HATCH-WAXMAN ACT

                  

What is Hatch-Waxman act?

It is the popular name for Drug Price Competition and Patent Term Restoration Act, 1984. It is considered as the landmark legislation which established the modern system of generic drugs in USA. Hatch-Waxman amendment of the federal food, drug and cosmetics act established the process by which, would be marketers of generic drugs can file Abbreviated New Drug Application (ANDA) to seek FDA approval of generic drugs. Paragraph IV of the act, allows 180 day exclusivity to companies that are the "first-to-file" an ANDA against holders of patents for branded counterparts.

In simple words “Hatch-Waxman act is the amendment to Federal, Food, Drug and Cosmetics act which established the modern system of approval of generics through Abbreviated New Drug Applications (ANDAs)”

Significant results due to Hatch-Waxman act-

• Prior to the Hatch and Waxman act the generic drug manufacturer had to do the entire clinical trials. After the passage of Hatch and Waxman act the generic drug manufacturer had to only prove bioequivalence of generic drug to the innovator drug by showing that the generic drug is 80-125% bioequivalent to the innovator drug.

• The time and cost involved for getting the generic drug into the market was significantly reduced.

• Low cost quality, safe and effective generic drugs were available to the patients.

• Since 1984, over 10,000 generic drugs have entered the market, and generics accounted for close to 50 percent of prescriptions filled (as on august 1, 2003).

• Billions of dollars in health care costs are being saved annually.

Patents and Exclusivity

Generic drug approval process isn’t less complicated as it involves patent and exclusivity issues. If any New Molecular Entity (NME) is approved, it is granted a exclusivity period of 5 years, which could be extended to 3 more years for supplements requiring clinical trials.

Patent Certifications

As per the Hatch and Waxman act, generic drug and 505 (b) (2) applicants should include certifications in their applications for each patent listed in the “Orange Book” for the innovator drug. This certification must state one of the following:

• (I) that the required patent information relating to such patent has not been filed (Para I certification);

• (II) that such patent has expired (Para II certification);

• (III) that the patent will expire on a particular date (Para III certification); or

• (IV) that such patent is invalid or will not be infringed by the drug, for which approval is being sought(Para IV certification).

A certification under paragraph I or II permits the ANDA to be approved immediately, if it is otherwise eligible. A certification under paragraph III indicates that the ANDA may be approved when the patent expires.

A paragraph IV certification, however, begins a process in which the question of whether the listed patent is valid or will be infringed by the proposed generic product may be answered by the courts before the expiration of the patent. Under the current regulations, the ANDA applicant who files a paragraph IV certification to a listed patent must notify the patent owner and the NDA holder for the listed drug that it has filed an ANDA containing a patent challenge. Until the effective date of FDA’s final rule, all patents submitted and listed in the Orange Book that are the subject of a paragraph IV certification require notice to the NDA holder and patent owner. The notice must include a detailed statement of the factual and legal basis for the ANDA applicant’s opinion that the patent is not valid or will not be infringed.

The submission of an ANDA for a drug product claimed in a patent is an infringing act if the generic product is intended to be marketed before expiration of the patent. Accordingly, the ANDA applicant who submits an application containing a paragraph IV certification may be sued for patent infringement. If the NDA holder or patent owner files a patent infringement suit against the ANDA applicant within 45 days of the receipt of notice, FDA may not give final approval to the ANDA for at least 30 months from the date of that notice. This 30-month stay will delay approval of the generic drug product unless the court reaches a decision earlier in the patent infringement case or otherwise orders a longer or shorter period for the stay.

180 Day Exclusivity

The Hatch-Waxman Amendments provide an incentive of 180 days of market exclusivity to the “first” generic applicant who challenges a listed patent by filing a paragraph IV certification and thereby runs the risk of having to defend a patent infringement suit.

The statute provides that the first applicant to file a substantially complete ANDA containing a paragraph IV certification to a listed patent will be eligible for a 180-day period of exclusivity beginning either from the date it begins commercial marketing of the generic drug product, or from the date of a court decision finding the patent invalid, unenforceable or not infringed, whichever is first.

180 Day Exclusivity could be granted to more than one applicant. The recent example is- 180 day exclusivity was granted to Ranbaxy and Watson Laboratories for marketing generic version of  Lipitor ( Atorvastatin calcium).

Keywords: Drug price competition and patent term restoration act-1984, ANDA, generics,180 day exclusivity, 80-125% bioequivalence,  505 (b) (2) application,  Para I certification, Para II certification, Para III certification, Para IV certification.

References-

1.       http://en.wikipedia.org/wiki/Drug_Price_Competition_and_Patent_Term_Restoration_Act

2.       http://www.fda.gov/newsevents/testimony/ucm115033.htm

P.S.-

A generic drug product is the one, that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use.

505 (b)(2) application

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

An application submitted under section 505(b)(1) of the Federal Food, Drug and Cosmetics act for a drug for which one or more of the investigations relied on by the applicant for approval of the "application 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"

In simple words “505 (b)(2) application is a type of NDA for which one or more investigation relied on by applicant for approval were not conducted by/for applicant and for which applicant has not obtained a right of reference”

Section 505(b)(2) was added to the Food, Drug and Cosmetics act by the Drug Price Competition and Patent Term Restoration Act of 1984 (popularly known as Hatch-Waxman Amendments).

What type of information can an applicant rely on ?

• Published literature

• The agency's finding of safety and effectiveness of an approved drug.

What kind of application can be submitted as a 505(b)(2) application?

• New chemical entity (NCE)/new molecular entity (NME)

• Changes to previously approved drugs

Examples of changes to approved drug products for which 505(b)(2) application should be submitted

• Change in dosage form.

• Change in strength

• Change in route of administration

• Substitution of an active ingredient in a formulation product

• Change in formulation

• Change in dosing regimen

• Change in active ingredient

•  New combination Product

• New indication

• Change from prescription indication to OTC indication

• Naturally derived or recombinant active ingredient

• Bioinequivalence

What can't be submitted as 505(b)(2) applications?

• An application that is a duplicate of a listed drug and eligible for approval under section 505(j) (ANDA)

• An application in which the only difference from the reference listed drug is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than the listed drug

• An application in which the only difference from the reference listed drug is that the rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the listed drug

Advantages of 505 (b)(2) application-

• A 505(b)(2) application may itself be granted 3 or 5 years of exclusivity

• Time-consuming , costly and duplication of clinical studies can be eliminated

• A 505(b)(2) application may be eligible to qualify for orphan and/or pediatric drug exclusivity

Challenge-

• 505(b)(2) application may be delayed due to patent or exclusivity protections covering an approved product

I found a useful link which is provided below, wherein you could get  useful information on differences between 2 types of NDA and ANDA, examples of medication approved under 505 (b)(2) application , Q & A related to 505 (b)(2) application, learning assessment etc

Understanding 505 (b)(2) by Lauren S. Schlesselman

Key Words- 505 (b)(2) application, Hatch-Waxman amendments.

Reference-

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079345.pdf
http://www.cedrugstorenews.com/userapp/appdown.html?CFID=2677216&CFTOKEN=82970149

Other useful Links-

The 505(b)(2) Alternative— An NDA that Saves Time and Money

The 505(b)(2) New Drug Application – A Rapid Approval Route

The 505(b)(2): Drug Development Pathway

New Drug Application (NDA)

What is a New Drug Application (NDA)?

The NDA is the vehicle through which drug sponsors (pharma companies) formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.

.

In simple terms “It is an application filed with USFDA to get approval for marketing a new pharmaceutical for sale in the U.S.”

Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization.

I. Goals of NDA-

The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:

• Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.

• Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.

• Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

II. Chemical type and review classification codes for NDA-

Chemical type classification

Number	Meaning
1	New molecular entity (NME)
2	New active ingredient (new salt, new noncovalent    derivative, new ester)
3	New dosage form
4	New combination
5	New formulation or new manufacturer
6	New indication [no longer used]
7	Drug already marketed without an approved NDA
8	OTC (over-the-counter) switch
9	New indication submitted as distinct NDA,  consolidated with original NDA after approval
10	New indication submitted as distinct NDA - not  consolidated

Review Classification

Letter	Meaning
P	Priority review drug: A drug that appears to represent an advance over available therapy
S	Standard review drug: A drug that appears to have therapeutic qualities similar to those of an already marketed drug
O	Orphan drug - a product that treats a rare disease affecting fewer than 200,000 Americans

 III. Facility and Drug Registration for filing an NDA-

 Within 5 days of filing the NDA-

•  The facility should be registered with FDA using form FDA 2656(Registration of Drug Establishment/Labeler Code Assignment form).

• The product(s)/Drugs to be listed with FDA using form FDA 2657 (Drug listing form) .

Note : From June 1, 2009 FDA is accepting only electronic submissions of forms FDA 2656 and 2657.

IV. Format and content of NDA-

The FDA recommends ICH’s CTD for filing the NDA.

Documents in each Module-

Module	Information
1	Administrative and prescribing information (region specific)
2	Summaries and overview
3	Information on product quality
4	Nonclinical study reports
5	Clinical study reports

Module 1- Administrative and prescribing information

Documents should be organized in the order listed below. Generally, all of the documents in Module 1 can be provided in a single volume. Environmental assessments should be submitted separately.

1. FDA form 356h

• The first document in Module 1 should be FDA form 356h.

2. Comprehensive table of contents

The next document in Module 1 should be the comprehensive table of contents for the entire submission. Each NDA submission is required to have a comprehensive table of contents or index for the entire submission (as per 21 CFR 314.50)

3. Administrative documents

a. Administrative documents

• Appropriate administrative documents should be provided with the submission. Examples of administrative documents are listed below. 21 CFR 314.50 consists of details on the administrative documents needed for NDA.

· Patent information on any patent that claims the drug, if applicable

· Patent certifications

· Debarment certification

· Field copy certification

· User fee cover sheet

· Financial disclosure information

· Letters of authorization for reference to other applications or drug master files (if applicable)

· Waiver requests

· Environmental assessment or request for categorical exclusion

· Statements of claimed exclusivity and associated certifications

*Environmental assessment should be provided as a separate volume.

b.Prescribing information

All copies of the labels and all labeling for the product should be included. Examples are provided below-

• Container and package labels
• Package inserts
• Draft labeling
• Patient leaflets
• Information sheets
• Medication Guides

c. Annotated labeling text           

A copy of the proposed labeling text with annotations directing reviewers to the information in the summaries and other modules that support each statement in the labeling should be provided.

 Module 2 – Common Technical Document Summaries

 Module 2 should include the summary documents. The documents for this module should be provided in the  order as described below.

1. Overall CTD table of contents

For the first document in this module, a comprehensive table of Contents should be provided  listing all of the documents provided in the submission for modules 2 through 5.

2. Introduction to the summary documents

Introduction to the summary should be provided as described in the guidance document M4: Organization of the CTD as a one page document.

3. Overviews and summaries

Module 2 should contain the following additional documents as described in the appropriate guidance documents (M4Q: The CTD -Quality, M4S:The CTD - Safety, M4E: The CTD – Efficacy):

·Quality overall summary (2.3, Module 2, section 3)

· Non clinical overview (2.4)

· Clinical overview (2.5)

· Nonclinical summary (2.6)

· Clinical summary (2.7)

The nonclinical summary and the clinical summary should be provided in separate volumes for ease of use by reviewers.

 Module 3 - Quality

Module 3 should include information on the drug and product that should be provided in the order described below.

1. Module 3 table of contents

The first document in this module should be a table of contents listing all of the documents provided for module 3. See the guidance document M4Q: The CTD Quality for the headings and order to be used in the table of contents, including numbering of section headings.

2. Body of data

Each individual subsection related to the drug and product should be provided as an individual document either bound separately or divided by tab identifiers, depending on the size of the subsection. The documents should be presented in the order in which they are listed in the table of contents.

3. Literature References

Each literature reference should be provided as an individual document, separated from the others by tab identifiers.

Module 4 - Nonclinical Study Reports

Module 4 should contain the nonclinical study reports and related information. The documents should provide for this module in the order described below-

1. Module 4 table of contents

The first document in this module should be a table of contents listing all of the documents provided for module 4. See the guidance to industry M4S: The CTD – Safety for the headings and order to be used in the table of contents, including numbering of section headings.

2. Study reports and related information

 Each study report and each related document should be provided as an individual document, separated from the other documents by binders or tab identifiers. These documents should be presented in the order in which they are listed in the table of contents.

3. Literature References

Each literature reference should be provided as an individual document, separated from the others by tab dividers.

Module 5 - Clinical Study Reports

Module 5 should contain clinical study reports and related information. The documents for this module should be provided in the order described below.

1. Module 5 table of contents

The first document in this module should be a table of contents listing all of the documents provided in Module 5. See the guidance to industry M4E: The CTD – Efficacy for the headings and order to be used in the table of contents, including numbering of section headings.

2. Study reports and related information

Each study report and each related document should be provided , such as tabular listings of all clinical studies, as an individual document separated from the other documents by binders or tab dividers. Tab identifiers be provided for each appendix in a study report. These documents should be presented in the order in which they are listed in the table of contents.

3. Literature References

Each literature reference should be provided as an individual document separated from the others by tab identifiers.

V. Number of Copies of NDA- The regulations requires archival, review, and field copies of NDAs

1.Archival Copy- The archival copy is a complete copy of the application. It serves as the official archive of the application and may be used during the review of the application.

2. Review copy- It includes the information needed by each review discipline for its evaluation. These copies facilitate the concurrent review of the application by the different review disciplines. Review copies that may be necessary according to 21 CFR 314.50 for an individual submission include:

· Quality (Module 3),

· Nonclinical (Module 4),

· Clinical (Module 5) - safety and efficacy documents for clinical reviewer

· Clinical (Module 5) - safety and efficacy documents for the statistical reviewer,

· Clinical (Module 5) - clinical pharmacology and pharmacokinetics documents

· Clinical (Module 5) – clinical microbiology documents.

Copy of Modules 1 and 2 should be provided in each review copy. Each review copy should be labeled and bound separately.

3. Field copy-The field copy should be a separately bound copy of the Quality section (Module 3) for the NDA.

VI. Paper size, font size, pagination, binder colors and mailing address-

 Paper size-Standard U.S. letter size paper (8.5 x 11 inches) should be used for all submissions.

Font size-Narrative text be submitted in Times New Roman 12 point font. Font sizes 9 to10 points are considered acceptable in tables.

Pagination-Page numbering should be at the document level and not at the volume or module level. (The entire submission should never be numbered consecutively by page.) In general, all documents should have page numbers. Since the page numbering is at the document level, there should only be one set of page numbers for each document.

Binder Colors for NDA Review Copies

Review copy for:	Binder color
Quality	Red
Nonclinical	Yellow
Clinical- pharmacokinetics and bioavailability	Orange
Clinical – microbiology	White
Clinical - safety and efficacy	clinical Tan
Clinical - safety and efficacy	statistical Green

Mailing Address for New Drug Applications (NDAs)

CDER Central Document Room:

FDA/Center for Drug Evaluation and Research (CDER)

Central Document Room (CDR)

5901-B Ammendale Road

Beltsville, MD 20705-1266

VII. Review Process of NDA-

NDA approvals by CDER for the year, 2011

References-

1. http://en.wikipedia.org/wiki/New_Drug_Application

2.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073276.pdf

3.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073308.pdf

4.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistrationandListing/default.htm

5.http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/PriorityNDAandBLAApprovals/UCM081953.pdf

6.http://www.fda.gov/Drugs/InformationOnDrugs/ucm075234.htm#chemtype_reviewclass
7.http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129720.pdf

Guidance documents for NDAs is provided in the following link-
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm

Keywords : NDA, NME,  form FDA 2656, form FDA 2657, CTD,  21 CFR 314.50,  CDER.

P.S-
1.This article is  intended to provide guidance only for filing  paper format of  NDA.
2. Part of the article is based on Draft Guidance.

Drug Approval Procedures in European Union

                         

  

Before starting off on drug approval procedures in European Union, I would like to present a table on European Union member countries and Non-European union member countries since the drug approval procedures are not necessarily the same throughout the Europe.

European Union member countries	Non-European union member countries
Austria	Iceland *
Belgium	Norway *
Bulgaria	Switzerland
Cyprus	Serbia
Czech  Republic	Montenegro
Denmark	Croatia
Estonia	Bosnia-Herzegovina
Finland	Macedonia (Former Republic of Yugoslav)
France	Albania
Germany	Andorra
Greece	Belarus
Hungary	Moldova
Ireland	Monaco *
Italy	San Marino
Latvia	Liechtenstein *
Lithuania	Vatican City
Luxembourg	Russia
Malta	Ukraine
Netherlands	Georgia
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom

The following Drug approval procedures are only intended for EU member countries and non EU member countries indicated with "*" in the above table.

1.Centralised Procedure-

• The centralised procedure, allows applicants to obtain a marketing authorisation that is valid throughout the EU (27 EU member countries).

• Application to market a medicinal product that is eligible for the centralised procedure is sent to European Medicines Agency (EMA) which is assessed by the Committee for Medicinal Products for Human Use (CHMP)

• The time limit for the evaluation procedure is 210 days

Centralised procedure is mandatory for the following-

• Medicinal products manufactured using biotechnological processes like recombinant DNA, Hybridoma technology, controlled gene expression, tissue-engineering.

• Orphan medicinal products

• Products containing a new active substance which was not authorised in the Community before 20 May 2004 and which are intended for the treatment of AIDS, cancer, neurodegenerative disorder or diabetes

Centralised procedure is optional for the following-

•  New active substances not authorised in the Community before 20 May 2004

• Products which constitute a significant therapeutic, scientific or technical innovation or for which a Community authorisation is in the interests of patients or animal health at Community level.

2. Decentralised Procedure-

• The decentralised procedure is used for products that have not yet received authorisation in an EU country.

Outline of Decentralised Procedure are-

(i)  Pre-procedural Step

(ii) Assessment step I

(iii) Assessment step II

(iv) National step

Involved members/groups in DCP-

RMS- Reference member state
RMS has the following roles-

-Acts as a link between the applicant (Pharma Company) and the CMSs

-Allocation of procedure number

-Starting the procedure

-Involved in the preparation of preliminary and draft-assessment reports, initial comments on- SmPC     (summary of product characteristics), labeling and package leaflets provided in the dossier.

-Stopping and restarting the procedure, before and after clock stop period.

-Closing the procedure if consensus is reached.

CMS(s)-Concerned member state(s)

-Involved in the approval/disapproval of RMS’s - preliminary and draft-assessment reports, initial comments on SmPC (summary of product characteristics), labeling and package leaflets

-Involved in earlier stages of DCP to avoid disagreements between CMS and RMS.

The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)

CMDh has following responsibilities-

-In case of disagreement between the Member States involved in a Mutual recognition or decentralised procedure on the Assessment report, the summary of product characteristics, the labelling or the package leaflet on the grounds of “potential serious risk to public health”, the points of disagreement are considered by the CMDh. The CMDh uses its best endeavours to reach agreement on the action to be taken within the 60 day time period foreseen in the legislation.

-To lay down, yearly, a list of medicinal products for which a harmonised summary of product characteristics should be drawn up, to promote harmonisation of marketing authorisations across the Community.

The Committee for Medicinal Products for Human Use (CHMP)-

If consensus is not reached at CMDh the points of disagreement will be referred to CHMP.

Note:

-RMS and CMSs are the countries where the applicant (pharma companies) intends to get marketing approval for its products

- CMDh and/or CHMP are only involved if there is disagreement between RMS and CMSs.

FLOWCHART OF DECENTRALISED PROCEDURE

3. Mutual Recognition Procedure-

• The mutual recognition procedure is used for products that have already received authorisations in one or more EU countries.

• The mutual recognition procedure is based on the principle of the mutual recognition by EU Member States of their respective national marketing authorisations.

• The drug should already be approved in the selected RMS.

• The time  period for the procedure is less than DCP and CP.

FLOW CHART OF MUTUAL RECOGNITION PROCEDURE

Note : Information on RMS, CMS, CMDh and CHMP is as that provided in DCP.

4. National Procedure-

• It is limited to the initial phase of mutual recognition procedure

• If the drug product is intended to be authorized in only one EU member state.

• Generally, not used now-a days.

Advantages of Drug approval procedures (CP, DCP, MRP)-

• The applicant need not go through the entire cycle of  Dossier filing-------Queries-------Reply to queries--------Approval in all the EU member countries.

• Approval in multiple countries through single procedure

• Time of approval in various EU member countries can be minimised

• Costs can be reduced

Note-

- Any product registered in France can be marketed in Monaco too, as Monaco delegated its responsibility of Drug approval to France.

-Any product authorized in the UK can be automatically sold in the Channel Islands (legally not part of the UK, but owes allegiance to the British Crown)


-Iceland has applied for EU membership


Keywords- EU, CP, DCP, MRP, NP, RMS, CMS, CMDh, CHMP.

References-

1.http://ec.europa.eu/health/authorisation-procedures-centralised_en.htm

2.http://www.bfarm.de/EN/drugs/2_Authorisation/types/euAuthProcs/cp/central-node-en.html
3.http://ec.europa.eu/health/authorisation-procedures-mutual-recognition_en.htm
4.http://www.hma.eu/47.pdf
5.http://wiki.answers.com/Q/Which_European_countries_are_not_in_the_European_Union

Further reading-
1. http://ec.europa.eu/health/files/eudralex/vol-2/a/chap4rev200604_en.pdf
2.http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap2_2007-02_en.pdf
3.http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Application_for_MA/DCP/CMDh-078-2005-Rev3-Clean_2011_09.pdf