DRUG DISCOVERY AND DRUG DEVELOPMENT

What is a Drug?
A drug is any substance other than food, that when inhaled, ingested, injected or absorbed after
administration in appropriate doses by other means causes a change in body functions (or in a pathogenic
agent) which can be exploited for clinical benefit prophylactically, therapeutically, or diagnostically. Drugs
may also act on physiological situations to achieve a wanted effect.

Using an excess dose causes toxicity, using too small doses doesnt give you the wanted effect.

How is a Drug Born?

It is a long and expensive process. It might take between 5-20 years after the discovery. The cost is normally
in the order of billion dollars.
The drug must be proven to have some requirements: it must product the wanted effect (efficacy) and it
must be safe. Of course, it might not be effective in every person, because of individual differences, but in
general for most of the population it must be.
Four Steps:
- Discovery: idea and development of a compound with a certain effect
- Preclinical evaluation: series of tests to assess what exactly the molecule discovered does, test for
effects that werent predicted, interactions with other drugs, safety assessments, toxicology studies,
drug metabolism studies, and so on. These testing is not initially done on humans, but in vitro instead,
and afterwards in animals. When the tests presumably tell you the compound will have positive
effects in humans, you can move to clinical evaluation
- Clinical evaluation: trials start with volunteers (phase I), usually 20-100 people for one month, then
move on to patients with the condition of interest, first on a small group, then enlarging the number
of patients
- Approval and marketing: before distribution, to put the drug into the market it must receive approval
from certain agencies, for example the EMA (Europiean Medicines Agency) in Europe, the Japanese
PMDA (Pharmaceuticals and Medical Devices Agency) and the American FDA (Food and Drug
Administration).
Some countries just trust what the FDA approves (eg: Argentina)
Furthermore, most of the European countries also have a national agency, for example in Italy there
is AIFA (Agenzia Italiana del Farmaco), but these agencies does not have that much power, each drug
is primarily approved by EMA.
Post marketing surveillance/Pharmacovigilance: the study of drugs and their effects does not stop
with marketing, pharmaceutical companies are legally obligated to continue to monitor them also in
the post marketing phase. This is mainly for 2 aims: to make sure that the drug you are selling is safe
& to check for effects that were not detected before. Some drugs may be found to have serious side
effects or to not have the wanted effect after they are already on the market, in this case they
probably will be taken off from the market
This is more common that it could be thought, for the following reasons:
pregnant women are not normally included in clinical evaluation, because it is not considered
ethical to give a potentially harmful compound that would harm two people at the same
time, so only after marketing you can discover potential dangerous effects a drug has on the
fetus
some effects only appear after extensive use, so the clinical tests may have not lasted enough
time to show them
some effects may be rare and the drug was tested on too few people for a serious side effect
to manifest.
 Example: Chloramphenicol is an antibiotic used only for salmonella or rarely for some form
of meningitis, but it is never used if possible because there is a high risk for agranulocytosis:
its actually a small risk, it presents itself in 1/35000 cases, but the consequences are severe).
This was discovered only after marketing
Another reason why a company is interested in keeping surveillance is that usually a drug is released
for a specific problem, it has restricted applications and the efficacy has been proved only in a specific
population that has been included in the clinical study (eg: the study has been conducted on adults,
so the drug is not proved to have the same effect on children). Many drugs though have more than
one indication, that might not even be known by the develoers themselves. For example, aspirin
treats fever, pain, rheumatoid arthritis, inhibits platelet aggregation; but initially aspirin wasnt
distributed with all these functions, lots of them were discovered later, thanks to post-marketing
surveillance, so further studies were performed and indications widened.

HISTORICAL DEVELOPMENTS: Milestones in regulation of drug development:

Until the early 40s drugs were just directly put on market.
The first regulation on drugs in the US was in 1938, thanks to the Sulphanilamide Elixir tragedy in
1937. This elixir was developed to treat infections, and was composed by sulphanilamide, that is an
antibiotic, plus a solvent that was toxic, and some raspberry flavouring. Animal testing was not
required for law and neither were premarket safety testing. More than a hundred people were
poisoned and died by taking that syrup.
The congress responded to public outrage by passing the 1938 Food, Drug and Cosmetic Act, that
required companies to perform animal safety tests on their proposed new drugs and submit the data
to the FDA before being allowed to market their products.
In 1959, the Thalidomide tragedy in Europe and Australia made us realize that drugs can cause birth
defects.
In a post-war era when sleeplessness was prevalent, thalidomide was marketed as a sleeping pill that
was extremely safe, both for mother and child, even during pregnancy, since the developers couldn
find a dose high enough to kill a rat. An Australian obstetrician discovered that the drug also
alleviated morning sickness. He started recommending this off-label use of the drug to his pregnant
patients, setting a worldwide trend. But later on he started to associate this so-called harmless
compound with severe birth defects in the babies he delivered. The drug interfered with the babies'
normal development, causing many of them to be born with phocomelia, resulting in shortened,
absent, or flipper-like limbs.
The problem is, how can you know if a drug will hurt the fetus since pregnant women are not included
in clinical studies? Only after marketing you can follow women who take the drug. There are additionl
tests though that can be performed in the preclinical phase, to try to collect as many information as
you can, for example whether the drug can or cant cross the placenta, mutagenic tests in vitro,
tests in pregnant animals, with which the correlation is not 100%, but if something is teratogenic in
animals it is almost for sure also in humans. If it isnt teratogenic in animals, you dont have the
certainty that it wont hurt human foetuses instead, but it is already a further positive hint.
This tragedy signed the beginnings of the rigorous drug approval and monitoring systems in place at
the United States Food and Drug Administration (FDA) today.
Only in 1962 there was the requirement by the FDA to show that the drug actually works. Before
that, no proof of efficacy was needed. In the UK this was introduced only after 1965. Before this, the
only requirement was to show that the drug did not harm
1989 International Conference (currently Council) on Harmonization
1995 Establishment of the European Medicines Agency
Size of registration dossiers: you can notice how the depth and number - Adrenaline (1938): 27 pages
of pages of the papers given to the agency for approval has increased - Parvon (1958): 439 pages
enormously in years. Together with this, also the cost to develop drug - Norlestrin (1962): 12,370 pages
has increased enormously. - Dantrium (1973): 456 volumes (1.5 tons)

The four steps in drug development

DISCOVERY:

Discovery can occur in different ways:

- Rational design: the molecular mechanism underlying a disease is understood, for example a
dysfunction in an enzyme. The drug developed acts to correct this dysfunction, either by acting on
the enzyme itself or on its products.
This approach is recent, drugs were used for thousands of years (Babylonians had them already!),
but their mechanism were studied and understood only starting from the 60-70s.
Example: Cimetidine works as an antagonist of the H2 receptor, with the aim to block secretion of
acid in the stomach. Acid in the stomach in fact is released when histamine binds to the specific
receptor H2 (specific gastric receptor, there are actually 4 different kinds of histamine receptors, with
different effects such as stimulating inflammation, vasodilation, bronchoconstriction,).
To develop such a drug, first of all the mechanism for the generation of a peptic ulcer was found to
be (among other reasons) acid secretion, since the acid affects the mucosa of the GI and can cause
erosion. Consequently, if acid is not present, aggression is not present. Therefore, the aim of a drug
with beneficial effects must be to reduce the secretion of acid. The next step was to understand the
signals at the base of the acid secretion mechanism, H2 receptor was discovered and its structure
was characterized (fundamental!). Eventually a molecule was designed that would sterically bind to
the receptor without activating it, preventing histamine from binding, so stopping the trigger for acid
release.

NB!: in the case of rational design, as it is clear from the example, the discovery of the drug is not the
first step of the process! First of all, there is a phase of target selection and validation, with the
following aims:
o Define the unmet medical need (disease)
o Understand the molecular mechanism of the disease
 o Identify a therapeutic target in that pathway (e.g gene, key enzyme, receptor, ion-channel,
nuclear receptor)
o Demonstrate that target is relevant to disease mechanism using genetics, animal models, lead
compounds, antibodies, RNAi, etc.
But determining a target is not enough! A compound must be found and proved to be able to interfere
with the normal target activity. So, the following evaluations must be made (these are valid
independently from which was the original way to achieve the discovery, eg: also if you produce a drug
by structural modifications This is my guess, these info were taken by the slides and not mentioned in class):
Develop an assay to evaluate activity of compounds on the target
- in vitro (e.g. enzyme assay)
- in vivo (animal model or pharmacodynamic assay)
Identify a lead compound
- screen collection of compounds (compound library)
- compound from published literature
- screen Natural Products
- structure-based design (rational drug design)
Optimize to give a proof-of-concept moleculeone that shows efficacy in an animal disease
model
Optimize to give drug-like propertiespharmacokinetics, metabolism, off-target activities
When this phase is completed, the compound such produced is the Preclinical Candidate, ready to go
through safety assessment

- Structural modification of a drug which is already known to cause an effect, with the aim to improve
the beneficial function.
Eg: Cimetidine was very effective and safe, but had side effects on the endocrine system, and needed
to be given 3 times a day because it was eliminated rapidly. Therefore, other companies tried to
improve these aspects, by modifying the original molecule, its conformation, to make it more specific
for H2, thus avoiding interactions with other targets, which is what causes side effects.
Curiosity: Nowadays new drugs that act directly on the proton pump to inhibit it are used, so
Cimetidine became obsolete
This process often creates a class of drugs, for example penicillins. Originally penicillin was only
effective on gram + bacteria, was modified by some enzymes in the body and couldnt be given orally
because was destroyed by gastric enzymes. Therefore, modifications of the original compound were
created and now there are penicillins with a wider spectrum of targets and some versions can be
given orally.
This approach is cheaper than producing drugs from rational design, since you can take advantage of
the knowledge collected previously about the target and the mechanism of the disease pathogenesis,
plus you already have a molecule to work with. The disadvantage is that the pharmaceutical company
following this approach wont be the first to put something new on the market, it wont own the
market, and it will have a lot of competition because other companies will be trying to do the same.
If it wasnt clear enough already, profit and money are obviously a leading theme in pharmacology.
Every time a new drug is developed through structural modification, the company will of course claim
that it is better than the original version. Is it true? In many cases it isnt. It might just be the same
and more expensive, or may even be worse, or simply there is not enough information to say it yet,
because not enough time has passed to observe possible side effects or to see effects on populations
not included in the clinical study.
How is this possible? Imagine the following example: a company wants to market a drug to treat
pain. Many drugs like these are present already. The company collects all the data, all the
experiments, and brings the dossier to the agency to be approved. Approval will simply require that
 the drug is better than nothing, it does not have to be better than those already present, it will be
the market itself to determine its success or its failure.

Curiosity box!
A drug is released with 2 information: the SPC (summary of product characteristics), for
the physician, and the patient information leaflet, much simpler, not comparative. It tells you the
use, when to take it, the dose, the possible side effects,.
Drug companies are not legally allowed to advertise a drug for a use they are not approved
for, but there are ways around this: a pharmaceutical company may present to a doctor a drug
that is approved for something, telling them that they also have positive evidences that it could
have a good effect on something else, such as gastritis. A doctor may be intrigued and carry on a
research on his own patients, monitoring the effect of said drug on a disease the drug was not
designed for. Getting better in 90% of the cases is thanks to a placebo effect, so patients may
actually get better independently from the actual effect of the drug on a biochemical level. The
doctor thanks to these positive results can then publish the research, go to conferences to present
it, and other doctors may decide to try that alternative use for their patients too.
Doing something like this is actually illegal, because the drug is being prescribed with an use for
which it was not approved, so it might have unknown consequences.
But this is a blurry grey area, in fact in other situations you may be legally justified to deviate from
the approved use (off label use). This is extremely common, in many fields, because there might
be no drugs approved for a given condition, so you try anyways to do something that seemed to
be useful in similar patients.

- Random observation, luck: the discovery happens thanks to chance + ability to pick up signals, its
not simply random luck. The majority of drugs are discovered in this way.
Example: beta blockers, that have function of blocking beta receptors for catecholamines.
Catecholamines increase the heart rate and might favour arrhythmias, so pharmaceutical companies
developed beta blockers originally with the idea of fighting arrhythmias. The results of the
administration of these drugs were mixed, in some cases arrhythmias increased, in some cases
decreased. But then it was observed that when given to people that had high pressure too, pressure
was lowered. Nowadays this is their main use. The understanding of the mechanism underlying this
effect took much more time.
- Random screening: its a method based on a mixture of rational design and random finding:
companies use automatized technological methods to synthesise automatically, at random,
hundreds of different molecules. These molecules are then used to test effects in biological systems,
to see to which receptor they bind to with high specificity or affinity. Afterwards they reason about
what that binding could be exploited for, what effect it will have in the human system, so for which
disease it might be useful. Paradoxically, the reasoning process has been reversed compared to the
process followed when starting from a rational design.

PRE-CLINICAL DEVELOPMENT

Objectives of Preclinical Drug Evaluation:

- Identify / select new molecules of potential therapeutic or diagnostic value
- Provide essential information to guide clinical drug development
- Provide necessary knowledge for rational clinical use (minimize risks, maximize benefits)
- Clarify mechanisms and implications of pharmacological / toxicological properties emerged during
clinical use
Example: Initial doses given to a volunteer are based on toxicity signals coming from this preclinical
evaluation
Components of Preclinical Documentation:

Chemistry and pharmaceutics: how is the drug preserved, in which environment it is stable; info
about how the drug has to be administered (encapsulated, dissolved in liquid, injected)
Pharmacology:
- Pharmacodynamic data: they describe what the drug does to the biological system you apply it
to, the effect of the drug on different systems, and the different effects resulting from a certain
drug concentration.
- Pharmacokinetic data: describe what the body does to the drug, how long it survives in the body,
the way it is excreted (feces, urine, sweat, breath), the route of elimination, the possible
modification of the drugs by the body (metabolized by body enzymes), the chance for it to be
metabolized into something toxic. In brief, it describes the drug concentration-time courses in
body fluids resulting from administration of a certain drug dose
This is important because if the body gets rid fast of a drug, you need to administer it many times
a day, while others may survive in the body for months and need less administrations.
The rationale for PK/PD-modelling is to link pharmacokinetics and pharmacodynamics in order to
establish and evaluate dose-concentration-response relationships and subsequently describe and
predict the effect-time courses resulting from a drug dose
Toxicology: is based mainly on experiments done in animals. To keep annoying animalists at bay,
regulations to do a study in animals are extremely strict!

Animal Studies:
- Not completely replaceable by in vitro studies
- Indispensable to ensure safety for human use
- Predictive of therapeutic and adverse effects in humans (as well as pharmacokinetics)
- Privilege utilization of species which are low in the phylogenic scale (rats and mice)
- Conducted under strict, ethically-driven regulations
- We try to use as much as possible in vitro systems to limit use of animals for costs and
ethical reasons
-

All these studies are performed according to special quality requirements, codified by international
regulations, to have rigorous standards in terms of ethics and science:
- GLP: good laboratory practice for preclinical studies
- GCL: good clinical practice for clinical studies
Its a very complicated process, to ensure that everything is documented. For example, a scientist applying
any small change to an experiment must write it down with the precise date when it happened and sign it.
Components of GCP and GLP (skipped in class)
- Appropriateness of equipment and logistics
- Trained, specialized personnel
- Chain of responsibilities defined and tracked
- Detailed protocols
- Standard operating procedures (SOPs)
- Registration of procedures and protocols
- Standardized data recording and reporting
- Internal and external quality control
- Ethics and safety paramount
Key Items Addressed in Pharmacology Studies
- Mechanism(s) of action: from a molecular point of view, making sure that the drug binds to what it
is expected to bind
- Activity profile in models predictive of therapeutic efficacy in the target indication, ie: use animals
that reproduce the disease in question. For example, Alloxan is a drug with toxic effects on beta cells
of pancreas, so you can use it to cause diabetes in rats, then you can test your potential drug for
diabetes on such produced experimental animals. Nowadays you can also produce genetically
modified animals that reproduce the genetical modification that causes a given disease to have an
even more accurate model
- Activity profile in other organs and systems: check if the drug affects other systems of the body, to
try to avoid side effects, to produce a safe drug, to advise not to include a certain category of patients
(eg: pregnant women), or also to find additional useful indications
- PK, including ADME: ADME is an abbreviation in pharmacokinetics for "absorption, distribution,
metabolism, and excretion," and describes the disposition of a pharmaceutical compound within an
organism. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues
and hence influence the performance and pharmacological activity of the compound as a drug.
- Drug interactions: people typically may take many drugs at the same time, so you want to find out if
your drug interacts positively with commonly administered drugs. These experiments are usually
performed in vitro

Specificity and selectivity

The tests we perform in the preclinical phase also help us understand which is the specificity and selectivity
of a drug and affinity for the receptor supposed to mediate the therapeutical effect. Specificity of a drug
refers to the fact that the drug may only be able to bind to one specific kind of receptor, and no increase in
the drug in question can activate any other kind of receptor. Selectivity of a drug means that the drug is able
to bind a certain subtype of a given receptor with greater affinity than to others.
Eg: drugs used as antidepressants. Problem: they are not specific for the target, they bind also to
other receptors, causing side effects, in particular many of them have anticholinergic effect. This can
be predicted in vitro by observing how different drugs bind to the muscarinic receptor

Prediction Power of Preclinical Models

To what extent are animal models predictive of the therapeutic activity in a patient?
It depends: if we understand exactly the biochemical mechanism and what receptor mediated the
therapeutic efficacy of a drug, predictivity is high, while if our knowledge is not complete, we do not know
precisely which mechanisms should mediate the therapeutic mechanism, predictivity is low.
Plus, models may have limited predictivity themselves, for example it may be hard to re-create some
conditions in animals such as dementia, depression, and so on. There are models, but they tend to be less
valid than models where we test effects of drugs on specific receptors or models for antibiotics. Drugs for
epilepsy are also easy to develop thanks to the presence of many animal models.

High Predictivity Limited Predictivity

Beta-blockers Antidementia drugs

Antibiotics Neuroprotectants
Antiepileptic drugs Antidepressants
Proton pump inhibitors

We have progressed a lot in understanding drugs interactions. Many drugs introduced in the body are bio-
transformed into metabolites. Now we know exactly for the majority of drugs what specific enzymes are
responsible for this. So we can test in vitro what a certain molecule does to the enzymes involved in this
process.
For example, statins: all of them are metabolized by the same cytochromes, enzymes in the liver (CYP3A3
and CYP3A4). You might want to develop a drug for any indication, and during the preclinical tests you find
out that your drug blocks the activity of these cytochrome enzymes. In this case you can know immediately
that if it is administered to a patient that is taking statins, the metabolism of statins will be stopped because
the enzyme responsible for it stops working. This will most likely stop the company from keeping developing
the drug, because it would have too much important interactions with drugs already on the market.
In the past the interactions we are speaking about were discovered during development or post-marketing,
by accident, nowadays screens are always made at the first stage in development of a drug to understand
interactions with the main drugs taken among the population. If interactions are found, development
stops, or the molecule is kept being modified until you get rid of the undesired interaction.

Examples: the following drugs were taken off the market, or stopped late in clinical development because
of adverse properties that could have been picked up very early in in vitro systems.

Drug Class Cause of withdrawal

Loreclezole Antiepileptic Saturation kinetics
Mibefradil Calcium antagonist CYP3A and CYP2D6 inhibitor
Remoxipride Antipsychotic CYP2D6 polymorphism
Terfenadine Anti-histamine Interactions with CYP3A4 inhibitors

Key concept: we can identify very early adverse effects of drugs including drug interactions, without the
need to test it in vivo

Toxicity testing
Fundamental! Aimed at identifying potential for adverse effects, target organs for toxicity, and their
dependency on dose and duration of exposure. The drug must be safe!
There are standardized tests that need to be done, classified based on duration of treatment and specific
objectives. They need to be performed in animals.
Acute: observe the patient toxicity after a single dose
Subacute: the animal is exposed to the drug for 4 weeks
Subchronic: 12 weeks
Chronic: at least 6 months
Special toxicology tests:
- mutagenesis, cancerogenesis, teratogenesis : possibility that the drug causes cancer or a birth defect
when given to pregnant women
- second generation effects: drugs that do not cause a congenital malformation in the offspring of an
exposed animal, but they may cause some other effect later in the development of the offspring. For
example, Valproic acid is a drug for epilepsy that can cause a number of malformations in a baby if
taken during pregnancy, but it was also discovered that it can casue impaired intellectual
development that only becomes evident when the child is 5/6 y.o., so the child may be perfectly
healthy at birth, but later on develop mental retardation. Another example, there was a drug used
to cause abortion and to treat endocrinology problems. In the first case there was no problem, but
in the second case, if afterward a woman gave birth to a female child, she would develop cervical
cancer when she reached puberty.
These effects can only be found thanks to studies that keep following over time the offspring of
animals exposed to the drug during pregnancy
 - developmental toxicology

Drugs with different clinical use require different testing:

o If a drug is designed just for a single dose use, occasional you dont need to test it on animals for long
periods of time, you just study:
- acute and subacute effects
- effects on reproductive function
- mutagenesis
o If a drug is designed for a chronic use, testing instead last at least 6 months
-Acute and chronic testing
-Effect on reproductive function
-Mutagenesis and teratogenesis
-Cancerogenic studies may or may not be performed, since we probably know sufficiently about the
mechanism for carcinogenesis to determine whether the structure of the compound is suspicious,
plus they would take too long and be extremely expensive

Acute toxicology test:

- Single dose administration, then follow the animal for 2 weeks
- Typically the dose it administered at least through two different routes
- At least 2 species must be studies, because drugs have different reactions in different animals (one
specie must be a not rodent)
- Evaluation of symptoms
- Evaluation of lethal dose (LD50): dose that kills 50% of exposed animals, gives you an idea of how
dangerous the drug is if a wrong dosage is given. A drug with a high LD50 is unlikely to cause death,
while if it has a low LD50 you must be careful with administration
- Exposure assessment: find out how much of the administered drug is going to be found in the blood
stream, because toxicity is dependent on how the drug is distributed, at which concentration, how
quickly it is eliminated. The same data will be collected in healthy volunteers and the amount of drug
found in human must be related with the amount that has been shown to produce toxic effect in
animals

Subacute and chronic toxicity tests:

- Compound is given repeatedly
- 2 species are needed, one must not be a rodent
- Administer different doses
- At least one route of administration
- Measure a number of changes:
body weight
behaviour
blood chemistry, haematology and urinalysis
After the observation is done, the animal is sacrificed and organs are examined one by one
to find potential damage
Histology of all organs is also performed for the same reason
NOAEL: No-Observed-Adverse-Effect Level Find the highest dose among the administered
that does not cause toxicity, including no signs of histological toxicity

- All the information on dosage are critical to determine if the drug will be viable or not to be given to
humans, ie: the first part of the preclinical tests are aimed at finding out which concentration is
 needed to produce a therapeutic effect, but if in this phase the dose needed for therapeutic effect is
found to have high toxicity, development stops
- Select species with a metabolic activity comparable to that in humans. How can you know this? There
is overlap between clinical and preclinical development, especially in chronic testing: before starting
the long term experiments, that require exposure of animals for months and cost huge amounts of
money, healthy volunteers will take a single dose and the fate of the drug in humans will be
evaluated, then you can start the long term experiment with animals and make sure that the drug
has comparable fate

Here he started speaking of stuff not mentioned on the slides, triggered by questions
How is the price of a drug determined?
It varies depending on which part of the world you live in. In the US, no regulations on prices are present, the
drug just needs to be approved according to the standards of safety and efficacy, but it is the company that
chooses the price. There might be some interference when a company needs to negotiate with the insurance
system or health care provider for a supply of medications to hospitals.
In Europe its more complicated, the EMA does the same work of the FDA, but after approval the company
has legally the right to market the drug in all the countries of UE, and legally allowed to set the price they
want (same as in the US). But there is a big difference: health care is largely provided by the national health
service in Europe (especially in the Western countries), so if someone needs to buy a drug, the price will be
reimbursed by his national health care system. In this situation if a company markets a drug at the price it
wants, Italys national health system for example is forced to take it in the market, but it can decide which
will be reimbursed for the patients and which will be not. So, a company is free to sell it, but people wont
receive it for free from the state, so they most likely will not buy it if they have another similar option that
instead is. Therefore, a company always negotiates the price for a drug with the national health care systems
of the different countries, to make sure that it will be reimbursed, otherwise people wouldnt pay for it.
NB! This system leads to the consequence that the same drug might have different prices in different
countries of the EU. But the EU is a free market, so a distributor might refurnish for a drug in a country where
the price is lower, such as Italy, repackage the packet to give information in German, sell it at the German
price and pocket the difference in price between the Italian and the German price. This parallel market causes
biased statistics of consumption of a certain drug, that in Italy results extremely high and in Germany
extremely low.

What is the difference between a generic drug and the brand?

Drugs are initially protected by a patent, with different duration (in general 10-20 y), so that when you put a
drug into the market other companies cant copy it, so you can recover your investment (usually in the order
of billions). After this period, anyone can manufacture the same drug: this is a generic drug. The only
difference is the brand name on the original one and the chemical name on the other one.
At this moment competition starts, all the companies can produce the same drug, and the price comes down.
This is because the cost of simply producing a drug is minimal, the huge amount of money is needed to
develop it. Also, the brand named drug lowers its price to stay in the market, but usually it stays slightly
higher.
Curiosity: the Italian national health care system only reimburses the price of the cheapest generic drug when
they start to be produced, if you wish to buy the brand or another generic that costs more you have to pay
the difference by yourself.
Are there differences in quality between the generic and the brand?
Drugs tend to be produced in countries where it is cheaper, for example India, but his is true both for brand
and generic, so the quality of the materials does not change.
The generic usually differs in appearance form the brand, in colour and shape. But do these differences affect
efficiency and safeness? The answer is complex!
A company cant just synthesise the active principle, package it and sell it directly, companies have to perform
studies to prove that their generic has the same quality as the brand, but they can skip all the tests about
concentrations, toxicity, and so on. Basically they need to perform two kinds of experiments:
- first, they need to produce a lot of documentation about the chemical and pharmaceutical quality of
the generic in comparison to the brand (presence of impurities, properties of the formulation, of the
compound)- in vitro experiment;
- second, they need to do experiments in humans to prove that the
generic works in the same way as the brand, to show that when you
give the generic the profile of the level of the drug in blood is super-
imposable to the profile you get after administration of the brand: if the
time course profile of the active principle is identical (same rate, same
level, same amount) there is no reason why the effects should be
different.

But! What does the same means? You test this on healthy volunteers, usually around 20-30 people, each is
given in a random way either the generic or the brand.
NB!By doing this you soon realize that there is variability: even if you give the brand twice to the same person,
with a time interval of a month, the level checked in blood will be different (even if the subject and the drug
are the same!). You then group the measurements and make a mean between these profiles, usually the
difference of any profile from the mean is in the interval of 80%-125%, with a confidence limit of 95% (ie:
95% of the profiles surely are comprised in the limit 0.8-1.25, but 5% may not be (?)).
You do the means with the measurements of both people who took the bran and people who took the generic
and end up having two curves. On average the two curves must be superimposable, which does not mean
that they need to be identical, but that to determine that the two curves
are equivalent the 95% confidence limit of certain parameters must fall
between 80% and 125% of the mean, ie: the ratio between all the profiles
with the brand and all the profiles with the generic must have confidence
limits that fall between 0.8 and 1.25 of the mean. If the generic has an
average that is the same as the brand, but the confidence limits are broader,
ie: the variability is bigger, it will not be approved.
The point is, the generic shouldnt be too far from the brand but since it is normal for variability to be present,
even if you take the same drug, they must not be identical, but simply not having a greater variability than
the intrinsic variability of the brand itself.

There are some exceptions: the drug levels may be too variable even for the brand, or drug levels may be
undetectable (eg: drugs for asthma, that are inhaled and act locally, reach the site of action directly without
entering the concentration). In this case the only way to mark the generic is to test it on patients with the
disease, but in this case you need at least 400 subjects. In this case you must prove that safety and efficacy
is the same as the brand. This is a longer and more expensive process.

Companies that sell brands of course do not like the coming of generics into the market. Therefore, there is
a huge investment to discredit generics. This is done by doing poor quality studies, cleverly designed, biased,
with the objective to show that generics are worse. These studies are then advertised to doctors and even
more to patients, so we should always be careful to filter the information received.

The evaluation of generics is the only way for a drug to get to the market without going through the EMA,
but simply through the national agencies, to not overload EMA. It does not require a lot of expertise to check
safety and efficiency of generics. If a generic is approved in a nation, then there is a process to enlarge the
approval also in the other European countries, so a company even if it starts the approval by going
peripherally, it can then spread generally anyways.

If you market a generic, the regulatory agency must be provided with researches and evidences explained
above. The generics are produces in eastern or developing countries (Bulgaria, Romania, Kazakhstan, South
Africa, India), but still they are strictly controlled and regularly checked by inspectors.

About brands, the drug sold by the same name may not actually be always equal, because a company may
decide for economical convenience to change excipients, ie: if a new excipient comes on the market and is
cheaper than the old one, they change the manufacturing process. They are basically doing the same process
to create a generic, and they need to bring the same proofs to the regulatory agency, but they dont tell you,
and you think you are buying the same compound when you are not. Not only, even the doctor does not
know that he is switching a patient from a certain product to one slightly different (while it is obvious when
switching to a generic), so if side effects were to be caused by these modifications he couldnt even think to
attribute it to the change in said excipients.

Typically, when generics are approved, the company brings all the documentation to get it approved, but
they also may sell that documentation to many other companies, allowing them to use the same
documentation to get the right to produce and market the product: the same exact generic in this way is
produced and sold by many different companies. So there isnt so much variability among all the generics on
the market in the end.
Also, it might happen that the company producing the brand may do the same, ie: give the right to a company
to sell a drug identical to the brand, but with a generic name. in this case the generic is actually exactly
identical to the brand.

The system if not full proof, there is potential for fraud, but it is not so common. There are ways to keep the
situation controlled, for example physicians that switch a patient to a generic are required by law to send
reports to AIFA if they find that suddenly there is a loss of therapeutical efficacy. If many reports about the
same pro++duct come up, its an alarm and the agency does the experiments that the company is also
required to do, to check if the results of the studies might have been frauded. Most of the times these are
false alarms, but in few cases fraud can be identified.

Example: Lamotrigine is a drug for epilepsy, one of the most common, very profitable. There were large
numbers of reports of problems switching to the generic. These were supported by scientific papers, mostly
financed by the company protecting its exclusivity for its own interest, that stated
that if you have 50 generics on the market, all fitting in the confidence limits 0.8-
1.25, they will all be approved. This approval is based on the comparison to the
brand, ie: they all have an equal or smaller variability compared to the brand.
But different generics may have very different confidence limits among
themselves, so you cant guarantee that two generics are equivalent, you can just
guarantee that the generic is equal to the brand. Ie: on average two different
generics can be very different, one having higher levels in blood, one having lower
levels. They might not respect the confidence limits one in respect to the other.
These papers caused a lot of fears especially in consumers associations in countries with a system like the US
(in Italy it is different because if you go to a pharmacy and ask for a generic of a specific company, even if
they dont have it they will be able to get it in the next 24 h). In the US if you ask for a specific companys
product in a pharmacy, they wont do that, they will just give you the first generic they have already there,
so you will keep switch among one generic and another (which is also bad because different generics have
different colours so it might create confusion).
The US government financed the FDA to perform studies to understand if this was actually a problem:
experiments were made, they selected the most extreme versions among the 50 generics of Lamotrigine and
it was proven that these extremes that were supposed to have different effects actually had the same effects.
They also took a large population of people with epilepsy and kept rotating between the two extreme
generics and no harmful effect was recorded. Then another study was performed specifically on those
patients that had complained about a loss of efficacy, in a double blinded way, so that they wouldnt know
about what they were receiving, if the brand or the generic. The result is that even if they were switched
form the brand to the brand, so no change was really applied, they got worse. The conclusion is that it was
just a reversed placebo effect caused by the fear of change.

NB! Not all the countries have so strict controls, for example in Brazil there have been many cases of herbal
medicaments claiming to be natural actually containing chemical compounds such as ibuprofen, or drugs
claiming to contain a certain active principle that were found to not even have a trace of it.

Curiosity: in some countries it is legal to market a generic with a brand name, which means not the same
name of the original one, but not necessarily the name of the chemical compound, a simply random name.
These are called Branded generics: they are generics but have a specific name, different from the other
generics, so that they cant be confounded.

CLINICAL DEVELOPMENT:

Objectives of Clinical Drug Development: obtain all the necessary information for approval:
Confirm pharmacological properties identified preclinically, including PK-> confirm they are also
present in humans
Determine therapeutic potential, safety and tolerability-> show that the drug does something and
quantify efficiency.
Safety and tolerability are similar concepts, but safety has more to do with serious side effects,
requiring stopping the drug, while tolerability is about side effects that you can tolerate, but are still
adverse.
Define:
- indications (conditions in which you are legally allowed to prescribe a drug)
- contraindications (conditions in which you are legally not allowed to administer a drug to a certain
category of patients, because there is a risk for them)
- mode of use (doses, route of administration, dosing schedules, precautions eg: monitoring the level
in blood,)
Obtain marketing approval (requires demonstration of efficacy and safety)
Continue postmarketing evaluation of efficacy, safety and additional indications / contraindications:
pharmacosurveillance, companies are legally bound to do this and to file a report every year (or
even more often) concerning what is happening mostly in terms of safety to the drug, plus also
information about how much the drug is being sold and used, where, I which conditions,

The Four Phases of Clinical Development:

1. Phase I: 20-100 healthy volunteers take the drug for about one month, with the main purposes of
determining pharmacokinetics and determine safety and tolerability
Information learned
1. Absorption and metabolism
2. Effects on organs and tissues
3. Side effects as dosage increased
 2. Phase II: several hundred health-impaired patients take the drug (treatment group) and the
development of their condition is compared to the development of the condition in a control group.
The aim is to provide proof of concept that the drug is efficacious in a given condition
Information learned
1. Effectiveness in treating disease
2. Short-term side effects in health-impaired patients
3. Dose range

3. Phase III: hundreds or thousands of health-impaired patients take the drug. The aim is to provide
evidence that the drug is safe and works under broader conditions of use
Information learned
1. Benefit/risk relationship of drug
2. Less common and longer term side effects
3. Labelling information

4. Phase IV: post-marketing surveillance

PHASE 1:
Peculiar use of drugs, borderline in terms of ethics. Normally you can apply an intervention only if
there is a reasonable chance of positive effect. If you give a drug to a healthy subject, you only do
that to look for negative effects, so the only thing that could happen is a worsening of the volunteers
health. This is justified because it is done with the aim of protecting patients from negative possible
effects. Volunteers are supposed to have a greater freedom than patients in deciding whether to
participate or not (this is also the reason why they must not be in economical need to be chosen and
they are not paid more than they would get paid in any other job for the same amount of time
Experiments in phase 1 are relatively cheap compared to the total investment for development: it
costs around 2-3 million dollars.
Objectives:
- Obtain preliminary evaluation of tolerability (adverse effects, maximum tolerated dose)
- Determine PK properties in humans (mostly done through blood samples and urine samples during
administration of single doses and multiple doses afterwards)
- Confirm (whenever possible) the pharmacological properties identified preclinically

Methodology: the priority is to minimize harm

- Need to have n=50-100 healthy subjects
- Single and multiple ascending doses: start by giving the lowest possible exposure (single dose) with
a concentration that you can reasonably consider safe on the basis of the preclinical evaluation. To
minimize any risk, there is a huge safety margin left in between, ie: if a certain dose causes a
concentration in blood that has been proven to be toxic, you start by giving a dose 1000x lower. At
this concentration no effect whatsoever could be produced. Then you gradually increase the dose,
until you find the first adverse effects. Typically, these will be effects that can be easily reversed such
as headache, nausea, decrease in bp, drowsiness, or signals in lab results such as altered blood
proteins levels, or altered liver markers.
At the end you know what the adverse effects are and which doses produce such effects.
There is a limit anyways, determined also by preclinical evaluations, above which even if no adverse
effects were found before, you stop. (usually effects show before anyways).
In some settings you might already know by preclinical studies, such as animal experiments, which
concentration of the drug is needed to produce the wanted effect. In this case what you need to find
out is the dosage to administer in healthy subject to reach that concentration in blood. In this case
 when you find this concentration, you may think you do not need anything else. Actually, most likely,
doses will still be increased to know which side effects the drug may produce, to know what to look
for in the next stage in patients.
- This is a rigorous scientific assessment: randomization, double-blind, placebo control
We have to make sure that the assessment is as scientific as possible. The basis for it to be scientific
is to have a control group for comparison. It is not sufficient to just report a change over time after
giving the drug, because said change may be caused by other factors. Even just the fact to be
undergoing an experiment may be the cause. So in these kind of studies a placebo control is used.
NB! The control group is also important because a lot of subject report adverse events when giving
the placebo. So if you dont have a placebo you cant understand if whatever happens when giving
the drug is due to the drug itself or not.
E.g.: all the subjects can have a degree of headache. This can be due to the drug or due to anxiety
and the environment around them. Usually experiments are done in a very safe environment,
people are confined in a clinical unit, for all the time needed to check for effects, so from some
days before administration to some days after administration. The fact of being in an experimental
trial, the stress, changing food habits, changing daily routine, will produce changes in laboratory
tests. It is very common to have an increase in liver enzyme when given placebo. If you dont have a
control group you cant be sure whether this is an effect of the toxicity of the drug on the liver or
simply a consequence of other factors.
Key element: assignment to the placebo or to the compound under investigation is done randomly
and the evaluation is double blind: neither the investigator, nor the subject know what medication
is being administered.
- Close monitoring of safety measures: check all vital parameters, often the investigations are driven
by information on the possible toxicity of the drug collected in the preclinical phase.
- Pharmacokinetics are also fundamental to be evaluated in this phase.
Less than 1/1000 compounds that start being experimented will actually end up being marketed.
Many are discarded during preclinical development. Then, only 1/100 (approximal estimation)
compounds tested in humans will reach the market, most of them are discontinued in phase one,
often because pharmacokinetics of the drug are undesirable. Predictability from animal models
about PK is limited, e.g.: drugs may be eliminated too quickly, not well absorbed. Another reason
to stop development is tolerability issues, for example side effects come up at a dosage not sufficient
to produce a therapeutic effect
- Applications, whenever possible, of measurements or models to evaluate pharmacodynamic (PD)
effects.
But! How can you assess the activity of a drug in a healthy volunteer?
Consider the following examples:
o Drug for pain: Healthy volunteers are not feeling pain, so what is done is to try to recreate the
situation of pain and see if the drug counteracts it. There are ethical limits, but the situation
recreated is usually trivial, not severe. For example, the volunteer has to keep the hand in a bucket
full of water and ice, and the time it takes to feel a level of pain too high to keep the hand in is
measured and compared between the case of the volunteer not taking any drug and when taking
the drug in question. Of course, if the drug does have an analgesic effect, the time will be longer.
o Drug acting as cough suppressant: The volunteer has to swallow distilled water, this normally
makes you cough, without any harm; you then try to make it when the drug was administered
and check if the same reaction happens or not.
o Drug for peptic ulcers: you can put a nasogastric tube going to the stomach of the volunteer to
see how the pH is changed in time when the drug is taken. If it does have suppressive activity in
the secretion of acid, you can measure the extent and determine the time course of the action of
the drug.
 o Drug against hypertension: check blood pression, also in people with normal blood pressure it
should decrease.
In some other situation this cant be done, e.g.: there is no way to test in a healthy subject an
antidepressant, or a drug for Alzheimer disease.
Only if you know the mode of action designing a way to monitor it in volunteers may be easier.

Other examples of PD models:

o Stimulation of dental pulp (analgesics)
o Gastric pH monitoring (proton pum inhibitors, H2 antagonists)
o Tachycardia induced by beta-stimulants or exercise (beta-blockers)
o Citric acid inhalation (antitussives)

PHASE 2
It is a critical phase, its aim is to reach an answer as reliable as possible, to the question: is this going
to be a valuable medication?
Performed on patients with the disease in question, but on a limited number
Objectives:
- Demonstrate with rigorous methodology the expected pharmacological / therapeutic properties
(proof of concept studies): the extreme scientific rigour is needed to get as much information as
possible about safety and therapeutic potential with a limited number of subjects.
Determine the proof of concept means that you have an hypothesis, the aim now is to understand
if it is correct and the drug will actually do what is meant to do.
- Obtain further data on adverse effect potential
- Characterize dose-response relationships and PK-PD relationships
The dosage is critical with respect to the risk to benefit ratio. When a drug is released physicians need
to have information about the relationship between dose and therapeutic effect, or a side effect.
Individuals are different among themselves and may answer differently.
- Assess potential drug interactions in the target population
Often, for ethical reasons, if you are developing a drug for which there is another treatment, it is
unethical to test it in a sick person, because you dont know if it works, plus someone must end up
receiving a placebo, so if it isnt a trivial condition people would be prevented from getting the best
treatment available. Therefore, usually phase II experiments are performed in people resistant to a
certain already existent treatment, the new drug is simply added on to the established treatment
they are already receiving. So already at this point it is important to check for potential interactions.
Curiosity: For this reason, it is common that initially drug are released only with the indication of people
not responsive to available treatment, then, when more information are acquired, the drug may start
to be used alone, not in addition to the other treatment.
This is also because if you only tested the compound on people taking also another treatment, you can
only get approval to do that. To get an approval to administer the treatment without concomitant
treatments, you have to conduct an experiment where that is done and checked.

Cost is relatively modest.

Methodology
- Patients with the target condition (n = 100-600), less than 1000 patients. these are few, but still if we
are testing a drug for a rare disease finding even just 50 people will be difficult
- Strict eligibility criteria: try to minimize variability, that is always an obstacle in finding out whether
a wanted effect is produced. This is achieved by minimizing variability in the population you select:
you build a very stereotyped population. The advantage is to have a clean and uniform experimental
setting to have the best conditions to evaluate the effects of the drug. But! The population in which
 you are assessing adverse effects is a very artificial population, e.g.: old people are usually excluded,
but they might not tolerate the drug as well as younger people.
Curiosity: It is more common to have males volunteering in phase 2, because women are excluded
as they possibly are child bearers. They might be included if they take contraceptives or are sterile.
In phase III instead all the variations will be included.
- Different doses, typically 3 to 6 different doses, to assess dose-response relationship
- Rigorous scientific assessment: randomization, double-blind, placebo (if ethically possible) or active
control
- Careful monitoring of clinical effects, including safety.

The ideal experiment compares the effect of placebo, of different doses (at least 3, selected on the
basis of the experiments in phase I). Also, it includes the standard treatment used for that condition
(if there is one).
In this way you can:
- Check what placebo does: your drug must do more
- Find lowest dose producing an effect
- Find highest tolerated dose
- Find the best dose in between these two limits (maybe studying 3 doses wont be enough for this),
but this will require lots of subjects and it will cost a lot
- Find how your drug compares with the already available treatment, possibly the gold standard. This
is not required for approval, you just need to prove it is better than placebo, but it can be a plus when
the drug gets to the market. Plus, this can be a way to gain more investors to finance phase III (that
is much more expensive).
NB: one company will probably not bias the study at this point, because it is useful also for them to
gain reliable information (if they want to go for fraud they will probably do it later). The problem is,
if the result of the study is not what they wished for, i.e: the competitor drug results to work better,
the study will never be published, since there is no legal obligation, and physicians will never know
that such a study was done and it could help them to choose the best treatment for their patients.

The concept of END POINTS:

Historically, we passed form a period where anybody could put any kind of drug on the market without any
control. Now everything is tightly regulated.
In the past you could have tested a drug in comparison to a placebo, by many different tests. For example, if
your drug is intended to treat migraine, you can administer either placebo or the drug and many different
measures can be considered to determine whether the drug is having an effect or not. For example, you can
count the migraine attacks when taking the placebo and then count the attacks when taking the drug, and
compare them. Eg: with placebo in a certain period of time you get 5 migraines, while in the same period of
time while taking the drug you get 2 migraines. This is what is called an end point: one measure you select to
determine whether there is an effect or not, the target outcome of your trial. In this case, the end point to
evaluate the effect of the drug against migraine would have been the total number of migraine attacks when
taking the drug vs placebo.
But there are other possible measurements you could choose. For example, typically you dont give the entire
does you think works initially, you start with a low dosage and then increase it gradually. This is mainly for
two reasons: some individuals may not tolerate the entire dose, so you can catch the beginning of adverse
effects before you expected them to appear only if you increase gradually. Plus, if you increase gradually the
dosage, the body adapts, so it can tolerate the drug more and more, and a patient may be able to be
administered a dosage that he would have never tolerated if it was given right from the beginning. This is
called titration phase.
Example: Primidone, drugs used for epilepsy. Typical average dose: 750 mg. But to tolerate it you need to
start with a low dose (a quarter of a tablet of 250 mg = 60.5 mg) for 4/5 days and then slowly increase. If you
start with the whole dose, awful side effects develop.
So, another end point could have been chosen by only restricting the comparison of number of migraine
attacks to the time during which patients were on maintenance treatment (taking the full dose), not
considering the titration period in the comparison.
Or, you could have chosen to use as a measure the time it takes from the moment you start treatment to
have the next migraine attack. The time period should be prolonged.
Or, you could take as a measure the time it takes to have the 4th migraine attack, and so on.
The point is, you could have chosen dozens of different end points to evaluate whether your drug works or
not compared to placebo. What was done in the past was to measure all of these things, and you might end
up with 6/10 end points being positive. On the majority of measures the drug was better than placebo, so it
could have been presented to the regulatory agency to be approved.
Now this cant be done anymore. The end point that will determine whether the drug is better than
placebo or not must be decided at the beginning, when you design a study. This measure is the
primary end point. You can also take all the other measures, stabilize other end points, but these
will be secondary end points.
You have to justify the choice of the primary end point, typically on the base of what is clinically
relevant.
Why is this so? You could measure 20 different end points. Only 1 results positive. This might simply be due
to chance, i.e.: if you keep repeating different measurements, simply by chance one will end up to be relevant
to what you are looking for. To design a statistical test properly, you should introduce a correction to take
into account that this positive result could be given just by chance.
Problem: if the primary end point wasnt determined a priori, the company may only publish what is
favourable, and hide all the rest. This was done in the past, now it cant be done anymore.
Something that might still be done is to evaluate, as you must do, one primary end point and a lot of
secondary end point to determine if your drug is better than placebo. If the primary end point results
negative, but all the other secondary end points are extremely positive, they might publish the study without
reporting what is the primary end point. This is actually a negative study published as positive, where rather
than lying they just omit the information.

Clinical outcome measures vs surrogate endpoints

A clinical endpoint is what eventually you need to achieve to give benefit to the patient.
A surrogate endpoint is a parameter that we think correlates to the ultimate clinical benefit.
Examples:
- Moderate high blood pressure doesnt cause symptoms, but still it is treated because it could lead to
serious cardiac problems (myocardial hypertrophy, atherosclerosis, leading to myocardial infarction,
cardiac failure, possibly blindness). People with moderate high pressure are treated to reduce risks,
not because of blood pressure itself. Blood pressure is a surrogate endpoint for what you actually
want to achieve, i.e.: prevention of complications
- INR, the standardized ratio to check when taking anticoagulant drugs, is a surrogate measure of the
benefit you want to achieve, i.e.: preventing conditions such as thrombosis
- Anti-dyslepidemic drug, given because dyslipidemia is related to severe complications.

Every time it is possible in development of a drug we try to measure what eventually is clinically relevant, but
if the evidence from using a surrogate endpoint is a reliable predictor of benefit, measurements can be based
on it.
Nb: of course there is some risk: it needs to be accepted that surrogate endpoint will translate into a clinical
benefit.
Eg: drugs for diabetes: for Metformin there are long term studies conducted for may many years, that have
shown exactly the mechanisms by which this drug reduces risks linked to diabetes: cardiovascular mortality,
diabetic retinopathy, diabetic neuropathy. Other new drugs instead for sure reduce sugar blood level, but it
cant be known if this will translate into reduced clinical risks.

PHASE III
Similar to phase II, but in a much broader population, closer to the real world, without so strict
inclusion criteria (but still not completely equal to the normal population)
Collect all the information necessary to get the permission to put the drug on the market
Cost of phase 3 is huge! 10s or 100s of millions of dollars. If a drug fails in phase III it is an economically
disaster, so a lot of efforts are placed to avoid this.
Objectives
- Confirm and characterize in greater detail efficacy and adverse effects
- Improve understanding of dose-response relationships and long-term effects
- Evaluate influence of variables (confounders) typically excluded from phase II studies, such as age,
concomitant diseases and concomitant treatments.
NB! Drugs that will eventually be used around 50% in elderly people in the real world, often at the
end of phase III will only be evaluated on a ridiculous proportion elderly, i.e. around 10-15% of the
total population that has been studied.
- Compare investigational drug with alternative treatments (gold standards or other), if not done
before.
NB! At this stage, companies may start to think about the possible benefit that a study could bring if it
gives good results, and studies unfavourable may be hidden
Methodology
- Larger populations than Phase II, and broadened eligibility criteria (n = 500-5000)
- Special groups (children, the elderly, patients with co-morbidities)
o Elderly
o Children: Children normally eliminate the drugs faster than adults, so companies should perform
studies to give to the physicians information about dosage. Sadly, usually companies dont, and
rely on off-label use to gather information after the drug is put on the market.
o Patients with co-morbidities should also be studied to determine dosages. E.g. dosage in a
patient with kidney disease, or with cirrhosis, or in a patient undergoing dialysis, or so on.
- Randomized double-blind controlled trials vs placebo or active controls, open-label follow-up
studies, specific safety studies

SUMMARY: Advantages and Limitations of Regulatory Trials

Advantages Limitations
Generally double blind Often conducted in artificial contexts
Placebo control Doses and duration of treatment may not refect optimal use
Standardized methodology Study endpoints differ from endpoints in routne clinical practice
Rigorous scientific standards N. of patients insufficient to identfy rare adverse effects

Remember the main problem about the difference with the true population with the disease and the
population included in the studies.
For example, a metanalysis compared patients with heart failure in general clinical practice with those
included in clinical trials:
Regulatory (clinical) trials: mean age = 62; 81% males.
In general practice (average target for the drug): mean age = 75; 47% males.
This can lead to unforeseen problems if no studies on females or elderly were done

PHASE IV
Post-marketing
Objectives:
- Improve knowledge on efficacy and adverse effects
- Asssess long-term outcomes
- Evaluate effects in population potentially at special risk
- Identify rare or delayed adverse effects
- Obtain data on drug utilization and pharmaco-economics. Pharmaco-economic evaluation is usually
done post marketing by national health service if the health is a public service (cost benefit ratio in
comparison to other drugs).

NB! Studies investigating new indications, new dosages or new models of use are classified as phase III.

Methodology: How is this control and surveillance achieved?

- Controlled and uncontrolled studies
- Case reports, mostly relate to rare adverse effects. They are sent by physicians observing adverse
effects on their patients, that are legally required to do so. These should also be published, so that
other physicians can keep an eye and look specifically for that rare but serious effect in their patients.
This can lead to the drug to be taken off the market.
Also, reports may be about unexpected benefits, and in the same way reporting it can stimulate other
physicians to notice it. This may justify a proper study to be performed to confirm if the noticed effect
actually occurs and may be included in the indications.
- Drug surveillance, to monitor safety (spontaneous reports, cohort studies, case-control studies,
PEM). This relies on two types of approaches:
o The spontaneous reporting by physicians of adverse effects is a legal requirement (for serious or
unexpected effects, not for all of them, or for specific additional requirements with which the
drug is released).
As far as Italy is concerned, this will first be sent to the ASL or to the Direzione sanitaria if one
works in a hospital, then it will be sent centrally to the national regulatory agency, and eventually
will be shared with the company producing the drug and with a worldwide database shared
among regulatory agencies in countries all over the world.
This is crucial to identify important side effects. Problem: there is huge underreporting.
o Special methodologies to investigate actively safeness of a drug during real world use with
prospective studies, i.e. cohort studies where you monitor a cohort (typically hundreds or
thousands of patients during follow ups), case-control studies to assess if an effect is actually
caused by the drug in question, and other methodologies.