Leading Off: How we can contribute to clinical research

Clinical trials constitute the cornerstone of evidence-based medicine. They are a part of a broader realm of clinical research, which determines the safety and efficacy of diagnostic or therapeutic interventions and examines their impact on at-risk patient populations. Most commonly, clinical trials compare therapeutic interventions between at least two sample populations. Other examples of clinical research include observational studies (e.g. case reports; case series; and epidemiologic studies, such as adverse event reporting) and field trials (large clinical trials).

Dawn Merton Boothe

Although normal animals can be evaluated in clinical trials, patients with or at risk to develop spontaneous disease comprise the optimal study population. As such, clinical trials are more appropriately implemented in collaboration with clinicians who have a vested interest in their patients' welfare, even if the animals evaluated provide an experimental model of the disease of interest.

However, clinical research struggles for acceptance in veterinary academic and private practice environments. Yet, we can improve this vital part of veterinary medicine in several ways.

CLINICAL TRIAL CHALLENGES

Academic commitment lacking

Academia is uniquely placed to assume a leadership role in promoting and facilitating multicenter clinical research studies, including clinical trials. But financial constraints and complicated accounting policies often lead academic administrators to passively support or even actively discourage funding for personnel, facilities, patient enrollment, or equipment to conduct clinical research. Fortunately, nearly half of North American veterinary colleges have dedicated some support to clinical research activities, and several sponsor Offices of Clinical Trials.

Colleges that commit resources to generating new medical knowledge should benefit from the expertise and recognition afforded by such achievements. Clinical research is inseparable from high-quality patient care, and clients who choose hospitals associated with a clinical research program will benefit from the program's strengths. Thus, the patient base may increase, particularly if research activities are promoted as part of high-quality patient care.

A clinical research program also strengthens recruitment and retention of clinical faculty. For academic environments that support clinical research, the timing may be optimal to more effectively promote the role of spontaneous animal diseases as models of like diseases in people. Clinical trials involving veterinary patients might bridge the distance between mouse models and spontaneous disease in people.

Limited dissemination of information

Academia has successfully promoted the tenets of evidence-based medicine, and practitioners increasingly apply them to patient care. Indeed, practitioners help identify the questions that clinical research answers. Yet, despite our profession's enthusiastic embrace of evidence-based medicine, veterinary journal reports are often limited to case studies, case series, and review articles (largely based on human medicine) rather than clinical trials. This limitation is due, in part, to the paucity of clinical trial data. Anecdotal evidence appears to continue to play an important role in therapeutic decision-making in veterinary medicine. For example, veterinarians have rapidly accepted specialty compounded drugs, human generic drugs, and dietary supplements as therapeutic modalities despite limited or no evidence of efficacy or safety.

Poor study design

Disconcertingly, poor study design often weakens the validity of conclusions drawn from veterinary clinical trials. Many clinical trials lack appropriate controls, randomization of treatment groups, or blinding procedures. Statistical support is critical in well-designed trials but is often not used or is reserved until data have been collected. A common sequela of insufficient or late statistical input is that only a small number of patients are studied, which leads to two common errors.

• First, investigators may use the same animal to study multiple therapeutic interventions. Thus, even if randomization and crossover are properly performed, the increased number of comparisons increases the risk that a difference will be falsely identified as significant.

• Second, a small sample size decreases the power of the study to detect true treatment differences. The investigator, and practitioner, often confound the mistake by interpreting the lack of significant difference as evidence that the treatment groups are the same, and thus, the treatments are equivalent—or in the case of a placebo-controlled study that the treatment had no effect. It is a veterinarian's responsibility to learn what constitutes a well-designed clinical trial and to be able to assess the validity of the investigators' conclusions.

Transparency of potential bias

Identifying bias is also important. Readers should be aware of a study's source of funding. As mandated by the Food and Drug Administration (FDA), manufacturer-sponsored studies that support drug approval generally test hypotheses that the manufacturer's product is not inferior to a positive control, rather than generate unique information. Frequently, only those reports in which their product performs well make it to peer-reviewed literature. Reports of studies sponsored by manufacturers should be considered biased but not necessarily suspect.

Need for greater practitioner participation

Although it is the investigator's responsibility to design clinical trials that provide valid conclusions, often the best design is circumvented by lack of practitioner participation. However, as clinical research continues to struggle for acceptance in academia, the role of practitioners becomes increasingly important. Practitioners have historically provided the patient base for industry-based clinical trials, and private practitioners are best-positioned to assume a leading role in implementing clinical research.

As a clinical pharmacologist, I have concentrated on clinical research. Our laboratory has implemented a number of clinical trials, often in partnership with private practices. I am humbled by the care and attention to detail that participating practitioners and their clients dedicate to our studies. However, some participants fail to follow study protocols, not realizing that doing so excludes that patient's data from the study and reduces the sample size.

Furthermore, we have difficulty identifying potential participating practitioners and clients. For example, we have three ongoing clinical trials, two that involve compounded preparations (including transdermal gels) and one that investigates antimicrobial resistance. Practitioners enthusiastically agree that the medical information to be generated by the successful implementation of these studies will meet practitioner and patient needs, yet we have not identified sufficient participants.

Practitioners express several concerns regarding participation in clinical trials, some of which can be resolved by improving investigator and participant communication. Other concerns require that practitioners take a more altruistic approach to generating new knowledge. At least three approaches might increase patient recruitment.

Ensure simple guidelines and thorough informed consent. Investigators must clarify and simplify guidelines that participants must follow so practitioners can and will take time to collect data correctly. In addition, the informed consent must be clear and complete since practitioners or their clients may also be concerned that patient health is put at risk. As little as 10 years ago, informed consent was basically a permission slip the owner signed to allow a pet to participate in a study. Today, the client informed consent describes, in lay terms, all procedures, risks (including possible placebo assignment or a description of any potential adverse events), benefits that directly affect the patient, confidentiality, and client costs of participating. A well-designed informed consent should also identify alternative therapies should the client choose not to participate and guarantee that choosing not to participate will not alter the level of care the pet might otherwise receive.

Practitioners might approach the informed consent as an opportunity to guide clients through the decision-making process and present the clinical trial as a therapeutic option that is not available through other venues. However, the fully-informed client should make the final decision regarding participation, thereby reducing practitioner risk.

If a study is blinded and precludes clinician knowledge about which therapy patients receive, fail-safe procedures (described in the informed consent) should be in place that allow codes to be broken (ending the study) if patient health is at risk for any reason. Practitioners might also be concerned about the continued availability of successful therapies once the study ends. The informed consent should address means by which therapy can be continued, if desired, and the anticipated client cost of continued therapy.

Consider alternative reimbursement for participation. Practitioners also are hesitant to dedicate their limited time to participation in a clinical trial. Financial reimbursement for participation is not unreasonably expected; certainly, physicians are compensated, as are practitioners participating in industry-sponsored field trials. Perhaps this is where the altruistic side of veterinary medicine might emerge: Colleges and private foundations that fund clinical trials in animals often cannot afford reimbursement for veterinary participation. Some innovative approaches to rewarding practitioners such as coauthorship (if appropriate), acknowledgments in the reports, or providing certificates of contribution suitable for display might encourage more participation.

Help develop and use a recruitment database. Among the biggest obstacles to patient recruitment for veterinary clinical trials is adequate promotion of trials available to animals. Human clinical trials recruit patients through media as diverse as magazines, subway walls, and Web sites. People can search the Web for clinical trials that target their ailment. In veterinary medicine, few means exist for shared communication regarding clinical trials. Each academic clinical trial center lists its ongoing studies on its Web site, and VIN members can communicate about studies, but the net thrown out to identify potential participants is limited in size and scope.

A centralized veterinary clinical trial Web site that matches investigators, trials, and patients is paramount to the continued growth of evidence-based veterinary medicine. Our profession is too small, funding is too limited, and the need for clinical trials is too great for an otherwise well-designed clinical trial to fail because of a lack of sufficient study participants, particularly if eligible patients exist. Such a Web site, which should provide the service at no or minimal charge, might also include a frequently updated description of ongoing or finished clinical research studies and, as deemed appropriate by investigators, updated results.

ADVERSE EVENT REPORTING

Practitioners can further contribute to clinical research by reporting adverse events, which include any undesirable response to a therapeutic or preventive intervention such as a drug, vaccine, therapeutic procedure, dietary supplement, food, diagnostic test, or medical device. Adverse drug events include medication errors. The term adverse generally implies a serious nature to the event such that the quality or quantity of life is affected. However, less serious side effects also are undesirable. Therapeutic failure (e.g. to compounded products or vaccines) also might be considered an adverse event.

It is important to report adverse events because although they might be discovered during the approval process, they more commonly emerge with postmarket surveillance when thousands of patients are receiving the product. This surveillance vitally depends on reporting by practitioners or clients. The only mechanism by which these reports will find their way back to the profession is if they are reported to an agency that collects, analyzes, and re-reports the data. This will only happen with practitioner input.

Reporting adverse events is a multi-step process: accepting that they may occur, knowing what to look for, recognizing the clinical signs, and alerting the client. Finally, the practitioner must take time (perhaps delegate the responsibility) to report the information to the manufacturer or the regulatory agency.

FDA-and USDA-regulated products

For drugs (animal, human, or compounded) and foods, the appropriate agency for reporting adverse events is the FDA Center for Veterinary Medicine (CVM) (www.fda.gov/cvm/adereporting.htm). For vaccines (and some other biologics), the United States Department of Agriculture (www.aphis.usda.gov) is the appropriate agency. By law, each manufacturer must report the adverse event information to its respective regulatory agency. The ASPCA also sponsors a poison control center. Although the center maintains extensive records regarding any type of adverse event, data collection is generally fee-based (with the intent of providing therapeutic advice), and the information is not accessible to the public.

Practitioners often express concern that clients will be less likely to use products if counseled regarding adverse events or that such counseling paves the way for future litigation should an adverse event occur. Yet data from human medicine indicate that patients are more likely to become angry with their caregivers if information is withheld. Informed clients tend to be happier clients. Although reporting adverse events is particularly critical immediately after a new drug, particularly a new drug class, is approved, practitioners should remain diligent and report all adverse events. It is only through continued data collection that more subtle adverse events might emerge, and only then might safety differences among drugs within the same class (e.g. NSAIDs) become evident.

Adverse vaccine events reported by practitioners or their clients are analyzed annually and then reported to the profession through veterinary journals. The path for reporting adverse drug events to the profession is less clear and would benefit from practitioner direction. Adverse drug events reported to the FDA-CVM have been posted annually and cumulatively on its Web site. However, because pharmaceutical companies do not provide information regarding the number of units of each drug sold, a popular drug might be interpreted as having a greater incidence of side effects, when, in fact, it is simply more commonly used.

Further, the cause and effect between the adverse event and the drug cannot always be confirmed through the reports, and reports are not always accompanied by risk factor information (e.g. overdose, underlying disease). Disconcertingly, the FDA-CVM has recently removed information regarding the incidence of adverse events to products from its Web site (www.fda.gov/cvm/ade_cum.htm), markedly limiting the usefulness of the information to practitioners. Equally important to practitioners reporting adverse events is the availability of collated and analyzed data in a useful format. Thus, in addition to reporting adverse events, our responsibilities include insisting (perhaps by working with the AVMA) that the FDA-CVM and manufacturers provide and maintain a robust reporting system that returns relevant information to the profession in a timely, user-friendly fashion.

Medication errors

Medication errors, including administration of the wrong dose, interval, route, medication, or drug or to the wrong patient, are a problematic subset of adverse events. In human medicine, up to 30% or more of adverse events associated with serious injury are preventable in that they reflect medical errors on the part of caregivers.1,2 As such, these adverse events were preventable. Our profession has no information regarding the incidence and impact of medication errors. Yet they occur.

As we improve our adverse event-reporting activities, we need to gain the self-confidence that will allow self-critique and, thus, facilitate medication error reporting. For example, because medication errors are more likely to occur (and more likely to be dangerous) in critical care patients, a Web site that allows anonymous entry of the adverse incident might be considered by veterinary emergency and critical care specialists. Such a Web site might begin the dialogue necessary for recognizing a potential problem.

EPA-registered products

Although the pathway to report adverse events is clear for approved drugs and vaccines, it is less clear for EPA-registered insecticides and parasiticides (the EPA has a limited role in veterinary adverse event reporting), some biological products, dietary supplements, diagnostic procedures, and medical devices. In contrast to drugs or vaccines, no federally mandated postmarket surveillance program exists for these products in veterinary medicine. Further, manufacturers are not compelled to share adverse event reports collected from practitioners or clients. Thus, adverse event reporting for these products will require practitioner demand for agencies that not only collect the information but allow its review in a user-friendly fashion by practitioners.

CONCLUSION

Through emerging molecular biology techniques, the last two decades have enjoyed a stunning improvement in the understanding of the pathophysiology of diseases in people and animals. Although the one medicine concept is commonly embraced at the molecular level, the clinical application of such information must be applied to a population of the target species at risk. It is at the point of clinical application that the one medicine concept begins to fail.

By definition, clinical research must be implemented in the target species, precluding extrapolation of data from other species. Accordingly, it is practitioners' responsibility to help investigators translate basic research in the clinical arena, whether through participation in clinical trials or adverse events reporting. It is only through these types of clinical research that new medical knowledge critical to the maintenance and improvement of high-quality patient care will continue to emerge.

Dawn Merton Boothe, DVM, MS, PhD, DACVIM, DACVCP

Department of Anatomy, Physiology, and Pharmacology

College of Veterinary Medicine

Auburn University, AL 36849

REFERENCES

1. Woods D, Thomas E. Frequency, types and severity of preventable adverse events in children. Abstr Acad Health Serv Res Health Policy Meet, 2002.

2. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 2003;289(9):1107-1116.