UNIT 5: DRUG DEVELOPMENT AND REGULATION

DRUG DISCOVERY

• The approaches of discovery and development of new

drugs or drug products:

RANDOM SCREENING

Screening for biologic activity of large numbers of natural

products, banks of previously discovered chemical

entities, or large libraries of peptides, nucleic acids, and

other organic molecules.

This is what is commonly employed in our institution

wherein we extract an active constituent from a plant or

animal or other natural sources and is tested for their

therapeutic activity.

CHEMICAL MODIFICATION OF A KNOWN

ACTIVE MOLECULE

,

resulting in a “me-too” analog.

Rational drug design

(_______) of a new molecule based on an

understanding of biologic mechanisms and drug receptor

structure.

o There is a need to make a drug design to make the

pharmaceutical products cross into the cell and bond

to a receptor to produce effect.

(DRUG SCREENING) (molecular, cellular, organ system, and

whole animal levels) (Drug Activity) (Drug Selectivity)

(_________________)

Assays at the (______, _________, _____, ______) are involved to define the

pharmacologic profile: (__________) (___________)

MOLECULAR LEVEL

• The compound would be screened for activity on the

target.

• For example, receptor binding affinity to cell membranes

containing the homologous animal receptors.

potential drug

is tested into a cell or a homologous

animal receptor and try to find out its affinity.

CELLULAR LEVEL

Determine whether the drug is an agonist (activates

receptor), partial agonist, inverse agonist, or antagonist

(blocks receptor) at relevant receptors.

• What would be its effect into the cell.

(WHOLE ANIMAL LEVEL) (organ system models)

(disease models) (lead compound)

(____________________)

• Generally necessary to determine the effect of the drug

on:

o (___________)

o (____________)

• The desired result of this screening procedure is a called

a (_____________). It is the leading candidate for a

successful new drug.

• After testing the drug or the potential chemical at the three

different levels, you now have a potential candidate for a

drug.

Phase 1

20-100 patients

of healthy volunteers (people

who do not have the disease)

• Pharmacokinetic measurements are also being done;

ADME is studied

• Either “open” or “blinded” trials

(Open)

(Blinded)

o (_____) → the patient knows what he or she is

receiving

o (________) → the patient is not aware of what drug he

or she is taking

phase 2

100-200 patients of patients with the target

disease to determine its efficacy (“proof of concept”).

• Would the drug really treat the target disease in a human

being?

(Single-blind) (25%)

PHASE II

(_______) design is used in phase II.

• At this point in time, a broader range of toxicities may be

detected.

• This has highest rate of drug failures, and only (____) of

innovative drugs move on to phase 3.

Phase 3

This is done to minimize errors caused by placebo

effects, variable course of the disease, and other factors.

• It is now tested to a large number 1000-6000 patients to further establish and confirm safety and efficacy.

(Double-blind and Cross over) (design) (expensive) (market)

(_______&_______) technique are employed

in phase III.

• Phase III is difficult to (_____) and execute and are usually

(______) because a large population group and more

observers are need.

• The drug is formulated as intended for the (_____).

• If the drug passes in all the phases of the clinical trials,

the drug sponsor or manufacturer will now apply for a

New Drug Application (NDA).

(FDA review) (phase 4)

Phase 3 results meet expectations, application is made

for permission to market the new agent.

• (_______) leading to approval (or denial) of the new

drug application may vary from months to years.

• Once approval to market a drug has been obtained,

(______) begins.

(fixed duration) (5) (20 years)

Phase IV has no (________).

• As with monitoring of drugs granted accelerated

approval, phase 4 monitoring has often been lax.

o Example: Covid-19 vaccines

• The time from the filing of a patent application to approval

for marketing of a new drug may be (__) years or

considerably longer.

• Lifetime of a patent is (_________) in the USA & PH.

(orphan drugs)

Drugs for rare diseases are called à (______).

o It can be difficult to research, develop, and market.

o Proof of drug safety and efficacy in small populations

must be established.

(NGO’s & NPO’s)

§ The disease is probably one in a million. Only

few people get this condition which is why not a

lot of companies will invest money on this.

§ It would be a waste of resources.

o It is a complex process.

o It is normally funded by (____&______).

0-2

ROUGH ESTIMATE OF LENGTH OF DRUG CREATION

(In vitro studies)

2-4

ROUGH ESTIMATE OF LENGTH OF DRUG CREATION

Animal testing

4-8/9

ROUGH ESTIMATE OF LENGTH OF DRUG CREATION

Clinical testing

9-20

ROUGH ESTIMATE OF LENGTH OF DRUG CREATION

Marketing

(vitro) (animal testing)

This phase is called in (_____) because we are testing it in

models or in test tubes.

• After that, the lead compound will now go to the next

phase, which is called “(____________)”.

PRECLINICAL SAFETY AND TOXICITY TESTING

“All chemicals are toxic in some individuals at some dose.”

(time-consuming) (expensive) (Large) (animals) (in vitro methods & computer) (unlikely to be detected)

1) Toxicity testing is (__________) and (_________). (2-6

years) (pay for committee, respondents)

2) (______) numbers of (_______) may be needed to obtain valid

preclinical data.

o In order to come up with statistically sound

conclusion, you need to use a large population group

of (4) (_______).

o Cell and tissue culture (__________&________)

modeling are increasingly being used, but their

predictive value is still limited compared to preclinical

testing in animals.

3) Extrapolations of toxicity data from animals to humans

are reasonably predictive for many but not for all

toxicities.

o Sometimes, there are toxicities that are not

discovered in animal studies but were seen in clinical

trials.

4) Statistically, rare adverse effects are (_____________) in preclinical testing.

(mechanisms) (relevant) (animals) (human)

Identifying potential human toxicities

• Designing tests to further define the toxic (__________).

• Predicting the most (_________) toxicities to be monitored in

clinical trials.

• First test it on (________), before applying it to (______) beings

(2 years) (efficacy) (selectivity) (mechanisms of

action)

• Referring back to previous diagram, animal testing would

take up to (______) in average.

• The goal of animal testing is to look at the (________) of the

lead compound, its (______), and its (___________).

(investigational New Drug) (FDA)

After animal testing, you can now apply for (_________________________). By this time, the lead compound will

become an IND and it is first applied in (_____).

(natural history) (Diseases) (Risk Factors) (Observer Bias)

CONFOUNDING FACTORS IN CLINICAL TRIALS

1 Most Diseases have variable (___________)

2 The Presence of Other (________) and (_________)

3 Subject and (____________) and Other Factors

Natural history

(__________) of disease, according to CDC, refers to

the progression of the disease process in an individual

over time in the absence of treatment.

o Most diseases may vary. It may evolve or mutate

especially if it was left untreated.

(large enough population) (crossover design)

To prevent this from happening: Evaluating a (____________) of subjects over a sufficient period

of time.

• The use of (____________), which consists of

alternating periods of administration of test drug, placebo

preparation (the control), and the standard treatment

(positive control), if any, in each subject.

(Crossover) (Proper selection and assignment).(valid methods of Randomization)

• (________) technique (when feasible)

• (______&______) of patients to each of

the study groups.

• Statistically (___________________) in

assigning subjects to particular study groups.

o There’s also inclusion and exclusion criteria in

research.

(Single-blind design)

(Double-blind design)

(Adherence)

• (__________) – reduces subject bias; participants

do not know what group they belong to or what treatment

they are receiving

• (____________) – reduces observer bias; the

observer (or doctor) and the subject do not know the

grouping, only the drug sponsor or drug manufacturer

• (__________) - confirmation of compliance with protocols;

observer needs to follow the protocols in doing the

research.

(The Food and Drug Administration Act of 2009)

Republic Act No. 9711 otherwise known as

“(___________________________________)”

(licensing, monitoring, and regulation) (safety efficacy) (quality)

The agency is responsible for (_______, _______, _______) of cosmetics, drugs, foods, household

hazardous products, medical devices and

electromagnetic radiation emitting devices, pesticides,

tobacco and related products, and vaccines for (_______) and (_____) in the Republic of the Philippines.

(Notice of IND) (FDA) (4–6 years) (Chronic safety testing)

A (________) must be filed with the (_____) once new

drug is judged ready to be studied in humans.

• It often requires (_______) of clinical testing to

accumulate and analyze all required data.

• (____________) in animals is usually done

concurrently with clinical trials.