Unlocking the Secrets of FDA's Orange Book: An Introduction to … · 2019-04-17 · QFive year exclusivity – for a new chemical entity. QPediatric exclusivity (6 months) QOrphan
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Organization of the Orange Book and how it is maintained;
Therapeutic equivalence codes – what they are and why they are important
Types of patents can be listed and codes associated with those patents;
Market exclusivity codes associated with products.
My goal is that you will leave this web conference with
– a through understanding and appreciation of the FDA's Orange Book
– how to use it to provide high level strategic advice to advance the goals and objectives of your company.
6
66
Hot FDA Topics
Increased focus on drug/device safety– Response to IOM critique– FDA pilot re-evaluation of New Molecular Entity safety – Separate safety center for drug post marketing issues– Strengthen science to improve device safety over product lifecycle
Reauthorization of the Prescription Drug User Fee Act– User fees for ANDAs– Increased resources for drug safety
New proposed legislation– Block authorized generics– Follow on Protein Products
Marketing unapproved new drugs– FDA is trying to clean up the marketplace
Improve export certification programConsolidation of FDA to White Oak campusStrengthen food safety
1313Full New Drug ApplicationSection 505(b)(1) of the FD&C Act
Full reports of investigations demonstrating safety and effectiveness
Components of the drug
Composition of the drug
Full description of the methods, facilities and controls used for the manufacturing processing and packaging of the drug
Samples, as required
Labeling
Patent number and expiration date which claims the drug or method of using the drug
14
1414New Drug ApplicationSection 505(b)(2) of the FD&C Act
An application where the investigations relied upon by the applicant for approval
were not conducted by or for the applicantapplicant has not obtained a right of reference from the person by or for whom the investigations were conducted
Constitution, Art. 1, Section 8: “The Congress shall have the power… to promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries.”
Basic philosophy is to encourage inventors to disclose their inventions to the public in return for the limited right to exclude others from practicing the invention.
24
2424
What is a Patent?
A limited grant from the U.S. government giving the inventor the right to exclude others from making, using, offering to sell, or selling the patented invention in the U.S.
The right to exclude is measured by how the claims of the patent define the invention
“Negative Right”--Not a right to do anything except exclude others from practicing invention for a limited period of time.
Right to exclude others from– Making– Using– Offering for sale– Selling– ImportingInvention in the U.S.
26
2626
Types of PatentsUtility—processes, machines, articles of manufacture, compositions of matter, methods of manufacture, methods of use, business methods
Design—ornamental aspects of an invention
Plant—plants that can be asexually reproduced (except plants that are not tuber-propagated or found in an uncultivated states)—right to exclude others from asexually reproducing the plant or selling or using the plant if it is asexually reproduced
Plant Variety—novel varieties of sexually reproduced plants (Dep’t of Agriculture)
it was up to Congress, not the Courts, to create an exception specifically geared to drug development.
– Soon afterwards, Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984 (“Hatch-Waxman”) which included § 271(e).
– This specifically overruled Roche v. Bolar
– Permitted generic companies to begin product development prior to patent expiration
Act of infringement – the submission of the ANDA
32
3232
35 U.S.C. § 271(e)
“It shall not be an act of infringement to make, use, or sell a patented invention (other than a new animal drug or veterinary biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act ... )) solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use or sale of drugs.”
Patents having only method of making (process patents) claims are not listable in the Orange Book
Proprietors of biological agents unable to list a patent in the Orange Book - may be loath to have a regulatory pathway allowing approval of a generic biologic, based on data they generated
No comparable Orange Book for Biologics at present– List of products approved by CBER– www.fda.gov/cber/products.htm
36
3636
Intellectual Property – Biologics
IP for Biologics
– for some biologics, only “method of making” patent claims are available
– naturally occurring biological agent and its activity (i.e., uses) may be known
– Patentable invention was developing a manufacturing process for commercial scale up
4. Lack of bioequivalence information was a roadblock to generic substitution
5. U.S. Congress Office of Technology Assessment (OTA) 1974 Report on Bioequivalence –recommendation that FDA prepare official list of interchangeable drugs
6. FDA proposed bioavailability/ bioequivalence regulations – June 1975
44
4444
Historical Development of the List (cont.)
7. FDA list of holders of approved drug applications for drugs presenting actual or potential bioequivalence problems (the “Blue Book”) 1976
8. FDA final bioavailability/bioequivalence regulations – 1977
9. FDA agreed to help New York prepare drug substitution Iist (Green Book) – later FDA agrees to help Illinois prepare a similar list (Illinois Formulary)
10. FDA realizes it can't serve individual state needs and prepares first Orange Book in Jan 1979
4. List of drug product that are regulated by the center for biologics evaluation and research (CBER) – these include drugs that are used in processing blood and blood products
5. List of discontinued products6. List of orphan drug designations7. List of drugs that must demonstrate in vivo
bioequivalence only if they fail dissolution
48
4848
Contents of the Orange Book (cont.)
8. Appendices – product listing by
- trade name- generic name- application holder;
List of uniform terms dosage forms and routes of administration
9. List of patent and exclusivity information- Searchable by patent number on line
1. Pharmaceutical Equivalents – same active ingredient(s); dosage form; strength or concentration; and route of administration
2. Pharmaceutical Alternatives – drugs that contain the same therapeutic moiety but are different salts, esters, or complexes of the moiety or are different dosage forms or strengths
3. Therapeutic Equivalents – drugs which an (1) approved by FDA as safe and effective; (2) pharmaceutical equivalents; (3) bioequivalent; (4) adequately labeled; and (5) manufactured in compliance with current good manufacturing practices
50
5050
Important Definitions (Cont.)
4. Bioequivalencea. The rate and extent of absorption of the test drug
are not significantly different from that of the reference product when administered under similar experimental conditions
b. The extent of absorption of the test drug is notsignificantly different from that of the reference product when administered under similar experimental conditions; the difference in rate is intentional, reflected in the labeling, is not essential to the attainment of effective concentrations, and is considered medical insignificant for the drug
Practitioner / User ResponsibilitiesEvaluations of therapeutic equivalence are based upon FDA’s scientific and medical evaluations
Products can be expected to have the equivalent clinical effect and no difference in their potential in adverse effects
Products may vary in shape, scoring configuration, release mechanisms, packaging, excipients (colors, flavors, preservatives) expiration dates and labeling (in certain situations - can exclude items that are are protected by patent/exclusivity)
54
5454
So the last time you went to the pharmacy to pick up a prescription…
Did you get or request a generic version, if it was available??
Drug product list arranged alphabetically by active ingredient; each listing contains:– Dosage form– Route of administration– Product name– Applicant name– Strength– NDA/ANDA number– Approval date for products approved on or after
January 1, 1982– Effective approval date where applicable
56
5656
Definition of Therapeutic Equivalence Codes
Codes which denote therapeutic equivalence ratings assigned by FDA
"A" codes – drug products that FDA considers to be therapeutically equivalent to other pharmaceutically equivalent products
"B" codes – drug products that FDA considers NOT to be therapeutically equivalent to other pharmaceutically equivalent products
AA Products in conventional dosage forms not presenting bioequilvalence problems
AN Solutions and powders for aerosolization
AO Injectable oil solutions
AP Injectable aqueous solutions
AT Topical products
“A” Products for which actual or potential bioequivalence problems have been resolved with adequate in vivo or in vitro evidence supporting bioequivalence are designated as follows:
AB Products meeting necessary bioequivalence requirements
58
5858
Explanation of Therapeutic Equivalence Codes (cont.)
“B” products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence:
These products often have such a problem with specific dosage forms rather than with the active ingredients.
BC Extended-release dosage forms (tablets, capsules, injectables)
BD Active ingredients and dosage forms with documented bioequivalence problems
BE Delayed-release, enteric coated oral dosage forms
BN Products in aerosol-nebulizer drug delivery systems
Explanation of Therapeutic Equivalence Codes (cont.)
BP Active ingredients and dosage forms with potential bioequivalence problems
BR Suppositives or enemas that deliver drugs for systemic absorptions
BS Products having drug-standard deficiencies
BT Topical products with bioequivalence issues
BX Drug products for which the data are insufficient to determine therapeutic equivalence
60
6060
Basis of Therapeutic Equivalence Determinations
1. Drugs products must be approved as both safe and effective
2. They must be pharmaceutical equivalents having identical amounts of active ingredient(s) in the same dosage form and route of administration, and must meet USP or other applicable standards of identity, strength, quality, and purity.
Basis of Therapuetic Equivalence Determinations (cont.)
3. They are bioequivalent in that the drugs do not present a known or potential bioequivalence problem and meet an acceptable in vitro standard; or there is data demonstrating in vivo bioequivalence.
4. The drug products are adequately labeled.
5. The drug products are manufactured in compliance with current good manufacturing practices.
62
6262
Products Rated by FDA as NOT Therapeutically Equivalent
1. Certain applications approved before passage of the Drug Price Competition and Patent Term Restoration Act in 1984
2. Products on the market without FDA approval
3. In the absence of data, FDA is NOT willing nor able to make therapeutic equivalence determinations
At the time of introduction of the first generic version into the market– either just before or at the same time
Brand Pharma entered into a manufacturing and distribution agreement with a generic company
Generic company or subsidiary of the Brand company sells a version of the drug manufactured under the NDA as a “generic” version– Attempt to preempt and capture a share of the generic
market – Sometime stem from out of court patent law suit settlements
68
6868
Examples of Products Marketed by Two Different Manufacturers Under the Same New Drug Application
6969Debate Regarding the Substitution of Generic for Brand Name NTI Drug Products
Is an FDA approved generic version of an NTI drug readily substitutable for the brand name drug?Should NTI drugs be subject to stricter bioequivalence standards?What about NTI drugs that have not gone through the FDA approval process?
70
7070
When I was in pharmacy school, I was taught the following products could present issues when switching patients from one company’s product to another…
– Amends section 351 of the PHS Act to authorize FDA to approve abbreviated applications for biological products that are “comparable” to previously approved (“reference”) biological products.
– A comparable biological product application must demonstrate that:
there are no clinically meaningful differences between the two products; the new product shares the “principal molecular structural features” of the reference product and the same mechanism(s) of action, if known.
– FDA has discretion on a case-by-case basis to determine what studies are necessary to establish comparability, and may require a clinical study or studies, but only if necessary.
– A comparable biological product application will be subject to user fees.
74
7474
Summary of ALSMA Provisions
– An applicant for a comparable biological product may elect, but is not required, to establish interchangeability.
tax credits for the cost of studies demonstrating interchangeabilitygrants the first applicant to obtain approval of an interchangeable version of a biological product a period of exclusive marketing during which no other interchangeable version of the product may be approved.
– Applicants for comparable biological products may elect to ask the holder of the reference product:
for a list of patents on the product;and may elect to notify the reference product holder and owner of one or more of the patents identified that the applicant has filed a comparable biological product application.If the applicant sends a notice, it must contain a detailed statement explaining why the identified patent(s) is invalid, unenforceable, or not infringed.If the reference product holder fails to disclose a relevant patent, it may not enforce that patent against that applicant.If no patent infringement action is brought within 45 days of notice of a
challenge, the remedy in any later action to enforce that patent against that applicant is limited to a reasonable royalty.
A biological product is “comparable” to a previously approved (“reference”) biological product if there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product, based on non-clinical studies and clinical studies, as necessary.
An “interchangeable product” is a product that can be expected to produce the same clinical result(s) as the reference product in any given patient.
76
7676Submission of Comparable Biological Product Applications.
– An abbreviated application for a comparable biological product to must contain information showing that, among other things:
the product is comparable to the reference product; the two products have comparable principal structural features; the two products have the same mechanism of action, if known; the proposed product label carries one or more of the approved indications for the reference product; and the route of administration, dosage form, and strength, are the same as the reference product.
– Can submit an application for a product that differs from, or incorporates a change to, the reference product, if the application contains sufficient information to show that the new product is safe, pure, and potent.
FDA Review of Comparable Biological Product Applications
Contains provisions that track the requirements of Hatch-Waxman for abbreviated application review procedures
Encourages FDA to meet with sponsors of comparable biological products and reach written agreements with them on the design and size of studies.
78
7878
Approval of Comparable Biological Applications
FDA must approve a comparable biological application unless:
There is insufficient information to show that the product is “comparable” to the reference product,for the condition(s) of use in the proposed labeling.
– If the mechanism of action of the reference product is known, the applicant must demonstrate comparability for at least one proposed condition of use. If the mechanism of action is unknown, the applicant must demonstrate comparability for each proposed condition of use.
There is insufficient information to show that product and reference product have comparable principal molecular structural features; There is insufficient information to show that the two products have the same mechanism(s) of action, if known;
Approval of Comparable Biological Applications (cont.)
The new product differs from the reference product in route of administration, dosage form, or strength; The inactive ingredients used in, or the composition of, the new product are unsafe; The controls used in manufacturing the product are inadequate to assure identity, strength, quality, and purity; The reference product has been, or is being, withdrawn for safety or effectiveness reasons; or
The application contains an untrue statement of fact.
The Secretary may also approve an enhanced version of a reference product if the application contains sufficient information to establish safety and efficacy.
80
8080Interchangeability Determinations, Labeling, and Exclusivity
The bill acknowledges that Interchangeable biological products would generate the greatest cost savings:– there currently is no equivalent of a simple “bioequivalence” study for
biologics; – significantly more costly and difficult to produce than comparable products
The bill therefore provides incentives for the development of interchangeable products, but does not require that each comparable biologic be interchangeable.
– Applicant may request an interchangeability determination. If adetermination is made before approval, FDA must publish a therapeutic comparability evaluation code for the product at the time of approval.
– Tax credits are made available for studies conducted to establish that a comparable biological product is interchangeable with the reference product.
– If FDA determines that a comparable biological product is interchangeable with the reference product, the bill permits the label of the product to state that the product is interchangeable with the reference product for the approved conditions of use.
8181Interchangeability Determinations, Labeling, and Exclusivity
– If an applicant is the first to establish that its product is interchangeable with the reference product, the bill prevents FDA from approving a subsequent application for an interchangeable version of the reference drug,until the earlier of:
180 days from first commercial marketing;1 year after a final court decision or dismissal with prejudice of all patent infringement cases instituted under this subsection;36 months after approval if such patent litigation is ongoing; 1 year after approval, if no such patent litigation was instituted.
– The bill also prohibits the marketing of a “rebrandedinterchangeable product” distributed with the authorization of the reference product holder during the exclusive marketing period.
82
8282
Final Action on ApplicationsFDA must approve or disapprove an application for a comparable biological product eight months after submission, or 180 days after the application is accepted for filing by FDA, whichever is earlier, unless the final action date is extended by joint agreement of the applicant and FDA. Provisions to prevent frivolous petitions from delaying the approval of comparable biologics. – FDA must not fail or refuse to take action by the final action date on
the ground that a third party has made such a request, nor may acourt enjoin FDA from taking final action or staying an approvalexcept by permanent injunction.
– A permanent injunction may not be issued unless the person seeking the injunction demonstrates an injury of more than irrecoverableeconomic loss.
– Requires a company who files a citizen petition to delay approval of acomparable biologic to do so at least 110 days before the effective approval date. A company may not file a lawsuit concerning a late-filed petition until 180 days after it was filed.
FDA must report to Congress any extension of the final action date and any failure to meet the final action date.
Early resolution of patent disputes is essential to ensuring that irrelevant or invalid patents do not delay
competition in the marketplace.
– Patent Requests. Applicants for comparable biological products may elect to ask the holder of the reference product for a list of patents related to the product.
The holder must respond within 60 days with a list of all related patents, including process patents, owned by or licensed to the holder, and may demand payment up to $1,000. For a period of twoyears, the holder must update the list within 30 days of the issuance
a new related patent or license.
84
8484
Patent Provisions
– Patent Notifications. The comparable biological product applicant may elect to notify the reference product holder and patent owner that it intends to challenge one or more patents from the list provided.Any notice must contain a detailed statement of the factual and legal bases for the claim of invalidity or non-infringement and identify a judicial district in which the applicant consents to be sued.
– Patent Remedies. The patent laws are amended by providing that if a patent is not disclosed in response to a request, that patent may not be enforced against that applicant.
If a patent is disclosed and is the subject of a notice, but no patent infringement action is brought within 45 days of notice in the judicial district identified in the notice, or is not maintained through a final decision or dismissal with prejudice, the remedies in any later action to enforce that patent against the submitter of the notice are limited to reasonable royalties. The federal law governing declaratory judgments is amended to prohibit reference product holders from bringing actions for a declaration of patent infringement, validity, or enforceability with respect to patents that were not subject to a notice.