Clinical trials and tribulations: a personal view of interacting with pharmaceutical manufacturers
David W. Scheifele, MD
Clin Invest Med 1997;20(3):188-192
[résumé]
This article is based on a presentation made at the Annual Meeting of the Pediatric Investigators Collaborative Network in Canada (PICNIC), San Francisco, Sept. 19, 1995.
(Original manuscript submitted Feb. 21, 1997; received in revised form Mar. 13, 1997; accepted Apr. 4, 1997)
Reprint requests to: Dr. David Scheifele, Vaccine Evaluation Centre, Rm. L427, 4500 Oak St., Vancouver BC V6H 3N1
Contents
See also p.193
Abstract
As grants from agencies shrink, universities and academic researchers are pursuing work on clinical trials funded by pharmaceutical manufacturers. The author, an investigator with a nonprofit research cooperative, offers insight and advice on industry-sponsored trials. He finds that the "doorways" to industry research are hidden, as are industry priorities. Researchers with limited experience have trouble "breaking in" and, when they do work on industry-sponsored trials, are usually given the less interesting work at first. Difficulties encountered during industry-sponsored trials include lack of researcher input, unreasonable enrolment requirements, delays by the sponsor and quashing of publication of unfavourable results. On the positive side, a good experience can include stimulating research, with the researcher playing a substantial role in all phases, an adequate budget, rapid turnaround and publication of the results. To succeed in this environment, trialists should have established expertise, technical and managerial abilities, appropriate resources and strong personal attributes; a national or international reputation is an asset. Researchers can benefit from universities' industry liaison offices and from strong oversight by institutional review boards.
Résumé
Au moment où les subventions d'organismes diminuent, les universités et les chercheurs universitaires poursuivent des études cliniques financées par des sociétés pharmaceutiques. Chercheur dans une coopérative de recherche sans but lucratif, l'auteur présente un aperçu et des conseils sur les études commanditées par l'industrie. Il constate que les «accès» à la recherche industrielle sont cachés, tout comme le sont les priorités de l'industrie. Les chercheurs qui ont peu d'expérience ont de la difficulté à «s'implanter» et, lorsqu'ils réussissent à participer à des études commanditées par l'industrie, on leur confie habituellement, au début, les tâches moins intéressantes. Parmi les difficultés connues aux cours d'études commanditées par l'industrie, mentionnons le manque de contribution du chercheur, des conditions d'admission déraisonnables, les retards du commanditaire et l'interdiction de publier des résultats défavorables. Du côté positif du bilan, une bonne expérience peut comporter une recherche stimulante au cours de laquelle le chercheur joue un rôle important à toutes les étapes, un budget suffisant, un temps de production rapide et la publication des résultats. Pour réussir dans cet environnement, les chercheurs qui participent à des études devraient avoir des compétences spécialisées établies, des capacités techniques et administratives, des ressources appropriées et de solides qualités personnelles. Une réputation nationale ou internationale est un atout. Les chercheurs peuvent tirer parti des bureaux de liaison entre l'industrie et les universités et d'une bonne supervision par les conseils d'examen des établissements.
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Tides of change
A defining characteristic of a medical researcher is the ability to secure project funding. Traditionally, the principal source of project funding has been granting agencies. Applicants with well-designed and relevant proposals could generally find support from federal, provincial or disease-specific agencies. In recent times, government-funded agencies have faced shrinking budgets, leading to stiffer competition for fewer awards. Agencies have tried to cope with diminishing resources in a variety of ways, such as holding fewer competitions, narrowing their terms of reference and capping awards (limiting totals, terms and uses). Nongovernmental agencies have been faced with an unprecedented number of applications, but their resources are limited as well.
The tides of change have forced universities and academic researchers to search for alternative sources of funding, washing them up on the shores of industry and cleansing away the stigma previously attached to such liaisons. The attitude shift during the past decade has been dramatic. Many universities now have institutes on campus to facilitate the commercialization of ideas spawned by faculty members and to foster collaborative ventures with industrial partners. Universities were quick to develop industry-liaison offices to deal more effectively with contracts, patent applications and negotiations. More recently, universities have recognized clinical trials of new drugs as sources of revenue and have formalized their expectations regarding overhead rates, contract provisions, indemnity arrangements, etc. Some centres have marketed aggressively to secure more clinical trials, generally in conjunction with measures to enhance the skills and efficiency of their investigators through local networks or consortia.
Pharmaceutical manufacturers have been willing partners in this new reality. The passage of the Patent Act Amendment Act in 1993 was accompanied by a gentlemen's agreement that companies would spend a portion of their profits on research conducted in Canada, creating expectations of greatly enhanced research funding for academic investigators willing to cooperate with them. While some increase in the number of sponsored clinical trials has been evident, slow diffusion of the new dollars through the large infrastructure of corporate-sponsored research has limited any windfalls for independent investigators.
To its credit, the federal government has actively fostered the interaction of universities and industry through its Networks of Centres of Excellence. Its flagship research agency, the Medical Research Council of Canada, has been particularly innovative in encouraging academic researchers to collaborate with industrial partners, without sacrificing the quality of science.
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A clinical trialist's perspectives on grants and contracts
My experience with clinical trials dates from 1988 and includes 60 studies, whose funding sources have been evenly divided between granting agencies and industry sponsorship. All studies dealt with aspects of immunization. Five companies, 4 of them multinational organizations, have provided the basis of my experience with industry-sponsored clinical trials. My base of operations is the Vaccine Evaluation Centre at British Columbia's Children's Hospital, a unique research cooperative that is shared by several investigators and operates on a nonprofit basis. The centre has about 25 employees, including project coordinators, research nurses, research assistants, a data manager, a statistician, a laboratory technician and administrators. The centre typically conducts several studies simultaneously. Every project undertaken to date has been successfully completed within the projected time frame. The centre can organize studies rapidly and enrol large numbers of participants. It has coordinated multicentre trials and passed external quality audits. I do not wish to boast but to indicate that even a capable organization is vulnerable to problems with industry-sponsored research.
Grant-funded research has a particular ethos, with good and bad elements. Its greatest virtue is autonomy: the principal investigator is wholly responsible for the research plan, along with its execution, timetable and budget. The investigator chooses his or her partners, presumably for their abilities to accomplish the objectives of the undertaking. External peer review ensures that applicants polish their submissions to the limits of their abilities and circumstances. Success in this arena brings deserved kudos and has been an important yardstick for academic advancement.
The disadvantages of grant-funded research are legion. No support is provided for the planning phase, arguably the most important part of a project. Periodic application dates and lengthy review processes hamper the pursuit of rapidly emerging themes. Rejection or provision of only partial funding can be discouraging. The specific nature of the questions addressed in clinical trials makes such grants nonrenewable, hampers pursuit of consistent themes and adds to investigators' insecurity. Trialists interested in drugs are limited to studying licensed products, since unapproved agents cannot be used except in collaboration with the manufacturer, a circumstance that limits options for grant proposals "at the leading edge."
Industry-sponsored clinical trials have an entirely different ethos, with a different mix of good and bad elements. An immediate challenge for an academic investigator who wants to work with a company is to establish contact. The doorways are hidden: there are no competition dates, no requests for proposals, no application forms. Priorities are also hidden, as product development agendas are closely guarded secrets. While manufacturers need the assistance of outside investigators to complete their product-documentation programs, they are free to chose from a wide, often global, constituency. Not surprisingly, corporate research directors look for outside investigators who can perform trials expertly, reliably and efficiently. When many experienced collaborators are available, those with limited experience have difficulty "breaking in."
Whereas academic investigators focus on procedural excellence, industry research managers are oriented toward rapid task completion. The dossier that must be assembled to apply for approval of a new drug involves numerous individual clinical trials, many of which simply enlarge experience or address mundane technical issues such as manufacturing consistency. It is usually the fate of less experienced or untested investigators to be offered lower-priority projects of this nature, in which the prospects for publication of the results are limited. Lack of intellectual stimulation is typically one of the challenges for academics new to working with manufacturers.
A defining characteristic of sponsored research is the strong element of sponsor control over every aspect of a clinical trial, including the protocol, case report forms, sample testing, data analysis and report writing. External monitoring of protocol compliance and expectations of strict adherence to a particular code of practices that is driven by regulatory agencies and is sometimes arbitrary are also likely to catch the novice collaborator unprepared.
These negative aspects of industry-sponsored research can conspire to make the trialist's first experiences with such studies an intellectual purgatory. The worst industry protocol can be excruciatingly painful, given the undesirable possibilities that exist. I will describe briefly some I have encountered, although these have never coexisted in a single protocol.
The least attractive protocol is offered up as a completed, fixed document, affording the investigator little or no opportunity for intellectual input or experience-based refinement. When multiple study sites are involved, there may be no opportunity for direct collaboration or communication among them. Project start dates can be repeatedly delayed by corporate or regulatory issues, causing the investigator to miss out on alternative projects during that interval. Delays may necessitate lay-offs or loss of research staff. The number of subjects to be enrolled per site may be too small to allow economies of scale, making investigators appear uncompetitively expensive as a result. The enrolment task can be made difficult by highly restrictive subject eligibility criteria or an unpalatable study plan involving too many demands on or too few benefits for participants. Company study monitors can be highly intrusive and inconsistent, inflaming and demoralizing study staff. Investigators are commonly denied any role in data or sample analysis, completion of which may be inordinately delayed, depending on corporate priorities. Finally, investigators may find that a manuscript is never produced, especially if the results of the trial are unfavourable and product development is altered or cancelled. In the worst-case scenario, an investigator does not derive intellectual stimulation, profit or a publication credit from taking part in a sponsored trial.
Fortunately, there is also a best-case scenario in collaborating with companies. In these instances, the academic investigator joins in addressing a stimulating research question, posed early in the product-documentation process, and takes the lead in planning a scientifically rigorous and cost-effective study. Monitoring follows a clearly defined plan and is constructive in tone. The investigator plays substantial roles in problem-solving, data analysis and even laboratory test performance. Laboratory tests to be done by the sponsor are completed rapidly so that results can be made available to investigators and subjects. The investigator leads in crafting abstracts and manuscripts, whether or not the results are favourable to the product. The budget for the study covers the costs of planning and execution and offers potential for a modest profit if the research team functions well.
The challenge for academic investigators is to discover how to find sponsored projects with favourable ratios of good and bad elements.
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Effective collaboration with industry
Collaborations with pharmaceutical companies can be engaging or repulsive, depending on the extent to which the academic researcher is permitted to participate. An initial period of testing is to be anticipated before a researcher is trusted sufficiently to take on larger roles in study planning or execution. Unfortunately, trust building is specific to each company; investigators must repeat the process almost from the beginning with each new sponsor.
To the uninformed, this system of graduated researcher engagement in sponsored studies may seem arbitrary and unfair. It is less mysterious if investigators view themselves as purchased services, selected by canny corporate buyers with a task to accomplish. What attributes of a clinical trialist are most desirable or marketable? Established expertise is foremost for principal investigators, and desirable for co-investigators too, as it speaks to their ability to complete a task successfully. The skill set includes technical and managerial abilities along with insight into practical study designs. The researcher needs appropriate resources such as an established team that can organize a study quickly and find sufficient numbers of potential subjects. Personal attributes of importance include reliability, flexibility in the face of changing timetables and plans, consummate organization, collegiality, consistent punctuality on key tasks and equanimity in the face of frustration. Having a national or international reputation among peers as a scientist or opinion leader is also a marketable asset. Put simply, the work of well-recognized scientists is more likely to be published and carries weight with regulatory agencies reviewing new drug submissions. Academics should carefully safeguard their reputations as independent scientists in collaborations with industry by maintaining high scientific standards and avoiding undue conflicts of interest. These prerogatives may create tensions with the sponsor during both study design and execution but are ultimately in the best interests of both parties.
Since few studies involve only 1 centre, additional assets include leadership ability, willingness to collaborate with others and established links with suitable colleagues. The trialist who can enlist reliable peers to join a sponsored study and can help to ensure that the experience is pleasant and productive for all is one who will be repeatedly sought by corporate research directors. The infectious diseases community in Canada has recognized the need for investigator networks and has responded very effectively, spawning collaborative groups within the Canadian Infectious Disease Society that are oriented toward investigations involving children and adults. These groups include HIV research networks, the Immunization Monitoring Program, Active (IMPACT), sponsored by the Canadian Paediatric Society and the Laboratory Centre for Disease Control, as well as other networks.
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Effective support from universities
In encouraging faculty members to seek out sponsored trials, colleagues, both administrative and academic, may be unaware of the potential difficulties and of the deleterious consequences of these difficulties for career advancement. Since involvement with sponsored clinical trials on a large scale is a recent development, few administrators have had personal experience with their pitfalls. At present, universities seem focused on promoting opportunities for sponsored research at their institutions and on managing the contracts and overhead allowances involved. Seldom are the pitfalls frankly discussed. It is ironic that indemnification against litigation -- a remote risk even in drug trials -- may preoccupy university administration, whereas there may be no protection against the greater likelihood of intellectual malnourishment.
Administrators should ensure that investigators considering sponsored clinical trials for the first time receive appropriate mentoring. Can the individual's career progress withstand some lacklustre or missed publication credits? Will promotion and tenure committees show tolerance for the "breaking-in" process that occurs with corporate sponsors? What will be the impact on the academic's publication record?
Deliberate strategies can be used to assist the entry of investigators into sponsored trials. Catalyzing the formation of local research teams, with appropriate infrastructure, resources and expertise, is a worthwhile investment. Effective teams of investigators are more attractive than individuals to corporate research directors because they can offer more expertise, a wider range of resources, built-in cross-coverage for absences and potential for value-added subprojects or special tests. Established investigators in such groups can ease the way for junior colleagues, helping them to move more rapidly from being a co-investigator to being a principal investigator.
Industry liaison offices within universities can assist investigators by developing standardized contracts with clauses that ensure timely access to all pertinent study results and safeguard the right of investigators to publish, whether or not outcomes are favourable to the sponsor. Institutional review boards (ethics committees) can also be powerful allies in a variety of situations, including amending proposals that are too demanding for subjects and demanding action when release of results is inordinately delayed. It would be a healthy development if boards routinely solicited information about the organization of sponsored trials, particularly the roles of investigators in data analysis and report writing. Keener attention by boards to the timely availability of results to both investigators and subjects after completion of a trial would be a helpful inducement to proper sponsor performance.
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Conclusion
Academic investigators are being pressured to collaborate with pharmaceutical companies to compensate for shrinking grants, but establishing productive liaisons with industry is not easy. Doorways and priorities are hidden. The playing field is uneven, slanted against inexperienced investigators. Even seasoned trialists are apt to be tested initially with mundane projects by each new corporate partner. Stimulating, academically rewarding involvement is possible for investigators who can offer what companies need most: expertise, reliability, efficiency and reputation. Local groups or networks of investigators are naturally more attractive than solo investigators because of their greater resources and resilience. Institutions should view development of appropriate groups and contract provisions as necessary investments to minimize the undesirable features of sponsored trials for investigators. Canadian investigators have been innovative in finding ways to attract the notice of corporate research directors in a global arena. Such measures are wise because the doorways to industry open from inside.
Acknowledgements
I am grateful to Drs. H. Dele Davies and John LeBlanc for encouragement and to Drs. Scott Halperin and Barbara Law for reviewing the manuscript.
