A perspective on vaccine evaluation research in Ca nada : Past and future

THE 1990s WlLL BE NOTEWORTHY POR A RENAISSANCE IN vaccine use. a mong other major developments in infectious diseases . The technology tree will yield its long-awaited fru it in increasing numbers and variety. providing a cornucopia of new vaccination options for infants and children. Governments intent upon contro ll ing the cos ts of health care can be expected to seize upon many of these new vaccines to implement new programs of disease prevention. There is little doubt that good vaccines we ll used are the most cost effective measure in modern medicine. We believe that vaccines represent the very best of high technology because their boWed magic is available to all, even the youngest tyke in the most remote vi ll age. In 1992. change already is afoot. Conjugate vaccines for prevention of HaemophiLus injiuenzae type b infections have made their debut in programs in virtually every province and territory. The innovation of conjugating bacterial polysaccharide to selected protein carriers allowed the age barrier in responsiveness to polysaccharide to be broken . The new programs. beginning at two months of age, can virtually eradicate H injluenzae type b infections within a few years. New programs are being organized to deliver recombinant hepatitis B vaccines to children, protecting them in advance of the peak risk in early adulthood. British Columbia initiated such a program for all grade 6 students in autumn 1992. the first province to do so. Many addition a l vaccines will be licen sed du ring this decade. The list will include a vaticella vaccine, inactivated hepatitis A vaccine, oral typhoid vaccine and acell u lar pertussis vaccines al l products that have already been licensed in some developed countries. Based upon studies now in progress, it is likely that the list will also include rotavirus and respiratory syncytial virus vaccines. The list of candidate products early in development. including human immunodeficiency virus vaccines, is too long to enumerate. Consumers, especially parents of young child ren, wi ll expect these new vaccines to be safe and convenient. Will ingness to accept the frequent occurrence of minor s ide effects (as with whole cell pertussis vaccine) or rare risks of serious adverse effects (as with oral poliovirus vaccine) already is diminishing. As less familiar and feared microbes are targeted, parents will demand convenient mixing of new vaccines with established ones a complex technological challenge. The abili ty to manufacture all components of a combination vaccine will become pat-amount, forcing manufacturers into cooperative a lliances and eliminating countryspeciJic products or formulations. Wilh so many changes predictably ahead, it is timely

T HE 1990s WlLL BE NOTEWORTHY POR A RENAISSANCE IN vaccine use.a mong other major developments in infectious diseases .The technology tree will yield its long-awaited fru it in increasing numbers and variety.providing a cornucopia of new vaccination options for infants and children.Governments intent upon controlling the cos ts of health care can be expected to seize upon many of these new vaccines to implement new programs of disease prevention.There is little doubt that good vaccines we ll used are the most cost effective measure in modern medicine.We believe that vaccines represent the very best of high technology because their boWed magic is available to all, even the youngest tyke in the most re mote vi ll age.
In 1992.change already is afoot.Conjugate vaccines for prevention of HaemophiLus injiuenzae type b infections have made their debut in programs in virtually every province and territory.The innovation of conjugating bacterial polysaccharide to selected protein carriers allowed the age barrier in responsiveness to polysaccharide to be broken .The n ew programs.beginning at two months of age, can virtually eradicate H injluenzae type b infections within a few years.New programs are being organized to deliver recombinant hepatitis B vaccines to children, protecting them in advance of the peak risk in early adulthood.British Columbia initiated such a program for all grade 6 students in autu mn 1992.the first province to do so.
Many addition a l vaccines will be licen sed d u ring this decade.The list will include a vaticella vaccine, inactivated hepatitis A vaccine, oral typhoid vaccine and acell u lar pertussis vaccines -al l products that have already been licensed in some developed countries.Based upon studies now in progress, it is likely that the list will also include rotavirus and respiratory syncytial virus vaccines.The list of candidate products early in development.including human immunodeficiency virus vaccines, is too long to enumerate.
Consumers, especially parents of young child ren, wi ll expect these new vaccines to be safe and convenient.Will ingness to accept the frequent occurrence of minor s ide effects (as with whole cell pertussis vaccine) or rare risks of serious adverse effects (as with oral poliovirus vaccine) already is diminishing.As less familiar and feared microbes are targeted, parents will demand convenient mixing of new vaccines with established ones -a complex technological challenge.The abili ty to manufacture all components of a combination vaccine will become pat-amount, forcing manufacturers into cooperative a lliances and elim inating country-speciJic products or for mu lations.
Wilh so many changes predictably ahead, it is timely lo review the proce s involved in lie n ing n w vaccines.Is Can ada ready for th is ch a lle n O"e? Who.pecifically.\viii he lp to meet it?

PRELICENSURE TESTING OF A VACCINE FOR CHILDREN
The pro e s of testing a cand idate vaccine for a common childhood infection begins in the laboratory wilh critical appra isal of manufacturing •ch mi try'.including pa ra me te rs s u c h as purity.pote ncy.stability and lot-to-lot consisten cy.Animal studies follow to assess toxicity of large do es.the deta iled nature of the immune response and.where models of infection exi t. the ability of vaccination to protect against infection.The manufacturer play the major role in preclin ical lud ies.butlhose in a nimals are often undertaken with academ ic pa rtners.particu la rly on e with s pecia l ex-perUse in defin ing immune responses lo the pathogen of inlerc l.
Clinical le ling of n ew vaccines follows a prescribed.lcp\vise eq u ence that i calculalecl lo minimize risks a nd closely ob erved by regu latory ag nc ics of counlrie where the testing is perfom1ed.'Ph ase l ' studies involve lhe first.tentative u ses in huma ns .c haracterized by involvem ent of small numbe rs of adull volunteers a nd emphas is on evalua tion of safe ly.The seconda ry objectives a rc dose finding and asses menl of immune re ponses lo what. is often a secondary stimulu s.
Wilh such 1 •eassura n ce .le ling en ters 'phase 2• where s tudies move stepwise from secondary stimu lation of immune responses in o lder c hildren (assuming lhc target is a common infection) lo ludie in the intended age group.Once again .protocol are designed lo include ju l enoug h ubj ect lo an wcr lh e desired question.Over a series of ludies s uch ques tions incl ude dclcrminalion of optima l do c a nd c hedu le .influ ence of age a nd m a te rnally derived a ntibody on responses.lol-lo-lol con i Le ney of immunogenicily a nd.through a ll. the continuing clo e as e me nl of a dverse effects.A confidence in lhe product inc reases.more ludie are initia led in paralle l lo assess vaccine performance in gen etica lly diver popula tions. in g ro ups al increa cd risk for the target infection a nd in conjunction \vilh othe r vaccines routinely used in the age group lo confi1 •m compatibility.These design s a rc s ufficie ntly a like lo perm it accumula tion of s ubsta ntia l numbers of observa tions o n immune responses a nd safe ly.The carlie t stud ied children of the target age a rc followed over lime to assess the s tability of immune 1 •espon sc and the need for a ny booster doses.'Phase 3' is the acid lest.t he a tte mpted demons tration of protective e fficacy .Wherca core of ludics miJ4hl be done in phase 2. a ingle la rge ludy is lhe rule in phase 3.This is underta ken in a n a rea where disease risk is high.pcm1illing rela tive ly limited enrollme nt and d uration of follow-up .The s tudy e nvironme nt mus t be controlled ufficie nUy so lh at resu lts will be accu rate a nd gene ralizable to most countries.The outcome measure can be a bsolute (vaccin e versus placebo) or relative efficacy (where a n older vaccin e exists for comparison) .Desig n a nd conduct of the trial must be rigorous to withstand extensive subsequent scrutiny by regu latory agencies a nd expert a dvisory groups.
A key pa rt of a phase 3 study is the search for a e ra logical corre la te of protection because this becomes lhe benc hmark for assessment of vaccine perfom1ance in other populations.B cause mo t phase 3 s tudies involve thousands of s ubj ects.they a lso provide a s ubla ntial body of safety data.
As the phase 3 study nears completion .U1e manufacturer generally will undertake a t least one safety and immunogenicity trial in each country where lice nsure will be sought: lhis famiiiarizes the regu latory agency wilh the product and can accommodate any unique requirem ents for licen s ure (eg, testing in expanded ethnic groups or in conjunction with parochial routine vaccines).While mosl fore ign manufacture rs have followed this tradition in Canada, the Bureau of Biologics h a no latutory authority lo require studies to be done h ere.
The period following licensu re is referred to as 'phase 4'.Po l marketing con cerns centre on the possibility of rare but serious adverse effects nol revealed by U1e limited scale of pre licen s ure testing and on lhe vaccine ability lo prev nt infection under 'real world' conditions of u se.Post.marketing safety studies increasingly are approach ed like e fficacy trials.where one large s ludy is conduc ted in the country of origin or first major marketplace country, often while licensure is awaited in other countries.S ince the outcome m eas ures in these studies are adver events r s ulling in doctor vis its or hospital a dmission .group h ealth organiza tions with computerized record systems a re wellsu ited to perform them.Measurement of di ease control requires data on large defined populations.Case-control designs are used to e timale vaccin efficacy in routine programs.Some pos t licensure issu es can lake decades lo eluc idate.such as lh duration of protection , need for booster doses.lhe na ture and severity of breakU1rough infections, and the leve l of immunity in a population needed to s top disease transmission.
A new and pressing aspect of phase 4 is comparison of competing products.A corolla ry of the n ew biotechnology is tha t new products will come lo market in compe ting plenty: lhis will fos ter price competition a nd • urviva l of the fille l' produ cts.but multiply the a lready huge costs of produc t. development.Mech anisms mu t valve under gov rnmenl sponsors hip to compa re products 'head to h ead' as rigorous ly a nd uniformly as possible to en able health adminis trators to identify the be l products.
Another pressing issu e for n ewly marketed vaccines for children is their integration, when possible.into combinations with routinely administered vaccines.Avoiding multiple injections per visit or extra visits is a high priority but constructing combination vaccines without loss of potency of any component technically is challenging.From a consumer's viewpoint, there is room for concern that combination 'packages' will not always include the best among new products because some manufacturers will be better positioned than others to offer combinations.

PARTNERS IN THE EVALUATION PROCESS
Clinical evaluation of new vaccines requires cooperation between the regulatory agency.vaccine manufacturer and clinical investigators, and each has a unique role.The regulatory agency is the referee, protecting the interests of participating subjects and future vaccinees above all else.In Canada, the regulatory function is served by the Bureau of Biologics within the Health Protection Branch of Health and Welfare Canada.Despite limited staffing, the Bureau of Biologics has earned a reputation for high standards.The United States' Food and Drug Administration accepts studies performed in Canada as equivalent to American ones, the only foreign studies given this status.
Among the five vaccine companies active in Canada, two produce some or all of their products here while three are vendors with manufacturing plants in other countries.This distinction is relevant because vendors understandably do most of their clinical projects close to home and have limited research departments in their foreign subsidiaries.The change of Connaught Laboratories to a multinational company could decrease the number of clinical trials it sponsors in Canada.This would be unfortunate because Connaught so far has been the major sponsor of vaccine trials in Canada.
The investigators who participate in field studies have included both public health physicians and academics from various disciplines.Until recent.ly,vaccine trials have been uninviting for academics.Companies exerted extensive control over protocol design, trial management and data analysis, leaving litt.le to challenge the intellect.Trials often emphasized multicentre designs for perceived 'political' credit rather than for scientific necessity.The ensuing small roles per centre and the limited credit available through multi-author publications further diminish interest.The Loken studies undertaken by foreign vaccine makers to support licensure applications were typically oflimited scientific value, being late phase 2 protocols duplicating work already completed (and often published).Investigators who sought grant funding from scientific agencies to address post licensure questions quickly discovered that agencies had a 'let the companies fund it' attitude .This is not to say that participation in vaccine studies cannot be worthwhile for academics.Certainly the need for additional evaluators is unprecedented at the global level given the pace of new vaccine development and the multiplicity of competing products.In the United States, a closer interaction between academic groups and manufacturers evolved in the past decade to mutual advantage; this was facil itated by the large number of United States based companies and their proximity to university centres.A giant assist came from a National Institutes of Health (NIH) program to sponsor six major 'vaccine centres' in various American universities.Each has a specific focus (such as enteric, respiratory or pediatric vaccines) and was given the wherewithal to pursue both basic vaccine development and clinical evaluation.including sophisticated measurements of immunity.Both the NIH-funded and other specialized academic groups had considerable expertise to offer to manufacturers in return for major responsibility for clinical trials design and completion.Shifting the locus of control had mutual advantages: investigators could function productively as clinical scientists and gain appropriate academic recognition while manufacturers obtained high quality studies from respected outside authorities.The NIH vaccine centres were ideally suited to undertake independent comparisons of products, including standardized laboratory testing.serving the needs of consumers and health authorities in an innovative manner.
In short, the relationship between manufacturer and investigator is negotiable if the latter can offer special expertise.In a general • climate of shrinking research agency support and growing respect for university-industry collaboration, the opportunity to work productively with manufacturers has been welcomed by many American academics.

THE VANCOUVER EXPERIMENT
In 1988 we looked critically at vaccine evaluation research in Canada and became concerned about its future.Involvement of academic investigators and foreign manufacturers was limited.Despite the abundance of new products, the unprecedented need for evaluators, the many intellectual challenges and the legislative requirement for companies to invest in more research in Canada, no movement was evident.There was an acute need for leadership in seeking more appropriate roles for academics and in facilitating company-funded and other vaccine research in Canada.Without some decisive changes, we feared that opportunities would be lost and vaccines would come to market with little or no Canadian testing beforehand.
We undertook an experiment towards finding an appropriate solution based on the concept of NIH vaccine centres.Our plan was to assemble a team of investigators and skilled managers with broad capabilities.particularly in the areas of clinical trials design.management and analysis.Lacking access to NIH, we would seek private establishment support.Since that could not amount to millions of dollars per year, we would forgo the infrastructure for basic research towards vaccine development (except as already existed) and concentrate instead on clinical evaluation.We would also forgo the limited focus of NIH centres, substituting instead a broad focus that would provide access to a wide range of funding sources.Since peer review is a key academic talisman, we would try to achieve a 40:60 balance between scientific agency and company funded projects.We chose from the outset to remain independent of industry, undertaking projects from all companies but accepting no infrastructure support or personal income from them.That impartiality would permit us to speak more effectively on behalf of vaccine consumers.
The key innovation was a team approach to facilitating vaccine research.We would gather the dozen or more local professionals with particular interest in vaccines into a collaborative group with broad collective expertise.We would encourage similar talent-pooling nationally to create a brains trust attractive to manufacturers and convincing to reviewers.At the operations level we would develop an organization to support clinical trials.The availability of skilled managers, coordinators and field staff would make it possible for individual investigators to undertake multiple projects simultaneously.Indeed, to keep such a team busy would require 10 or more projects annually.That level of activity offers economies of scale that would permit us to be highly cost competitive.A mixed venue of projects would diversifY funding sources and offer more stability from year to year than would be possible with attachment to one company or one type of vaccine.
Our goal was to develop a centre of excellence for vaccine trials that would be recognized intemationally.Our expectation was for investigators to exert scientific control over most (if not all) projects, restoring their academic nature.Our hope was to gain access to company-sponsored projects that would otherwise have been done outside Canada, with early phase 2 studies a priority.We guessed that it would take five years of gradual attitudinal shifts and trust-building before we could tell if the experiment would work.
As of the three-year mark (December 1991), there has been substantial progress.Over 30 studies have been undertaken or completed, with budgets totalling over $2,000,000.Thirteen studies have been grantfunded (17 industry-funded); seven were multicentre trials coordinated by us.The team of local investigators included five different principals (one in Vancouver on sabbatical) and six co-investigators, most being medical health officers.Their cooperation in providing access to children attending public immunization clinics has permitted efficient recruiting for large trials.The support team at the centre includes 20 employees encompassing an administrative manager, assistant and secretary, a data manager and data entry staff, several coordinators and research assistants, a pool of experienced research nurses and a serology technician.We have also been privileged to work with two independent field research teams with long experience with vaccine trials.
Nationally, we have been able to collaborate with nine other investigators distributed nationwide.These included peers in infectious diseases, as well as colleagues in govemment, particularly at the Laboratory Centre for Disease Control.The range of interactions has been as diverse as training research nurses for new investigators, helping others to prepare appropriate budgets, and receiving help with project designs and specialized serological tests.
The best news is in the category of 'academic fulfillment'.Among the 17 industry funded studies, eight were planned totally and five partially by our group.Four different manufacturers are included in these figures.The attraction of an efficient, reliable organization proved to be powerful.Companies needed little convincing of the value to them of high quality studies performed by outside investigators.The Bureau of Biologics was strongly supportive of such arrangements, without which our initiatives would have been abortive.Major granting agencies were persuaded of the need to fund certain types of vaccine studies, opening the door wider for all investigators.Publications totalled 19 but some papers are still in press and some studies have not concluded (see Bibliography).
The mixture of project themes was eclectic, as intended.A partial list includes large scale studies of rubella immunization, 12 studies involving three different H injluenzae b conjugate vaccines, three studies of influenza vaccination, four studies of reactions to diphtheria-pertussis-tetanus vaccines and their basis, a study of parent education methods and a pilot study of a country-wide, hospital-based network for surveillance of vaccine adverse reactions.
Despite this level of activity, the centre has not been able to achieve long term financial self-sufficiency.Projects employ many of the staff continuously but there remain planning, staff development and administrative costs that cannot be recovered from projects.To date such overhead expenses have been met by an establishment grant from our host hospital but this is finite, keeping us searching for an NIH-like sponsor.
A potential concem in developing a vaccine centre is to draw opportunities away from vaccine-oriented colleagues in other provinces.We have tried hard to avoid this.Many industry sponsored projects listed above would not have been done in Canada had we not been able to compete effectively for them.This included the prospect of three large, multicentred phase 3 trials.While they were not funded, the planning process required recruitment of colleagues into a Canada-wide network.As the exercise was repeated we all realized that the pediatric infectious diseases community has a remarkable willingness to work together on major pro-jects.This is a rare asset that we and others continue to market on behalf of the group.While megaprojects are too few to sustain a large network, there have been positive developments nonetheless.Some colleagues have been 'tumed on' to vaccine studies and will continue to participate.Others are following our lead in developing vaccine centres.with our strong encouragement and full cooperation.As we reach our capacity, prospects for some industry-sponsored projects are being redirected to interested colleagues in other centres to keep the work in Canada.

CONCLUSIONS
Unprecedented activity is going on in vaccine development.creating great opportunities for clinical evaluations.While not always the case, approaches exist to make involvement in prelicensure trials academically rewarding.Opportunities for such involvement tend to be limited by the small size of the Canadian marketplace and the limited number of Canadian-based vaccine companies.This tendency can be offset if Canadian investigators are prepared to stand tall and stand together, offering collectively the powerful inducements of special skills and efficiency.Just as Finland has played a disproportionately large role in vaccine studies in the 1980s, Canadian investigators can do likewise in the 1990s.The opportunity is ours to seize, collectively.
CAN j INFECT DIS VOL 4 No 2 MARCH/ APRIL 1993 Vaccine evaluation research in Canada