Terms of Interest

Research may be more attractive to companies if they fully understand what’s involved.

By Douglas Kalman
PhD, MS, RD, CCRC, FACN

At some point in a product’s lifecycle, customers or potential customers will probably ask a company to explain its product’s claims. How you address this situation could make the biggest difference in whether or not they remain a customer.

Think of product claims as an un-paid sales force. This is the best sales force to have because it requires low overhead and zero staff management. For this kind of sales force, however, you do need research—research that can be used to help reach new customers and build a stronger allegiance with existing ones.

Companies can perform various forms of research, from taste tests to clinical trials to consumer polling. The good news is any form of research you use to improve a product or product line could be considered part of “research and development.” In other words, if your marketing department conducts a study to investigate consumer preferences with respect to your product, it is as tax credible as if you sponsored a randomized, double-blind clinical trial comparing your product to placebo. (The IRS will allow you to credit up to $0.75 per dollar spent, or 75%, on in-house/outsourced research.)

Still, many companies shy away from clinical trials and other forms of research because they lack genuine understanding of what’s entailed. But it is the hope of this column and Nutraceuticals World that the industry will become more motivated about conducting research in the future, particularly because it is always better to have “owned re-search” on your product rather than borrowed science. Perhaps some key definitions would help. What follows are some terms used by the research community and various regulatory agencies that may help you gain a deeper understanding of the language used by researchers. And for those of you who are still confused, feel free to communicate your re-search questions to us!

Research & Regulatory Terms

Adverse Event: The ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) defines an adverse event as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment (see ICH Guideline: Clinical safety data management: definitions and standards for expedited reporting). For non-marketed drugs/product, or new indications of marketed drugs/product, an adverse event is referred to as an adverse reaction when there is a reasonable possibility that it was caused by the medicinal product (i.e. a causal relationship cannot be ruled out).

Adverse Reaction: Unwanted effect(s) (i.e., physical and psychological symptoms and signs) resulting from treatment. A less rigid definition of adverse reaction includes the previous definition plus any undesirable effect or problem that is present during the period of treatment and may or may not be a well-known or obvious complication of the disease itself. Thus, many common personality, physical, psychological and behavioral characteristics that are observed in medicine studies are sometimes characterized as adverse reactions even if they were present during baseline. Synonyms of adverse reactions generally include adverse medical effects, untoward effects, side effects, adverse drug/product experiences, and adverse drug/product reactions. Specific distinctions among some of these terms may be defined operationally. For example, the term adverse reaction is used to denote those signs and symptoms at least possibly related to a medicine, whereas the term adverse experiences is used to include non-medicine-related medical problems in a trial such as those emanating from trauma or concurrent illness. Distinctions among side effects, adverse events, and adverse reactions are illustrated in the definitions of the two former terms.

Serious Adverse Event (SAE): An adverse event that leads to death, permanent disability or (prolongation of) hospital admission. These events are of obvious importance to authorities and fellow researchers working on the same drug/product and have to be reported to the local and international authorities with the greatest possible urgency. The details of the reporting are given in the study protocol. (Note: This definition should be a familiar one to the nutraceuticals industry since the AER law became effective in late 2007.)

Serious Adverse Reaction (SAR): Multiple definitions are possible and no single one is correct in all situations. In general usage referring to subjects in clinical trials, a serious adverse reaction may be (1) any bad adverse reaction that is observed, (2) any bad adverse reaction that one does not expect to observe, (3) any bad adverse reaction that one does not expect to observe and is not in the label, or (4) any bad adverse reaction that has not been reported with standard therapy. Definitions may also be based on the degree to which an ad-verse reaction compromises a subject’s function or requires treatment. A commonly used definition is “an adverse event that leads to death, permanent disability or (prolongation of) hospital admission.” The details of reporting these events are often given in the study protocol.

Side Effect: Any effect other than the primary intended effect(s) resulting from medicine or non-medicine treatment or intervention. Side effects may be negative (i.e., an adverse reaction), neutral or positive (i.e., a beneficial effect) for the subject. This term, therefore, in-cludes all adverse reactions plus other effects of treatment. See also the definition of adverse reaction.

Med Watch (FDA-AER’s): The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA’s post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The ultimate goal of AERS is to improve public health by providing the best available tools for storing and analyzing safety reports. (It is very important that nutraceutical companies become familiar with MedWatch as the new AER Law asks consumers, healthcare professionals and nutraceutical companies to use this method to report AE’s, which must be saved for six years. The FDA receives adverse drug reaction reports from manufacturers as required by regulation. Healthcare professionals and consumers send reports voluntarily through the MedWatch program. These reports become part of a database. The structure of this database is in compliance with the international safety reporting guidance (www.fda.gov/
medwatch/report/iche2b.pdf) issued by the International Conference on Harmonisation. The guidance describes the content and format for the electronic submission of reports from manufacturers. FDA codes all reported adverse events using a standardized international terminology, MedDRA (the Medical Dictionary for Regulatory Activities). Among AERS system features are: the on-screen review of reports; searching tools; and various output reports. The reports in AERS are evaluated by clinical reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to detect safety signals and to monitor drug safety. They form the basis for further epidemiological studies when appropriate. As a result, the FDA may take regulatory actions to improve product safety and protect public health, such as updating a product’s labeling information, sending out a “Dear Health Care Professional” letter, or re-evaluating an approval decision.

Types of Research Studies

It should be noted that these definitions are pharmaceutically oriented since currently the DS industry has not developed singularly-accepted definitions for the phases of research in natural product development.

Open-Label Study: No blind is used. Both investigator and subject know the identity of the medicine or product.

Single-Blind Study: The subject is unaware of which treatment (intervention) is being received, but the investigator has this information. In unusual cases, the investigator and not the subject may be kept blind to the identity of the treatment.

Pilot Study: A pilot trial is used to obtain information and work out the logistics and management deemed necessary for further clinical trials. Although pilot trials are often not blind and use open-label medicines/products, they may also be single- or double-blind and may include tight control on all appropriate variables. The term “pilot” or “exploratory” refers to the purpose of the trial.

Phase I Study: Clinical pharmacology studies are carried out in healthy volunteers (sometimes subjects) to determine the safety and tolerability of the drug/product, other dynamic effects and the pharmacokinetic profile (absorption, distribution, metabolism and excretion—ADME). Evidence of efficacy may be gained if subjects, disease models or biomarkers are used.

Phase II Study: Clinical investigation studies are carried out in subjects with the target disease (condition), to determine efficacy, safety and tolerability in carefully controlled dose-ranging studies.

Phase IIa Study: Pilot clinical trials are carried out to evaluate efficacy (and safety) in selected populations of subjects with the disease or condition to be treated, diagnosed or prevented. Objectives may focus on dose-response, type of subject, frequency of dosing, or numerous other characteristics of safety and efficacy.

Phase IIb Study: Well-controlled trials are conducted to evaluate efficacy (and safety) in subjects with the disease or condition to be treated, diagnosed, or prevented. These clinical trials usually represent the most rigorous demonstration of a medicine’s efficacy.

Phase III Study: These formal clinical trials are carried out as large-scale placebo-controlled and active comparator studies in subjects to confirm efficacy, and to provide further information on the safety and tolerability of the drug/product.

Phase IIIa Study: These trials are conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug/product Application (NDA) or other dossier. These clinical trials are conducted in subject populations for which the medicine is eventually intended. Phase IIIa clinical trials generate additional data on both safety and efficacy in relatively large numbers of subjects in both controlled and uncontrolled trials. Clinical trials are also conducted in special groups of subjects (e.g. renal failure subjects), or under special conditions dictated by the nature of the medicine and disease. These trials often provide much of the information needed for the package insert and labeling of the medicine.

Phase IIIb Study: These types of clinical trials are conducted after regulatory submission of an NDA or other dossier, but prior to the medicine’s approval and launch. These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials (e.g., quality of life, marketing) or phase IV evaluations. This is the period between submission and approval of a regulatory dossier for marketing authorization.

Phase IV Study: These studies are represented as post-marketing surveillance to expand safety and efficacy data in a large population, including further formal therapeutic trials and comparisons with other active comparators.

Other Definitions of Interest

Randomization: Each subject has a known chance, usually equal chance, of being given each treatment, but the treatment to be given cannot be predicted. The idea of randomness accords with our intuitive ideas of chance and probability, but it is distinct from those of haphazard or arbitrary allocation.

Safety: A relative concept referring to the freedom from harm or damage resulting from adverse reactions or physical, psychological, or behavioral abnormalities that occur as a result of medicine or non-medicine use. Safety is usually measured with one or more of the following: physical examination (e.g., vital signs, neurological, ophthalmologic, general physical), laboratory evaluations of biological samples (e.g., hematology, clinical chemistry, urinalysis), special tests and procedures (e.g., electrocardiogram, pulmonary function tests), psychiatric tests and evaluations, and determination of clinical signs and symptoms.

Good Clinical Practice: A standard to ensure protection of research subjects and data integrity in clinical studies of new drugs/products.

Efficacy: A relative concept referring to the ability of a medicine to elicit a beneficial clinical effect. This may be measured or evaluated using objective or subjective parameters, and in terms ranging from global impressions, to highly precise measurements. Efficacy is assessed at one or more levels of organization (e.g., subcellular, cellular, tissue, organ, whole body) and may be extrapolated to other levels.

Clinical Significance: The quality of a study’s outcome that convinces physicians to modify or maintain their current practice of medicine. The greater the clinical significance, the greater is the influence on the practice of medicine. The assessment of clinical significance is usually based on the magnitude of the effect observed, the quality of the study that yielded the data, and the probability that the effect is a true one. Although this operational definition is presented from the physician’s perspective, the term could operationally be defined from the subject’s perspective. Subjects are primarily concerned with results that will lead to an improved quality of life or a lengthening of their life. In addition, clinical significance may be applied to either positive data of efficacy or negative safety data such as for adverse reactions. Synonyms include clinical importance, clinical relevance and clinical meaningfulness.NW

References:
1. Cohen A, Posner J. A Guide to Clinical Drug Research 2nd Edition. 2002. Kluwer Academic Publishers. Dordrecht, The Netherlands.
2. Spilker B. Guide to Clinical Trials. 2000. Lippincott, Williams & Wilkins. Philadelphia , PA.
3. Association of Clinical Research Professionals. www.acrpnet.org Accessed December 22, 2004
4. Food and Drug Administration website (Center for Drug Evaluation and Research): http://www.fda.gov/
cder/drugsatfda/glossary.htm
5. Gallin, J.I. 2002, Principals and Practice of Clinical Research, Academic Press, California.
6. http://www.mayoclinic.com/invoke.
cfm?id=SA00073 Accessed January 24th, 2005.
7. http://www.cfsan.fda.gov/~dms/
guidance.html#ds Accessed December 3, 2007.