Richard F. Clark and Alicia B. Minns
Division of Medical Toxicology, UCSD Medical Center, San Diego, CA, USA
You are working in a community Emergency Department at 1 o’clock in the morning on Saturday night. The local ambulance company has just delivered your next patient with a history of ethylene glycol poisoning into a major treatment room. On physical examination, the patient has normal vital signs but appears intoxicated. He admits to having consumed half a bottle of antifreeze because it tasted good and he had run out of malt liquor. You order basic chemistry panels, serum osmolarity, and laboratory testing for ethylene glycol, methanol, and ethanol. You are not certain whether your pharmacy stocks an antidote for this poisoning or if it is even indicated. You are also not certain if dialysis is the best way to manage this patient or if you can get a nephrologist to see the patient at this time of the morning.
Performing research on under-represented patient populations like this is challenging. The National Institutes of Health is unlikely to have much interest in contributing to research in areas such as toxic alcohols. However, for some diseases with which there is a potential to have an effective and marketable antidote, antivenom, or other therapy, a pharmaceutical or device manufacturing company may be the answer. Capitalism spawns innovation; the potential for innovation fuels the pharmaceutical and medical device industries; and the clinical researcher is vital to the success of both of these industries.
Conducting an industry study in an acute care setting such as the emergency department (ED) can be an adventure. In this setting, we depend on “enrollable” patients walking into our ED, often unsolicited. They could come in at all hours, when both the principal investigator and research staff are absent. In addition, guidelines adopted at many institutions in the past decade have altered the incentives for researchers in these areas. Finally, stricter and more frequently changing rules regarding informed consent have excluded some potential areas of acute care research where intellectual capacity is of question.
Several years ago your authors experienced first-hand the problems with ED enrollment of patients with rare disorders in an industry-funded study. We became part of a clinical trial examining the use of fomepizole for patients with toxic alcohol poisoning [1]. Many of the leading research institutions in toxicology were involved, and both the lead investigator and the pharmaceutical company funding the study knew that the incidence of toxic alcohol poisonings in this country is rare. In order to accrue enough subjects, they enlisted multiple sites in the clinical trial. Getting the study approved by our institutional review board (IRB) was difficult, but typical of such a study where the ability of the subject to give informed consent could be limited. However, many site investigators like us trod through the process and gradually were granted approval and received the study drug. Unfortunately, even with all the time and effort devoted to the study, quite a few institutions were unable to enroll a single subject during the study period. In the end, only sites who contributed cases were granted co-authorship. Many investigators were disappointed that their efforts failed to result in a scholarly work simply because not even one case had come through their ED doors.
Unpredictability aside, however, participating in industry studies can be rewarding in many ways. We will try to outline special aspects of this type of research.
Coming up with a research question for an industry-sponsored study can be approached in two ways (Chapter 3). In many cases, pharmaceutical or other medical companies will reach out to investigators to seek sites for enrollment [2, 3]. Most of these studies will be multicentered, with numerous investigators and institutions involved. Industry sponsors may identify potential sites through responses to advertisements, referrals by word of mouth, or by the sponsor personally seeking out known and proven investigators. These studies will usually fall into the categories of phase 2 or phase 3 trials (see the later section Types of industry studies or clinical trials) and often will not offer co-authorship for most investigators.
A second category of industry research involves the investigator developing a biological agent, technique, or device that attracts sponsorship from an industry partner. The process of research and development of a drug or device can be costly and often requires the backing of a company or investment group. However, smaller investigator-initiated studies are also possible. For example, several years ago when ondansetron was first marketed as an antiemetic, its indications initially included only postoperative and chemotherapy-induced nausea. We believed ondansetron could be effective in treating drug overdose-related emesis [4]. We generated a proposal to use ondansetron in such cases and formulated a budget to perform a pilot study of our hypothesis. Realizing the cost of ondansetron at the time would be a limiting factor in instituting our study, we contacted the pharmaceutical company marketing ondansetron and solicited a donation of drug. The company donated the drug for our study based on our proposal [5]. Since our study was investigator-initiated and meant not changing the package insert, it was not subject to the same IRB scrutiny or cost of a true industry-funded clinical trial. For example, since we did not intend to modify the original drug package insert and our drug (or device) was already approved by the FDA, an IND (investigational new drug) application was not required (Chapter 23 provides more details about INDs). This saved us time and resources in the approval process for our study. Drug acquisition costs are often the largest part of budgets for investigator-initiated studies, but companies are frequently willing to donate medications or supplies for local trials that may enhance the utility of their agent [6–10].
Some medical industries will sponsor animal or bench research at outside institutions [6]. However, much of this part of pharmaceutical and device development is now internal at laboratories and vivariums funded by the manufacturer. Academic institutional animal and bench research is largely funded by a mixture of governmental organizations, such as the National Institutes of Health, local, regional or institutional seed grants, or by the increasingly common partnership and contracting between private industry and academic institutions such as schools of medicine or pharmacy [7, 8].
Industry-sponsored studies or clinical trials in humans have traditionally fallen into three categories (Table 17.1). Phase 1 studies or trials usually involve studying the pharmacokinetics and initial safety of the product. Phase 1 studies are generally small studies with few participants and a lesser budget with a shorter timeline. Participants are often healthy volunteers testing the effects and doses of a product on the body, or affected individuals in small numbers [11].
Table 17.1 Phases of clinical trials in industry studies.
| Phase of study | Purpose | Number of investigators; patients | Type of volunteers |
| 1 | Safety, pharmacokinetics | One or small number of investigators; small number of patients | Often healthy, without disease |
| 2 | Safety, dose finding | Limited number of investigators; number of patients often powered to detect difference in dose and effect | Patients with disease or disorder being studied |
| 3 | Efficacy, safety | Large number of sites and investigators; large number of patients powered to detect meaningful difference in outcome | Patients with disease or disorder being studied |
Phase 2 studies or trials are usually designed more for dose finding. Groups of participants who usually are affected by the illness or disorder targeted by the study drug are given varying doses to determine an efficacious dose range. Safety is also considered in Phase 2 trials, but some may not be powered to detect small differences in outcomes. Placebos are often employed in Phase 2 trials [2].
Phase 3 studies or trials are usually prospective, multicentered, double-blinded studies involving large numbers of patients. Power analyses are important in setting up the needed number of subjects in each group to adequately compare efficacy and safety of the drug or device. Multiple institutions are usually required to get the desired number of subjects needed. Due to growing pressure to fully assess toxicity and efficacy of a product prior to release on the market, there is more scrutiny of results by agencies, leading to an increased cost to conduct a Phase 3 trial [3, 12].
Investigators can have different expectations of remuneration in the above studies based on the type of study, the company, and other factors. In Phase 3 trials, for example, investigators are often compensated for the time and effort in getting IRB approval and for entering a certain number of patients. However, large multicenter Phase 3 trials, in which there may be a large number of co-investigators, rarely reward individual investigators with authorship on publications unless the investigator was instrumental in the planning stages of the study or a limited numbers of institutions take part.
When a drug or device manufacturer sponsors a study, it will often request to approve the methodology used by the investigator prior to funding. The more resources the sponsor is asked to contribute, the more involved it will generally be in how the study is performed. This can be of benefit to the investigator, since statisticians employed by an industry sponsor can be helpful in planning sample sizes, analyzing data, and even planning the project design. Phase 3 trials that seek to judge efficacy will require a power analysis to calculate the minimum number of patients that must be included. In Phase 1 trials that we have worked on with industry, the sponsor may be more “hands off” with the proposed design, as long as the testing is done in a verified manner at a reputable laboratory [11].
There are two potential pitfalls in the proposal of methods to an industry sponsor. Firstly, in some early or Phase 1 proposals, industry sponsors have asked for more elaborate designs requiring higher costs. If the company is willing to fund the enhanced version, this can work out well for the investigator and the institution. However, the investigator must be certain that the augmented proposal can reasonably be finished with the resources offered by the company. More and more academic institutions are employing development and clinical trials offices that can assist investigators in these negotiations and at times provide leverage to the investigator.
The second potential pitfall is that when an investigator submits a proposal to industry for an extensive project, the company may either turn down or delay approval of the project based on the cost. This second situation is more often encountered by experienced researchers who have realized that industry often will seek to study an outcome for the least amount of research and design dollars. The economics are clear in that research and design costs erode eventual profit, especially when many agents or devices are never marketed. Therefore, companies will often negotiate the lowest cost methodology design until profit from the proposed device or drug becomes inevitable. Your authors have been forced to walk away from research funding proposals from industry in which they would not be able to obtain meaningful results with the resources being offered. It should be kept in mind that research with methodological flaws caused by funding limitations is almost never worth the effort. Institutions know this also and have, therefore, become much more involved in these processes as they also cannot afford the cost or liability issues resulting from poorly-funded trials.
After a clinician develops a question or hypothesis worthy of a clinical study and has developed a sound methodology, including analysis of results, the next step is to establish funding. If the research is aimed at a specific drug or device, the most likely source of funding is the pharmaceutical or device manufacturer of the drug or device, or a sponsor with the potential to have some financial gain from the proposed research. We have seen companies desire to assist in clinical research in several ways, either intimately involved in the process or at a distance. Often the sponsors will gauge their potential gain from the proposed research as a way of determining the investment. Perhaps the simplest and least “strings-attached” approach by an investigator is to seek a “donation” of a drug or device to perform the research. Industry sponsors often have excess stock or even almost-expired product that they are frequently willing to donate on behalf of research. Small studies using donated stocks, if well performed, can often convince industry sponsors that further research from the investigator or the institution may be worthwhile, and lead to more significant funding. The other way we have approached seed funding from industry is to identify and directly contact the company representative responsible for research and development. The person is often a clinician or former clinician and is frequently helpful in quickly assessing the viability of obtaining resources from the sponsor. The representative can then assist in giving details on how and where to submit proposals to the sponsor.
Another way of getting started with funding for industry research is to obtain a small seed grant from a local institution, such as a university academic senate, or from national organization, such as the Emergency Medicine Foundation. Usually, the organization providing the seed funding will assess the grant proposal for likelihood of further grant funding if results are positive. These preliminary results can then be used as part of a larger proposal to the device or pharmaceutical manufacturer.
Most industry-sponsored studies with Phase 3 implications will require a data safety monitoring board (DSMB) to oversee the study. The DSMB is usually a panel of respected researchers not involved in the current trial but who have some knowledge of research about the specific drug or device being studied. The DSMB will review the methods being used prior to the study and review the results as they are collected. The main purpose of a DSMB is to insure a non-biased overview of the safety of a study, as there is a belief that some investigators can develop a bias to continue a project even in the face of undesirable outcomes. The DSMB will review all expected and unexpected adverse outcomes to ensure subject safety. For the investigator, this means more scrutiny over study results and methods, but this greater level of safety has proved to be the standard for large trials. Some IRBs will not approve certain clinical trials without a DSMB in place.
A material safety transfer agreement is a legal contract that establishes the conditions and terms of transferring “tangible” research material between a provider, such as a principal investigator, and a recipient, such as a pharmaceutical company. It is meant to protect the rights of both parties while documenting the transfer. This would include blood or tissue collected as part of a study from patients at an academic institution, and would protect these samples from indiscriminant use by the receiving entity. This has become more important in recent years, as stem cell transfers have increased between institutions for oncology and other research involving cell lines. Many of these cell lines have potential proprietary value. These agreements outline the use of the transferred material and specify the criteria by which scientific publications can be produced from work involving the transferred resources. Without an agreement in place, both parties have potential legal liability arising from the study or published results. Examples of material often requiring material safety transfer agreements include blood, tissue, vectors, plasmids, databases, devices, and software. However, a material safety transfer agreement is usually not required when blood or tissue is being transferred or shipped for routine testing in connection with a clinical trial. Many institutions have differing interpretations of when a material safety transfer agreement is needed and there is usually an institutional office at most academic centers dedicated specifically to helping investigators with this process.
Various forms of compensation exist for industry-sponsored research. The most important compensation for institutions and investigators is either monetary support or the opportunity to co-author scholarly works resulting from the study. Both of these goals are cherished by academic institutions as well; although monetary support for research has somewhat surpassed the name recognition in some areas.
Industry can financially support a project in several ways. Most obviously, the study could be funded to cover part of the salary or benefits of the faculty or associates required to perform it. Research nurses or assistants, statisticians, laboratory workers, and others within the institution can receive funding for clinical trials or bench studies. Once the research team is funded and in place, they can work together to secure more and future funding from other sources. Institutions have guidelines for salary support and a clinical trials office can assist in the set-up of a budget that will cover all salary and benefit needs. In addition to salary and benefits, institutions will usually require compensation for the services of the clinical trials office and IRB. These fees are generally covered either by specific costs that are added as line items in the budget at the time of negotiation or included as “overhead” in the negotiating process.
Overhead costs have fluctuated over the years, but have usually increased as the institutional overhead costs have increased. Overhead for government-sponsored studies has been around 50% or greater of the total cost of study for academic institutions. However, industry sponsors will often refuse extensive overhead charges, and at times have been willing to shift funding to institutions or investigators with lower fees. Each investigator will need to work with their clinical trials office when overhead fees are discussed in order to keep costs in ranges that industry sponsors require, without sacrificing the quality of the methods or necessary investigator support. We have again found that allowing a clinical trials office to assist in this process can be quite helpful. The clinical trials office staff are often versed in what an industry sponsor is likely to accept in the way of overhead fees and can balance what can be received with what is needed for completion of the study. In our experience, we have almost never failed to agree on a research budget due to an unwillingness of our clinical trials office to negotiate with an industry sponsor.
Another potential form of compensation involves resource materials derived from an industry study. Equipment that is purchased for one study could be used for future research. Laboratory machinery and reagents, computers and software, and other material can often be budgeted into an industry study but used in other research. Institutions and sponsors are at times more willing to purchase these types of resources for investigators than to fund salary support. Such compensation must be acknowledged and disclosed when writing up a paper for publication. Obtaining compensation for research creates an inherent conflict of interest that can be managed, but must be disclosed to the reader in order to determine how much, if any, bias it may have produced.
The publication of scholarly work resulting from the research should be considered as another form of compensation for performing industry-sponsored research. Many departments within academic medical centers require scholarly work as one of the criteria for academic advancement. Although a researcher could be valued by an academic institution only for bringing in research money, publications arising from their research are important. For this reason, we often seek co-authorship potential as a necessity for participation in clinical trials and industry-sponsored research. Authorship potential should always be clearly discussed before agreeing to participate in the study. We have seen a variety of rules on authorship used by industry for a number of reasons. At times, industry sponsors have sought to have complete decision making capacity over publication of results. This could be important to the sponsor if the result were negative, and has obvious ethical and academic implications. Many investigators who are offered authorship will reserve the right to publish results regardless of the outcome, but at times the industry sponsor will retain the final publication decision. An academically healthy arrangement involves retaining the right of the investigators to publish regardless of the outcome, but allowing the sponsor the option to pre-review (but not edit) the manuscript prior to submission; this allows them to express any concerns, ask for clarification, and make any internal preparations for the dispersal of the results to the public.
Once an industry-sponsored study is approved for publication, determining authorship can also be problematic. The industry sponsor will often coordinate the publications and set the rules of authorship. Sponsors (and the lead author) are often reluctant to include large numbers of authors on a publication; some journals will limit author number as well. It then becomes an issue of who “deserves” to be included as an author. This can be decided in several ways. In smaller industry studies, we have seen the principal investigators of all sites given co-authorship, without regard to subjects enrolled or completed. At these situations, each institution is allowed to have one co-author who is decided upon at the initiation of the study. This method has worked well and is often the most equitable way of including all investigators. Other trials have included only those investigators as authors who enroll a certain number of subjects, or who take part in the conception and implementation of the trial. In either case, investigators should have a clear understanding of authorship prior to taking part in the trial if this is important.
Some of the pitfalls encountered in industry studies performed in the emergency department are indicated in Box 17.1.
The greatest pitfalls in industry-sponsored research that we have encountered involve inadequate funding, overzealous enrollment expectations, and unexpected study changes by the sponsor. Funding difficulties have been described above, and we have realized over the years that underfunding a clinical trial or industry-sponsored study is worse than not getting approval to be a study site investigator. Younger researchers who are anxious to begin taking part in clinical trials may be willing to take less salary support or do without certain resources in order to be included as an investigator. The usual hope is that participation in the study will improve one’s opportunity for industry-sponsored research in the future. To a certain extent this is true, in that many industry sponsors seek investigators with “experience” for their trial. However, we have seen that the complications involved in underfunding a study outweigh the potential benefits from future trials. Again, involving a clinical trials office in industry-sponsored study negotiations can help eliminate some of these problems.
Understanding enrollment limitations for one’s institution is also important when planning industry studies. We have had several studies in which we met all criteria for enrollment, jumped through all the regulatory hoops, received IRB approval, and then were unable to enroll subjects. This can be frustrating for both the investigator and the sponsor, and potentially lead to adverse considerations of future industry associations. Many times, a failure to enroll subjects is a matter of bad luck. Patients have to present with a certain disorder in order to be enrolled. However, some clinical trials, such one we have done with some antivenoms, require the rare event of an envenomation, thus leaving us at the mercy of both nature and patient’s selection of an emergency department for treatment. We have tried in several cases to educate both community and emergency medical service (EMS) agencies with targeted advertising. This advertising at times improves enrollment, but rare disorders are still rare.
When enrollment for studies is low, such as with rare events like envenomations, other pitfalls can occur. To continue employing research assistants, one needs to garner income from study sponsors. If subjects are not enrolled, this income source slows, and many assistants prefer not to work under these uncertain terms. To counter this uncertainty, principal investigators will sometimes also serve as the enrolling research assistant. This can be difficult when the principal investigator has other duties, such as clinical shifts or administrative activity. In the past we have also used a “commission” offered to residents or other clinicians to aid the principal investigator in entering subjects when research assistants are not available. However, IRBs have taken an increasingly negative view of these gifts, citing the potential for conflict of interest.
Another problem with sparse enrollment of industry studies is the interaction with an institution’s investigational pharmacy. Investigational pharmacists have become increasingly important to industry studies. While they have historically been subsidized by academic institutions, this is becoming less common, and most large medical institutions now require investigators to add a stipend in their industry-sponsored budget for pharmacy participation. This usually covers drug shipping, storage, preparation, and administration. While most institutions employ one or two pharmacist to fill this role, enrollment of subjects on nights and weekends can be problematic. Our institution actively cross-trains night and weekend pharmacists to aid investigators in obtaining study drug during these off times. However, we have seen many situations where less-experienced pharmacists cover nights or evening shifts and are expected to cover the investigational pharmacy. At times, we have been unable to enroll patients under these situations due to the study complexities of blinding and preparation of study drugs at these hours. In other situations, we have had study drugs inappropriately stored by non-investigational personnel, resulting in loss of all study drug vials.
A final pitfall we have encountered is unexpected market changes. Pharmaceutical companies develop drugs or devices based on a perceived need for use. With rising research and development costs, companies are reluctant to devote resources to product development when the expected return may not be profitable. Several years ago we participated in methodology design with a company that was developing an antibody to reverse tricyclic antidepressant poisoning. Animal trials and a few isolated human case reports of compassionate use demonstrated the product’s efficacy [13]. Plans were developed to perform a larger Phase 2 trial of the study drug at multiple institutions and investigators spent significant amounts of time with project design. Shortly before full-scale implementation of the project was to occur, the company announced that they were abandoning the effort, citing a lack of marketability of the product. Needless to say, there are multiple potential pitfalls, many unforeseen, when taking part in industry studies.
Investigators face several possible conflicts of interest when taking part in industry studies. Industry sponsors often offer financial incentives to investigators. For example, for Phase 3 trials, investigators and assistants often take part in research planning meetings in preparation for enrollment. The economy of scale in getting investigators from multiple sites together in one location for teaching and information dissemination is obvious. However, as incentive, these meetings have often been held in exotic or resort sites, and include impressive meals and other perks. While many institutions have no regulations over these activities, a growing number do, and administrators are becoming more careful to scrutinize institutional leaders in these activities. Another common industry incentive is speaker’s bureaus for lecturing at sponsored events. Significant honoraria are often offered to speakers for these affairs. Industry sponsors market these talks by arguing that there is no one more credible to speak of the virtues of the new drug or device than an investigator. In reality, more academic institutions are examining participation in these sponsored activities as potential conflicts of interest. And more and more publishers and national organizations require speakers and authors to acknowledge participation in any activity that others may deem could be considered a conflict of interest.
Institutional pharmacy and therapeutics committees are increasingly looking for conflicts of interest when considering new drug approval. Clinicians who propose new medications for formulary addition at our institution are asked to list financial relationships with the drug or device manufacturer. Clear direction on how to apply these potential conflicts when considering new agents has not been well established but acknowledgement could affect committee decisions.
Finally, IRBs in modern times are giving members a greater awareness and responsibility for identifying potential conflicts of interest in reviewed proposals. This evolving area is discussed in more detail in the next section.
Navigating the IRB at academic institutions has become more challenging. IRBs are now tasked by institutions with more complex goals than just protecting the safety of subjects. In the past decade, our local IRB asked our committee to be “fiscally responsible” when reviewing research proposals. It has become important for the IRB to protect the institution from industry-sponsored “shifting” of costs due to a subject’s insurance. In addition, the IRB has increasingly applied conflict of interest criteria to studies. Investigators are asked about financial or other relationships they may have with the industry sponsor. These relationships are somewhat loosely used in the approval process, but are discussed in every review of industry studies.
In the past few years, IRBs have also begun asking for financial compensation for review of industry studies. IRBs members have traditionally spent long hours in careful review of an increasing number of studies. Academic institutions have embraced the idea that industry sponsors should share the cost involved in review of these projects and have begun charging fees for the process. Initially, these fees were small and not applied uniformly. More recently, they have become standard inclusions in investigator budgets, similar to investigational pharmacy fees.
Positive aspects of IRB review of industry-sponsored studies include the committee’s assurance that the methodology has undergone several layers of analysis, thus suggesting that statistical design and power analyses of these studies is sound. In addition, Phase 3 industry studies almost always employ a DSMB which assists the IRB in overseeing subject safety.
Many young investigators may feel great relief after completing IRB review and site enrollment for industry studies. Unfortunately, the true challenge occurs when recruiting subjects. If the disease or disorder being studied is common and presents predominantly during daytime hours, then recruitment can be easy. But ED patients may present at unconventional times and days, requiring around-the-clock monitoring for enrollment. Most industry studies are not confined to “convenience sampling” and this requires employing multiple research assistants or even co-investigators to cover all times for potential recruitment. Since most IRBs and industry sponsors prefer a limited number of staff in an ED to act as co-investigators for study entry, the burden of entering subjects falls onto the investigator either to be on-call indefinitely or to maintain an active research staff of assistants. Many investigators will end up terminating a project early due to slow or sporadic enrollment of subjects that does not support the research staff.
We have used many types of advertisements to enhance industry study enrollment. Our IRB has now mandated review of all public advertisements and requires each be stamped with an approval authentication. Investigators utilizing unapproved advertisements can be sanctioned. We have posted approved placards for our studies around our campus to recruit volunteers. If our need for industry study volunteers is small, we have often employed our own staff, with co-authorship as an incentive. In some studies where sparse enrollment is anticipated, we have utilized EMS providers to increase study awareness. Our investigators have visited local EMS conferences and meetings to teach about topics related to our research and remind EMS providers about ongoing studies.
Industry-sponsored research can be both academically and financially rewarding to investigators and institutions. As a source of research dollars, medical companies can lead to support for both present and future studies, and provide seed funding for principal investigators, co-investigators, and multiple research staff. Recent legislation and institutional rules regarding conflict of interest have necessitated caution both from an investigator and institutional perspective, and have caused some shifting in funding expectations. But when experienced research staff is assembled and institutional support generated, industry-sponsored studies continue to emerge as important step in the delivery of medical devices and drugs to the general public, as well as sources of funding for academic departments. After all, fomepizole, the drug of choice for the patient mentioned at the beginning of this chapter, was originally developed in such a manner.