S1B5 - Drug Developmend and Approval

Question 1

Assays can be developed to screen for molecules that activate or inhibit a molecular target. What is the name for the compounds that are discovered this way?

Answer 1

Lead compounds can be discovered in a variety of screening assays.

Question 2

Derivatives of a lead compound are synthesized to search for a compound with the required properties of a drug. Which step in pre-clinical drug development is this?

Answer 2

Medicinal Chemistry

• Derivatives of a lead compound are synthesized to search for a compound with the required properties of a drug.
• Drug properties
  
  • Affinity (lower (Memantine) or higher), activity, or more selectivity
  • stability in vivo and bioavailability - adsorption, distribution, metabolism, excretion (ADME)
  • toxicity and adverse effects

Question 3

What does GLP stand for in the context of drug development?

Answer 3

GLP; Pre-clinical research must meet good laboratory practice standards (GLP).

• Set of rules that dictate study design, facilities, and personnel to proper documentation of data.

Question 4

Is pre-clinical drug testing done in vitro or in vivo?

Answer 4

Pre-clinical testing

• In vitro testing;
  
  • The pharmacological profile of the compound can be determined using in vitro assays. The goal of these experiments is to determine the potency and selectivity of the compound.
  • Cell culture assays (activity, selectivity, toxicity)
  • Tissue slices grown in culture (activity, selectivity, toxicity)

Question 5

What does IND stand for in the context of drug development?

Answer 5

Investigational New Drug Application (IND)

• If pre-clinical testing, both in vitro and in animals, justifies human testing, an Investigational New Drug Application (IND) is filed
  
  • The application also includes plans for human testing. A review by a panel organized by the FDA determines if it is reasonably safe to move forward with human testing.
  • Clinical trials require review and approval of an IND. Also, approval of the Institutional Review Board (IRB) is required.

Question 6

What does IRB stand for in the context of drug development?

Answer 6

Institutional Review Board (IRB)

• Protection of human research subjects
  
  • Informed patient consent!
  • fully informed of their risks and have given informed consent.
  • informed that they have alternatives
• promptly report adverse events
• placebo vs drug
• new drug vs standard of care
• comprised of scientists and non-scientists that oversees the clinical trials.
• Reviews and approves the clinical trial protocols.
• The protocols describe the patient population, the criteria for patient inclusion or exclusion, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, measurable outcomes, and the study’s objectives.

Question 7

What is a randomized control trial?

Answer 7

Randomized Control trial is a research study in which participants are randomly allocated into an experimental group or a control group and followed over time for the variables/outcomes of interest.

Question 8

What is the formal step for submitting a drug for approval for marketing in the United States, and who do you sent it to?

Answer 8

A New Drug Application (NDA) is the formal step for submitting a drug to the FDA for approval for marketing in the United States.

Question 9

Describe the 5 schedules of drugs with abuse potential.

Answer 9

1. Schedule I; no accepted medical use and a high potential for abuse. Heroin, marijuana (cannabis)
2. Schedule II; high potential for abuse, severe psychological or physical dependence. cocaine, methamphetamine, methadone, oxycodone, methylphenidate
3. Schedule III; moderate to low potential for physical and psychological dependence. Combination products with low amounts of
4. Schedule IV; a low potential for abuse and low risk of dependence. Xanax, Ambien
5. Schedule V; lower potential for abuse than Schedule IV and consist of preparations containing limited quantities of certain narcotics. Antidiarrheal, antitussive, and analgesic purposes.

Question 10

What does REMS stand for in the context of drug development?

Answer 10

Risk Evaluation & Mitigation Strategies (REMS)

• Another tool the FDA uses to increase drug safety are Risk Evaluation and Mitigation Strategies (REMS).

Question 11

What is orphan drug status in the context of drug development?

Answer 11

Orphan Drug Status

• An orphan drug is developed specifically to treat a rare medical condition (an orphan disease). Orphan drugs status can provide longer patent exclusivity, tax incentives. and financial incentives
  
  • orphan status if a drug is intended to treat a disease affecting less than 200,000 American citizens
  • seven-year market exclusivity
  • tax credits on development costs
  • fast-track approvals of drugs indicated for rare diseases

Question 12

What are the three typical steps in pre-clinical drug development?

Answer 12

Typical steps in pre-clinical development

1. Lead compound discovery
2. Medicinal chemistry
3. Pre-clinical testing

• In vitro studies

Question 13

What are the major drug properties that drug developers are looking for in the medicinal chemistry step of pre-clinical development?

Answer 13

Drug properties

• Affinity (lower (Memantine) or higher), activity, or more selectivity
• stability in vivo and bioavailability - adsorption, distribution, metabolism, excretion (ADME)
• toxicity and adverse effects

Question 14

What does GCP stand for in the context of drug development?

Answer 14

GCP; Clinical trial research must meet good clinical practice (GCP) standards.

• Set of rules that dictate key aspects of clinical trials from study design, facilities, and personnel to proper documentation of data.

Question 15

What does IACUC stand for in the context of drug development?

Answer 15

IACUC

• Institutional animal care and use committee
  
  • Approves protocols for care and use of vertebrate animals in research
  • Animal care
  • Minimize stress and pain
  • Minimize animal numbers, but ensure that experiments are adequately powered.

Question 16

What two important things does animal studies address in drug development?

Answer 16

Animal studies address safety and efficacy

• Experiments in animal models are used to address
  
  • efficacy of a drug candidate and other issues
  • pharmacokinetic properties
  • adverse effects and toxicity

Question 17

What is the purpose of phase IV clinical trials?

Answer 17

Phase IV trials detect long-term adverse effects associated with widespread use and can result in a drug being withdrawn from the market. In other words, phase IV trials ask the question “can the drug stay?”

Question 18

What is the study design of phase III clinical trials?

Answer 18

Phase III clinical trials involve a large number of patients with the disease to be treated (approximately 1,000 - 3,000 subjects) who are randomly assigned to one of two groups:

• The treatment being investigated or
• The best treatment currently available (or placebo)

Question 19

What is the purpose of phase II clinical trials?

Answer 19

Phase II trials determine appropriate dosing, efficacy, and adverse effects. In other words, phase II trials ask the question “does the drug work?”

Question 20

What is a clinical trial? What is the purpose of clinical trials?

Answer 20

Clinical trials are experimental studies with human participants. The purpose of these studies is to compare the therapeutic benefits of two or more treatments (or to compare a treatment with a placebo).

Question 21

For a new medication, during which phase of clinical trials is efficacy first determined?

A) Phase IV

B) Phase II

C) Phase III

D) Phase 0

E) Phase I

Answer 21

Phase II

Answer Explanation

During Phase 0, a single, subtherapeutic dose is given. The goal is to obtain preliminary pharmacokinetic and pharmacodynamic data.

Phase I trials determine safety, pharmacokinetics, and pharmacodynamics.

Phase II trials identify/prove efficacy and adverse effects.

Phase III trials compare the treatment to the existing gold standard. This differs from Phase II in that Phase II merely seeks to show that the drug works for the proposed indication.

Phase IV consists of post-marketing surveillance.

Question 22

What is a typical study sample in phase II of a clinical trial?

Answer 22

Phase II trials involve a small number of patients (generally fewer than 100) that have the disease to be treated.

Question 23

What is the purpose of phase III clinical trials?

Answer 23

Phase III trials compare the treatment being investigated to the current “gold standard” treatment. In other words, phase III trials ask the question “is the drug as good or better?”

Question 24

What is a typical study sample in phase I of a clinical trial?

Answer 24

In phase I trials a small number of healthy subjects (between 20 and 80 subjects) receive a single dose of the treatment of interest.

Question 25

What procedural improvements can increase the validity and reliability of a study?

Answer 25

The quality of a clinical trial is improved when the study is:

• Randomized
• Controlled
• Double-blinded or triple-blinded (double-blind means neither the patient nor the doctor knows which treatment group the patient is in. In triple-blind studies the researchers analyzing the data are also blinded)

Question 26

During Thanksgiving dinner, your uncle starts telling you about a “great investment” he recently made. He purchased stock in a pharmaceutical company because he read about a new drug that had recently gone through clinical trials. He says, “This drug is great! They proved in clinical trials that it was safe, had no side effects, and it worked!” Which phase of clinical trials does this medication still need to undergo?

A) Phase IV

B) Phase 0

C) Phase I

D) Phase II

E) Phase III

Answer 26

Phase III

Answer Explanation

During Phase 0, a single, subtherapeutic dose is given. The goal is to obtain preliminary pharmacokinetic and pharmacodynamic data.

Phase I trials are to determine safety, pharmacokinetics, and pharmacodynamics.

Phase II trials identify/prove efficacy and adverse effects.

Phase III trials compare the treatment to the existing gold standard. This differs from Phase II in that Phase II merely seeks to show that the drug works for the proposed indication.

Phase IV consists of post-marketing surveillance.

Question 27

What are the purposes of phase 0 clinical trials?

Answer 27

Phase 0 clinical trials are also known as “microdosing” studies. A small number of healthy subjects are given a single subtherapeutic dose for one or more of the following purposes:

• Gather preliminary pharmacokinetic and pharmacodynamic data
• Select promising lead candidates for further testing
• Check if the agent behaves in humans the same way it behaved in animal studies

Note: Phase 0 clinical trials do not replace phase I clinical trials.

Question 28

What is the purpose of phase I clinical trials?

Answer 28

Phase I trials test safety, pharmacokinetics, and toxicity. In other words, phase I trials ask the question “is the drug safe?”

Question 29

What is a phase IV clinical trial?

Answer 29

Phase IV clinical trials are post-marketing studies (i.e. after approval) that gather information on the drug’s effects in various populations.

Question 30

What is a cohort study?

Answer 30

A cohort study is a research study that compares two groups (cohorts) of patients, one that received the exposure of interest and one that did not, and follows these cohorts forward for the outcome of interest.

Question 31

What is a case-controlled study?

Answer 31

A case-controlled study is a research study which identifies patients with the outcome of interest (cases) and patients without the same outcome (controls), and looks back to see if they had the exposure of interest.

Question 32

What is a case series report?

Answer 32

A case series is a report on a series of patients with an outcome of interest. No control group is involved.

Question 33

What is included in a NDA?

Answer 33

An NDA includes all of the animal and human data, analyses of dosage, metabolism excretion, adverse effects, and efficacy.

Also, documentation on manufacture of the drug is included.

Question 34

How long does the FDA have to decide whether to review the NDA?

Answer 34

The FDA then has 60 days to decide whether to review the NDA. The FDA can refuse to file an application that is incomplete and require further studies.