Biotech Values

[bob smith]

http://people.musc.edu/~cooperjc/FDAapproval.htm


The FDA Approval Process

Lecturer: Jason C. Cooper, Pharm. D.
Assistant Professor
Clinical Specialist, Drug Information



Goals: To have a basic understanding of how the FDA reviews and approves prescription drugs.

Objectives: Following this discussion the student should be able to:

1) Recognize and understand the differences between an IND, NDA, and an ANDA.

2) Know the difference between Phase I, II, III, and IV trials.

3) Be familiar with the classification system of and designators given to prescription medications undergoing FDA approval.

4) Describe the overall process for drug approval by the FDA.

5) Be familiar with the average time frame for the drug approval process (e.g., from synthesis to marketing; FDA approval after NDA submission; Phase I, II, and III trials)

6) Describe and define mechanisms the FDA has in place for increased and/or faster accessibility of experimental drugs to patients.





















The FDA Approval Process


I. History of Drug Regulation in the US

A. 1906 - Pure Food and Drugs Act - Required that drugs not be mislabeled (having to do with the composition of the drug) or adulterated. Must meet standards for strength and purity.

B. 1912 - Sherley Amendment - Prohibits false therapeutic claims of medications.

C. 1938 - Food, Drug, and Cosmetic Act - Required the manufacturer to prove safety of their product before the drug could be marketed. This law was passed in response to 107 people dying after taking the drug sulfanilamide in 1937.

D. 1962- Kefauver-Harris Drug Amendment - Required manufacturer to demonstrate efficacy and safety before marketing any new drug. Also required manufacturers to operate under current good manufacturing practices (CGMP) and stated that the FDA had to formally approve an NDA before marketing of a drug. This law was passed in response to several women in Western Europe giving birth to deformed babies after taking the drug thalidomide.

E. 1983 - Orphan Drug Act - Provided tax incentives and exclusive marketing rights for drugs used to treat rare diseases.

F. 1984 - Drug Price Competition and Patent Restoration Act - Expanded the number of drugs suitable for abbreviated new drug applications (ANDAs). Allows for restoration of patent time for time lost in the FDA approval process.


II. Current FDA Drug Classification Scheme

A. Classification by Chemical Type

Type 1 - New molecular entity not marketed in the US
Type 2 - New salt, ester, or other derivative of another drug marketed in US
Type 3 - New formulation of a drug marketed in the US
Type 4 - New combination of drugs already marketed in US
Type 5 - New manufacturer of a drug product already marketed by another company
Type 6 - New indication for a product already marketed

B. Classification by Therapeutic Potential

P - Priority, Therapeutic Gain
S - Standard

C. FDA Supplementary Designators

AA - Drug used for AIDS or complication of that disease
E - Drug used for a life threatening or severely debilitating illness
F - Drug under review for fraud policy: validity of data submitted being assessed
G - Drug originally given type F designation, but now has new validation
N - Product with nonprescription marketing for some indication
V - Orphan Drug

III. Drug Approval Process

A. Investigational New Drug (IND)

1. Filed after preclinical testing is done in animals.
2. Sponsor must have the following before submission:

a. Pharmacologic profile of drug
b. Acute toxicity data (done in at least two species of animals)
c. Short-term toxicity data (2 weeks to 3 months)

3. IND is forwarded to one of nine divisions based on the therapeutic classification of the drug
4. FDA has 30 days to review IND

B. Phase I (after approval of the IND)

1. Clinical pharmacology studies
2. Done in 20 - 80 patients
3. Last an average of 6 months to 1 year
4. Purpose: Determine basic safety and pharmacological information

C. Phase II

1. Controlled studies in patients having the specific disease or condition that the drug is supposed to treat.
2. Involve 100 -200 patients
3. Average 2 years in duration
4. Purpose: Determine efficacy

D. Phase III

1. Multicenter, controlled and open trials
2. Involve 600-1000 patients
3. Average of 3 years in duration
4. “Pivotal studies” are usually Phase III trials that get the drug approved by the FDA
5. Purpose: Establishes safety and efficacy

E. NDA (New Drug Application)

1. NDA includes the following:

a. Preclinical data
b. Clinical data (Phase I, II, and III)
c. Manufacturing methods
d. Product quality assurance information
e. Relevant foreign market experience or testing
f. All published reports of experience with the drug
g. A proposed package insert

2. NDA is submitted to one of nine divisions for review
3. NDA is assigned a classification rating and number (this will determine the speed at which the FDA reviews the NDA)
4. Average time for FDA approval: 24 months (range 2 months to 7 years)


Note: An abbreviated new drug application (ANDA) may be submitted for generic products. Phase I, II, and III data are not required, but proven bioequivalence to the brand-name product is required.

F. Phase IV (Post-marketing surveillance)

1. Conducted based on the approved indication
2. May evaluate the following:

a. New doses
b. Effects of extended therapy
c. Safety in patient populations not represented in previous clinical trials

3. May be conducted to expand the indications for the drug

Average time from synthesis to approval = 100 months

Follow this link to FDA's Web Page on the Drug Approval Process
(Print off image of FDA's Drug Approval Process for class)
IV. Increased Accessibility of Experimental Drugs to Patients

A. Parallel track - Drugs may be made available after the completion of Phase I trials to patients who are ineligible for enrollment in the clinical trials and are unable to benefit from current therapies. Developed by US Public Health Service in response to the HIV virus.

B. Treatment IND - Allows the investigator to provide the drug to patients with life-threatening diseases for which there is no satisfactory alternative therapy available.

1. Must meet the following criteria:

a. The drug must be intended to treat a serious or immediately life-threatening disease.
b. There must be no satisfactory alternate therapy for the patient.
c. The drug must be under investigation in controlled clinical trials (usually Phase III).
d. The sponsor must be actively pursuing FDA approval of the drug.

2. Does not allow for use of medications earlier than Phase II.

C. Individual Investigator INDs (Compassionate INDs) - Allow the release of a drug for use on a single patient basis. Both FDA and IRB (Institutional Review Board) approval are required.

1. May be obtained for a marketed drug to be used for a new indication.
2. May be easier to obtain drug than filing for a treatment IND or using the parallel track method.

D. Emergency INDs - Allow shipment of a drug by the sponsor prior to the submission of an IND. The emergency IND is intended for use in a patient with a life-threatening disease, where all other options have been exhausted.

1. FDA must approve emergency IND.
2. FDA may approve emergency IND over the phone, but the sponsor must then fill out the formal application as soon as possible.

E. Expedited Review (Accelerated Approval Process)- Designed to get the new product to the open market more quickly.

1. May reduce the time for approval from synthesis to marketing to 3 to 4 years. (Average time is about 8 to 9 years)
2. Done often with new AIDS drugs
3. Surrogate endpoints (e.g., CD4+ counts) are used to determine efficacy
4. “Telescoped” trials - Involve the enrollment of larger patient populations in Phase I and II trials, often eliminating the need for Phase III trials.
5. Concern regarding release of ineffective or unsafe therapies to the public.


V. Resources for Locating Recently Approved Drugs or Those Currently in Clinical Trials

A. FD&C Reports (The Pink Sheets)
B. NDA Pipeline
C. FDA Homepage (www.fda.gov)
D. Doctor’s Guide to the Internet (www.pslgroup.com)