A Critical View
Title I of the Act (Table 1), which addressed drug price competition, specifically authorized Abbreviated New Drug Applications (ANDAs) and prohibited the FDA from asking for more than bioavailability studies for approval. In that regard, this piece of legislation was unique because it tied the hands of a regulatory agency in the area of public health by specifying that the FDA could require bioavailability studies only for ANDAs. In contrast, five-year data exclusivity for new molecular entities (NMEs) provided for a period of exclusivity such that once an NME was approved, a generic version could not be approved for five years (Table 2). The Act also called for a three-year data exclusivity period for supplements requiring clinical trials.
Table 1 Title I: Amendments to the Federal Food, Drug, and Cosmetics Act
1. Generic drug “ANDA” applicants must:
• show the FDA the therapeutic equivalence or bioequiva-lence to the pioneer product.
• show the FDA that manufacturing,processing,and packing facilities and controls meet FFDCA requirements.
• inform the FDA about the patent status of the pioneer product (from data filed earlier by the pioneer), or certify invalidity, non-infringement, or inapplicability of the pio¬neer patent with regard to the ANDA product.
• notify the pioneer NDA holder and patent holder of the ANDA applicant’s grounds for challenging the validity of the pioneer’s patent or the patent’s applicability to the pioneer product upon which the ANDA is based.
2. Generic drug ANDA applicants no longer need to:
• conduct well-controlled clinical safety and efficacy studies to support application for approval of a drug that is identical to the pioneer product.
• show that the generic product is safe if it is identical to the pioneer product (although FDA has authority to deny or withdraw approval of the generic on safety grounds not related to the pioneer product).
• demonstrate that the generic drug is identical to the pio¬neer product, but only if the FDA approves a petition allowing this difference. cialis soft tablets
According to the Act, one of four certifications (now referred to as paragraphs I, II, III, and IV) had to be made upon the filing of ANDAs (see drug and patent listing requirements in Table 3). Manufacturers had to certify:
1. that the drug had not already been patented, or
2. that the patent had already expired, or
3. that the generic drug would not go on the market until the expiration date of the name-brand drug’s patent had passed, or
4. that the patent was not infringed or invalid.
The need for patent certifications arose from the legislative intent:
1. to permit the marketing of generic copies of pioneer products immediately upon the expiration of any relevant patents.
2. to encourage generic companies to challenge innovator patents.
3. to provide a timely, effective mechanism for patent holders to protect their rights in cases of patents alleged to be invalid or not infringed by the generic product.
4. to prohibit FDA’s approval of any ANDA application whose marketing would infringe a valid patent covering the pioneer product until the parties have had a meaningful opportunity to attempt to resolve the problem.
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While the Hatch-Waxman legislation was pending, a major hurdle involved paragraph IV certification. If a generic company said that the patent was invalid or not violated, how long would the FDA need to wait before approving the generic drug for marketing? For much of the debate, that period was 18 months; however, through the work of the research industry, that time period was changed to 30 months. Thus, a 30-month litigation (cooling-off) period exists, so that after a generic company determines that the patent is invalid or not breached, it must notify the patent owner. The patent owner has 45 days in which to file an infringement action and then another 30 months of exclusivity before an ANDA can be approved.
Table 2 Marketing Exclusivity Periods for Innovators of New Drugs (per the Hatch-Waxman Act)
The Hatch-Waxman Act:
1. provides exclusive marketing rights outlined below for “new drugs” (or “new chemical entities”);however,it does not pro¬vide such rights for “new biologicals”
2. prohibits the FDA from approving generic copies of new chemical entities before expiration of the following periods:
• five years + the ANDA review period for post-1984 “new chemical entities” [NCEs]
• up to 2.5 years may be added to the five-year + exclusivity period for post-l984 NCEs to pursue litigation if the patentee promptly files an infringement action
• three years for new indications for post-l984 non-NCEs if supported by new clinical investigations (other than bioavailability studies) essential to approval
• special transitional l0-year exclusivity for NCEs approved during 1982-1984
• special transitional two-year exclusivity for non-NCEs and new indications for NCEs approved during l982-l984 and for “changes” in pre-l982 drugs
Up to 2.5 years may be added to any other specified period for all other drugs and indications to pursue litigation after the generic company gives notice ofANDA filing (whether or not the exclusivity period has expired) if the patentee promptly files an infringement action.
The part of the Hatch-Waxman Act that addresses patent term restoration generally appears in Title 35 of the U.S. Code.
Title II of the Act (Table 4) outlines the preconditions and restrictions for patent extensions. Unfortunately, these are very long, complicated provisions. For the patent term restoration period, a pioneer company receives an extension term equal to one-half the time of the investigational new drug (IND) period (running from the time in which a pioneer company can begin human clinical trials) plus the NDA period (the period during the NDA review). The maximum extension is five years, and the total market exclusivity time cannot exceed 14 years.
Table 3 Drug and Patent Listing Requirements
The drug and patent listing provisions in the Hatch-Waxman Act:
1. require all NDA holders and NDA applicants to file with
• the patent number and expiration date of any effective patents that “claim the drug or a method of using such drug” (but not patents claiming a method of manufacturing)
• notification of claimed periods of market exclusivity for drug products under Title I of the Act
2. require all ANDA applicants to file with the FDA:
• an acceptable bioavailability or bioequivalence study or protocol (where in vivo studies are required)
• a certification for all relevant patents on the approved drug upon which the ANDA filed one of the following:
• no patent information has been filed by the NDA holder, a the patent has expired
• the date on which the patent will expire, or
• the patent filed is invalid or will not be infringed by the manufacture, use or sale of the new drug for which the application is submitted
3. require the FDA to:
• publish and update monthly a list of all marketed drugs approved for safety and effectiveness along with their approval dates. (This publication, The Approved Prescription Drug Product List, is also referred to as the Orange Book.)
• specify in the “List” whether in vitro and/or in vivo bio-equivalence studies are required for approval of the ANDA of each listed drug
• publish patent information and information about periods of market exclusivity for submission or approval of ANDAs for specific products that are required to be supplied by pioneer companies under the Act
• publicly release the safety and efficacy data of approved NDA products after the first ANDA approval
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The length of the exclusivity periods was determined by strictly arbitrary legislative numbers. Pipeline drugs (drugs for which applications were pending when the Act was passed) received two years or less of exclusivity; it was assumed that if they were in a pipeline already, they would be approved in a year or two, so there was no need to give them more time.
Table 4 Title II: Amendments to the Patent and Trademark Act
Patent Term Restoration
1. Drugs, biologicals, food and color additives, and medical devices are eligible for patent term restoration.
2. Key conditions for patent extensions:
• The patent must not have expired before the application for an extension is filed.
• The patent has never been previously extended.
• No other patent has been extended for the same regulatory review period for the product (the applicant can select which patent is to be extended—”product,” “method of use,” or “method of manufacture”).
• The regulatory approval of the product covered by the patent is the first permitted commercial marketing of that product (except for patents claiming a method of manu¬facturing with recombinant DNA technology where the regulatory approval must be the first permitted commer¬cial marketing of the product made by that process).
3. Restrictions on the period of patent extensions:
• The calculated period of patent extension for drugs, bio-logicals, and medical devices shall equal half of the period that the IND or IDE became effective and the NDA, BLA, or PMA/5l0 (k) is filed plus all of the period that elapses between the filing of the NDA, BLA, or PMA/5l0(k) and the FDA approval or licensure of the NDA, BLA, or
• Similar rules for other products are based on half of the length of major health/environmental safety testing period plus the total agency review period.
• A five-year maximum is required for patents issued after September 24, l984,and for patents issued after that date if the regulatory review period began after that date.
• A two-year maximum is required if the patent was issued and the regulatory review period began before September
• All of the foregoing rules are subject to a l4-year cap on the total period between the date of regulatory approval of any product and the date that the product’s extended patent expires.
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Last, the pioneer company must exercise due diligence in order to achieve patent term restoration, or a period of lack of diligence will be subtracted from the equation; that provision has never been used. Thus, the day after the patent is ineffective or has expired, competing generic drugs arrive on the pharmacy shelves and are ready to be dispensed to patients.