practitioners to develop and maintain improved documentation and recording of vaccine delivery. Although it is unlikely that a combination vaccine will have more adverse effects than the separately administered components, such events have been described. 44 Administration of combination vaccines will, therefore, have to be specified as such; recording of only individual components will make it difficult or impossible for anyone other than the original immunizer to know whether the component responsible for a significant local adverse reaction can ever be defined. Development of a nationally standardized vaccination record form, machine-readable bar codes on vaccines, and a national immunization registry are strategies designed to improve the accuracy of vaccine information. 6,15 Despite the potential economic advantages of currently available combination vaccines, it remains unclear whether introduction of more complex combinations will be cost neutral, more expensive, or cost-saving for the provider. It has been suggested that one way to determine economic impact is to develop computerized, individual practice based economic algorithms to permit providers to achieve the economically most favorable vaccine purchase and utilization policies. One such algorithm has been developed by the Centers for Disease Control and Prevention THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2003

6 Pediatric Combination Vaccines IMPACT OF COMBINATION VACCINES ON MANAGED CARE ORGANIZATIONS Combination vaccines present managed care organizations (MCOs) with a potential for benefits and concerns, many of which are shared with individual providers. An added consideration, however, for MCOs is the large number of subscribers who, either willingly or as a result of changes in employment, renegotiate their healthcare coverage. These high turnover rates multiply manyfold the problems facing individual providers. Considering that a solo practitioner may care for 2000 children whereas a large MCO may cover >1 million children, the differences in the economic dimensions of the problem become clear. Currently, the broadest disease coverage provided by a combination vaccine in use in the United States is the recently licenced (December 2002) pentavalent DTaP-HepB-IPV vaccine. As larger combinations are introduced, providers will find it necessary, in the short run, to maintain greatly increased vaccine inventories, to provide frequent extra immunizations of superfluous antigens, and to develop ever more complex systems for recording of immunizations (immunization registries). 2 The expenses generated by these requirements will be considerable. Conversely, once these vaccines become accepted and widely used in the medical community, significant savings will be realized by providers through reductions in inventory, wastage, administrative overhead, supplies, and nursing time. For MCOs with individual practitioners under contract, a cutback in the number of injections may result in reduced billing and, by freeing up examination rooms more quickly, could permit an increase in the number of available appointment slots. The possible achievement of improved immunization compliance, although intuitively probable 34,46,47 but unproven, remains an important factor for reducing the burden of disease in subscribers and in improving an MCO s competitive position with subscribers through its achievement of goals and standards set by the National Committee on Quality Assurance through the Health Plan Employer Data and Information Set. CONCLUSION The development of combination vaccines has brought many potential benefits and some uncertainties. Their use will achieve the immediate advantages of convenience and fewer injections; over the long term, they will permit reduced inventories and overhead expenses and, it is hoped, improved compliance. The complexity of development, licensure, and manufacture of combination vaccines indicates that these benefits may come at an increased cost. Purchasers, providers, and recipients of these vaccines must determine how much of a premium they are willing to pay to achieve the advantages. Ultimately, pharmaceutical corporations, pledged to provide a profit for their stockholders, must decide whether, in the face of ever increasing expenses, they want to continue development of combination vaccines. REFERENCES 1. Peter G, ed Red Book: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, Ill: American Academy of Pediatrics; Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices and the American Academy of Family Physicians. MMWR Morb Mortal Wkly Rep. 2002;51 (RR-2): Parkman PD. Combined and simultaneously administered vaccines: a brief history. Ann N Y Acad Sci. 1995;754: Schmitt H-J, Knuf M, Ortiz E, et al. 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Reverse engineering a formulary selection algorithm to determine the economic value of pentavalent and hexavalent combination vaccines. Pediatr Infect Dis J. 2001;20:S45-S Dietz VJ, Steveson J, Zell ER, et al. Potential impact on vaccination levels by administering vaccines simultaneously and reducing dropout rates. Arch Pediatr Adolesc Med. 1994;148: Ball TM, Serwint JR. Missed opportunities for vaccination and the delivery of preventive care. Arch Pediatr Adolesc Med. 1996; 150: THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2003