Module 1 Section 5 (Drug Development and Testing)

Question 1

What is the first step in the drug development process? Provide an example.

Answer 1

Identifying a biological target for the potential drug is the first step in the drug development process.

Ex: a target for a new potential drug could be a receptor that, when activated, causes an increase in blood pressure. Once a compound that binds well to the receptor is identified, it will be studied to determine the pharmacological effects at the molecular, cellular, organ, and whole animal level.
- For instance, in the example of developing a new drug to lower blood pressure, the effect of the drug on blood pressure would be studied. If a compound shows promise in these initial studies it is identified as a lead compound, and enters more detailed studies for safety and efficacy.

Question 2

How long does the discovery stage last?

Answer 2

In general, the drug discovery stage of research can take anywhere from 2 to 8 years (sometimes more), and up to 25,000 different chemical compounds can be tested before the discovery of a handful of lead compounds (i.e. compounds that have shown promise as potential drugs) are made.

Question 3

What are the substages, number of components and results of the Drug Discovery (3-6yrs) stage?

Answer 3

Sub-stage: Research and discovery of target

• Number of compounds: up to 25,000
• Result: discovery of lead compounds

Substage: Preclinical testing

• Number of compounds: up to 30
• Result: determine safety and potential efficacy

Question 4

What are the substages, number of components and results of the Clinical Trials (6-7yrs) stage?

Answer 4

Substage: Phase 1

• Number of compounds: 5-30
• Result: Safety and tolerability

Substage: Phase 2

• Number of compounds: 2-3
• Result: Effectiveness, safety, and pharmacokinetics

Substage: Phase 3

• Number of compounds: 1
• Result: Effectiveness and safety

Question 5

What are the substages, number of components and results of the Health Canada/FDA approved Drug (0.5-2yrs) stage?

Answer 5

Substage: Health Canada Review and Manufacturing

• Number of compounds: 1
• Result: Drug approval and production

Substage: Phase 4

• Number of compounds: 1
• Result: Long term efficacy

Question 6

Why are preclinical studies conducted?

Answer 6

Preclinical studies are conducted prior to testing the new drugs in humans and can range from molecular and cellular studies, to tissue and whole animal studies.

Question 7

What are the 2 main preclinical study categories? Provide an example.

Answer 7

1) Pharmacology studies: these studies determine the detailed mechanism of action of the new drug.
- Ex: if the drug has been developed to treat high blood pressure, it would be determined how the drug lowers blood pressure (e.g. does the drug dilate blood vessels?).

2) Toxicology studies: these studies determine the safety and tolerability of the new drug.
- Toxicological studies are conducted to determine the effect of the new drug on organ systems other than the targeted organ, which would be considered adverse effects.
- Ex: when testing a new drug to decrease blood pressure, organ systems other than those that regulate blood pressure would be studied. These studies are expensive and can take up to six years to complete.

Question 8

What are the 4 different types of toxicology studies?

Answer 8

1) Acute toxicity study: these tests are designed to determine the toxicity of the drug after a single administration, or after a limited number of administrations over a short period of time (i.e. a few days).
- Several different doses are studied to determine the dose that does not produce toxicity (termed the no effect level), and the largest dose tolerated by the animal (termed the maximal tolerated dose).

2) Sub-chronic toxicity study: these tests last a few weeks to three months and are usually conducted with three different doses of the drug or drugs that were found to be well tolerated from the acute toxicity studies.
- In general, two species of animals are given the drug daily, and the toxic effects of the drug on the animals is determined.

3) Chronic toxicity study: these tests are generally conducted over a period of six months to two years, again with two species at three or more doses.
- The toxic effects of the drug are measured throughout the study and any organ damage is determined at the end of the study.

4) Other studies: depending on the intended use of the drug, the drug may also be tested for its ability to cause cancer, to interfere with reproduction, to cause birth defects, or to cause changes in genes.

Question 9

What’s the main goal of preclinical studies?

Answer 9

The main goal of preclinical studies is to identify any potential toxicities of the new drug.

Question 10

What are the initial steps of a clinical trial?

Answer 10

Once a drug has passed the preclinical stage of development, the pharmaceutical company or other group developing the drug will apply to the appropriate drug regulatory body (e.g. Health Canada) for permission to proceed to clinical trials.

1) The manufacturer is required to submit proof of the safety and the efficacy of the drug in several animal species to the government regulatory agency in the particular country concerned.
- In Canada, this is the Health Protection Branch, and in the U.S.A. it is the Food and Drug Administration (FDA).

2) The detailed methodology of the proposed clinical trial in humans is required.
3) The submission is carefully evaluated by qualified scientists in the regulatory agency. If they are satisfied with the submission, permission will be given for highly qualified investigators, usually clinical pharmacologists, to begin investigation of the drug in humans.

Question 11

How many compounds make it into the initial steps of clinical trials?

Answer 11

Anywhere from 5 to 30 compounds make it through preclinical testing and into clinical trials.

Question 12

What are the most important studies of the drug development process?

Answer 12

The most important studies of the drug development process are the clinical trials, which are studies conducted in humans. Since differences between humans and animals exist, clinical trials are the only studies that will tell us if a drug is truly safe and effective in humans for the intended purpose.

Question 13

What’s the first phase of a clinical trial?

Answer 13

Phase 1 drug studies are the first studies conducted in humans, and are usually conducted in a limited number of healthy volunteers (i.e. 20 to 100).

Question 14

What is the purpose of phase 1 clinical trials?

Answer 14

The purpose of phase 1 studies is to establish doses of the drug that are tolerated by humans and which can be used in further studies.
- In the case of drugs that are expected to have serious toxicities (e.g. cancer chemotherapy drugs), patients with the disease may be used.

Question 15

How is a phase 1 clinical trial conducted?

Answer 15

When conducting the study, the new drug is administered to only a few subjects at first. Once results from these first subjects are obtained, and it is determined that the risk to the subjects is acceptable, more subjects are included in the study.

Several doses will be tested, but eachsubject will usually receive just one dose. On occasion, a subject will receive increasing doses of the drug over a defined period of time (e.g. one or two days).

Question 16

What is the design of phase 1 clinical trials?

Answer 16

The design of these studies is usually open, meaning that the investigator knows what drug and dose they are giving the person, and the person being administered the drug knows exactly what they are taking.

Question 17

What is monitored during phase 1 clinical trials?

Answer 17

After the drug is administered, the response of the subject is carefully monitored for safety and tolerability.

Limited absorption, distribution, metabolism, and excretion studies are also conducted.

Phase 1 studies are conducted in research clinics established for this purpose with properly trained personnel.

Question 18

How many drugs proceed from phase 1 to phase 2?

Answer 18

It is estimated that about 50% of drugs that enter phase 1 trials fail to proceed to phase 2.

Question 19

Can you think of any limitations that may arise in an open study?

Answer 19

An open study risks bias, as both the patient and the researcher are aware of which groups are receiving what type of treatment. This could unintentionally alter the behaviour and/or conclusions from either party.

However, since this is the first time the drug is administered to humans, the safety of the participants outweighs the potential bias, allowing for an open study.

Question 20

What are phase 2 clinical trials?

Answer 20

Phase 2 studies are the first time that the drug is administered to patients with the disease for which the drug is intended to treat. Phase 2 clinical trials determine whether the drug is effective in treating the condition it is recommended for, in a limited number of people (i.e. 100 to 500). Careful attention is paid to the safety of the drug.

Question 21

What 3 things occur during phase 3 clinical trials?

Answer 21

1) Patients are randomly assigned to one of two groups, the experimental drug group, or the control group.
2) Study subjects in the experimental drug group will be further sub-divided into groups, and each group will receive a different dose of the new drug.

3) Study subjects in the control group will be given the current gold standard drug (the drug that’s accepted by the medical community as the best available treatment for the specific disease at that time) for treating that specific disease.
- However, if a gold standard drug is not available, then a placebo is used

Question 22

What is a placebo?

Answer 22

It’s a tablet that does not contain any active drug but is identical in appearance, colour, taste, and size to the tablet containing the active drug.

In other words, a placebo is a fake drug.

Question 23

True or false: phase 2 studies may be single blind or double blind designed studies.

Answer 23

True

Question 24

What are single blind studies?

Answer 24

Single blind designed study is when the person administering the drug to the patient knows whether the patient is receiving the new drug or the control drug, however the patient does not know which drug they are receiving.

Question 25

What are double blind studies?

Answer 25

Double blind designed study, both the person administering the drug to the patient, and the patient are unaware whether the drug is the new drug or the control drug.

Question 26

How many drugs proceed from phase 2 to phase 3?

Answer 26

Approximately 75% of drugs studied in phase 2 fail to advance to phase 3.

Question 27

True or false: many drugs will fail phase 1 or phase 2 clinical trials. As such, usually only one or two of those drugs will make it to phase 3 clinical trials.

Answer 27

True

Question 28

What is the purpose of phase 3 clinical trials?

Answer 28

These trials, often called controlled randomized clinical trials, are one of the main studies used for the licensing and marketing of the drug.

The goal of a phase 3 clinical trial is to determine whether the drug is safe and effective in a larger number of people (usually one thousand or more).

Question 29

How long are phase 3 clinical trials?

Answer 29

These studies are usually longer than phase 2 studies (months to years), and are conducted at centers in many cities (multi-centered), as one center usually does not have the required number of or diversity of pts.

Question 30

How much do phase 3 clinical trials cost?

Answer 30

Phase 3 trials are the most expensive part of drug development.

A phase 3 trial may cost anywhere from one million to 50 million dollars.

Question 31

Why are contract research organizations used in phase 3 clinical trials?

Answer 31

Drug companies may retain the services of contract research organizations to oversee the conduct of the study.

The contract research organization will monitor the conduct of the study to ensure that each center is running the study the same way, according to the agreed protocol.

It is important that each center conduct the study in the same way, and that the results are collected in a consistent manner, so that data from all centers can be pooled for analysis.

Question 32

What occurd after the successful completion of the initial phase 3 trials?

Answer 32

At the successful completion of the initial phase 3 trials, the manufacturer will submit to the regulatory body a new drug application containing the detailed results of the clinical trials. The results are again reviewed by regulatory scientists. If the drug is deemed to be effective, and the toxicity is acceptable, it will be granted approval.

Question 33

What will the drug be named?

Answer 33

A drug’s formal chemical name is too complex for general use. If a drug undergoing development shows promise and a manufacturer wishes to place it on the market, then a generic name for the drug is selected.

• Ex: ibuprofen -> Advil
• Ex: Acetaminophen -> Tylenol

The manufacturer will also apply for a patent with a brand name for the drug, which will give the company exclusive rights to market the drug for 20 years. The 20-year life of a patent begins when the patent is filed, usually during the preclinical development phase.
- The effective patent life of a drug is in the range of 10 to 12 years. After a patent on a drug expires, other manufacturers can make copies of the original brand name drug, and sell it under their own brand name.

Question 34

What are bioavailability studies?

Answer 34

A comparative bioavailability study is conducted, which compares the blood levels after administration of both the brand name drug and the new brand name/generic drug to healthy volunteers under controlled conditions.
- This is done to ensure the two drugs are bioequivalent (two drug products, generic and brand name, which contain the same active ingredient(s) and give similar blood levels are said to be bioequivalent).

Strict regulations are in place so that drugs made by different manufacturers are bioequivalent.
- This also ensures that all generics are as effective as the original brand name drug.

Question 35

What is the purpose of a phase 4 (post-market surveillance) clinical trial?

Answer 35

The purpose of phase 4 studies is to obtain information on safety and efficacy of the drug after marketing.

This is important since some drug toxicities occur with an incidence of 1 in 10,000 and can only be detected after the drug is on the market and used in a large number of patients.

Question 36

How are phase 4 clinical trials designed?

Answer 36

Phase 4 studies can be designed as an active trial, where patients prescribed the new drug are monitored for any toxicity, or the post market surveillance can be voluntary, with practitioners reporting observed adverse events.

Question 37

Five volunteers are given Drug Y, and the volunteers are monitored for adverse effects. These individuals are most likely in which phase of a clinical trial?

a) Phase 1 clinical trial
b) Phase 2 clinical trial
c) Phase 3 clinical trial
d) Phase 4 clinical trial

Answer 37

a) Phase 1 clinical trial

Question 38

Which one of these statements regarding drug naming is correct?

a) The generic name of a drug is a proprietary name
b) Drug products made by different drug companies usually yield very different blood levels
c) If a drug is marketed by more than one company, it may have several brand (proprietary) names
d) The chemical names of drugs are commonly used and easy to remember.

Answer 38

c) If a drug is marketed by more than one company, it may have several brand (proprietary) names