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References
https://t.me/medicina_free
27© Springer Nature Switzerland AG 2021
L. H. Powell et al., Behavioral Clinical Trials for Chronic Diseases,
https://doi.org/10.1007/978-3-030-39330-4_3
Chapter 3
Behavioral Treatment
Development
This chapter proposes a progressive, translational model for developing
behavioral treatments for chronic diseases. It begins by describing the long-stand-
ing, evolving, and widely accepted process of drug development. It then draws on
basic elements of this process to present the revised ORBIT model for developing
behavioral treatments for chronic diseases. This model pushes toward Phase III
behavioral efcacy testing in three progressive phases: (1) Discovery of an impor-
tant clinical problem and a basic science underpinning for a behavioral treatment
that could solve it; (2) Design of the treatment by rst assembling basic elements
and then rening them to enhance efciency without sacricing efcacy; and (3)
Derived from the Dutch verb quacken (to boast), “quack” is a word people use
to describe medical charlatans. Quacks peddled adulterated and mislabeled
medicines throughout the United States without penalty until 1906 when the
Congress passed the Food and Drug Act that outlawed the practice [1]. In the
United States, the Food and Drug Administration (FDA) regulates a vast array
of products, including drugs, medical devices, and some dietary supplements,
foods, and cosmetics. However, there is no regulation for medically indicated
behavioral treatments for chronic diseases. Thus, it is difcult for consumers to
distinguish between behavioral treatments that work and ineffective treatments
promoted by behavioral “quacks.”
Fundamental Point
Development of behavioral treatments for chronic diseases is a cross-
disciplinary, translational process featuring a progression of questions, a
variety of study designs linked to them, and lots of tinkering. The aim of this
process is to provide the evidence needed to determine if it is plausible that
a behavioral treatment can improve an important clinical outcome, and it is
feasible to answer this question in a rigorous, randomized efcacy trial.
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Preliminary Testing of a xed protocol using proof-of-concept studies, feasibility
studies, and Phase II behavioral trials with behavioral and biomedical outcomes.
Recommendations for fostering translational behavioral treatment research are
suggested for funding agencies, publication practices, and investigators.
SCIENTIFIC PRINCIPLE
The Drug Development Model
The process of drug development has evolved in response to public health need and
is now widely accepted and well regulated. It provides an excellent model for a
process of developing a behavioral treatment for a chronic disease, a process which
is considerably less well understood and accepted.
Regulations Protect Consumers
US federal regulations are intended to protect consumers from falling victim to
fraud and misrepresentation (Table3.1) [1–3]. Regulations respond to the evolving
need for consumer protection. In the early 1900s, the goal was to insure drug purity
to protect consumers from the proliferation of medicinal products of unknown com-
position. In the late 1930s, the goal was safety to protect consumers from accidents
such as the deaths of 107 persons from sulfanilamide, an antibiotic drug whose
toxicity had been known. In the early 1960s, the goal was to insure efcacy and to
put the burden of proof on the manufacturer to support the claim that a drug was safe
and efcacious. This was triggered by the epidemic of birth defects and deaths in
infants that resulted from the drug thalidomide. Since the burden of proof was now
on the manufacturer, throughout the 1970s and 1980s, guidelines for scientic qual-
ity were issued by the FDA.In the late 1980s and 1990s, acceleration of the process
of approval was demanded by consumers who were facing urgent threats to life in
the face of the AIDS epidemic [4]. Since AIDS was an international problem, har-
monization of standards for the drug approval across countries was facilitated by the
formation of the International Congress on Harmonisation [5].
Public health crises and the need for consumer protection triggered regulatory
actions to insure the purity, safety, efcacy, and rapid dissemination of drugs.
Behavioral treatments for chronic diseases have not been heavily regulated, possi-
bly because they are unlikely to be used in the face of acute public health crises to
save lives. This leaves the purity, safety, efcacy, and standardization of behavioral
treatments unregulated.
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The Process ofDrug Development
Table 3.2 summarizes the widely accepted process of drug development [6]. It
begins with a period of Discovery during which a link is made between a therapeutic
need and a drug candidate. Promising compounds progress to a Non-clinical phase
characterized by testing in vitro and in animals for biologic activity and safety.
These studies form the basis for the case made to the FDA to obtain approval to test
the drug in humans. Human Pharmacology studies focus on closely monitored
healthy volunteers to evaluate human safety and pharmacology. Success in healthy
subjects justies progression to patients. Therapeutic Exploratory studies focus on
a small number of highly selected and closely watched patients to provide a prelimi-
nary understanding of safety and efcacy. The cost of high failure rates in these
early studies of humans is minimized by keeping them small and studying accessi-
ble subjects, often in quasi-experimental pre-post designs. These small studies do,
Table 3.1 History of drug legislation
Goal
Public Health
Crisis Legislation Actions
Ensure Purity Proliferation of
drugs of unknown
composition
Food and Drug
Administration Act
(1906)
Drug was required to meet
standards for strength and purity.
Burden of proof on the regulators.
Assure Safety Accidental deaths
from the antibiotic
sulfanilamide
Federal Food, Drug,
and Cosmetic Act
(1938)
Drug was required to be safe, with
penalty for fraudulent or
misleading claims.
Burden of proof on the regulators.
Promote
Efcacy
Deaths and birth
defects from
thalidomide
Kefauver-Harris
Amendment (1962)
FDA Guidelines
(1970s–1980s)
Drug was required to be safe and
efcacious.
Burden of proof on the
manufacturer.
Guidelines for quality of scientic
data including: investigator
qualications, trial management,
patient safeguards, and adherence
and protocol monitoring.
Encourage
Dissemination
Need for rapid
response to AIDS
epidemic
FDA Regulation
(1987)
FDA Modernization
Act (1997)
International
Congress on
Harmonisation
(1995–present)
“Accelerated” approval if drug
provides benet over existing
treatments on surrogate endpoints.
“Fast-track” approval if drug
concerns a serious or life-
threatening condition.
A forum for harmonizing
standards for drug approval across
countries.
Scientic Principle
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however, provide the clinical evidence needed to justify a Phase III Therapeutic
Conrmatory efcacy trial which investigates the impact of the drug on clinically
meaningful endpoints in a larger, more diverse sample of patients using a rigorous,
randomized design. These Phase III trials are the key to FDA approval and introduc-
tion into the commercial market [3, 6]. Therapeutic Use studies conduct ongoing
monitoring to identify rare side effects and need for optimization for special popula-
tions or real-world conditions. Since these studies often draw on big data sources
such as registries and electronic medical records, they are likely to become increas-
ingly common in the future.
Table 3.2 The process of drug development
Phase:
Objective Central Goal Common Methods Milestone
Discovery Identify a promising
candidate
Integration of clinical need
with advances in
pathophysiology,
pharmacology, computer
science, and chemistry
Drug has desired
biologic activity
Non-Clinical Non-human safety and
biological activity
Animal and laboratory
studies invitro, ex vitro,
invivo
FDA permission
to test drug in
humans
Phase I:
Human
Pharmacology
In healthy volunteers,
short-term safety,
tolerability,
pharmacokinetics,
pharmacodynamics
Short-term studies of a small
number of healthy subjects
who serve as their own
controls and are monitored
carefully for dose-response
and drug interactions
Drug is safe and
has biologic
activity in healthy
humans
Phase II:
Therapeutic
Exploratory
In patients, short-term
safety, tolerability, and
efcacy
Short-term studies of a small
number of well-dened
patients who serve as their
own controls and are
carefully monitored on
surrogate endpoints
Drug is safe and
has biologic
activity in
patients
Phase III:
Therapeutic
Conrmatory
In diverse patients, safety
and efcacy on clinical
endpoints over long-term
use
Randomized efcacy trial
with morbidity/mortality
outcomes
FDA permission
to market the
drug as therapy
for an important
clinical endpoint
Phase IV:
Therapeutic
Use
Rene risk/benet and
implementation in general
populations and in special
populations and
environments
Registries, electronic
medical records, randomized
trials, pharmacoeconomic
studies
Ongoing
optimization and
renement
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General Features oftheDrug Development Process
The drug development process has several features that are known, accepted, and
expected in the effort to bring a drug to market.
Multidisciplinary Collaboration
The time, cost, and range of studies needed to bring a drug to market make it obvi-
ous that this is a multidisciplinary effort. Close connections between clinical med-
icine and basic science are forged by the “clinician-scientist” training model which
features didactic instruction at the intersection of basic and clinical research with
forward and backward translation from clinic to lab and vice versa [7].
Sophistication in solving emerging problems is enhanced by, among other things,
computer science, information technology, and bioinformatics. Standards for
quality of evidence have been set by methodologists in basic science, epidemiol-
ogy, and biostatistics, are accepted by scientists and stakeholders throughout the
world, and serve to regulate industry’s prot-oriented goals.
High Failure Rates
Drug development is an uphill battle that is costly in time and money. The Tufts
Center for the Study of Drug Development Research reported an average clinical
phase duration of 6.8years across all types of drugs [8]. Price Waterhouse Coopers
estimates that the cost to bring a single drug to market now exceeds $1.3 billion [8].
This is due, in large part, to high failure rates which are increasing over time [9] and
are most common in Phase III efcacy trials and in drugs for chronic diseases [10].
Among drugs that survive long enough to be tested in humans, 80% fail to receive
FDA approval [8]. Calls for reform include more intensive surveillance in early
phase studies to reduce later, and more costly, failures [8].
Progressive Development
Drug development is a logical, but not necessarily linear, progression of small early
studies that are used to support and plan for larger, more denitive trials. International
guidelines proposed by the International Conference of Harmonisation [5] encour-
aged a shift away from classifying studies by phases (e.g., Phase I, Phase II) and
toward their classication by purpose (e.g., Exploratory, Conrmatory) because a
study with the same purpose may occur at several different phases. The goal is for
approval to market the drug, which generally requires at least one well-designed
Phase III clinical trial with additional supporting evidence. Marketing of the drug is
planned well before the drug is introduced into the market by studying need,
demand, pricing, appeal, and accessibility.
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Progressive development has two important features. First, it minimizes the costs of
failure. In the face of suboptimal results, there is relatively low risk in rening and
trying again if the study, and its budget, is small. Second, it studies signal under a
progression of noise. A weak signal under highly controlled conditions may lead to
a judgment of futility. But a strong signal under highly controlled conditions fosters
interest in progressing to less controlled conditions to study erosion of the signal
and explore renements that may potentiate it. An understanding of the range of
signal-to-noise ratios can inform decisions about whether any gain in disease man-
agement is worth the effort needed to optimize use.
CHALLENGES FOR
BEHAVIORAL TRIALS
Some have come to believe that there would be distinct advantages if regulatory
approval was required for medically justied behavioral treatments for chronic
diseases [11]. They argue that while a number of ofcial documents describe cri-
teria for evidence-based treatments, there is no regulatory system for introducing
these treatments into practice. Thus, advances made in prevention research in the
past decades are not reected in a parallel improvement in practice, and there is a
proliferation of ineffective preventive treatments available to patients. Allocation
of resources for the delivery of ineffective treatments is of particular concern in
the context of overstretched healthcare systems. A regulatory system that evalu-
ates behavioral treatments in a way that is logically consistent with the evaluation
of drug therapies could enhance the translation of behavioral treatments from
research into practice.
Multiple Perspectives onBehavioral Treatment Development
A number of investigators have proposed processes for developing evidence to sup-
port a behavioral treatment [12–23]. These efforts to standardize have two general
characteristics.
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Discipline-Specic Models
In the metaphor of the blind men and
the elephant, the blind men attempted
to gure out what they were observ-
ing by focusing on only one particu-
lar part of the elephant. Those who
examined the ear said it was a fan,
and those who examined the tail said
it was a rope (see box). This is an apt
metaphor for current attempts to
standardize the process of behavioral
treatment development. Each effort
examines a different part of this com-
plex process. Some are specic to the problem, focusing on treatments for obesity
[16] or drug abuse [17]. Some are specic to the treatment, focusing on psycho-
therapy for mental health problems [18]. Some are specic to the disease, focusing
on cancer [19] or chronic diseases [15]. Some focus on early treatment develop-
ment, including intervention mapping [20, 21], multiphase optimization [22], or
mixed methods [23], while others focus on later phases of treatment development
[13, 14]. Basic elements of these discipline- and time-specic models are funda-
mentally compatible. But there have been no efforts directed toward harmonization
of them.
Culture-Specic Models
Scientic understanding is embedded within cultural traditions which have their
own unique spirit of inquiry [14, 24]. In behavioral treatment development, two
traditions predominate. Translational research focuses on health outcomes and
develops treatments progressively. Efcacy is a prerequisite for effectiveness.
Without knowing if a treatment works under optimum conditions, a null result in
real-world conditions could be explained either by an inefcacious treatment or by
an implementation failure [14]. In contrast, social program evaluation focuses on
a variety of health and social outcomes embedded in dynamic, real-world systems.
Although randomized designs are preferred, they can be foregone in the face of
complex interventions, poorly understood causal mechanisms, difculties in
reaching widely dispersed target populations, and the fact that many social pro-
grams have already been implemented before any evaluations have been con-
ducted [13].
Challenges forBehavioral Trials
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Consequences ofNot Being Guided by aModel forTreatment
Development
Investigators have the freedom to develop, test, and implement behavioral treat-
ments as they see t. This freedom is part of what makes an academic career so
compelling. But it comes at a price.
Treatments Not Optimized
The signicance and sophistication of a behavioral treatment is a cross-disciplinary
product. The popular clinician-scientist model in the biomedical sciences cultivates
interactions between basic and applied scientists. But it is uncommon in the behav-
ioral sciences, thus making crosstalk difcult. Without an in-depth understanding
of pressing medical problems faced in clinical practice, the signicance of a
behavioral treatment in solving these problems may be underestimated. Without an
awareness of fundamental processes underlying maintenance, motivation, emotion,
self-regulation, and decision-making, the strength and sophistication of behavioral
treatments may not be optimized.
Progressive development maximizes strength. Observation leads to hypothesis for-
mation, testing, refutation, and then a new, more rened hypothesis [25]. The cul-
ture that has emerged in behavioral treatment development is less progressive and
more consistent with “one fell swoop” research. Funders, reviewers, and investiga-
tors all converge on the strategy of answering all relevant questions in one trial with
one standard design. New treatments are often tested in noisy real-world settings
with stringent control groups, stacking the odds against their success and running a
high risk of abandonment in the face of failure. Promising treatments are untested
in rigorous and inuential Phase III efcacy trials. Without incentives to push
toward Phase III efcacy trials, the behavioral treatment has not been subjected to
the ultimate gold standard in medicine, the ticket to publication in high- visibility
medical journals, and the key to implementation in clinical practice.
Variable Standards for“Evidence Based”
Standards for the quality of the scientic evidence for a new drug are consistent
across regulatory agencies, professional societies that set practice guidelines, and
third-party payers. But the quality of evidence to support a new behavioral treatment
is often “in the eye of the beholder.” Standards for the quality of a single behavioral
trial have been established [12, 13, 26]. The US Preventive Services Task Force issues
guidelines for elements of effective treatments (www.ahrq.gov). The National
Registry of Evidence-Based Programs and Practices provides a list of programs for
mental health and substance use interventions rated by the quality of the evidence
(https://knowledge.samhsa.gov/ta.centers/national-registry-evidence-based-pro-
grams-and-practices). But there remains a vagueness about what is, and what is not,
an “evidence-based” behavioral treatment. To say that a behavioral treatment is “evi-
dence-based” can mean that it has support from several high-quality Phase III clinical
trials, one low-quality Phase II clinical trial, a quasi-experimental community study,
a pilot study, or an observational study.
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Vulnerable Patients
The absence of an accepted chain of sci-
entic evidence supporting the safety and
efcacy of a behavioral treatment leaves
patients vulnerable on several fronts.
They are vulnerable to “quacks” who
offer treatments that sound attractive but
lack evidence to support their claims (see
box). Half of the recommendations made
on popular medical talk shows such as
“The Doctors” and “Dr. Oz” have either
no evidence to support them or are contradicted by the best medical evidence, and con-
icts of interest are rarely disclosed [28]. On the “Dr Oz” show, 43.2% of the advice
offered is for such behavioral risk factors as diet or weight loss [28]. Without regulation,
these claims can be made without fear of legal ramications. Patients are vulnerable to
harms which could range from a serious adverse event, such as mortality, to the time and
money wasted for an ineffective treatment. But the ultimate vulnerability for patients is
the need to make decisions based upon inadequate data. They must decide, on their own,
whether or not to try a behavioral treatment on the faith that its claims are valid, it is safe,
and its costs in time and money will be justied by its benets for health.
OVERCOMING THESE
CHALLENGES INA
BEHAVIORAL TRIAL
The ORBIT Model forDeveloping Behavioral
Treatments forChronic Diseases
Background
When the purpose of a behavioral treatment is to improve a chronic disease out-
come, treatment development is well suited to a translational research tradition, and
the Obesity-Related Behavioral Intervention Trials (ORBIT) model is useful as a
guide for the process [15]. Like all of the comparable models for behavioral treat-
ment development, ORBIT is specic rather than general. Because a dening fea-
ture is the focus on chronic disease as a primary outcome, it has been aligned closely
with the process of drug development, using similar basic principles and terminol-
ogy. Because the biggest gap in knowledge exists in the pre-efcacy phases of
behavioral treatment development, this is the primary focus. Although the model
was developed within the context of obesity, the process can be applied to any
behavioral treatment aimed at improving any chronic disease outcome.
Vulnerable Patients
A “quick-x” weight loss product
called Sensa Weight Loss Crystals
was ned and forced off of the market
for “false and deceptive advertising”
but not before the company turned a
$4.6 billion prot [27].
Overcoming These Challenges inaBehavioral Trial
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