Chapter 14

What are the four possible certification for an ANDA or 505(b)(2)

Paragraph III certification: if there are patents on the drug and the ANDA applicant does not want to challenge them, the applicant must submit a Paragraph III certification, and the FDA cannot approve the application until the patents have expired. Paragraph II: if the patents have already expired Paragraph I: Patent information has not been filed Paragraph IV: claiming that the patent is invalid or will not be infringed by the manufacture, use or sale of the new drug for which the ANDA is being submitted- (risk of getting sued and if you get sued- 30 month hold on approval by FDA)

Where do you find the regulations for New Drug Product Exclusivity?

The regulations are at 21 CFR 314.108.

. What is the definition of a "new clinical investigation"?

FDA interprets "new clinical investigation" as an investigation in humans, the results of which (1) have not been relied upon by FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any indication or of safety in a new patient population and (2) do not duplicate the results of another investigation relied upon by FDA to demonstrate a previously approved drug's effectiveness or safety in a new patient population. A clinical investigation that provides a "new" basis for approval of an application can qualify for exclusivity. In this context, "new" is intended to convey a lack of prior use of a clinical investigation rather than any temporal requirement.

Do the new drug product exclusivity provisions of the Act provide any protection from the marketing of a duplicate version of the same drug product if the duplicate version is the subject of a full new drug application submitted under 505(b)(1) of the Act?

No, the new drug product exclusivity provisions do not provide any protection under these conditions.

Why is new drug product exclusivity also known as the Hatch/Waxman exclusivity?

On September 24, 1984 the President signed into law the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch/Waxman Amendments). Title 1 of the Hatch/Waxman Amendments amended the Federal Food, Drug, and Cosmetic Act (the Act) to expand the universe of drugs for which FDA would accept ANDAs. The Hatch/Waxman Amendments also provided for New Drug Product Exclusivity and are often referred to as Hatch/Waxman exclusivity since Senator Hatch and Congressman Waxman sponsored the amendments in Congress to encourage research and development, as well as to speed entry of generic drugs into the market.

How long does an applicant holder have to submit patent information?

Patent information is required to be submitted with all new drug applications at the time of submission of the NDA. Patent information is published after approval upon receipt of post approval submitted FDA form 3542. For patents issued after approval of the NDA, the applicant holder has 30 days in which to file the patent to have it considered as a timely filed patent. Patents may still be submitted beyond the 30 day timeframe but the patent is not considered a timely filed patent. ANDA holders are not required to make a certification to an untimely filed patent if the generic application is submitted before the patent.

What is the difference between patents and exclusivity?

Patents and exclusivity work in a similar fashion but are distinctly different from one another. Patents are granted by the patent and trademark office anywhere along the development lifeline of a drug and can encompass a wide range of claims. Exclusivity is exclusive marketing rights granted by the FDA upon approval of a drug and can run concurrently with a patent or not. Exclusivity is a statutory provision and is granted to an NDA applicant if statutory requirements are met. See 21 C.F.R. 314.108. Exclusivity was designed to promote a balance between new drug innovation and generic drug competition.

Why does the exclusivity expire before the patent? Patent before exclusivity? Why does a particular drug product only have patents? Only have exclusivity? Have neither?

Patents can be expired before drug approval, issued after drug approval, and anywhere in between. Exclusivity is granted upon approval of a drug product if the statutory requirements are met. Some drugs have both patent and exclusivity protection while others have just one or none. Patents and exclusivity may or may not run concurrently and may or may not encompass the same claims. Exclusivity is not added to the patent life. Expired patents and exclusivity are not included in the published list.

How long is a patent granted for?

Patents expire 20 years from the date of filing. Many other factors can affect the duration of a patent.

Where can I find patent and exclusivity regulations in the C.F.R.?

See 21 C.F.R. 314.52 Notice of certification of invalidity or noninfringement of a patent. See 21 C.F.R. 314.53 Submission of patent information. See 21 C.F.R. 314.95 Notice of certification of invalidity or noninfringement of a patent. See 21 C .F.R. 314.107 Effective date of approval of a 505(b)(2) application or abbreviated new drug application under section 505(j) of the act. See 21 C.F.R. 314.108 New drug product exclusivity. See 21 C.F.R. 316.31 Scope of orphan-drug exclusive approval. See 21 C.F.R. 316.34 FDA recognition of exclusive approval.

True or False , Once NDA is approved the FDA is required to publish information in the Orange Book?

True

Are there other types of exclusive marketing available?

Yes, there is orphan drug exclusivity, pediatric exclusivity, 180-day generic drug exclusivity, and patent protection (For an explanation of orphan drug exclusivity, pediatric exclusivity, and patent term extension/also referred to as patent term restoration. See the Small Business Assistance: Economic Assistance and Incentives web page.

. What is an abbreviated new drug application (505)(j)?

An abbreviated new drug application is described under section 505(j) of the Act as an application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use, among other things to a previously approved application (the reference listed drug (RLD). ANDAs do not contain clinical studies as required in NDAs but are required to contain information establishing bioequivalence to the RLD. In general, the bioequivalence determination allows the ANDA to rely on the agency's finding of safety and efficacy for the RLD.

9. What is the definition of an "active moiety"?

An active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.

What is the definition of "Conducted or sponsored by the applicant"?

An investigation conducted or sponsored by the applicant means that before or during the investigation, the applicant was named in Form FDA 1571 filed with FDA as the sponsor of the investigational new drug application under which the investigation was conducted, or the applicant or the applicant's predecessor in interest, provided substantial support for the investigation. An applicant who has purchased exclusive rights to a study should be able to obtain new drug product exclusivity. Applicants cannot qualify for exclusivity by simply collecting and submitting to FDA information from the literature or buying the results of tests already done and submitting them to FDA without obtaining exclusive rights for those tests.

Is there a specific format in which patent information needs to be submitted to the agency?

As of August 18, 2003, patent information is required to be submitted on FDA form 3542a or FDA form 3542 depending on the approval status of the application. Form FDA 3542 is the only form that will be used for Orange Book publication

What is the regulatory review period composed of?

Testing phase and Review Phase

Where do you find information on drugs that have received New Drug Product Exclusivity?

The Orange Book & Supplements/Electronic Orange Book, has an addendum with patent and exclusivity information. The Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations,identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act

Why don't I see some antibiotic drugs products listed in the Patent and Exclusivity section of the Orange Book?

Title I of the 1984 Amendments did not apply to drug products submitted or approved under the former Section 507 of the Federal Food, Drug, and Cosmetic Act (antibiotic products). Therefore, (1) holders of approved applications for antibiotic products did not need to submit the patent information required of other NDA application holders, (2) these antibiotic products were not eligible for exclusivity protection, and (3) applicants submitting abbreviated applications for these antibiotic products were not required to provide the patent certification statement that was included in ANDAs. Antibiotics submitted after the effective date of the Food and Drug Administration Modernization Act (FDAMA) are covered or subject to the provisions of Title I. See Guidance for Industry and Reviewers Repeal of Section 507 of the Federal Food, Drug and Cosmetic Act for more information.

Testing Phase for a drug product begins when

effective date of an IND application and ends on the date a NDA is submitted to to the FDA.

Review phase begins and ends when

is the period between the submission and approval of the NDA

Three Year Exclusivity

may qualify for the application (full 505b(1) NDA, 505(b)(2) application or a supplement to either) if the application is for an active moiety that FDA previously approved and if the application contains reports of new clinical investigations( other than bioavailbilty studies) that were essential to approval of the application and that were conducted or sponsored by the applicant.

what is the three year exclusivity referred to as?

new clinical investigation, new use

Five year exclusivity

sometimes called the NCE exclusivity. NCE exclusivity prevents the approval of a generic application for the approved active ingredient or any salt or ester of the approved active ingredient for five years. However 5 year exclusivity does not prevent FDA from approving or a company from submitting a full section 505(b)(1) NDA for the same drug

what happens if the list drug is covered by an Orange Book-listed " method of use patent which does not claim a use for which the ANDA applicant is seeking approval"

the applicant must contain a statement that the method of use patent does not claim such a use aka section viii statement

what does FDA require each NDA sponsor to submit with its application?

the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the NDA or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture use or sale of the drug.

Which two types of patent interim extensions are available?

1. interim patent extensions available during the review phase of the statutory regulatory review period 2. interim patent extensions available during the PTOs review of an application for patent term extensions.

patent extension can occur if the following if

1. term of the patent has not expired 2. the patent has not been previously extended 3. the extension application is submitted by the owner of record within 60 days of the NDA approval 4. the product use, or method of manufacturing claimed has been subject to a regulatory review period before it is commercially marketed and 5. the NDA is the first permitted commercial use of the drug product

What are the time periods of new drug product exclusivity?

A 5-year period of exclusivity is granted to new drug applications for products containing chemical entities never previously approved by FDA either alone or in combination. No 505(b)(2) application or ANDA may be submitted during the 5-year exclusivity period except that such applications may be submitted after 4 years if they contain a certification of patent invalidity or noninfringement. A 3-year period of exclusivity is granted for a drug product that contains an active moiety that has been previously approved, when the application contains reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the sponsor that were essential to approval of the application. For example, the changes in an approved drug product that affect its active ingredient(s), strength, dosage form, route of administration or conditions of use may be granted exclusivity if clinical investigations were essential to approval of the application containing those changes.

What is a full new drug application 505(b)(1)?

A 505(b)(1) application is described by section 505(b)(1) of the act as an application that contains full reports of investigations of safety and effectiveness, in addition to other information. The data in the application is either owned by the applicant or is data for which the applicant has obtained a right of reference.

What is a 505(b)(2) application?

A 505(b)(2) application is one described under section 505(b)(2) of the act as an application for which one or more of the investigations relied upon by the applicant for approval "were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted" (21 U.S.C. 355(b)(2)). This provision expressly permits FDA to rely for approval of an NDA, on data not developed by the applicant such as published literature or the agency's finding of safety and effectiveness of a previously approved drug. 505(b)(2) applications are submitted under section 505(b)(1) of the act and are therefore subject to the same statutory provisions that govern 505(b)(1) applications that require among other things, "full reports" of safety and effectiveness.

What is the definition of a "new chemical entity"?

A new chemical entity means a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the Act.

What is an interim patent extension

A patent that is scheduled to expire before a term extension application can be submitted to the PTO, (e.g if the patent will expire before the NDA is approved) an interim patent extension can be granted.

Patent Extension under Title II of the Hatch Waxman Act

Certain patents related to products regulated by the FDA are eligible for extension if patent life was lost during a period when the product was undergoing regulatory review.

How long can a patent term be extended?

For a period of time that is the sum of one half of the time in testing phase plus all the time in the review phase. The regulatory review period must be reduced by any time that the applicant did not act with due diligence.

. What types of applications can receive 5 year and 3 year periods of exclusivity?

Full new drug applications under 505(b)(1) and 505(b)(2) can receive 5 years of exclusivity for a new chemical entity drug product. A 505(b)(1), 505(b)(2) application or a supplement to a new drug application can receive 3 years of exclusivity.

How long is exclusivity granted for?

It depends on what type of exclusivity is granted. Orphan Drug (ODE) - 7 years New Chemical (NCE)- 5 years "Other" Exclusivity - 3 years for a "change" if criteria are met Pediatric Exclusivity (PED) - 6 months added to existing Patents/Exclusivity Patent Challenge - (PC) - 180 days (this exclusivity is for ANDAs only) See 21 C.F.R. 314.108 New Drug Product Exclusivity.

How is an NDA holder notified if their application is granted exclusivity by the FDA?

No letters are sent to the sponsor indicating the grant of exclusivity. The Orange Book is the official vehicle for dissemination of this information.

Is the original applicant required to conduct the complete study to obtain exclusivity?

No, FDA interprets the Act to allow for exclusivity where the applicant has conducted or sponsored the study by providing 50 percent of the funding or by purchasing exclusive rights to the study.

1. What is new drug product exclusivity?

New Drug Product Exclusivity is provided by the Federal Food, Drug, and Cosmetic Act under section 505(c)(3)(E) and 505(j)(5)(F). Exclusivity provides the holder of an approved new drug application limited protection from new competition in the marketplace for the innovation represented by its approved drug product. This limited protection precludes approval of certain 505(b)(2) applications or certain abbreviated new drug applications (ANDAs) for prescribed periods of time. Some exclusivity provisions also provide protection from competition by delaying the submission of 505(b)(2) applications and ANDAs for certain periods of time. Exclusivity is available for new chemical entities (NCEs), which by definition are innovative, and for significant changes in already approved drug products, such as a new use. New drug product exclusivity includes two categories of exclusivity (described in Q & A #6) both NCE and "other significant changes" exclusivity.

How do you apply for New Drug Product Exclusivity?

There is no requirement to apply. The Center for Drug Research and Evaluation (CDER) makes exclusivity determinations on all relevant applications. There is a procedure in CDER that provides review of all relevant applications, with or without a request from the applicant, for an exclusivity determination.

What are the PED designations on patents and exclusivity as listed in the Orange Book?

When pediatric exclusivity is granted to a drug product, a period of 6 months exclusivity is added to all existing patents and exclusivity on all applications held by the sponsor for that active moiety. Pediatric exclusivity does not stand alone. PED is annotated in the exclusivity column and is linked to exclusivity formerly granted. In the patent column, the patent is shown twice-once with the original patent expiration date and a second time reflecting the six month period of EXCLUSIVITY that links to that particular patent. Related information can be found on the Pediatric Medicine Page and Pediatric FAQ page.

Can the six months of pediatric exclusivity be added to the 5 or 3 years of new drug product exclusivity?

Yes, pediatric exclusivity is the only exclusivity that runs from the end of other exclusivity protection (New Drug Product and Orphan Drug) or patent protection. A six-month pediatric exclusivity that attaches after a patent term is not a patent extension; it is a FDA-enforced exclusivity period that begins at the termination of the patent.

a new clinical investigation is?

an investigation in humans, the results of which have not been relied on by FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any indication or of safety for a new patient population and do not duplicate the results of another investigation that was relied on by the agency to demonstrate effectiveness or safety in a new patient population of a previously approved drug product an investigation is essential to approval of an application if there no other data available that could support approval of the application