Full text of DOI:10.1177/00912700022009657

HE20VETOAHTL-HUCTEANIONTNDUOCRYOFLADBRDUUVRAGNNDCEEVSELINOPDMRUENGTDEVELOPMENT
An Evolution of Drug Development and Clinical
Pharmacology during the 20th Century
Gene Heath, PhD, and Wayne A. Colburn, PhD, FCP
The current state of clinical pharmacology and drug
and promotion of the purported remedies to processes that
exploited unknowing patients to a process that now requires
concept generation, discovery, research, planning, and de-
velopment with many checks and balances for the protection
of human subjects. The factors that contributed to this pro-
gression from inappropriate use of potions, concoctions, and
snake oil to the highly regulated drug development process of
today is described in some detail.
development did not just happen. Clinical pharmacology
and the drug development process were born, evolved, and
have come to the fore during the past 100 years. The past cen-
tury has been one of accelerating progress in science and
medicine. The progress has not been a straight line but rather
more like a sidewinder moving across the desert. Drug devel-
opment has moved from small experiments with concoc-
tions, extracts, and potions along with the manufacturing
Journal of Clinical Pharmacology, 2000;40:918-929
©2000 the American College of Clinical Pharmacology
his review of the evolution of clinical pharmacol-
regulations to protect the public. The pharmaceutical
industry has grown from manufacturers and packagers
of crude mixtures to a research-based industry that pro-
duces ever more potent and specific chemical or bio-
logical treatments for diseases.
Discoveries of sulfonamides, penicillin, and vac-
cines as well as the discovery drugs for arsenic poison-
ing have stimulated improvement throughout the cen-
tury. Many of these discoveries have been shaped by
the politics of two world wars. The influence of the mil-
itary has focused efforts to protect and treat our sol-
diers. Scientific discoveries and observations were
used to build a knowledge-based foundation that was
then used to establish and propel our fundamental
mechanism-based understanding of disease processes
and therapeutic interventions.
But this has not been a well-planned and/or smooth
journey. In medicine, there has been a movement
through the century to segregate experimenters from
developers from practitioners that continues even to-
day. In addition, the use of evolutionary scientific
methods and statistical tools has played a major role in
our journey.
The ebb and flow of funding during this century has
been another source of control over basic and applied
research and development. Public funding through
federal and state governments has determined when,
where, and how basic and applied research was con-
T
ogy and drug development during the 20th cen-
tury reveals an explosion of science, a beginning of
better disease process understanding, and, more im-
portant, a development of better systems to ensure ac-
ceptable risk-benefit ratios for patients who require
therapeutic intervention (Figure 1). These changes
have occurred because of phenomenal interplay be-
tween science, technology, government legislation/
regulation, and public and private interests. Without
the right things in the right place at the right time, it
could have turned out quite differently. Although there
have been dramatic improvements overall, there also
has been some backsliding along the way.
Starting from an era dominated by concoctions,
potions, and extracts, we have generally arrived at
pure synthetic chemicals, formulated to deliver one
drug for not only symptomatic relief but also, in some
cases, for disease modification. At the same time,
through technological advances, we now have com-
plex biotechnology-derived products that result from
recombinant DNA technology. Our progress has been
shaped by many factors. Disasters, such as formulation
toxicity and drugs that cause birth defects, have forced
From MDS Harris, Inc., Lincoln, Nebraska (Dr. Heath) and MDS Harris,
Inc., Phoenix, Arizona (Dr. Colburn). Address for reprints: Dr. Gene Heath,
MDS Harris, Inc., 621 Rose Street, Lincoln, NE 68502.
918 J Clin Pharmacol 2000;40:918-929

EVOLUTION OF DRUG DEVELOPMENT
Figure 1. Factors influencing drug
development during the 20th century.
ducted. Public-funded research was countered by an
explosion in private funding coming from the phar-
maceutical industry, venture capitalists, and John Q.
Citizens such as Bill Gates. Today, private spending
on medical research far exceeds that of government
funding.
Increased funding, along with a better informed
public, has resulted in more being done earlier in the
drug discovery and development processes: preclinical,
preclinical-to-clinical links, and early clinical studies
in healthy subjects as well as patients. More detail will
be provided in the text and tables that follow.
reau of Chemistry, established his “poison squad” to
evaluate the safety of additives in foods using healthy
volunteers. The 1902 Biologic Control Act was passed
to ensure the safety and purity of serums, vaccines, and
other biological products. The 1906 Food and Drug Act
tried to control misbranded and adulterated foods,
drinks, and drugs. Certain types of substances such as
narcotics and alcohol were controlled through the Har-
rison Narcotics Act and later through Prohibition.
Major chemical manufacturers established toxicol-
ogy research programs for worker health. Major ad-
vances in toxicology assessment were made possible
because inbred strains of rodents were developed for
research purposes. Many toxicology studies evaluated
contaminants in illegal liquor during Prohibition as
well as the effects of pesticides in the environment. In
1906, the Food and Drug Act provided impetus for the
use of animals to evaluate food, drugs, and chemicals.
In 1911, the National Safety Council was created, fol-
lowed by the U.S. Public Health Service, Division of
Industrial Hygiene in 1914. The 1930s saw the forma-
tion of the National Institutes of Health (NIH) and the
first journal dedicated to experimental toxicology:
1901-1935
The government, in response to concerns for public
safety, began reviewing the issue of safety of food, food
additives, and concoctions (Table I). Regulations dur-
ing the early part of the century were primarily in re-
sponse to real issues of public safety and the use of
treatments for the public. During this era, regulations
did not require safety or efficacy of the products that
were used to treat patients. Dr. Wiley, chief of the Bu-
20TH-CENTURY ADVANCES IN DRUG DEVELOPMENT
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HEATH AND COLBURN
Table I The First 35 Years: 1901-1935
Legislated regulation
Event
Effect
Adulteration of biologics, drugs, and food
Limited information on drug use
Formed medical societies and published clinical
results in hopes that MDs would accept best practices
Small individual investigator clinical studies
Wiley’s Poison Squad
New drugs such as insulin, arsenicals, sulfa drugs,
and vitamins
Limited animal toxicology
Enrolled healthy volunteers
Developed effective treatments
Impurities and environmental chemicals
Inbred rodents
Increased animal toxicology
Improved toxicology studies
Archiv für Toxikologie. Clearly, science and, specifi-
cally, toxicology had established its place in the
drug/chemical development process.
ings and published in a few journals that tried to sanc-
tion good science and use of appropriate treatments in
medical practice. These organizations, along with early
pioneers in human experimentation, used sound scien-
tific methods, which surely saved numerous lives and
helped improve the practice of medicine in the early
part of this century.
The concept of larger clinical trials progressed
slowly, with more patients being included in studies to
evaluate risk-benefit ratios in the practice of medicine.
During the 1920s, arsenicals were first used to treat
syphilis. In 1933, the federal government became in-
volved in larger clinical trials with the infamous “Syphi-
lis Study,” which included a placebo group to evaluate
the progression of the disease without appropriate
intervention.
Clinical drug development was in its infancy. The
medical community was not well educated on the use
of drugs and primarily focused on treatment with con-
coctions, plant extracts, and other unproven treat-
ments. A few medical centers and physicians were in-
volved in small clinical studies to evaluate medical
products. Information from animals was lacking for the
most part, and little information was available to aid
these physicians during the conduct of early clinical
trials. The medico-scientific community was not well
organized and did not recognize the complexity of the
issues involved in treating patients with these untested
materials.
A brief look at the preclinical-to-clinical link in drug
development reveals a lack of any process other than
expediency and/or greed. From 1901 to 1935, advances
were hard to come by and were generally the result of
crisis management once an atrocity was identified. Ac-
tions were haphazard and often did not directly ad-
dress the issue that had been raised by one or more of
the poorly coordinated disciplines that were lumped
into the medico-scientific community. Most advances
in medicine and treatment of patients were led by small
university research centers and were initiated to ad-
dress some public or government concern. In parallel,
the American Therapeutic Society (ATS) was promot-
ing publication of relevant information for medical
treatment so practicing physicians could use best-in-
practice information for their patients.
During the first third of the century, discoveries such
as insulin, vitamins, sulfonamides, penicillin, radioac-
tivity, bioassays, and expanded use of the scientific
method were the humble beginnings of the explosion
in medical information.
These discoveries formed a foundation for later de-
velopments such as purification processes, production
processes, and larger clinical studies.
1936-1970
Proof of safety was not required for new treatments un-
til 1938 (Table II), after more than 100 people were
killed by a toxic formulation of sulfanilamide. The
sulfanilamide disaster greatly expanded the need for
animal safety and toxicology studies prior to human
exposure. The Food and Drug Administration (FDA)
reviewed drugs not for just safety per se but for safety in
the use of the product in the context of treating patients.
Clinical experimentation in the early part of the 20th
century was limited to a few clinical research hospitals
and teaching institutions. Studies of small numbers of
patients were conducted and presented at ATS meet-
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EVOLUTION OF DRUG DEVELOPMENT
Table II The Second 35 Years: 1936-1970
Event
Effect
Lethal formulation of drugs
War needs of military
Implemented safety legislation
Discovered, developed, manufactured, and used penicillin
Expanded the pharmaceutical industry
Legislated ethics-based regulation
Increased drug discovery
Clinical trial atrocities
Government-funded research
Funding by National Institutes of Health
Radiation experimentation
Inappropriate use of drugs by public
Polio vaccine
Expanded clinical studies
Increased medical school research and education
Identified ADME, X-ray diagnostics, and cancer treatment
Required prescription-only medications
Developed new immunization concepts
Legislated safety and effectiveness regulations
Decreased money for medical research
Increased use of larger clinical studies
Thalidomide disaster
Medicare
Increased statistical involvement
More research centers, medical schools, and institu-
tions were getting involved in the evaluation of drugs.
Congress was also involved in deciding which medi-
cines would be made available to the public. Although
it was directed by government agencies, funding for
medical research was available. Following World
War II, more money to evaluate the safety and effec-
tiveness of drugs began to come from the pharmaceuti-
cal industry.
Penicillin had been discovered during the 1930s,
but only now was production developing with the help
of a few pharmaceutical companies. The first patient
was treated in 1941, followed by expanded clinical
trials and designation of all penicillin for military
use. This research and production effort was a good
example of close collaboration among the military,
university medical centers, government, and industry.
Penicillin was not available to the general population
until the war was over in 1945.
The war and the use of DDT added new applications
of chemicals and radiation to the research agenda.
Many studies were being conducted on the biological
effects of chemicals and radiation. Development of
antimalarial drugs demonstrated the need to use non-
human primates for toxicology testing. Experimental
pathology of chemical- and radiation-induced cancers
increased the understanding of the mechanisms of
carcinogenesis. Animals were also used extensively to
evaluate safety and efficacy, and this information was
used as a foundation for human studies. However, ap-
plication of animal toxicology information to human
dose selection was still predominantly guesswork.
In 1950, passage of the Durham-Humphrey Amend-
ment required some drugs to be prescribed by a physi-
cian. Later that decade, the “Deleney Clause” was
added to this amendment to prohibit the use of sub-
stances that caused cancer in animals.
Funding by the NIH, its distribution to medical
schools, and influx of basic research programs estab-
lished unparalleled systems to promote innovation
and discovery. A polio vaccine, new drugs, mecha-
nisms of drug action, DNA, and the metabolism of
chemicals were new areas of research that were begin-
ning to evolve during this period. The pharmaceutical
industry developed into a significant research-based
provider of medicines. Many drugs such as antiepilep-
tics, antihistamines, antibiotics, diuretics, anesthetics,
steroids, stimulants, neurotransmitter mimics and
blockers, and vaccines were developed and marketed.
Surfacing of the “thalidomide tragedy” in 1962 re-
quired a better understanding and evaluation of the ef-
fects of chemicals on the embryo and fetus. Toxicology
research exploded in the 1960s. The 1962 Kefauver-
Harris Drug Amendments added a requirement for
proof of effectiveness to the existing proof-of-safety re-
quirement for new products prior to marketing ap-
proval. The FDA later contracted with the National
Academy of Science/National Research Council to
evaluate the effectiveness of all drugs approved be-
tween 1938 and 1962. This retrospective assessment
brought safety and efficacy standards to bear on all
marketed products.
The 1960s ushered in an expansion in all activities
related to basic and applied clinical research. Drug me-
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HEATH AND COLBURN
tabolism and the use of radiolabeled drug molecules to
The ability of the pharmaceutical industry to com-
mercialize penicillin, discover new antibiotics and
vaccines, and market antimigraine, antihistamine,
antipsychotic, hormone, and diuretic drugs changed
the practice of medicine and made the lives of the pub-
lic better during the second third of the century. Also,
during this time, major discoveries in medicine, phar-
macology, and genetics set the stage for the final three
decades of the 20th century. In addition, discovery of
new diseases, new drugs, genetic influence, and com-
puter power have set a foundation for continued expo-
nential growth in medical information throughout the
final 30 years of the 20th century.
study absorption, distribution, metabolism, and excre-
tion processes were starting to evolve. Improvements
in analytical techniques such as liquid chromatogra-
phy, mass spectrometry, and radioimmunoassays pro-
foundly affected the discipline of toxicology. It was
possible to measure chemicals in animals and humans
in small concentrations never envisioned by regula-
tors, Congress, or the public.
Patient studies had taken a significant turn, focusing
on safety of clinical trial participants. The atrocities of
war, followed by the Nuremberg trials, had sensitized
the public on ethical conduct toward participants. Eth-
ical principles for conducting medical research were
published in 1964 and finalized in the “Declaration of
Helsinki” that issued later in that same year.
1971-2000
Regulation, together with innovation, moved clini-
cal research into larger studies as statisticians began to
assert themselves in the drug development process. Sta-
tistical principles were being applied to the decision-
making process for the first time. The package insert be-
came a legal document, not just a document for pre-
scribing, and required pharmaceutical companies to
provide data for review on all safety and efficacy state-
ments on the label. This did not, however, change the
practice of medicine. Physicians were not required to
follow this document because this would imply that
the government was dictating the practice of medicine.
Implementation of Medicare during the mid-1960s
started changes in funding of basic and applied re-
search that continued through this era. Medical centers
began to move away from medical research and toward
delivery of medical care. This not only started the move-
ment to managed care but away from government-
funded research.
Drug development was being defined by phases,
with each phase having a different function in the over-
all process. Clinical researchers began to specialize be-
tween early focused safety studies and larger efficacy
studies to prove both safety and effectiveness. Today’s
definitions include the learning and confirming phases
of drug development, which provide insight into the
molecule and evidence for regulatory approval, respec-
tively. The pharmaceutical industry, including regula-
tory, academic, pharmaceutical, and a newfound con-
tract research organization (CRO) industry, started to
“rush to market.” To the investment community, pa-
tient advocacy groups, pharmaceutical industry, and
CROs, this came to mean a rush to phase III and large ef-
ficacy trials. Somehow, this rush to market translated
into a few quick-and-dirty studies that generated little,
if any, early dose/regimen or mechanism of action
information.
During this 30-year period (Table III), the explosion of
research and the important breakthroughs in medicine
and treatment required specialization and cooperation
to move a new chemical entity to a standard of practice.
The importance of any group or constituency cannot be
minimized since this transformation required scien-
tific expertise from many specialties, including phar-
macology, toxicology, clinical medicine, pharmacoki-
netics, clinical pharmacology, genetics, molecular
biology, biotechnology, and chemistry. The degree to
which these specialists communicated and cooperated
during drug development determined the degree to
which the process succeeded.
By 1971, the pieces had started to fall into place.
Bioanalytical method capability and capacity had be-
gun to converge. Clinical pharmacology had begun to
form a foundation for better safety and efficacy trials by
establishing dose, dose regimen, and plasma drug/
metabolite concentrations as drivers for resulting bene-
ficial and adverse effects. Societal/regulatory need and
technological capability came together to force drug
development into a new era. Pharmacokinetics (PK)
and pharmacodynamics (PD) were being employed
during preclinical pharmacology and toxicology as
well as clinical development. Doses were being related
to concentrations in animals, and this information was
subsequently used to try to make the transition from
animal models to first-human exposure.
Those involved in the drug development process be-
gan to recognize the need for early studies to define
more than just the safety and tolerance of new molecu-
lar entities (NMEs). They wanted to assess safety and
tolerance plus mechanism of action. They also wanted
to assess a variety of dosing regimens as well as to
characterize the disease processes in the intended pa-
tient population with and without the new therapeutic
intervention.
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EVOLUTION OF DRUG DEVELOPMENT
Table III The Final 30 Years: 1971-2000
Event
Effect
Continued implementation of Medicare
Focused on delivery of medicine
Decreased medical school funding
Government purchased drugs from Italy
Neurotransmitters (L-DOPA)
Contributed to bioequivalence assessments
Expanded neuroscience
Electronic miniaturization-analytical improvement
Developed more sophisticated instrumentation such as
GC, HPLC, RIA, GC/MS, LC/MS/MS
Environmental toxins
Love canal
Established EPA
Increased fetal/mutagenic assessments
TCDD
Developed mechanistic toxicology, including in vitro
methods
“Belmont Report”
Caused “Common Rule”
Biotechnology
Orphan drugs
Attempted to control drug prices
Advanced in toxicology and pharmacokinetics
AIDS
Developed human insulin, interferon, TPA, and so on
Reduced regulatory requirements for rare diseases
Approved generic drugs
Developed toxicokinetics and exposure concepts
Caused public pressure/accelerated approvals/benefit-risk
balance
Perceived slow drug approval
Dietary supplement regulations
Implemented Users Fee Act (PDUFA)
Reverted to 1901 for CMC
Combinatorial chemistry and high-throughput
screening (HTS)
Stressed archaic drug development system
Transgenic animals
Improved pharmacology and toxicology through human
tissues in animal models
Human genome project
Raised concern over genetic testing and treatment
Perception that women and children were not
represented in clinical trials
Required inclusion of women and children in clinical
trials
Rush to market
Minimized information from well-controlled clinical
studies
Global registration
Supported ICH efforts
Perceived inefficient FDA
Legislated Food and Drug Administration Modernization
Act (FDAMA)
Small clinical studies were once again being con-
ducted so that PK and PD properties could be used to
choose doses and dosing regimens to better understand
the mechanisms involved in both beneficial and ad-
verse effects. The results from these small PK/PD stud-
ies were then used to design large clinical trials that
confirmed or negated preliminary observations and ex-
panded these observations to larger numbers of pa-
tients. However, it became apparent that even large
multicenter trials did not evaluate sufficient numbers
of patients to adequately assess safety issues that may
arise in postmarketing when millions of patients begin
to self-medicate in the real world.
During the 1970s, the Environmental Protection
Agency was established, medical devices were regu-
lated, and Congress stopped the FDA from banning sac-
charin but required a warning label stating that a sub-
stance causes cancer in animals.
Toxicology and residue studies followed the “Love
Canal” exposé. This was later followed by the forma-
tion of the National Center for Toxicology Research and
the development of point mutation assays to assess
mutagenicity. The evaluation in the 1980s of TCDD tox-
icity forced the industry to look at how the mechanism
is important in testing. This changed the view of toxi-
cology and started the transition from one of observa-
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HEATH AND COLBURN
tion to one that included mechanistic studies to under-
stand the observations.
were beginning to make their way into clinical proto-
cols for the evaluation of safety and efficacy in healthy
and diseased populations. Early clinical studies began
to rely on more predictive tools to evaluate potential
harm to volunteers, including exposure measure-
ments, dose-effect relationships, and adverse event
profiles. These tools provided a rationale for predicting
dose-effect relationships in healthy volunteers and pa-
tients, which could allow drug developers to answer
two critical questions: (1) do we spend a hundred mil-
lion dollars to further develop this compound, and (2)
when do we spend the money?
During these final decades of the 20th century, polit-
ical and technological events set the foundation for the
future of drug development in the century to come.
AIDS and cancer brought the need for accelerated
approval based on biomarkers surrogate endpoints
rather than clinical outcomes. Biomarkers were used to
evaluate safety, efficacy, and toxicity. Application of
allometry to dose selection for clinical trials was being
tested. The FDA was trying to move from Cmax, tmax, and
AUC to exposure concepts for bioavailability, safety,
and efficacy. Combinatorial chemistry was creating
more NMEs. High-throughput screening (HTS) was
supposed to translate this expanded compound library
into additional clinical lead compounds at a faster rate.
The jury is still out on whether this potential will come
to fruition. Genetic polymorphism in drug metabolism
and cellular transporters such as P-glycoproteins were
shown to alter the safety and efficacy profile of drugs.
During the 1980s, public and congressional pressure
resulted in the Orphan Drug Act to encourage research
and approve drugs for rare diseases and the Generics
Act to expedite the availability of less expensive ge-
neric drugs.
Since the federal government could not fund these
additional legislated activities, the Prescription Drug
User Fee Act (PDUFA) of 1992 required drug and vac-
cine manufacturers to pay application and supplement
fees as well as annual establishment and product fees.
The PDUFA was followed by the Dietary Supplement
Health and Education Act (DSHEA) in 1994, which de-
fines dietary supplement and ingredients and classifies
them as foods.
Meanwhile, the FDA was trying to decide if nicotine
was a drug and if a cigarette was simply a drug delivery
device. Finally, Congress reauthorized the 1992 act in
the Food and Drug Administration Modernization Act
(FDAMA) and mandated that the FDA change its prac-
tices, accelerate approval of devices, and regulate the
advertising of drugs and devices as well as health
claims for foods.
Toxicology moved from “did the animals die and
which ones died?” to “how did they die and at which
doses did they die?” Toxicology progressed from sim-
ple testing to rigid, inflexible, protocol-driven testing to
more mechanistic testing with opportunities to use
in vitro data and whole-animal disease models to pre-
dict the safety and efficacy for early human studies.
Standard testing protocols were developed to provide
some level of safety prediction in humans using single
and multiple doses over various intervals. Results from
toxicokinetic and animal ADME/exposure concept
studies added information that was applied to human
dose selection. In vitro techniques have also proven
useful for carcinogenic, genotoxic, antigenic, and meta-
bolic evaluations. Toxicology began to focus on mecha-
nistic studies to ask why and how questions that arose
from standard protocols. Information was being gener-
ated to improve the preclinical evaluations of new mo-
lecular entities using a variety of techniques, including
in vitro and genetic tests, cassette dosing, and transgen-
ic animal models.
A SUMMARY OF THE CENTURY
Clinical pharmacology expanded from a few small uni-
versity centers such as Rockefeller University, Cleve-
land Clinic, University of Chicago, Harvard, and Yale to
other medical centers, universities, individual investi-
gative sites, and CROs. A clinical pharmacology and
drug development function has developed within the
pharmaceutical industry as well as in the National In-
stitute of Health, Centers for Disease Control and Pre-
vention (CDC), military, and at the FDA. Many scien-
tific and medical societies—including but not limited
to the American Therapeutics Society, the toxicology
societies, the American Medical Association, regula-
tory bodies, American Society for Pharmacology and
Experimental Therapeutics, basic science societies,
American Society of Clinical Pharmacology and Thera-
peutics, and the American College of Clinical Pharma-
cology—guided this progress.
Preclinical pharmacology had moved from in vitro
models and general whole-animal pharmacology to
safety pharmacology studies to evaluate the pharmaco-
logical and toxicological effects in animal models of
disease. Resulting data increased knowledge and were
applied to later clinical evaluation of safety and effi-
cacy of drugs. Biochemical, genetic, and effect-based
biomarkers that were identified in preclinical studies
Focused clinical research and specialization of med-
ical practice generally have not been good for the prac-
tice of medicine. There is a definite lag between collec-
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EVOLUTION OF DRUG DEVELOPMENT
tion of information needed by the medical community
Table IV Critical Drug Development and Clinical
and relay of that information to the practicing medical
community. During the drug development process, we
have tried to prove safety and efficacy for regulatory ap-
proval while providing information in the package in-
sert on how to properly use the new drug to treat pa-
tients and modify the disease. More often than not, use
of drugs does not follow the directions in the package
insert; a legal document is jointly agreed on by the
pharmaceutical sponsor of the NDA/BLA and the FDA.
Knockout animals brought animal models of disease
closer to humans. Improved analytical and diagnostic
methods continued to allow for increased sensitivity
and specificity for both small and large molecules as
well as methods to identify human disease earlier. The
Genome Project and the industry it created made it pos-
sible to identify genetic causes of future disease. From
genomics came functional genomics/proteomics that
moved the genetic information downstream to the pro-
teins and other biomaterials such as phospholipids and
carbohydrates that can cause disease. Biotechnology
started to have an influence by providing new drug
molecules as well as by providing tools to study disease
and therapeutic interventions.
Pharmacology Elements: Past, Today, and Future
We have observed the following events leading to more
legislation/regulation:
Subpotent drugs
Toxic additives
Addiction
Lethal formulations
Risk of cancer
Thalidomide
Misuse of subjects and patients
Rx pricing
Orphan indications
Fraud
Public opinion and greed
Public and industry pushing for better drugs
Cost control
We are currently learning the following:
Balance participant protection with need for new
treatments
New therapeutics need to be understood by the medical
community
New therapies need to be accepted by medical
community
Many clinical pharmacologists had begun to work in
the preclinical-to-clinical transition arena to determine
if the drug is safe and to determine if it could function
as a treatment for a disease. The need for continuity
from concept to discovery, to preclinical research to
preclinical development, and to clinical development
to market approval and marketing required people who
were able to communicate to ensure that knowledge
was translated across the functional groups. Clinical
pharmacologists were being asked to evaluate risk to
healthy subjects, risk to patients, risk of clinical failure,
and risk of financial failure. This remains the same to-
day. A great deal of information is generated that may or
may not be converted to knowledge and passed on to the
next group in the process. Those who convert informa-
tion to knowledge and communicate it to the next group
in the drug development process will be the victors.
It is apparent that drug development and advances
in the treatment of clinical illness have been shaped by
past mistakes, lack of understanding, atrocity, and dis-
regard for individuals. The current process for registra-
tion of new drugs has been shaped by disasters causing
regulations; specific disease discoveries such as AIDS,
prompting changes in direction; and technological
breakthroughs leading to different therapeutic ap-
proaches. Future drug development will build on the
past. Advances in clinical pharmacology and drug de-
velopment during the 1980s and 1990s have set the
foundation for the future (Table IV).
Control of medical resources must consider long-term
outcomes
Politics of profit—supplements versus nutraceuticals
Regulation is not the most efficient method to improve
drug development
Science is being separated from medical practice
We hope to do the following:
Improve safety pharmacology
Increase understanding of disease and therapeutic
processes
Improve the drug development and approval processes
Better coordinate science, drug development, and
medicine
Improve treatment to decrease postmarketing adverse
drug reactions
Improve standard of practice
Employ rational cost-effective approaches to medical
payment
SO, WHAT IS IN THE FUTURE?
Initially, the separation of scientific information, clinical
pharmacology, drug development, and clinical practice
will continue. This process will slow and finally re-
verse as we develop new treatments for patients with
well-understood diseases rather than drugs for syn-
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HEATH AND COLBURN
dromes. The information gathered from many scien-
deal of information that still needs to be converted to
knowledge and then applied to the next opportunity.
We have just begun to establish a better understand-
ing of genetic and environmental bases for differences
in absorption, distribution metabolism, and excretion
between certain individuals within a certain race and
region as well as between different races and regions of
the globe. Similarly, gender and age differences will
continue to be an integral part of a global drug develop-
ment process. Differences mediated through enzymes,
receptors, transporters, and other active processes
will continue to be studied both in vitro and in vivo.
Moving from qualitative comparisons to qualitative
and quantitative comparisons across species and dif-
ferent subpopulations will set the tone for the early 21st
century.
Imaging techniques have been used in clinical medi-
cine for diagnosis and, in some cases, treatment.
However, MRI, CAT, SPECT, and PET have only re-
cently begun to be applied and accepted as reasonable
approaches in drug development. Imaging will be used
during drug development to identify receptors, localize
NMEs, and modify disease cascades to confirm the
mechanism of intervention for the NME in the disease
process. Use of imaging techniques as biomarkers and
surrogate endpoints for drug development and ap-
proval should help the process become more effective
when these techniques are applicable. Measurement of
biochemical biomarkers will also become more impor-
tant as pharmaceutical companies and regulatory agen-
cies establish the role of biomarkers and surrogate end-
points in the development and approval processes.
With respect to the preclinical-to-clinical link, we
still have a way to go. What about more predictive ani-
mal models for human exposure? Although there has
been a great deal of retrospective work with allometry,
it has generally ignored absorption, the most important
factor in the ability or inability to use animal models to
predict human exposure to most new drugs. Allometric
scaling only has power when it is predictive and when
interspecies similarities are real rather than visually
appealing because exponents have been used to bring
dissimilar observations closer to a correlation line. Per-
haps we should think about using animal models to
predict systemic exposure while using computer simu-
lations to predict human absorption.
tific specialties such as genomics, proteomics, toxicol-
ogy, disease models, biomarkers, and imaging will be
incorporated into the new molecular entity approval
and marketing procedures. Treatments will include di-
agnostic assessments, economic assessments, prescrip-
tive assessments, therapeutic intervention, prognostic
assessment, and outcome evaluations. This should
provide the right treatment for the right patient with the
right follow-up.
New and existing analytical methods will need to
continue to improve with respect to sensitivity, speci-
ficity, and reproducibility. Analytical methods will be
applied across multiple applications, including but not
limited to such things as genomic and proteomic iden-
tification, pharmacokinetic and pharmacodynamic
quantification, and diagnostic, prescriptive, and prog-
nostic identification and quantification. Existing meth-
ods such as immunoassays, GC/MS/MS, and LC/MS/
MS will serve as the foundations for new methodolo-
gies, but imaging will also become more quantitative
and therefore more appropriate for analytical measure-
ment. Noninvasive methods are currently in the works,
which will allow physicians and/or patients to quan-
tify biomarkers of disease as well as drug concentra-
tions at the bedside. These technologies will have an
impact on both drug development and patient care by
characterizing drug effects and disease progression.
The human genome is almost sequenced, but the job
has just begun. Genomics will facilitate a better under-
standing of propensity for disease, disease mechanism,
and effects of intervention. A functional understanding
of proteins and their interactions as well as evaluation
of systems or cascades of enzymes will lead us to
disease-modifying NME use. This understanding will
be a major driver for use of biomarkers during drug de-
velopment and for establishing the linkage between a
biomarker and a clinical endpoint to establish a surro-
gate endpoint. These surrogates will then be used for
diagnosis, intervention selection, and prognosis in the
treatment of patients.
More information will be available, but we have lim-
ited bioinformatics to assimilate the information and
get it into a form that we mere humans can convert to
knowledge. There is a misguided notion that informa-
tion is power. Information is useless unless it is con-
verted to knowledge that can be used to address the
next opportunity. The genome now needs to be trans-
lated into functional genomic/proteomic information
that can be used to better understand disease processes
and how drugs, gene therapy, stems cells, and ap-
proaches that we have not even dreamed of yet can be
used to alter disease processes. Today, we have a great
Continuing societal pressure and improved in vitro
models will allow us to limit the number of animals
used to assess various aspects of NME pharmacology,
toxicity, and pharmacokinetic studies. There will even
be an effort to use in vitro systems together with
computer-simulated whole-animal experiments as we
gain better understanding of mechanisms involved in
926 J Clin Pharmacol 2000;40:918-929

EVOLUTION OF DRUG DEVELOPMENT
toxicity and efficacy. More information from early pre-
clinical trial designs to establish effectiveness and
safety. Limitations will be imposed to protect the pub-
lic from another form of potions, concoctions, and
witchcraft. With these outcomes, we should see the
benefit of botanical medicines effectively developed
and added to our armamentarium to treat disease.
Clinical pharmacologists will continue to play a crit-
ical role in drug development and will need to bring
clinical pharmacology concepts to bear on the practice
of medicine. Ideal therapeutic agents will have limited
impact if they are not readily accepted and appropri-
ately applied to patient diagnosis, treatment, and prog-
nosis by the medical community. The clinical pharma-
cologists of the future will need to communicate their
knowledge and understanding to the management and
marketing teams at pharmaceutical companies as well
as to the medical community that will either accept or
reject the rationale for improved therapy. Computer
simulation referenced above can be a great tool in this
process. Clinical pharmacologists must play a role as
communicators and educators to bring the various stake-
holders together to improve the practice of medicine.
Global development is probably an incorrect phrase,
in that drugs cannot be developed identically for all re-
gions. Nevertheless, ongoing “globalization” efforts,
according to the ICH, allow drugs to be developed simi-
larly for several regions and should help to optimize
the development process. More insight into mecha-
nisms behind ethnic differences alluded to earlier, to-
gether with in vitro experiments and computer-
simulated clinical trials, should provide the founda-
tion for more far-reaching drug development programs.
The conventional drug development paradigm is no
longer optimum. Accelerated approvals have gotten
much-needed drugs to the market earlier without any
evidence to date that these drugs have been unsafe. In
contrast, several conventional approvals have led to
drugs that needed to be withdrawn shortly after ap-
proval. What is wrong with smaller, more focused stud-
ies to ensure efficacy and preliminary safety, followed
by large postmarketing studies to ensure confirmatory
safety? Is there a new and better drug development/
regulatory paradigm that will improve therapeutics
while streamlining the process and reducing costs?
Perhaps it is time to apply accelerated approval con-
cepts to regular approvals and to capture adequate
safety information using improved postmarketing sur-
veillance techniques. Based on the relative safety of
regular and accelerated approval products over the
past few years, it might be a better and more cost-
effective approach.
clinical mechanistic studies as well as from early clini-
cal safety and proof-of-concept studies will be needed
to optimize the use of computer-simulated clinical tri-
als. As we gain a better understanding of disease pro-
cesses and drug mechanisms of action, the quality of
our models and their predictive capability should im-
prove. By using improved models and creating the
right collaborative teams, we should be able to simulate
treatment in a large number of patients with a variety of
complications associated with complex, heterogeneous
diseases. Drug development companies of the future
will not only develop NMEs but also associated tools
for the effective treatment of patients (Table IV). Some
have already started.
Computer programming and processing capability
and capacity will continue to limit drug develop-
ment. Computer-simulated functional organ systems,
whole-animal disease, pharmacology and toxicology
modeling and human disease, and pharmacology and
toxicology modeling will play a greater role as drug
development becomes even more complex. Although
efforts are under way, there is a long way to go before
adequate model development will allow reasonable
simulations to be accomplished. We are currently con-
strained by our limited understanding of disease pro-
cesses and mechanisms of drug action. The future
holds a great deal of opportunity in this area of research
and development.
Passage of the Dietary Supplement Health and Edu-
cation Act seems to have opened the doors to the 20th
century, not the 21st century. Without the appropriate
controls, science, and clinical studies, we might well
reenter the era of concoctions, snake oil, and potions.
The 21st century finds us with a plethora of dietary and
herbal supplements that confound the practice of med-
icine. It is now becoming apparent that these herbal
and dietary supplements wreak havoc on prescription
and other over-the-counter medications that have been
regulated by the FDA. Currently, there are two options
to get botanical medicines on the market: (1) the sup-
plement approach that allows products on the market
without adequate clinical information or (2) the NDA
route, which is currently limited by CDER’s perception
that all drugs must be approved according to a single
set of requirements. If we want the botanical issue to
go away, regulators may want to consider a more
CBER-like approach to approve new botanical drugs.
FDA-regulated botanicals would be better than the cur-
rent FTC “close your eyes and hope for the best” ap-
proach. Discussions between the regulatory authori-
ties, scientists, and other stakeholders will focus on
guidelines for good GMP procedures and appropriate
Drug development will continue to be a challenge.
Continued discussion will refine risk-benefit accep-
20TH-CENTURY ADVANCES IN DRUG DEVELOPMENT
927

HEATH AND COLBURN
tance criteria, and some algorithm will be developed to
therapy can kill, while well-conceived gene therapy
has the potential to cure “bubble boy disease.”2
If we play our cards right, the future is very, very
bright.
predict the benefits of new treatments for the patient
and society. Regulations will continue to be promul-
gated, which can be classified as “regulatory creep,”
but with the better use of risk-benefit information, the
industry should be able to balance the needs of the pub-
lic versus a rigid process of approval.
APPENDIX
Web Sites
Events during the 20th century set the tone for the
regulatory creep that we continue to see growing today.
Regulatory creep during the first 75 to 80 years of the
20th century was necessary to protect the public and to
improve the processes involved in drug development,
approval, and regulation. Society has begun to ask for
therapeutic interventions without risk. Regulatory
agencies continue to add requirements for conven-
tional approvals that do not meet the risk-benefit crite-
ria that have been applied to accelerated approvals. As
technology expands the horizons for further study, we
may need to step back and ask the question, “Is it all re-
ally worth the added price that we must pay?” Activists
demand better drugs, faster with no risk. Congress, in
an effort to guarantee reelection, provides legislation
that appears to meet this demand but does not explain
that the cost will need to increase or that the time to de-
velop the new treatments will increase. The vice presi-
dent looks at pharmaceutical company profit margins
and claims that these are not warranted.1 Yet, he forgets
that U.S. pharmaceutical companies dominate the in-
dustry with new technologies and treatments because
they have a profit structure that can support it. Coun-
tries that have forced lower profits on their pharmaceu-
tical industries are paying the price today with fewer
innovative treatments. Is continuing regulatory creep
warranted? Are mandated profit reductions for phar-
maceutical companies warranted? Perhaps the answer
is yes, until you or a family member needs that next
new treatment that will not be available because the re-
search was not funded. Better products, faster at less
cost—pick any two.
Department of Health and Human Services: www.hhs.gov/
about/hhshist
HHS: Historical Highlights
Food and Drug Administration: www.fda.gov/opacom/
7history
Milestones in U.S. Food and Drug Law History, August
1995
Milestones in U.S. Food and Drug Law History, May 3, 1999
Food and Drug Administration: www.fda.gov/nctr
National Center for Toxicological Research: 25 Years of
Excellence
Food and Drug Administration: vm.cfsan.fda.gov
The Long Struggle for the 1906 Law “The Long Struggle,”
Food and Drug Administration, FDA Consumer, June
1981
The Story of the Laws behind the Labels: Part I. 1906 Food
and Drugs Act, Food and Drug Administration, FDA Con-
sumer, June 1981
The Story of the Laws behind the Labels: Part II. 1938—The
Federal Food, Drug, and Cosmetic Act, Food and Drug Ad-
ministration, FDA Consumer, June 1981
The Story of the Laws behind the Labels: Part III. 1962 Drug
Amendments, Food and Drug Administration, FDA Con-
sumer, June 1981
Inside FDA: Center for Food Safety and Applied Nutrition
National Institutes of Health: www.nih.gov/od/museum/
history
A Short History of the Institutes of Health by Victoria A.
Harden, PhD, NIH Historian
As happened during the previous century, technol-
ogy and societal needs will continue to converge to al-
ter the future of drug development and clinical phar-
macology during the early 21st century. A convergence
of medical and information technology, along with the
aging baby boomers and cost control, will collide to
force politics and ethics to create new medical para-
digms. Is it appropriate to keep people young until they
are at least 100 years of age? Is it appropriate to invest
health care dollars to improve duration of life without
improving quality of life? The tools are or will become
available to accomplish many medical feats that were
not possible just 5 to 10 years ago. For example, early in
2000, we discovered that poorly implemented gene
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