Washington University in St. Louis School of Law
January 11-15, 2010 Intersession Course Part II

Biotechnology Law: From Patents to Food-Drug-Planting Approvals

FDA - What Does it Regulate?

The U.S. Food & Drug Administration (FDA) regulates drugs, devices, and other products based on the "intended use" of those products. It is the intended use of the product that governs whether the FDA has regulatory jurisdiction over the product. The intended use is determined primarily by the manufacturer's claims about the product, specifically on the product label

21 C.F.R. §201.128 defines intended use for a drug as the objective intent of the persons legally responsible for labeling the drug

1. Objective intent as expressed by labeling claims, advertising matter, and oral or written statements by legally responsible persons
2. Objective intent provided by circumstances surrounding the distribution of the drug

Drugs:

1. Articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the Untied States, or official National Formulary, or any supplement to any of them;
2. Articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;
3. Articles (other than food) intended to affect the structure or any function of the body of man or other animals; and
4. Articles intended for use as a component of any article specified in (1), (2), or (3) immediately above.

Biologics:

1. A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings

Medical Devices:

1. An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part or accessory, which is:
   1. recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,
   2. intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
   3. intended to affect the structure of any function of the body of man or other animals,
2. and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

Combination Products:

Four types:

1. Two or more regulated components produced as a single entity (drug/device)
2. Two separate products packaged together
3. Office of Combination Products (OCP)
4. Lead Center depends on primary mode of action

Sponsor may submit Request for Designation (RFD) to OCP

Phases of FDA Regulatory Process

Pre-Clinical - In vitro and animal data

Phase 1: First in Man (usually healthy volunteers)

1. 1a safety and tolerability
2. 1b nonclinical absorption, distribution, metabolism and elimination (ADME), dose ranging

Phase 2: Dose finding and target indication identification

1. 2a proof of concept and dosing
2. 2b safety and effectiveness to plan Phase 3

Phase 3: Intended dose and population for duration

1. Sufficiently robust to permit risk/benefit consideration and provide for labeling
2. Two replicate "pivotal" trials; multicenter

Phase 4: Postmarket requirements (PMR) under law or regulations

1. Accelerated approval
2. Pediatric
3. FDAAA
4. Postmarket commitments (PMC) cannot be enforced as a matter of law but are committed to by Sponsor
5. Searchable database to track status/compliance
6. Studies address special populations, additional safety information, drug interactions, etc.
7. Labeling
8. Promotional Claims
9. Records and Reports
10. Manufacturing and Quality Control

The Hatch-Waxman Amendments of 1984

The Hatch-Waxman Amendments represent a compromise between the competing interests of pioneer drug manufacturers and generic drug manufacturers.

1. Provided patent term extensions and non-patent exclusivities for pioneers.
2. Created two abbreviated pathways for subsequent versions of drug products already approved under Section 505 of the FD&C Act.
   1. 505(j) - product same as the referenced product
   2. 505(b)(2) - product similar to the referenced product

Patent Term Extension

The method for calculating the patent term extension is as follows:

1. One half of the time spent during the testing phase, and
2. All of the time spent during the approval phase.

Patent Term Restoration

1. A maximum of 5 years can be restored to the patent.
2. In all cases, the total patent life for the product with the patent extension cannot exceed 14 years from the product's approval date, or in other words, 14 years of potential marketing time. If the patent life of the product after approval has 14 or more years, the product would not be eligible for patent extension.

Non-Patent Exclusivities

1. Five year new chemical entity exclusivity
   1. NCE exclusivity runs from time of NDA approval and bars FDA from accepting for review any application under 505(j) (ANDA) or 505(b)(2) for a drug containing the same active moiety for:
      1. Five years if the application does not contain a paragraph IV certification to a listed patent
      2. Four years if the application contains a paragraph IV certification to a listed patent
2. Three year new clinical studies exclusivity

There are also several non-patent exclusivities that were not created by Hatch-Waxman.

1. Seven year orphan drug exclusivity
   1. Six month pediatric exclusivity 5-Year New Chemical Entity Exclusivity (NCE)
      1. Granted to a drug that contains no active moiety that has been approved by FDA under section 505(b). Active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance
2. 3-Year New Clinical Study Exclusivity (NCE)
   1. Granted to a drug when applications or supplement contains reports of new clinical investigations (not BA studies) conducted or sponsored by applicant and essential for approval.

If new studies are in an NDA, new clinical study exclusivity runs from time of NDA approval and bars FDA from approving, for a period of 3 years, any 505(j) or 505(b)(2) application for the "same conditions of approval."

If new studies are in a supplement, FDA may not approve any 505(j) or 505(b)(2) application for the change approved in the supplement for 3 years from the date the supplement was approved.

Orange Book Listing of Patents and Exclusivities

1. Purpose is to provide notice to generics
2. NDA applicants shall file patents which claim:
   1. An active ingredient
   2. A formulation
   3. A method of using the drug
3. NDA applicants shall also list NCE and New Clinical Study Exclusivity in the Orange Book.

Incentives for Generics

Two Abbreviated Pathways - Hatch-Waxman created two abbreviated pathways for subsequent versions of drug products already approved under Section 505 of the FD&C Act:

1. 505(j) - Applicant submits an Abreviated New Drug Application (ANDA). The drug product is the same as the referenced listed drug product (true generics)
2. 505(b)(2) - Applicant submits a New Drug Application (NDA). The drug product is similar to the referenced listed drug product (paper NDAs)

Controversies:

1. "Authorized Generics"
2. "Agreements to delay Generics" to avoid costly litigation
   Under Monsanto example, if MON's licenses in Europe expire in 2017 for RR1 soybeans, can others enter EU market? No, unless they are licensed

ANDA under Section 505(j)

When patents or other periods of exclusivity expire, manufacturers can apply to the FDA to sell generic versions.

The ANDA process does not require the drug sponsor to repeat costly animal and clinical research on ingredients or dosage forms already approved for safety and effectiveness.

To gain FDA approval, a generic drug must:

1. contain the same active ingredients as the innovator drug (inactive ingredients may vary)
2. be identical in strength, dosage form, and route of administration
3. have the same use indications
4. be bioequivalent
5. meet the same batch requirements for identity, strength, purity, and quality
6. be manufactured under the same strict standards of FDA's good manufacturing practice regulations required for innovator products

180-Day Exclusivity

1. The first applicant to submit a substantially complete ANDA with a paragraph IV certification is entitled to 180 days of market exclusivity upon approval.
2. 30-Month Stays
3. An innovator who sues for patent infringement within 45 days of receiving notice of the paragraph IV certification is entitled to a 30 month stay, i.e., the FDA can't approve an ANDA for 30 months.
4. As originally enacted, innovators could receive multiple 30 month stays.

Entry of Medical Device

1. Premarket Notification (510(k))
2. Premarket Approval (PMA) Application
3. Product Development Protocol (PDP)
4. Humanitarian Device Exemption (HDE)

Exception: Investigational Device Exemption (IDE)

510(K)

1. Standard: The subject device is "substantially equivalent" to an existing legally-marketable "predicate"; typically applicable to Class II devices
   1. Required:
      1. When the device is being introduced into the market for the first time;
      2. Before a significantly modified version of a currently marketed device is distributed; or
      3. When there has been a major change or modification to the intended use of a marketed device.

PMA

1. Most demanding type of device marketing application.
2. Class III Devices
3. Support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury.
4. Standard: the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use.
   1. Data from well-controlled clinical trials are typical of this process.
   2. A pre-approval GMP inspection of the manufacturing facility is generally required.

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