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OCR for page 8
2. The Development of Drugs
The number and kinds of new molecular entities entering into development are
to a large extent a direct result from the activities undertaken and the
judgments made in the drug discovery phase. In view of the close relationship
between research and development, let us consider some characteristics of drug
research and discovery before going into the development process.
Although research in various biomedical disciplines relevant to drug discovery
takes place in academic, governmental and industrial laboratories, the
development process is largely industry sponsored and takes place in industrial
divisions and in clinical research settings, often in academic institutions.
Historically, close relationships between industry, academia and government
have been crucial to drug discovery and development (87~. During the
twentieth century the interdependence of industrial, academic, and
governmental research has intensified (47,134~. On the one hand, industrial
laboratories exploit basic biomedical and clinical knowledge accumulated in
academic and governmental settings, including the discovery of biologically
active compounds (93~. On the other hand, basic research findings are also
made in industrial laboratories, whereas the availability of new drugs often
permits advances in basic, non-industrial, research to be made (31~. This
reciprocal relationship refutes the popular perception that equates basic
research with academia, and subsequently, in a linear fashion, equates applied
research and drug development with industry. With the emergence of the
biotechnology industry, the reality of this complex interdependence has received
new prominence.
it, ~ ~
Since the origin of the pharmaceutical industry in the nineteenth century, the
nature of the drug discovery process has changed substantially. In the second
half of this century drug discovery has, to a large extent, moved away from the
random screening of thousands of compounds -- the prevalent mode of
operation in Paul Ehrlich's days -- to the more rational design of drugs. This
transition was made possible by a burgeoning number of research tools (such
as electron microscopes, X-ray crystallography, and molecular modeling)
advances in biochemical theo~, and an increasing knowledge of physiological
processes in health and disease. However, both serendipity and empirical
processes of trial and error remain important elements of drug discovery today
~ A powerful incentive for industrial collaboration with Federal
laboratories, such as NTH, in R&D projects was provided by the Federal
Technology Transfer Act of 1986.
8
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(130). According to Maxwell (96), four drug discovery approaches can be
identified at present:
1. The basic approach This approach entails studies to elucidate new
biochemical leads or biomedical hypotheses, which may lead to the
synthesis of new compounds.
2. Screening of compounds This screening is usually targeted, i.e. based
on a distinct rationale, for instance, blocking of a particular receptor.
Because compounds may show unexpected therapeutic activity in other
areas, it can be valuable also to perform some general screening.
3. Molecular modification Because the first candidate in a therapeutic
class is rarely optimal, the objective of molecular modification is to
discover improved agents from a "lead compound", with, for instance, a
longer duration of action and/or greater selectivity. Maxwell distinguishes
between "enlightened opportunism" and "unenlightened opportunism".
The former refers to the molecular modification of pharmacological
compounds, identified at an early stage of their development, in order to
develop an improved agent. The latter refers to making a close chemical
variation of a drug, which often is already widely diffused on the market.
This distinction, however, is not always easy to make (see below), since
much of this research seek] to overcome shortcomings of the marketed
drug.
4. Clinical observations The final source of new drugs can be the clinical
observation that a (new) compound has unexpected therapeutic actions in
patients9.
9 The following examples would come under this category: "all the main
classes of psychotherapeutic drugs (tranquilizers and anti-depressants); thiazide
drugs for diabetes insipidus; anti-parkinson action of amantadine; anti-
inflammatory action of steroids and pheny~butazone; anti-gout action of
abopurinol; anti-arrhythmic action of phenytoin and lidocaine; uricosuric action
of probenecid; acetazolamide for glaucoma and epilepsy; diazepam for status
epilepticus; protective effects of beta blockers (and the probable protective
effects of platelet modulators, including aspirin) against myocardial infarction
and coronary death; use of aspirin and sulfinpyrazone in preventing stroke; non
surgical closure of patent ductus arteriosus in premature babies by
indomethacin". See, Wardell WM, Sheck LE. (138~.
9
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1 - - 1
That these strategies are not mutually exclusive can be
illustrated by the discovery and development of beta-blockers. In
the late 1940s, clinical research on nerves revealed that the
stimulation of one set of nerve pathways, producing epinephrine
and norepinephrine, made the heart beat faster and increased the
need for oxygen. This research also suggested the existence of
two types of receptors in the human body, alpha and beta
receptors, that mediated the effects of norepinephrine and
epinephrine (1~. This work resulted in the hypothesis by Black,
one of the 1988 Nobel laureates for Medicine or Physiology, that
blocking one of these receptors, would diminish the heart's demand
for oxygen, possibly providing relief to angina sufferers. Black
and his colleagues at Imperial Chemical Industries (ICI) tried to
develop analogues of an earlier discovered compound dichloro-
proteronol (118~. This compound had been found to have beta-
adrenergic blockade activity, but also had partial agonist
(sympathomimetic) activity. They first developed pronethalol
(15), which was found to have considerable human side effects,
such as nausea, vomiting and light-headedness. They then
developed propanolol (16), first marketed as Inderal, which was
free of the agonist activity of dichloro-protereronol and the side
effects of pronethalol. The discovery and development of beta-
blockers thus demonstrates the importance of "the basic approach"
and the interaction with strategies 2 and 3. In the words of the
Nobel committee's citation, "while drug development had earlier
mainly been built on chemical modification of natural products,
they (the laureates) introduced a more rational approach based on
the understanding of basic biochemical and physiological
processes" (109~. Following the introduction of beta-blockers
into clinical practice, it was observed that beta-blockers also
played a role in lowering blood pressure, preventing heart attack
and coronary death. Finally, the proliferation of various beta-
blockers has resulted in a number of more selective drugs as well
some as so-called "me-too'' drugs (54~°.
a One caution needs to be made in this respect. As the research and
development process is so lengthy, a number of companies may have started
working on a clinical problem at roughly the same time, but reach the market
at somewhat different times. Regarding beta-blockers, for instance, the British
{CI and the Swedish ASTRA started roughly at the same time, but ICI was
first to market. Astra's subsequent beta-blocker can not be simply defined as a
me-too drug.
10
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Over time, the drug discovery and research process has become increasingly
complex and sophisticatedly. Interesting compounds are extensively screened
both in vitro and in Volvo for pharmacological and toxicological effects~2. There
has been a rapid increase in the number and kinds of toxicological tests
(~S,153,154~. Following short-term animal tests, long-term animal studies are
initiated to detect possible mutagenicity, carcinogenicity, and teratogenicity.
These studies often continue for a number of years concurrent with initial
human trials. In testing biotechnology-based drugs, however, toxicology studies
in animals do not always make sense when the new biologicals are products of
human genes and are functionally species specific. More in general, animal
tests sometimes have variable relevance for predicting the effects of an agent in
humans.
The changes in preclinical testing are reflected in the time spent in this stage
of the research process and the costs incurred. While the duration of
preclinical (animal) tests was approximately one year in the mid 1960s, it
increased to approximately three and a half years in the early 19SOs, with a
concomitant increase in costs (76,95~. Yet, uncertainty remains a crucial
element in drug discovery and preclinica] research: the attrition rate
traditionally has been such that of roughly each 10,000 compounds synthesized,
1,000 wait go into animal research, and only 10 wait initiate human testing (141~.
In the United States, the decision to proceed with the development of a
compound, including its clinical evaluation, in first instance involves a drug
company and the Food and Drug Administration (FDA). Subsequently it
engages clinical investigators, Institutional Review Boards (IRBs), and the
research subjects themselves. The 1962 amendments to the Food, Drug and
Cosmetic (FD&C) Act require a sponsor to apply to the FDA for permission
to initiate human testing with an Investigational New Drug (IND). The
purpose of such an IND application is to protect human subjects, in part by
making sure that the proposed clinical investigations are as efficient as possible
to minimize the numbers of patients exposed to the risks of such trials. An
7~ Drug discovery and preclinical research is governed directly by federal
Good Laboratory Practices (GEP) regulations, however, the investigational new
drug regulations exert strong feedback pressures on how research is
undertaken, especially to~cologica] research.
]2 Patent protection is extremely important to drug research. Usually
patents are filed early in the research process, preferably when there is a clear
distinction between the active and inactive compounds. There are 3 types of
patents: of a compound; of the use of a compound for a specific purpose; of
procedural methods of manufacture.
11
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IND application must contain essentially all of the information then known (the
mean size of an IND is 1,250 pages) on the nature of the new compound,
formulation and identification methodologies, stability information,
manufacturing methods, the methods and results of preclinical animal studies,
the proposed clinical development plan for trials, and the identity and
qualifications of clinical investigators~3.
The FDA classifies IND applications according to a compound's chemical type
and its potential benefit, to determine priority for review. In principle, clinical
trials can start 30 days after the FDA receives an IND application, unless the
agency orders a "clinical hold". After an IND application has been approved, a
multi-stage process of clinical investigation starts: the demarcation lines
~ . .~ .
w
between tne various phases are somewhat fluid.
Human testing is initiated with Phase ~ studies, which ordinarily last between 6
months and ~ year. These studies usually involve 20 to 100 healthy human
volunteers, except in the case of drugs with potentially high toxicity levels --
such as neoplastic or AIDS drugs -- where it is considered ur~ethica] to subject
healthy humans to the risk of these side effects, and thus patients are involved
from the beginning. The objective of Phase ~ studies is to provide information
on the dose of an experimental drug that might be used, how often, and
especially on potential side effects. While drug absorption, metabolism,
excretion, and some effects on tissues and organs are measured, a major
concern is acute side effects in humans. Drug administration begins at very
low single doses (for instance, one-eighth of the lowest dose that has caused a
measurable effect in the most sensitive animal species), followed by multiple
doses if no adverse effects are encountered as the dose is increased (83~.
Safety concerns in this phase may include acute cardiovascular reactions,
gastrointestinal `disturbances, CNS disturbances, bronchopulmonary reactions
and anaphylactic reactions (154~. These studies generally involve both
laboratory testing and clinical observation.
]3 Part 312, Title 21, the Code of Federal Regulations, specifies the
procedures surrounding a "Notice of Claimed Investigational Exemption for a
New Drug". Over the years the IND regulations have continuously been
revised, resulting in a very complex system of requirements. Concerns were put
forward that the interpretation of these regulations were unduly delaying the
drug development process. An attempt was therefore made to rewrite these
regulations in 1987, but according to the former legal counsel of the FDA this
rewrite did not result in any significant changes (10,42~.
12
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Development was discontinued during Phase I studies of 20 percent of the
drugs that initiated human testing 14~136~. The reasons for these
discontinuations are in safety (S percent of the 20 percent), efficacy (6 percent
of the 20 percent), and lack of commercial interest (6 percent of the 20
percent). Not uncommonly, chemical and pharmacological research on back-
up compounds is pursued in case the compound undergoing development is
discontinued due to side effects or lack of efficacy. For example, the anti-
arthritic drug, pirox~cam, was the third member of a new chemical series (the
oilcans), but the first one to make it to the market.
Simultaneous with Phase ~ clinical studies, technical development activities take
place to improve a particular compound's formulation. In developing a
suitable tablet or capsule formulation, a number of physical, chemical, and
pharmacology issues need to be resolved, such as the use of stabilizing agents
(e.g., anti-ox~dants), micro-encapsulation, or the development of slow release
forms to achieve the optimum rate of absorption.
Phase IT clinical studies involve a few hundred patients and usually they may
take several months to two years. The main emphasis in Phase IT studies is to
examine the efficacy of a compound in treating the clinical problem for which
it is intended75. At this point, the endpoints are selected that wall be pursued
both in Phase rat and in Phase TIT studies. A major issue is the choice of
endpoint, should one focus solely on intermediate endpoints, such as changes in
biochemical, physiological and anatomical parameters, or should one also
include clinical endpoints, such as effect on mortality, morbidity, or quality of
life. These decisions, involving complex considerations regarding the disease,
14 This FDA study (136), analyzed a cohort of 172 NCEs initiating human
testing in the years during 1976 through 1978. Not unexpectedly, new molecular
entities developed outside of the US are less likely to be discontinued than US-
developed ones (14% versus 24%), as the foreign developed entities have-
usualI~ already been clinically tested outside the US.
1 One of the major changes embodied in the 1962 amendments was to
include the provision that a sponsor needs to provide Insubstantial evidence!' of
"effectiveness" as weld as of "safety" (Federal Food, Drug, and Cosmetic Act, as
amended, Sec. 505 Odds. While effectiveness refers to the probability of
benefits under average conditions of use, efficacy refers to this under ideal
conditions of use. The law uses the term effectiveness to make explicit that
drugs are approved and labeled for use under the genera] conditions of
medical practice, not the more idealized conditions often found in an
investigational setting (107~. Extending this argument, it is for this very reason
that we will use the term efficacy in the context of pre-marketing clinical
investigations.
13
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the time frame of treatment, and the scientific and regulatory acceptability of
the relationship between intermediate endpoints and disease treatment. They
can have a considerable impact on the scope of the development process.
Traditionally, a number of intermediate endpoints, such as lowering blood sugar
in diabetes or lowering blood pressure in severe hypertension, have been
accepted as valid by the various parties involved in drug development. In
other, more recent cases involving intermediate endpoints, such as clot lysis in
myocardial re-infarction or the increase of hematocrit levels in anemic dialysis
patients, there has been considerable disagreement about their value. For
instance, in the development of recombinant erythropoietin (epo), a stimulator
of red blood cell development, a nine-center, 300 patient efficacy trial
demonstrated significant increase of hematocrit levels, while none of the
patients developed antibodies to epo. The FDA found hematocrit increase
alone insufficient proof of efficacy, and required additional evidence of clinical
benefit. The company was able to demonstrate a reduction in the number of
transfusions, and improvements in exercise tolerance and patient welI-being.
The license application is being reviewed (38~. A number of factors may
influence the acceptability of the kind of endpoints to pursue. For example, in
hyper-cholesterolemia clinical endpoints such as myocardial infarction (death)
may take a long time to develop, and thus practical reasons dictate the use of
intermediate endpoints such as reduction of EDL-cholesterol. In this case the
acceptability of intermediate endpoints is heightened because the association
between the intermediate endpoint and the clinical problem is perceived to be
strong (33~.
The crucial question, however, often is not whether to pursue intermediate or
clinical endpoints, but which endpoint should be pursued at which stage in the
development process (especially pre- or post-approval). This question is
important because the traditional notion of what constitutes valid clinical
endpoints is evolving. Since many therapeutic agents for today's chronic
`degenerative diseases only treat symptoms, the focus in clinical evaluations is
shifting toward measuring long-term benefits and risks. Furthermore, it is
increasingly apparent that risks and benefits should be measured not only in
terms of reducing mortality, but in terms of improving functional status and
quality of life. Such quality of life studies are becoming more important in the
pharmaceutical area. Recent examples are provided by quality of life
evaluations of auranofin and captopri] (12~.
Phase II studies also attempt to detect short-term side effects. The safety
concerns in Phase IT and in Phase ITI studies include cumulative organ toxicity,
hypersensitivity reactions, metabolic abnormalities, endocrine disturbances, and
if women of childbearing age are involved, teratogenicity (154~.
14
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The Food, Drug and Cosmetic Act requires "substantial evidence ... of safety
and effectiveness ... consisting of adequate and well-controlled investigations".
Phase IT studies mostly are double-blinded, randomized controlled clinical trials.
While placebo-controf is the design of choice, the agency will accept no-
treatment controls, standard treatment, and even historical controls (107~. The
well-designed randomized controlled trial (RCr) is generally regarded as the
statistically most powerful method to determine efficacy26 (102~. The essence
of a RCr is that patients are randomly assigned to a treatment group, which
receives the experimental drug or a control group, which receives a placebo,
standard treatment or no treatment. According to Chalmers (27), a clinical
trial is ideally quadruple-blinded: the therapy is disguised to physicians and
patients (double-blinded), as is the randomization process and the ongoing
results. Both randomization and blinding reduce biases; the differences in
health outcome can thus be attributed to the intervention, within the limits of
statistical methodology. In a welI-designed trial, the numbers of patients
and the endpoints are chosen to obtain clinically important and statistically
significant results.
The degree of complexity in determining efficacy and safety depends on the
therapeutic class to which the experimental drug belongs. At one end of the
spectrum are the anti-infectives. Efficacy testing of these compounds is a
relatively straightforward assessment of whether the compound kills the
microorganism at the site of infection. Due to the acute nature of most
infections, there may be less need for chronic toxicity testing. At the other end
of the spectrum are psycho-pharmacological drugs. Determination of efficacy
in psychiatric diseases, with a complex interplay of neurobiological,
environmental and psychological factors, is difficult. There are fewer objective
tests for psychiatric disorders and one often deals with 'soft' measures, thus a
drug is subject to a wider range of tests. As these drugs may often be taken
for long periods, chronic toxicity tests are needed. These varying degrees of
complexity are reflected in the duration of the development process; for
example, the development of psychopharmacological agents takes 3.1 years
longer than cardiovascular drugs, and 7.3 years longer than anti-infective agents
(76~.
]6 Were are a number of design variations, such as crossover, stratified,
matched and factorial designs (56~.
]7 Randomization reduces selection and blinding reduces observer bias.
~8 For example, the size should be such as to avoid both Type ~ errors
(the likelihood that an observed difference is due to chance) and Type IT
errors (the chance that a difference of interest is missed due to too few
patients).
15
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Within the total clinical development spectrum the highest drop out rate for
new molecular entities occurs during Phase IT studies when 39 percent are
discontinued (136~. The FDA analysis lists as reasons for these
discontinuations safety (13%), efficacy (12%) and economic considerations
(15%~. That efficacy and 'lack of commercial interest' are prominent reasons
is not unexpected if one considers that the main objective of Phase IT studies is
to determine efficacy, and that the line between "no efficacy" and "not enough
efficacy to be competitive" may be quite fluid. With the rising costs of
development (see Chapter 5), increasingly studies of the potential market for a
drug occur during Phase IT and Phase ITI studies. The relative prominence of
safety reasons is in part due to the fact that the results of long term animal
studies are usually obtained at this point in the development continuum.
At the end of Phase IT studies, a recent change in the U.S. regulatory scheme
permits a sponsor to obtain a so-called Treatment IND for comoouncIs
intended] to treat immediately life-threatening ~iseases~9.
@ ~ ~ .~ ~ ~ - ~ ~ - ~ ~
This system makes
experimental drugs available at a reasonable cost before marketing approval
for terminally ill patients not enrolled in clinical trials. A recent example of a
Treatment IND drug is pentostatin, for patients with hairy cell leukemia. With
drugs for very serious (but not immediately life-threatening) diseases, a sponsor
may request a treatment IND in the course of Phase ITI studies.
During Phase IT and Phase Ill clinical studies much industrial effort is directed,
usually by chemists and engineers, toward process optimalization and 'scaling
up' for productions.
The scaling up for ail efficient production process,
Involving pilot plant operations and various other process and quality control
measures, is a crucial part of the development process.
By the time an investigational drug is ready for Phase Ill studies, quite a good
picture of its safety and efficacy usually has emerged, at least for a market
approval decision. Only 5% of the compounds initiating Phase Ill trials are
]9 The agency already had some experience with such an approach, for
instance, since the mid 1970s promising anticancer drugs (so-called group C
cancer drugs) were distributed on a limited basis prior to approval through the
National Cancer Institute (152~.
20 The process by which a compound is initially synthesized and milligrams
to grams of materials are made at the laboratory bench is not only
quantitatively but is also qualitatively different from the large-scale production
process. For instance, laboratory chemists may use reagents to prepare small
quantities of a compound, that can not be used in a large-scale production
setting, which may need to produce a ton of a particular compound per year.
16
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discontinued. These trials commonly involve up to several thousand patients
(2,000 - 3,000), usually they are multi-center trials, and often they are
multinational in scope. On average they last between ~ to 4 years. The
purpose of these controlled trials and open (uncontrolled) studies is two-fold;
to further carte a compound's therapeutic effects, for example by studying
dose levels and schedules in larger patient groups, and to provide information
on the side effects and possible toxicity of the drug candidate. These Phase Ill
studies are important in determining what wall be in a package insert for the
drug and thus what market claims can be made for a new entity in advertising.
There are inherent limits to how much can be known about a drug prior to its
general use in everyday practice. It is weld accepted that the detection of
delayed or rare (less than 1:10,000) adverse events may require long time
periods of exposure, a latent period to have expired or the exposure of
thousands of patients. Wardell(139) points out that a sample size of 306,000
for each group would be needed to detect a difference between an incidence
rate of I/10,000 and 2/10,000 at the 90% power level (using a two-sidec} test, a
= 0.05~. Some serious toxicity may occur much less frequently, for instance
chioramphenicol induced aplastic anemia probably occurs only in 1:40,000 to
1:50,000 exposures (84~. However, for side effects of drugs that have less than
fatal consequences but are medically important the important difference to
detect is between 1:500 and 1:1000 or 1:10,000. Furthermore, as Wiener(149)
argues, failure to detect adverse effects in Phase IT! studies may be more than
a matter of time and numbers. Side effects may be influenced by
environmental factors, and variations in physician or patient characteristics
(such as differing pharmaco-genetic profiles, or the use of other drugs, etc.~.
The occurrence of these side effects may go unnoticed in carefully controlled
and selected pre-marketing studies; their detection will require actual patient
care settings. While the full picture of the risks involved may become apparent
only with the widespread diffusion of a drug, this argument equally can be
made about benefits. The full range of information on effectiveness of a drug
cannot be expected to emerge in Phase IT! clinical trials that are designed to
test the null hypothesis of efficacy. The eligibility criteria for these trials
almost invariably excludes a spectrum of at risk patients, such as those with
multi-morbiclities, those using many drugs, and special patient croups. such as
I-- r--7 ~
pregnant women, newborn, children or the very of. Thus, the findings of
RCrs may not easily be applicable to the total patient population, especially if
linearity cannot be assumed in extrapolation (91~. It follows that pre-marketing
clinical studies are of necessity incomplete in developing information that can
_,
2 Increasingly, if a drug is expected to be used extensively in a particular
population such as the elderly, it is studied in that specific population.
17
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be used to optimize medical use of a drug. A marketing approval decision
therefore can never be an all benefits known and no-risk situational.
At the end of Phase Ill trials a New Drug Application (NDA) or, in the case
of a biological, a Product License Application (PLA) is usually submitted to the
regulator agency, with a request for approval to market a specific compound
for the indications specifies] in the application. The FDA ranks NDAs
according to their review priority (41~. A drug, for instance, that is a "new
molecular entity", not previously marketed in the United States, and that
promises to provide "important therapeutic gain" (i.e. may diagnose or treat a
disease not adequately treated or diagnosed by any marketed drug), receives
the highest priority rating. An NDA contains detailed information on the
laboratory formulation and chemistry of the drug, the results of all
investigations, the manufacturing process, quality control procedures, the
labelling of the drug, and samples of the drug in its proposed dose and form.
Commonly an NDA encompasses over 100 volumes of information containing
60,000 pages each. Electronic NDAs, which contain the data in machine
readable form, are becoming more common and may prove important in
facilitating the FDA review process. This review process involves a team
consisting of at least a medical officer, a pharmacologist and a chemist24. If
22 Unless, of course one would be willing to delay the marketing of new
drugs for extremely long periods of time. This, however, would increase
another kind of risk, i.e., the risk of not having a new or improved drug
available on the market.
23 The following classification of TNDs, and also of New Drug
Applications, exists according to chemical type: 1.a new molecular entity not
marketed before in the US; 2.a new derivative from an active ingredient
already marketed; 3.a new formulation of a drug already on the market; 4.a
new combination of 2 or more compounds; S.a duplicate of an already
marketed drug; 6.a new indication of use for an existing drug. With regard to
the potential benefit, the following distinction is made: A."important gain", i.e.
may effectively treat or diagnose a disease not adequately diagnosed or treated
by any marketed drug; B."modest gain", i.e. offers modest, but read advantage
over existing products; C."little or no gain", i.e. essentially offers similar
therapeutic benefit as already marketed drug. Orphan drugs, i.e. drugs
developed for rare diseases (in principle with less than 200,000 american
patients), are handled under a different system, which explicitly incorporates
marketing and tax advantages for the sponsor. Such systems also exist in other
regulatory schemes, within the U.K. Committee on the Safety of Medicines,
e.g., the "fast track" system.
24 The chemist in the team, among other things, requests an inspection
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applications concern significant new drugs or involve complex issues, they may
be referred to an advisory committee for review and. recommendations (79~.
With regard to biologics, licensing committees are used to provide the expertise
as appropriate to the product. The FDA review time on average takes 2.5 to
3 years (76~.
After a new drug is approved for marketing, coverage and reimbursement
decisions by third-party payers can affect the diffusion of a drug and hence the
development continuum25. These decisions should be placed within the context
of a country's health care reimbursement policies. At present, these policies
are changing in an attempt to contain health care costs; see, for instance,
Medicare's prospective payment system, pro-generic substitution laws, and
restrictive hospital formularies. With these changes, coverage is becoming a
more important decision point in the process, as illustrated by the heated
debate surrounding Medicare's decision not to authorize extra reimbursement
for tissue plasminogen activator (TPA). One consequence is that cost analyses
and cost effectiveness studies are becoming a much more prominent part of a
drug's evaluation; for instance, cimitidine.. However, these analyses and their
influence on decision making are outside the scope of this paper26.
Following the marketing approval decision, a new drug generally diffuses into
clinical practice (with the active help of marketing professionals). With the
present-day chronic diseases, some of the most important therapeutic
information, both on rare and delayed. side effects and on long-term
effectiveness, can be. prodded only after a new drug has been used in everyday
practice. The objective of so-called Phase IV (or post-marketing) studies is to
report to be made to ensure that the sponsor adheres to good manufacturing
practices (43~.
25 At this point a firm needs to also determine its price. The pricing
~ . ~ . ~ ~ . ~ . ~. . ~ ~ ~ ~ ~ .
mechanisms, and the subsequent drug prices, as well as the health insurance or
social security schemes differ considerably per country. In the US, there are
few government restrictions on setting drug prices. In Britain, however, the
prices of drugs are controlled under the Price and Profit Regulation Scheme.
Under this scheme, the government and the specific pharmaceutical industry
agree upon a reasonable rate of return. This scheme thus institutes a target
rate of return (in essence it controls profits), and it allows price increases only
to work through new products, thus providing an incentive to innovate (98~.
26 One development deserves mentioning as it directly influences drug
development. In view of rising health care costs, 3rd party payers are some-
times refusing to reimburse even the routine costs of medical care associated
with clinical trials of experimental drugs.
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provide this information. This can be done by performing additional controlled
clinical trials or by using observational (non-experimental) surveillance systems.
The importance of these studies is underlined by the fact that new indications
often are discovered only in clinical practice and subsequently drugs may be
prescribed for these (unapproved) indications. One should realize that the
FDA only regulates the introduction of new drugs and not their use in medical
practice. Only experimental Phase IV studies may be used to request approval
for a new indication and to change the drug labelling. In addition, these
studies have sometimes been encouraged by manufacturers from a marketing
standpoint, to create a pool of physicians familiar with the drug (99~.
Most industrialized countries have some kind of post-marketing surveillance
system to detect potential adverse effects. Such a system generally depends on
a variety of methodological approaches, as no single method is fully effective.
One approach depends on adverse effect reporting (75~. In the United States,
physicians traditionally report suspected adverse effects voluntarily to the
company (the FD&C Act requires manufacturers in turn to immediately report
these effects to the FDA). In addition, physicians may voluntarily report
suspected adverse effects directly to the regulatory agency, the medical
literature, or to disease or specialty registries27. While advantages of adverse
effect reporting are its potential coverage of the entire population and low
operation costs. important weaknesses are found in incompleteness and
,
_ ~ . . · . ~ ~ . . ~ · ·
inaccuracy. For example, due to a variety of factors, there is considerable
under-reporting; the overall return on the U.K. Yellow Card System is
estimated to be only 10 percent. - ~ ^^
warn adverse ettect reporting one also cannot
measure the incidence of the risk. Furthermore, this reporting is by nature a
hypothesis generating activity, the subsequent testing of the hypothesis will
depend on other methods.
Methodological approaches for further analysis of adverse events reported by
physicians or manufacturers (and for monitoring signals of suspected adverse
effects) include experimental and observational methods. While experimental
methods have especially been applied to further examine efficacy post
approval, risk measurements in specific patient populations are sometimes also
undertaken. At present, however, there is increasing interest in epidemiological
studies, such as case control and cohort studies. to measure adverse drug
effects28. The advantage of cohort studies is that they can establish the likely
27 In the United Kingdom, for example, the well-established system of
physician reporting to the Committee on the Safety of Medicines operates
through the so-called Yellow Card system.
28 Cohort studies compare people exposed to a drug with those unexposed,
20
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incidence of the risk.
Disadvantages are that they are potentially expensive
and may yield the results more slowly than case control studies. Case control
studies are useful if the frequency of events is very rare (up to 1:10,000~.
Disadvantages are that controls are often difficult to establish and the studies
can not establish absolute risk.
The proliferation of large-scale automated data bases, such as those maintained
by HMOs or Medicaid, may open up exciting possibilities to study a drug
under general conditions of use. These data bases may contain demographic
data, drug prescription data, or patient hospital admission and discharge data.
With advances in computer capabilities, it is increasingly possible to link
different data bases, for instance, pharmacy record with medical record data
bases (20~. In essence, the Drug Surveillance Research Unit, initiated by
Inman (72) in the United Kingdom in 1980, is based on this principled. In the
same vein, the FDA has carried out a number of hypothesis testing studies
using Medicaid and other medical record linkage data bases. Industry is also
increasing its efforts in pharmaco-epidemiological research. As these large-
scale data bases exist for other reasons, their operating costs are much lower
than those associated with registries. In addition, they may lack the reporting
bias and the inadequate follow-up that renders case studies problematic (146~.
However, limitations exist in the adequacy of the data collected in these data
bases (see below).
As argued above, Phase IV studies also need to examine the long-term
effectiveness of a drug. Since the early 1970s, the FDA has sometimes
requested post-approval research as a condition of approval, often with good
reason (see, for instance, the approval of levo dope). Studies done post
approval to examine the benefits of a drug, in different patient populations or
using different dosages, are usually an extension of the type of studies done
and analyze differences in adverse events between both groups. Case control
studies compare groups exhibiting a particular event with those not exhibiting
this event, and then they examine differences in exposure to a particular drug.
See, Report Joint Commission on Prescription Drug Use, for an extensive
discussion of these methods (74~.
29 This system has become a second national scheme to detect adverse
drug reactions (ADRs) greater than one in 10,000, and to evaluate the balance
of risks and benefits of a drug. Using prescription based cohorts as a starting
point, this system actively solicits responses from physicians.
The response rate
is 70%, approximately 22,000 general practitioners report regularly, and the
system catches nearly 50 million people. Monitored events are followed up by
analysis of the medical records of the patients.
21
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pre-marketing approval (94~. In addition a number of large-scale randomized
trials have also been undertaken post approval that were funded not by the
sponsor, but, for instance, by. the National Heart Lung and Blood Institute. In
view of the very high costs associated With these large-scale trials, between $10
million and $100 million dollars, the number of such RCrs is limited (86~.
Furthermore, as mentioned above, the RCr may not always be most helpful as
a foundation for therapeutic decisions.
It has therefore been proposed that modern observational methods could play
an important complementary role to the RCr for assessing the effectiveness of
a drug. Major weaknesses traditionally associated with these methods have
made the determination of. the cause-and-effect relationships between drug use
and outcomes more difficulty. However, in recent years there have been
advances in the design and the execution of observational studies, which may
address some of these weaknesses (see Chapter 5~.
30 For example, the series of cases has been found to be subject to
different kinds of physician and patient bias. Cohort studies, for example, may
include limitations such as the exact specification of the cohorts, limited quality
of the data in terms of reproducibility and validity, difficulty to analyze the
attributable agents, and the occurrence of detection bias. The US Surgeon
General's first report on smoking listed 5 supporting criteria to establish a
cause-effect relationship: consistency of the association; temporal relationship
between cause and effect; coherence with existing insights; specificity of the
relationship; strength of the association. See also, Feinstein (45~.
22
Representative terms from entire chapter:
clinical trials
