Basic Terms Research Used in Psychopharmacology

Question 1

Acute Phase

Treatment Phase in Psychopharmacology

Answer 1

• Treatment of symptoms of an active disorder, usually immediately after the disorder onset (if the patient seeks treatment…ironically, for many psychiatric disorders patients may wait for months or years prior to seeking treatment)
• Goal of treatment is to alleviate severity of symptoms and help the patient resume their previous level of function
• This is often referred to helping the patient return to their “baseline”
• Increasingly, mental health care professionals, including psychiatrists, are interested in helping patients achieve recovery

Treatment Phase in Psychopharmacology

Question 2

Continued Phase

Treatment Phase in Psychopharmacology

Answer 2

• Treatment is continued after acute phase to prevent reemergence of acute symptoms
• Unfortunately, little empirical research exist for determining how long many psychopharmacological agents should be continued
• Prescribing professionals are usually encouraged to use evidence from clinical history for determining duration of continuation treatment
• The average duration of studies submitted to the Federal Food and Drug Administration (FDA) for approval is 6-8 weeks

Treatment Phase in Psychopharmacology

Question 3

Maintenance Phase

Treatment Phase in Psychopharmacology

Answer 3

• Treatment is continued beyond continuation phase to prevent relapse of symptoms
• May occur in two basic forms:
  
  • Continuous treatment with pharmacological agent.
  • Discontinuation of treatment with expectation treatment will resume
    if active symptoms reemerge.
• Treatment strategy used depends of type of disorder and clinical presentation. Continuous treatment more likely if the disorder is:
  
  • Cyclical nature of disorder (Bipolar or Schizophrenia)
  • Has a short duration between episodes
  • Symptoms are severe (and result in substantial loss of quality of life)
  • Patient is less aware of symptom onset (e.g., mania or hallucinations/delusions)
  • Symptom onset is rapid
• Also important! Patient concerns:
  
  • Cost
  • Adverse events
  • Personal meaning ascribed to use of medications

Treatment Phase in Psychopharmacology

Question 4

Treatment Phases

Treatment Phase in Psychopharmacology

Answer 4

Acute>Continued>Maintenance

Treatment Phase in Psychopharmacology

Question 5

Drug Actions

Psychopharmacological Definitions

Answer 5

• Specific molecular changes produced when an molecule binds to a target site or receptor. Examples:
  
  • Gene expression
  • Receptor sensitivity
  • Receptor desensitization
  • Receptor blockage (antagonism)
  • Receptor facilitation (agonism)

Psychopharmacological Definitions

Question 6

Drug Effects

Psychopharmacological Definitions

Answer 6

• Physiological and behavioral changes as a result of drug actions. Examples:
  
  • Improved mood
  • Decreased cravings
  • Induced sleep

Psychopharmacological Definitions

Question 7

Drugs may produce both intended and unintended effects:

Psychopharmacological Definitions

Answer 7

• Adverse events (what used to be called side-effects, public still uses this term, but it has fallen out of use in the scientific community):
  
  • Unintended effects of drug-receptor interaction
  • Adverse events occur because drugs interact with receptors throughout the brain and body
  • The more receptors a drug interacts with, the more likely adverse events will occur

Psychopharmacological Definitions

Question 8

There can also be nonspecific effects:

Psychopharmacological Definitions

Answer 8

• Characteristics unique to the individual that effect reaction to a drug, may include:
  
  • Drug experience (tolerance)
  • Expectations: Changes in behaviors or physiological functioning that are not medication induced…think gluten diets (for people who don’t have gluten conditions, such as celiac disease)!
  • Feeling immediate reaction to drug, when this is counter to known drug-receptor functioning
  • Results because the drug is introduced into a particular neurochemical state at a particular time…state-dependent learning!

Psychopharmacological Definitions

Question 9

Efficacy

Psychopharmacological Definitions

Answer 9

A treatment has evidence of producing a treatment response or remission

Psychopharmacological Definitions

Question 10

Effectiveness

Psychopharmacological Definitions

Answer 10

How well a treatment works in the “real” world or with the end
consumer

Psychopharmacological Definitions

Question 11

Off-label use

Psychopharmacological Definitions

Answer 11

• Use of a drug in a manner that is NOT what the drug is approved for by the federal Food and Drug Administration
  
  • This is a common practice in medicine AND psychiatry
  • This practice is not illegal, as many people assume
  • Usually, a drug’s known adverse-event(s) are used to address a symptoms a patient is experience
  • For example, some drugs used for depression or schizophrenia are sedating, so these medications are prescribed to facilitate sleep but not address depression or psychosis
  • A prescribing professional may have trouble if he/she uses a drug in an off-label way that other prescribing professionals consider reckless or dangerous. This could result in a law suit for malpractice

Psychopharmacological Definitions

Question 12

Randomized Controlled Trial (RCT)

Food and Drug Administration and Drug Approval

Answer 12

The preferred study for establishing efficacy (evidence that a treatment works).

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Question 13

What elements are in a Randomized Controlled trial, or RCT?

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Answer 13

• Random assignment of participants to two or more groups
• Control group: Participants receive placebo or sham therapy
• Experimental group: Participants receive active medication or therapy
• Double blind: Both participants and experimenters are unaware if the participant is in the experimental or control group

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Question 14

Control Group

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Answer 14

Participants receive placebo or sham therapy

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Question 15

Experimental Group

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Answer 15

Participants receive active medication or therapy

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Question 16

Double Blind

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Answer 16

• Both participants and experimenters are unaware if the participant is in the experimental or control group

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Question 17

Most research with humans in determining usefulness of medication requires the use of?

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Answer 17

double blind randomized controlled clinical trials

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Question 18

Most research with humans in determining usefulness of medication requires the use of double blind randomized controlled clinical trials:

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Answer 18

• Participants are measured pre, post, and at follow-up on prominent symptoms and adverse-events
  
  • Just a word on this….usually in a drug trial if a participant complains of a change in functioning, the research is required to record that change in functioning. HOWEVER, that change in functioning may not be due to the drug…it could have resulted from a virus, other illness, or the patient’s expectations

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Question 19

Comparisons are…

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Answer 19

between groups and between baseline and endpoint

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Question 20

RCTs are considered the GOLD STANDARD, but have issues:

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Answer 20

• Participants are not similar to those encountered in everyday practice…oftentimes participants are screened out for medical/psychiatric conditions resulting in the research participants being a very unique group of individuals who have limited symptoms or severity (no psychiatric or medical comorbidity)
• Placebo response is around 30% while medication response is around 50%-may not be a large enough difference to demonstrate a medication has efficacy statistically
• Placebo may work well because of expectancies, that is a patient expects to get better and therefore does
• Researchers now using double blind placebo run in period in which a placebo is given, but neither the physician or participant knows when it may be given
  
  • Using this strategy, placebo responders may be dropped from the study

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Question 21

RCTs are considered the…

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Answer 21

GOLD STANDARD

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Question 22

Open Label Studies:

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Answer 22

• Patients and researchers are aware of medication status
  
  • Usually does not include control group
  • Usually considered a “pilot” study of medication for symptoms or people
    (e.g., older adults, children) not considered included in initial RCTs

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Question 23

Continuation Studies:

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Answer 23

• Patients in a drug trial continue to be followed longitudinally and receive open label medication
  
  • Problem is dealing with expectancies
  • Provides data on the long term use of medications

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Question 24

Head to Head Studies:

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Answer 24

• Two medications are compared to each other in terms of efficacy, time of onset, and side-effects
  
  • Can be blinded or open label
  • Need more of these! But drug companies reluctant to have done because they don’t want their molecule to not be seen as less efficacious

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Question 25

Why should you pay careful attention to criteria used to judge efficacy?

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Answer 25

It may influence judgment regarding usefulness of a drug

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Question 26

Response and Remission

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Answer 26

Two common endpoints used in psychopharmacological research.

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Question 27

Response

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Answer 27

50% reduction in symptoms from baseline on some measure

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Question 28

Remission

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Answer 28

• Extremely decreased score on some measure compared to baseline.
• Usually, patients would be considered to be asymptomatic. Example:
  
  • Rush et al. (2006) defined remission as a score of 0-5 on the QIDS-SR-16, which ranges in score from 0-27 using a 0-3 response scale

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Question 29

How many steps are in the “Drug Development Process” with the FDA?

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Answer 29

Five

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Question 30

What is the first step of the “Drug Development Process”?

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Answer 30

Discovery and Development

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Question 31

What is the process of Step 1: Discovery and Development?

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Answer 31

Discovery
Typically, researchers discover new drugs through:
* New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease.
* Many tests of molecular compounds to find possible beneficial effects against any of a large number of diseases.
* Existing treatments that have unanticipated effects.
* New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material.

At this stage in the process, thousands of compounds may be potential candidates for development as a medical treatment. After early testing, however, only a small number of compounds look promising and call for further study.

Development
Once researchers identify a promising compound for development, they conduct experiments to gather information on:
* How it is absorbed, distributed, metabolized, and excreted.
* Its potential benefits and mechanisms of action.
* The best dosage.
* The best way to give the drug (such as by mouth or injection).
* Side effects or adverse events that can often be referred to as toxicity.
* How it affects different groups of people (such as by gender, race, or ethnicity) differently.
* How it interacts with other drugs and treatments.
* Its effectiveness as compared with similar drugs.

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Question 32

What is the second step of the “Drug Development Process”?

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Answer 32

Preclinical Research

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Question 33

What is the process of Step 2: Preclinical Research?

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Answer 33

Before testing a drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity. The two types of preclinical research are:
* In Vitro
* In Vivo

FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for preclinical laboratory studies. The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies. These regulations set the minimum basic requirements for:
* study conduct
* personnel
* facilities
* equipment
* written protocols
* operating procedures
* study reports
* and a system of quality assurance oversight for each study to help assure the safety of FDA-regulated product

Usually, preclinical studies are not very large. However, these studies must provide detailed information on dosing and toxicity levels. After preclinical testing, researchers review their findings and decide whether the drug should be tested in people.

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Question 34

What is the third step of the “Drug Development Process”?

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Answer 34

Clinical Research

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Question 35

What is the process of Step 3: Clinical Research?

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Answer 35

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or trials, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins.

This step is comprised of the following:
* Designing Clinical Trials
* Clinical Research Phase Studies
* The Investigational New Drug Process
* Asking for FDA Assistance
* FDA IND Review Team
* Approval

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Question 36

Step 3: Clinical Research
Designing Clinical Trials

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Answer 36

Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol, that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide:
* Who qualifies to participate (selection criteria)
* How many people will be part of the study
* How long the study will last
* Whether there will be a control group and other ways to limit research bias
* How the drug will be given to patients and at what dosage
* What assessments will be conducted, when, and what data will be collected
* How the data will be reviewed and analyzed

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.

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Question 37

Step 3: Clinical Research
What are the Clinical Trial Phases?

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Answer 37

Clinical trials are research studies that involve people. Most clinical trials to test new cancer treatments are done in a series of steps, called phases.
If a new treatment is successful in one phase it moves to the next phase. Let’s take a look at the three main phases of clinical trials.
* Phase 1 trials are small enrolling less than thirty patients. Phase 1 trials are designed to find a safe dose of the new treatment, determine how the treatment should be
given, and learn how it affects the body. If a safe doses found the new treatment goes to phase 2 testing.
* More patients are enrolled, usually 100 or less. Phase 2 trials study have the treatment effects the body, and how the treatment works for a certain type of cancer. If a new treatment is found to be safe and have some benefit, it goes to phase 3.
* This is when many participants are needed, usually more than 100 and sometimes thousands. Phase 3 trials compared the new treatment with the current treatment to see which one is better.
One thing is certain with any phase trial, by taking part you will help future patients by helping today’s scientists learn more about cancer.

For more information about clinical trials, including their possible risks and benefits for you go, to cancer.gov/clinicaltrials

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Question 38

Step 3: Clinical Research
Clinical Research Phase Studies:
Phase One

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Answer 38

Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.
Length of Study: Several months
Purpose: Safety and dosage

During Phase 1 studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers or people with the disease/condition participate in Phase 1. However, if a new drug is intended for use in cancer patients, researchers conduct Phase 1 studies in patients with that type of cancer.

Phase 1 studies are closely monitored and gather information about how a drug interacts with the human body. Researchers adjust dosing schemes based on animal data to find out how much of a drug the body can tolerate and what its acute side effects are.

As a Phase 1 trial continues, researchers answer research questions related to how it works in the body, the side effects associated with increased dosage, and early information about how effective it is to determine how best to administer the drug to limit risks and maximize possible benefits. This is important to the design of Phase 2 studies.

Approximately 70% of drugs move to the next phase

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Question 39

Step 3: Clinical Research
Clinical Research Phase Studies: Phase Two

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Answer 39

Study Participants: Up to several hundred people with the disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy and side effects

In Phase 2 studies, researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed. Typically involving a few hundred patients, these studies aren’t large enough to show whether the drug will be beneficial.

Instead, Phase 2 studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods, and design new Phase 3 research protocols.

Approximately 33% of drugs move to the next phase

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Question 40

Step 3: Clinical Research
Clinical Research Phase Studies: Phase Three

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Answer 40

Study Participants: 300 to 3,000 volunteers who have the disease or condition
Length of Study: 1 to 4 years
Purpose: Efficacy and monitoring of adverse reactions

Researchers design Phase 3 studies to demonstrate whether or not a product offers a treatment benefit to a specific population. Sometimes known as pivotal studies, these studies involve 300 to 3,000 participants.

Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side effects might have gone undetected. Because these studies are larger and longer in duration, the results are more likely to show long-term or rare side effects

Approximately 25-30% of drugs move to the next phase

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Question 41

Step 3: Clinical Research
Clinical Research Phase Studies:
Phase Four

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Answer 41

Study Participants: Several thousand volunteers who have the disease/condition
Purpose: Safety and efficacy

Phase 4 trials are carried out once the drug or device has been approved by FDA during the Post-Market Safety Monitoring

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Question 42

Step 3: Clinical Research
The Investigational New Drug Process

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Answer 42

Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research. In the IND application, developers must include:
* Animal study data and toxicity (side effects that cause great harm) data
* Manufacturing information
* Clinical protocols (study plans) for studies to be conducted
* Data from any prior human research
* Information about the investigator

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Question 43

Step 3: Clinical Research
Asking for FDA Assistance

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Answer 43

Drug developers are free to ask for help from FDA at any point in the drug development process, including:
* Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research
* After Phase 2, to obtain guidance on the design of large Phase 3 studies
* Any time during the process, to obtain an assessment of the IND application

Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet Federal standards, FDA allows wide latitude in clinical trial design.

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Question 44

Step 3: Clinical Research
FDA IND Review Team

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Answer 44

The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities.
* Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor.
* Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete.
* Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data.
* Pharmacologist: Reviews preclinical studies.
* Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes. Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules.
* Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc.
* Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes.

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Question 45

Step 3: Clinical Research
Approval

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Answer 45

The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials. FDA responds to IND applications in one of two ways:
* Approval to begin clinical trials.
* Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including:
* Participants are exposed to unreasonable or significant risk.
* Investigators are not qualified.
* Materials for the volunteer participants are misleading.
* The IND application does not include enough information about the trial’s risks.

A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In most cases, if FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the proposed study.

The developer is responsible for informing the review team about new protocols, as well as serious side effects seen during the trial. This information ensures that the team can monitor the trials carefully for signs of any problems. After the trial ends, researchers must submit study reports.

This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials.

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Question 46

What is the fourth step of the “Drug Development Process”?

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Answer 46

FDA Drug Review

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Question 47

Step 4: FDA Drug Review

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Answer 47

If a drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file an application to market the drug. The FDA review team thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve it.
Find out how the FDA is Speeding Up the Approval Process.

New Drug Application

A New Drug Application (NDA) tells the full story of a drug. Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied.

A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include:
* Proposed labeling
* Safety updates
* Drug abuse information
* Patent information
* Any data from studies that may have been conducted outside the United States
* Institutional review board compliance information
* Directions for use

FDA Review

Once FDA receives an NDA, the review team decides if it is complete. If it is not complete, the review team can refuse to file the NDA. If it is complete, the review team has 6 to 10 months to make a decision on whether to approve the drug. The process includes the following:
* Each member of the review team conducts a full review of his or her section of the application. For example, the medical officer and the statistician review clinical data, while a pharmacologist reviews the data from animal studies. Within each technical discipline represented on the team, there is also a supervisory review.
* FDA inspectors travel to clinical study sites to conduct a routine inspection. The Agency looks for evidence of fabrication, manipulation, or withholding of data.
* The project manager assembles all individual reviews and other documents, such as the inspection report, into an “action package.” This document becomes the record for FDA review. The review team issues a recommendation, and a senior FDA official makes a decision.

FDA Approval

In cases where FDA determines that a drug has been shown to be safe and effective for its intended use, it is then necessary to work with the applicant to develop and refine prescribing information. This is referred to as “labeling.” Labeling accurately and objectively describes the basis for approval and how best to use the drug.

Often, though, remaining issues need to be resolved before the drug can be approved for marketing. Sometimes FDA requires the developer to address questions based on existing data. In other cases, FDA requires additional studies. At this point, the developer can decide whether or not to continue further development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal.

FDA Advisory Committees

Often, the NDA contains sufficient data for FDA to determine the safety and effectiveness of a drug. Sometimes, though, questions arise that require additional consideration. In these cases, FDA may organize a meeting of one of its Advisory Committees to get independent, expert advice and to permit the public to make comments. These Advisory Committees include a Patient Representative that provides input from the patient perspective. Learn more about FDA Advisory Committees.

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Question 48

What is the fifth step of the “Drug Development Process”?

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Answer 48

FDA Post-Market Drug Safety Monitoring

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Question 49

Step 5: FDA Post-Market Drug Safety Monitoring