International Nonproprietary Names (INN)

Subpart D—Exemptions From Adequate Directions for Use

A device which, because of any potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use is not safe except under the supervision of a practitioner licensed by law to direct the use of such device, and hence for which «adequate directions for use» cannot be prepared, shall be exempt from section 502(f)(1) of the act if all the following conditions are met:

(a) The device is:

(1)(i) In the possession of a person, or his agents or employees, regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of such device; or

(ii) In the possession of a practitioner, such as physicians, dentists, and veterinarians, licensed by law to use or order the use of such device; and

(2) Is to be sold only to or on the prescription or other order of such practitioner for use in the course of his professional practice.

(b) The label of the device, other than surgical instruments, bears:

(1) The symbol statement «Rx only» or «[rx] only» or the statement «Caution: Federal law restricts this device to sale by or on the order of a ___», the blank to be filled with the word «physician», «dentist», «veterinarian», or with the descriptive designation of any other practitioner licensed by the law of the State in which the practitioner practices to use or order the use of the device; and

(2) The method of its application or use.

(c) Labeling on or within the package from which the device is to be dispensed bears information for use, including indications, effects, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the device can use the device safely and for the purpose for which it is intended, including all purposes for which it is advertised or represented: Provided, however, That such information may be omitted from the dispensing package if, but only if, the article is a device for which directions, hazards, warnings, and other information are commonly known to practitioners licensed by law to use the device. Upon written request, stating reasonable grounds therefor, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso.

(d) Any labeling, as defined in section 201(m) of the act, whether or not it is on or within a package from which the device is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the device, that furnishes or purports to furnish information for use of the device contains adequate information for such use, including indications, effects, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to employ the device can use the device safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented. This information will not be required on so-called reminder—piece labeling which calls attention to the name of the device but does not include indications or other use information.

(e) All labeling, except labels and cartons, bearing information for use of the device also bears the date of the issuance or the date of the latest revision of such labeling.

www.accessdata.fda.gov

ELIMINATION KINETICS

Definition Zero-order elimination kinetics : «Elimination of a constant quantity per time unit of the drug quantity present in the organism.»

Definition First order elimination kinetics : «Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration.»

Fig. 1. Zero-order kinetics

Fig. 2. First-order kinetics (linear y-axis)

Fig. 3. First-order kinetics (log y-axis)

Description

Zero-order elimination kinetics :

The plasma concentration – time profile during the elimination phase is linear (Fig. 1). For example 1.2 mg are eliminated every hour, independently of the drug concentration in the body.

Order 0 elimination is rather rare, mostly occurring when the elimination system is saturated. An example is the elimination of Ethanol.

First-order elimination kinetics :

For first order elimination, the plasma concentration – time profile during the elimination phase shows an exponential decrease in the plot with linear axes (Fig. 2.) and is linear if plotted on a semi-logarithmic plot (plasma concentration on logarithmic axis and time on linear axis; Fig. 3.).

For example, 1% of the drug quantity is eliminated per minute. Many drugs are eliminated by first order kinetics.

The time course of the decrease of the drug concentration in the plasma can be described by an exponential equation of the form:

C = drug concentration

C(0) = extrapolated initial drug concentration (see Volume of distribution)

λ = elimination rate constant (see Half-life)

The elimination rate constant λ can be calculated by fitting the data points during the elimination phase to a single exponential; yielding in this example a λ of 0.34 h -1 . An alternative method (see Fig. 3.) consists in plotting the logarithm of the drug plasma concentration as a function of time, which will yield a straight line. The steepness of this line equals –λ.

Clinical Implications

In clinical pharmacology, first order kinetics are considered as a « linear process », because the rate of elimination is proportional to the drug concentration. This means that the higher the drug concentration, the higher its elimination rate. In other words, the elimination processes are not saturated and can adapt to the needs of the body, to reduce accumulation of the drug.

95% of the drugs in use at therapeutic concentrations are eliminated by first order elimination kinetics.

A few substances are eliminated by zero-order elimination kinetics, because their elimination process is saturated. Examples are Ethanol, Phenytoin, Salicylates, Cisplatin, Fluoxetin, Omeprazol.

Because in a saturated process the elimination rate is no longer proportional to the drug concentration but decreasing at higher concentrations, zero-order kinetics are also called “non-linear kinetics” in clinical pharmacology.

sepia.unil.ch

2019 Suggested Inhaler Sequence

BOLD ALL CAPS indicate BRAND NAMES

• long–acting beta–agonist = LABA
• short–acting, anticholinergic (muscarinic) = SAMA

Clear boxes in the chart indicate “short–acting” medications:

• short–acting beta–agonist = SABA
• short–acting anticholinergic (muscarinic) = SAMA

Suggested Sequence of Administration

1.) Take short–acting drugs at least 2 hours before long–acting drugs in the same class to avoid interfering with the long–acting drug’s action.

2.) If you MUST take the short acting medications FIRST, ALWAYS wait at least 2 hours before taking any long–acting medications! If SABA is used on a regular scheduled basis, always take it after the LABA, and never less than 2 hours before it.

If you MUST take the SABA agonist before taking the LABA, wait at least 2 hours before taking the LABA after taking the SABA!

3.) If you must use a SABA on a rescue basis, wait at least 2 hours before taking your next dose of LABA.

4.) If you use a SAMA in addition to your LAMA, ALWAYS take it after the LAMA and never less than 2 hours before the LAMA.

Updated October 28, 2016 Noah Greenspan, DPT, CCS, EMT–B & Mark W Mangus (updated 4/27/17), Sr, BSRC, RRT, RPFT, FAARC

Page last updated January 2, 2019 O₂ Text & Images © 2001–2019, EFFORTS O₂ Privacy Policy O₂ Emphysema Foundation For Our Right To Survive

emphysema.net

FDA Drug Approval Process

Medically reviewed by Leigh Ann Anderson, PharmD Last updated on Apr 13, 2020.

Steps from Test Tube to New Drug Application Review

FDA Approval Process

The U.S. Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) is a science-led organization in charge of overseeing the drug approval process before a drug is marketed. CDER ensures that both brand and generic drugs work correctly and that the health benefits outweigh the known risks. They review each drug closely using an independent team of clinicians and scientists who evaluate safety, efficacy and labeling of the drug product. After approval, FDA follow-up continues to make sure new drugs continue to be safe and effective.

It takes over $2.6 billion for a manufacturer to get a new drug from the laboratory onto the pharmacy shelf, according to the Tufts Center for the Study of Drug Development. The full research, development and approval process can last from 12 to 15 years. What happens during this time period to be sure that the drug you pick up at the pharmacy is safe and effective?

Investigational New Drug (IND) Application

In the manufacturer’s early phases of drug discovery (preclinical research) they are synthesizing and screening a drug candidate for toxicity in animals before the medicine moves on to human trials. The sponsor files an Investigational New Drug (IND) Application that details specifics such as chemistry, manufacturing and the initial plans for human testing.

The IND is reviewed by the FDA to ensure that clinical trials will be safe for humans and that adequate informed consent is included to protect humans subjects.

Once a company develops a drug, it undergoes several years of laboratory testing before a New Drug Application (NDA) is made to the FDA to begin testing the drug in humans. Only one in 1000 of the compounds that enter laboratory testing will ever make it to human testing.

Phases of Human Testing for Investigational Drugs

If the FDA gives the green light, the investigational drug will then enter three phases of clinical trials:

• Phase 1: About 20 to 80 healthy volunteers to establish a drug’s safety and profile, and takes about 1 year. Safety, metabolism and excretion of the drug are also emphasized.
• Phase 2: Roughly 100 to 300 patient volunteers to assess the drug’s effectiveness in those with a specific condition or disease. This phase runs about 2 years. Groups of similar patients may receive the actual drug compared to a placebo (inactive pill) or other active drug to determine if the drug has an effect. Safety and side effects are reviewed.
• Phase 3: Typically, several thousand patients are monitored in clinics and hospitals to carefully determine effectiveness and identify further side effects. Different types and age ranges of patients are evaluated. The manufacturer may look at different doses as well as the experimental drug in combination with other treatments. This phase runs about about 3 years on average.

New Drug Application (NDA)

For an NDA, the company writes and submits an application which includes thousands of pages to the FDA for review and approval. The NDA is the official request for US approval of a drug. The NDA includes all animal and human data, plus side effects, dosing, and effectiveness. Other information, such as pharmacokinetics (how the drug moves through the body), and specifics of manufacturing are also addressed. The FDA team has 60 days to review the NDA and determine if it will be filed for further review.

Once an NDA is filed, the FDA review the product label (package insert) to be sure the clinical information needed to safely use this drug is outlined. The FDA also takes action to inspect manufacturing plants where the drug will be made.

• PDUFA: Some companies will pay for an expedited review with the FDA through a process known as an PDUFA (Prescription Drug User Fee Act), enacted in 1992. PDUFA allows the FDA to access more resources to quicken the drug approval process. Many important drugs have been approved through PDUFA, including medicines for cancer, AIDS and heart disease.
• Accelerated Approval: The Accelerated approval process began in 1992 to allow promising therapies for serious or life-threatening conditions to come to market more quickly. This method uses a «surrogate endpoint» that predicts a reasonable clinical benefit of the drug. However, standard endpoints must still be proven after a drug is approved under post-marketing clinical trials to prove it’s benefit. If further post-marketing studies fail to verify the predicted clinical outcome, FDA may withdraw approval.

Drugs that may be the first available treatment for an illness or with a significant benefit over existing drugs may receive a special designation:

• Fast Track: Drugs that treat serious medical condition and fill unmet medical needs may receive fast-track designation based on positive human or animal data. This FDA process, requested by the manufacturer, can get new drugs to patients who need them more quickly.
• Breakthrough Therapy: Preliminary clinical research demonstrates that a drug candidate for a serious condition may provide substantial improvement over available therapy. A drug designated for Breakthrough Therapy is also eligible for the Fast Track process. The sponsor must request this designation from the FDA.
• Priority Review: During Priority Review, the FDA takes action on a new drug application within six months, compared to 10 months under standard review. These drugs receive higher priority because they can significantly improve the treatment, diagnosis, or prevention of serious conditions.

FDA Advisory Board

A group of independent physicians and other clinicians, called an FDA Advisory Board, meets to discuss the NDA with the FDA reviewers and manufacturer of the product. These meetings often take one or two days. After the meeting, the Advisory Board will make a recommendation for approval, or not, to the FDA, usually through a vote. The FDA often follows the advice of the Board, but is not obligated to do so. This advisory team includes physicians, pharmacists, chemists, pharmacologists, statisticians, and even patient representatives.

Final Drug Approval

After final approval, the drug becomes available for physicians to prescribe. However, drugs may not come to the market immediately because of patents disputes, manufacturing issues, or controlled substance designation from the DEA. Pricing is usually revealed after approval, but the FDA does not consider drug pricing or economics as part of the FDA approval process. This is in contrast to many other countries that do consider the economic impact of new drugs in their society.

MedWatch: At this stage, the drug company will continue to report cases of adverse reactions and other clinical data to the FDA. Patients and healthcare providers can also report side effects or other concerns through the MedWatch Program run by the FDA. When a new risk of a drug is identified, the FDA will update the product label to inform everyone. MedWatch can be access online or at 1-800-FDA-1088. See up-to-date FDA MedWatch Alerts here.

Phase 4 post-marketing studies may take place in groups of patients who are using the drug in a real-world setting. These studies may identify additional uses, long-term effectiveness, and previously undetected side effects. Rare side effects that occur in fewer than 1 in 5,000 patients are unlikely to be seen in Phase 1 to 3 studies before approval, but groups of patients this large are not usually studied. These rare side effects are more likely to be found when large numbers of patients use a drug after it has been approved and marketed.

Sources

• DiMasi J et al. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics. 2016:47;20-33. https://doi.org/10.1016/j.jhealeco.2016.01.012
• Suvarna V. Phase IV of Drug Development. Perspect Clin Res. 2010;1(2):57–60. PMID: 21829783.
• Development & Approval Process — Drugs. US Food and Drug Administration (FDA). Accessed April 13, 2020 at https://www.fda.gov/drugs/development-approval-process-drugs

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

www.drugs.com

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