Standardization

Replicability is a hallmark of the scientific method. Specifically what is tested (e.g., a substance, treatment procedure, or system of practice) must be defined, described, and stabilized so that it can be delivered reliably from patient to patient and study to study. Standardization is a great strength of modern medicine’s pharmacotherapeutics. Natural medicine does not have as definitive a codex. Rather, its practices evolve over time, with some areas highly dependent on current scientific discovery, whereas others are used empirically, rather than rationally, in procedures that are hundreds or thousands of years old.

The organized natural medical professions have variably definitive articulations of philosophy and clinical strategies. What constitutes a competent practitioner in a given discipline often remains uncertain,⁸ and many natural medicine approaches, like those of indigenous practices, are unlikely ever to be codified. Even with the licensed practices (e.g., naturopathic medicine, acupuncture, and chiropractic), health insurance coverage with regulation by practitioner-review panels is recent. It is only in the last two decades that coding systems for alternative practices have begun to describe the array of interventions available in the United States.⁹ The current emphasis on research in CAM practices calls for speeding up the process of standardization toward replicability.

Communication about natural medicine research issues can be problematic when using standard clinical practice and biomedical research metaphors. One way to understand the problem is to say that natural medicine’s critical practices lack articulation and operationalization of accepted and, within the respective practitioner groups, widely understood memes. Memes are collective concepts: ideas, behaviors, or skills that are transferred from one person to another by imitation and replicable on a population basis (see Richard Dawkins’ book The Selfish Gene, from 1976)^9a. A meme, as a phrase, invokes meaning beyond those of the words themselves, such as in the principle vis medicatrix naturae (the healing power of nature). Dictionaries of memes may be needed for the collective concepts of natural medicine practice that may be identified as the practices are investigated. The development of memes through which to express the syncretic concepts of natural medicine and which may have broad applicability is one of the benefits of researching the practices.⁵ The dearth of articulation of natural medicine’s concepts accounts in part for its remarkable variation among practitioners. Its transfer from mentor to student may be imprecise or misinterpreted even before practitioner preferences and personalities are brought into play. This is not to say that the concepts of natural medicine practice are not reliably transmitted from mentor to student, only that they are not yet always articulated in ways that have been operationalized for clinical trials.

Standardization of natural remedies is becoming better understood. To perform a single-agent controlled trial of herbs in a specific disease, numerous choices should be made about the intervention. The Policy Announcement on the Quality of Natural Products of the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM) has brought some clarity to the botanical standards for NIH sponsored trials (http://www.nccam.nih.gov/research/policies/naturalproducts.htm). Studies should begin with verification of plant species used, growth and harvesting conditions, and the stability of purported active compounds. Selections should be made among plant parts, various crude extracts, or specific chemical constituents that may be concentrated in various ways and to varying degrees of purity. Crude fresh extracts, which traditional herbalists prefer, are highly susceptible to deterioration. In more sophisticated systems of botanical medicine preparation, a product is standardized to guarantee the minimum or maximum concentration of a number of ingredients for a given period, for example, EGb 761 (Schwabe GmbH, Karlsruhe, Germany), the Ginkgo biloba, which has been the most researched botanical and is standardized on four constituents. Standardizing on particular constituents has its challenges. Active ingredients in plants are often classes of molecules (e.g., polysaccharides, saponins, terpenes) that are difficult to distinguish in biological activity. Different compounds in a single species may have similar, possibly complementary effects, such as the polysaccharides and isobutyramides in Echinacea species. During in vitro assays, which guide fractionation of the crude extract toward a single active molecule, it is not uncommon for activity to increase but then diminish as greater purity of an identified molecular species is reached, as was the case of the terpenes of Andrographis paniculata (AndroVir, Paracelsian, Inc., Ithaca, NY) in cell signaling. A few botanicals are standardized on an in vitro biological activity. The industry standard, porously applied, is chemical standardization on actives and certified Good Manufacturing Practices.

Nutrition can be divided into dietary practices and nutritional supplements. Studies in dietary interventions are demanding. The gold standard for dietary intervention is a residential facility to maintain adherence to the therapeutic regimen, but this solution is expensive and recruitment is difficult. A long observation time is frequently needed in dietary studies because diets are often intended as preventives or restoratives.

Some nutritional supplements are cultures, such as probiotics (live bacteria taken to normalize commensal bacterial populations) and algae. Studies in these types of interventions have some of the same complications as botanical medicine studies, as well as the issues of organism viability and interactivity with commensal microorganisms and the internal conditions for proliferation.

Homeopathy is a special case in standardization, in that chemical standards are largely irrelevant for remedies that rely on ultradilutional remedies that may contain no molecules of the material originally potentized. Biological testing of homeopathics is in its infancy, and reliability is not ensured. Thus, only the manufacturing process can be standardized at this time.

“Body, mind, spirit” is a leitmotif of natural medicine. The interplay of psychodynamic and spiritual phenomena and physical health are only partially encompassed by the behaviorist approach of most health psychology research, but this has been greatly augmented by recent studies in “mind–body” medicine with numerous reviews in various specialties in publication. Advances have been made in the neuroscience of expectancies in the placebo effect, with the size of the placebo effect recognized as different in different conditions, but despite the ubiquitous use of placebo in practice,¹⁰ operationalization and manipulation of placebo effects remain fraught methodologically and ethically. Placebo use in medical encounters continues to be explored, but raises more questions than answers;¹¹ however, hope remains for advances in future studies.¹²

While they represent a small proportion of all health studies, questions about spirituality remain of investigative interest, although with few authoritative and widely used research methods. Operationalization of spiritual experience is likely to be idiosyncratic or culture specific. The 4th edition of the Diagnostic and Statistical Manual (DSM-IV, 1995) reinstated the possibility of a religious or spiritual problem. Definitions of spirituality in the medical literature may refer to hope and meaning or to a personal relationship with God, serenity, or connectedness, all perhaps related to states of the patient’s consciousness.^13,14 A number of thinkers continue to bemoan the lack of definition in the area.¹⁵ Although efforts to present cogent, broadly acceptable definitions have been made, they have not been successful.^16,17 Better approaches to specifying spiritual interventions may be needed before they will be accessible to replicable research. Recent reviews of the health effects of intercessory prayer, an observable phenomenon, have been equivocal.¹⁸

Individualization of Treatment

Natural medicines’ disease taxonomies (classifications of human illness) are not always congruent with those of Western molecular biomedicine. Primary variance (differences in outcome) of efficacy is more likely to vary with the conditions of a practice’s native taxonomy than with a foreign one. For example, “strengthening the immune system,” “decreasing toxicity,” and “fortifying the will to health” are common goals in natural health therapeutics but are rare in conventional practice. Treatment response would be expected to have a different profile because different diseases are being treated. Thus, the speed to healing, as well as the disease being treated, may be confounded in the evaluation of one system by the other’s definitions and rules. These concepts are themes to be described more explicitly in natural medicine diagnosis.

Some natural medicine concepts may no longer have or may never have had a biomedical equivalent. An example is the concept of “constitution” used in naturopathy, homeopathy, and Asian medical systems. This is a patient’s given biological potential, tendencies, and patterns of long-standing psychophysical strengths and weaknesses that are genetically and embryologically determined. Others are the “biological terrain” (the background physical health and individual context for the immediate medical problem) and the “vital force” (the motive plan or spirit animating mind and body expressed as physiologic and psychological functionality and adaptability). Biomedical equivalents exist in some parameters for system control concepts; however, they are therapeutically exploited more thoroughly by holistic practitioners. Such concepts are balance (as in the immune system, among microbial symbionts, hormones, and neurotransmitters); deficiency (not just nutritional but organ deficiencies, such as hypochlorhydria and hypothyroidism); functional reserves; endogenous and exogenous toxicities; and dysmetabolisms (e.g., syndrome X). An important concept is that a disease syndrome may be an attempt by the body to adapt to ecologic stress and so should not be unnecessarily suppressed. This is of interest not only because it is an independent variable (baseline factor), but also because it influences the measurement of the dependent variable (outcome).

A skilled natural medicine practitioner necessarily expects success through individualization of treatment regimens. Individualization means that remedies are prescribed not solely on the basis of disease entities but also according to other characteristics of the patient. Such characteristics may be transient, constitutional, or representative of the entire constellation of the patient’s health problems, strengths, and his or her capacity for self-care. The lack of fit of a person’s health syndrome with a conventional disease model, expressed perhaps in the inability or reluctance of a conventional practitioner to diagnose a particular health problem, may be the very reason a patient turns to natural medicine. A medical system that does not recognize an entity is unlikely to have an effective therapy for it. The complaint will be managed as something else, resulting in ineffective treatment while exposing the patient to the side effects of the “remedy.” Conversely, a medical system that provides an adequate explanatory model for a patient’s symptoms—their origin, aggravators, and ameliorators—has a better chance of effective treatment or management of the condition. Thus, individualization of treatment is a strength of natural medicine rather than merely a research problem. Compromises may be made in practice to make a trial of specified therapy possible, such as by semi-protocolized treatments, but they may alter therapeutic effect. If the need for individualization is neglected in natural medicine research design, the design will fail to apply the medicine as practiced and thus to evaluate its potential benefit.

Combination Therapeutics: Effect Size, Response Rate, and Safety

Combination treatment is almost a rule among natural medicine practitioners, who use multiple remedies individualized for each case. This complicates the design of clinical trials, yet the evaluation of combination interventions is critical to assessing an examined practice. Single natural agents may have a true effect small enough that a very large patient sample size is necessary to detect a treatment difference. However, the size of the effect of several agents acting together, especially if they act by different mechanisms, may work by cumulative or synergetic interactions. Combination treatment may also afford the practitioner latitude in choosing the correct remedies for a patient’s condition, thereby increasing the treatment responder rate. Another strategy in choosing elements of combinations is tailoring them to a case to efficiently address multiple conditions simultaneously, thereby achieving better global outcomes. Yet another is to use some agents as “governors” (the term in Chinese herbal medicine) to ameliorate potential side effects of primary remedies.

The possibility of adverse events could theoretically rise with combinations. Although the problems of additive and synergetic actions, inhibition, and toxicity associated with multiple synthetic and novel pharmaceuticals in combination are both formidable and ubiquitous, the history of use of natural remedy candidates and the experience of clinicians in using combinations of natural products in various clinical populations mitigate these problems in everyday practice. For example, when whole botanicals are used at a traditional use dose, early toxicity is most likely to result in nausea and vomiting or diuretic action. More serious adverse events (e.g., anaphylactoid reactions) are rarer with nutrients and botanicals of traditional medicinal use than with novel drugs of a single molecular species. Modern practitioners of natural medicine also combine modalities (e.g., homeopathy and counseling, or manipulation and herbs) that are extremely unlikely to lead to a deleterious interaction, but that, if successful, could each stimulate improvement by a completely different route. Because of the breadth of options for affecting a condition, a skilled practitioner can avoid remedies that pose a risk in a particular case while still attaining the targeted pharmacologic action. There is no systematic study of the safety of combinations, but data from licensing authorities and professional liability companies for practices covered show modest levels of adverse experience.

Nonspecific Healing Effects

A confounder in a clinical trial is an apparent therapeutic effect that can be attributed not to the test treatment but to a factor associated with the treatment, disease, or population studied. This is a risk inherent to all research and is the reason why randomization, blinding, and objective measures are valuable in distinguishing true differences in effect among medications. The most honest scientists may have conscious or unconscious behaviors that could bias study results if differentially applied to study groups. Yet similar behaviors are at work in everyday clinical practice to induce affiliation, confidence, commitment, and satisfaction in patients and are the responsibility and sine qua non of skilled healers.

An important confounder that may be integral to treatment is intentionality. (See Chapters 6, Placebo and the Power to Heal and 7, Positive Mental Attitude.) The potential therapeutic action of pure intention, which is not mediated by language or any well-known material force, might be espoused explicitly by only a minority of holistic practitioners, although actually it might be widely practiced among them. This may be called “psychic healing” or simply “healing”. If the intent is to determine whether these techniques have effect on disease, surprisingly, there may be no particular difficulties in conducting studies than those already addressed here. Trials of intercessory prayer may provide a model.¹⁹ Design differences may be called for if the therapists are special (gifted) versus ordinary people, or if the healing energy is directed or willed versus invoked (as from God or spirits). Little has been written on the capacity of intention to influence physical outcomes; there is implicit rejection of the idea based on cartesian mind–body duality. Nevertheless, a number of studies suggest its existence.^20,21 Studies of the effect of prayer or other spiritual practices also may be relevant here and raise the possibility that specific kinds of intentionality may make a difference.²²

Intuition is a similarly nebulous practitioner-associated quality that may have an influence on outcome. It might be thought to bear on diagnosis as a source of data or on therapeutics as a guide among possible alternative strategies. Although intentionality and intuition are not typically listed in the educational catalogs of natural medicine academic institutions as requisite health care skills to be acquired, they may be common concepts in the culture of the institutions. Generally they are not considered antiscientific concepts that should be expunged from the awareness of students. They might be acknowledged and even honored as possible sources of data and therapeutic direction as long as their “discoveries” are not contradicted by harder evidence. The informality of the inclusion of intention and intuition in practice compounds the difficulty of including these concepts in some reproducible way in research protocols.

Health care is practiced within a culture whereby practitioners and patients have roles and expectations that reinforce belief in expected outcomes. Some studies have indicated that good practitioner–patient communication results in better health outcomes. Thus, some of the magnitude of effect may depend on the setting in which care is offered. Differences in outcome between medical practices may also hinge on the difference between research and nonresearch settings. For example, it is possible that research participants who refuse random assignment have a psychological orientation that may work synergistically with the physical effects of the practices of a medical culture that they prefer or to which they are native. If this is true, the evaluation of systems of practice relative to each other would preclude simple randomization. Trials that should be of real interest to policymakers are those that determine not simply whether a practice works for anyone to whom it is applied, but whether it works (and is cost effective) among those who choose it. A study design that could determine the added value of the availability of some form of natural health care in those who choose it would be one that randomly assigns patients to either a group that undergoes further randomization to strict assignment of alternative or conventional care or a group offering them a choice of alternative or conventional care.²³ Such a four-group trial including randomization with choice would compare the effect of the different practices among those patients who discriminatively select among them versus those who are simply assigned to them.

Natural medicine has little language for placebo and other nonspecific healing effects despite the fact that many conventional scientific authorities think this is an area in which there is much to offer. Both unintentional nonspecific healing effects and intentional psychospiritual medicine are areas in which the discovery and definition of important memes, especially those that may serve research, are poorly evolved not only for natural medicine, but also for Western biomedicine.

Outcomes and Measures

Because natural medicine addresses the holistic, it is expected by practitioners to have broad benefit (e.g., correcting deficiencies, strengthening and balancing metabolic processes, and “removing the obstacles to cure”). If a natural medicine intervention for a particular disease is shaped and delivered, a benefit is likely to affect more than one disease condition at a time. Randomized clinical trials (RCTs) are typically designed to provide higher validity on a few measures and tend to overlook effects on diseases other than the target disease, neglecting effects on overall well-being. (See discussion on “Cure and Suppression” in Chapter 5, Philosophy of Naturopathic Medicine.) Clients, who often use CAM for overall health and wellness,²² expect to see positive results not only in objective disease parameters but also in general body functions (e.g., fatigue and energy, pain, inflammation, digestion, mental and emotional function) at a perceptible level. Thus, methods to assess the efficacy of the medicine should use holistic measures accounting for effects throughout the body systems and over the life cycle, if possible, and in an intervention’s influence on social roles, productivity, and cost. Beyond the effectiveness of medicine for the individual patient, measures of an entire holistic practice may reasonably be expected to address public health as well as environmental, social, and economic outcomes.

Strides have been made in the development of measures that assess individual health globally.²⁴ There has been progress with the development and wide adoption of instruments, beginning with the Medical Outcomes Study SF-36 and its successors, and of measures such as “quality-adjusted years of life saved.” However, there remains a lack of sensitivity to changes in disease at higher levels of function. The lack of sensitivity relates to the general absence of health measures (e.g., productivity) as opposed to disease measures in clinical trials. Gentle natural treatments may show smaller, more gradual improvements than may be expected from pharmaceutical and surgical interventions, and instruments sensitive to change are needed if trials are to be relatively short. Ultimately, the possibility of the superiority of natural health care in a few areas, such as longevity, the incidence of chronic disease in aging, and the incidence and prevalence of disease in progeny, ideally will require multidecade evaluation. Online tools available and in development for patient-reported outcomes hold potential for large, long-term studies with whole person measures.^24a

Controls and Blinding

The choice of appropriate comparison controls is an important issue because every alteration of control answers different questions. The different questions in the comparison of a test intervention with placebo, a specific standard of care, usual care (the patient’s baseline care), or time–attention behavior controls are all of interest. Sometimes ethical constraints may prevent a natural medicine therapy from being evaluated without a concomitant conventional therapy. Some cases of special interest are whether natural health care leads to lower overall morbidity and mortality (1) in patients who are randomly assigned to natural health care compared with those who are not; (2) in patients to whom it is equally available on the basis of cost and access compared with those to whom it is not; and (3) in patients who would actively pursue it in the presence of health system structural resistance (e.g., devoted consumers) compared with those who would choose it only if it were equally available or with those who would explore it only under special circumstances. The answers to these questions involve belief, motivation, cost, the restraint of use because of cost (from the consumer’s side), the restraint of access because of cost (from the provider’s side), and compliance. These answers may be fundamental to determining both the efficacy and efficiency of the inclusion of various forms of natural medicine in a rationally structured health care delivery system.

Treatments can be categorized simply into substances (drugs and remedies), procedures, and interactions (verbal and behavioral medicine). The double-blind RCT test system is easily applied with the evaluation of substances. Nonmaterial process interventions, such as manipulation, exercise, acupuncture, other forms of point work, and psychological and spiritual treatment, are more methodologically problematic in the RCT desideratum of blinding. Blinding is likely to prove difficult for most dietary manipulations, psychospiritual practices, and any whole practice intervention. In these cases, blinding often may be at least partially maintained by separating evaluation from treatment and blinding the evaluator. In considering the value of blinding, one should remember that studies that blind the practitioner and patient decrease or eliminate the possibility that intentionality will contribute to a positive outcome. However, CAM theories accommodate blinding and expectation as contributors to outcome.

Whole Practice Models

Given that individualized combinations of modalities and remedies generally are the rule in natural medicine and that their selection is guided by a health system’s own principles and guidelines, evaluation of models of whole practices is most likely to reveal their potential health benefit. The main difficulty that arises is in attaining replicability of the intervention. (See Chapter 2, Functional Medicine, for a presentation of a methodology for systematizing individualization.) Although they remain both innovative and challenging, a number of intervention models are possible in approaching the ideal.

The simplest is a fixed combination of remedies, although this approach abandons individualization. If it is applied in trials with specific inclusion and exclusion criteria, however, the loss of individualization may be tolerable. A slightly more ambitious approach to whole practice is a menu of choices applied to several possible etiologies in a symptom manifestation (disease) under study. As alternative medicines have been studied in recent years, pragmatic trials have been explored using a practitioner of given qualifications as the unit of intervention, treating the practitioner and his discipline as a “black box.” A further step in sophistication is the intervention driven by guidelines or algorithms from the principles and body of knowledge of the discipline. Such guidelines may be derived through expert practitioner panels. The design and replicability of best practice protocols derived by experts from discipline principles are being studied in naturopathic²⁵ and Chinese medicines.²⁶ The complex models that have resulted may be facilitated operationally by manualization for the guidance of practitioners, who must be well trained to assess patients and deliver a standardized intervention flexibly.²⁷ A new question that would arise in such studies of manualized practice is the degree of adherence by the provider to the protocol. Another method is artificial intelligence programs that seek to emulate the decision-making processes of clinicians so that personalization can be standardized according to the algorithms practitioners use, often unconsciously.

The inability to distinguish the effects of single agents in pragmatic and whole practice studies frequently diminishes enthusiasm among grant review committees, since a whole practice is not easily transferable to other practitioners. However, whole practice studies are essential to determining the effectiveness and safety of natural medicine disciplines.