Tuesday, 24 January 2012

Abbreviated New Drug Application (ANDA)

What is an ANDA?

An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's Center for Drug Evaluation and Research (CDER), Office of Generic Drugs (OGD), provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public.

In simple words “It is an application which is filed with USFDA for generic drug approval of an existing licensed medication or approved drug.”

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

I. Important facts about generics and generic drug applications (ANDA)-
  • Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. 
  •  Generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). 
  • Bioequivalence is generally determined by measuring the time taken for generic drug to reach the bloodstream in 24 to 36 healthy, volunteers. This gives the rate of absorption, or bioavailability, of the generic drug, which can be compared to that of the innovator drug. 
  • The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug
  •  The basis for approving generic copies of drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the "Hatch -Waxman  Act". 

II. Facility and Drug Registration for filing an ANDA-
  •  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.
III.Format and content of ANDA-
The FDA recommends ICH’s CTD for filing the ANDA.
Documents in each Module
Administrative and prescribing information (region specific)
Summaries and overview
Information on product quality
Nonclinical study reports
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. Forms and cover letter-
  •       Cover letter

2. Comprehensive table of contents
The next document in Module 1 should be the comprehensive table of contents for the entire submission. Each ANDA submission is required to have a comprehensive table of contents or index for the entire submission (as per 21 CFR 314.94)

3. Administrative documents
a. Administrative documents
  • Appropriate administrative documents should be provided with the submission. Examples of administrative documents are listed below. 21 CFR 314.94  consists of details on the administrative documents needed for ANDA.
  • Field copy certification
  • Debarment certification
  • Financial Certification
  •  Patent information on any patent that claims the drug, if applicable
  • Patent certifications
  • Letters of authorization for reference to other applications or drug master files (if applicable)
  • US Agent Letter of Authorization
  • Proprietary name request (if applicable )
  • Basis of ANDA submission
  • Comparison between Generic Drug and RLD-505(j)(2)(A)
  • Request for waiver
  • Draft labeling
  • Listed drug labeling
  • Labeling requirements
  • Financial disclosure information
  • 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. Labeling comparison
For the ANDA, the comparison of labeling should be provided that is described in 21 CFR 314.94(a)(8).
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 -QualityM4S:The CTD - SafetyM4E: 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
For an ANDA submission Module 4 is not necessary.

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.
 For information in module 5 specific to an ANDA, refer -ANDA filing checklist.

V. Number of Copies of ANDA- The regulations requires archival, review, and field copies of ANDAs
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 314.94 for an individual submission include:
 Quality (Module 3),
 Clinical (Module 5) – Bioequivalence  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 ANDA.
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 ANDA Copies
Binder color
Archival Copy
Review Copy
Field Copy

Mailing Address for Abbreviated New Drug Applications (ANDAs)
Office of Generic Drugs (HFD-600)
Center for Drug Evaluation and Research
Food and Drug Administration
Metro Park North VII
7620 Standish Place
Rockville, MD 20855 

Thursday, 19 January 2012

Tools for Understanding Drug Regulatory Process in USA

At the onset of New Year, 2012 I was pleasantly surprised to see a new look of  FDA's website where the browsing through the contents was a pleasure. You may be wondering, why I post many articles related to Drug Regulatory Process in USA ? Understanding Drug regulatory process in USA is a easy task , thanks to the various tutorials and tools offered by FDA and its affiliated websites. In this post I will give the links in FDA and its affiliated website where we could get useful tools for understanding Drug Regulatory Process in USA.

The tools and resources are as follows-

1. CDER Learn
CDER Learn has the following course list-
  • CDER World
  • The Past, Present, and Future of FDA Human Drug Regulation
  • Bringing an Unapproved Drug Into Compliance 
  • Risk assessment and communication
  • FDA Medwatch and Patient Safety 
  • Field Investigators: Adverse Drug Effects (ADE) Investigators (2000)
  • The FDA Process for Approving Generic Drugs  
  • An Introduction to the Improved FDA Prescription Drug Labeling  
  • The courses are taught through a video interface .
  • There is also a knowledge check section .
This section provides the resources related to drugs, ranging from the guidances , types of applications, drug approvals and databases etc.

This is a recent addition to the FDA's website where the FDA's senior leadership and staff  write regarding various current topics of interest.

Hence, I  believe there is no point in wasting money for buying books and other resources for understanding Drug Regulatory Process in the USA. Of course, it is my personal opinion. I think that EMA and other advanced regulatory authorities could come up with learning tools on the lines of CDER learn etc to understand drug regulatory processes in their respective regions.


1.Click on the  name of the tools or resources highlighted in red to directly go to the web page of FDA/its affiliate website. For example-CDER Learn (or) you could alternatively click on the references which I have Provided below.

2. There could be other useful resources provided by the FDA.

Keywords : CDER Learn, FDA Drug Compliance, Information for Industry (Drugs), FDA Voice.  


Friday, 6 January 2012


I. What are Orphan Drugs?

In the USA, Orphan Drugs are defined as “those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but it is not expected to recover the costs of developing and marketing a treatment drug”.

In the EU, Orphan Drugs are defined as “those that are intended for diagnosis, prevention or treatment of diseases that affect fewer than 5 in 10,000 people across the EU.”

In simple words “Orphan Drugs are those, which are intended for the treatment of rare diseases.”

The Companies which are involved in the research and development of Orphan Drugs are provided incentives by the Governments of various countries which are discussed below.

II. What is the need for designation of drugs used in the treatment of rare diseases as orphan drugs and providing incentives to pharmaceutical companies which are involved in developing orphan drugs?

For the development and commercialization of new medicines, lot of money and time is involved and moreover, the success rate of new medicines is less. Hence, we cannot expect a pharmaceutical company to work on medicines used for the treatment of rare diseases, since the market for rare diseases is very less.  Hence there is a need for providing incentives in order to encourage pharmaceutical companies which are involved in developing orphan drugs.

The following may be the general incentives provided by governments of various countries:
  • Tax incentives.
  • Enhanced patent protection and marketing rights.
  • Clinical research financial subsidization.
  • Creating a government-run enterprise to engage in research and development

III. Significant Legislations related to Orphan Drugs in USA and EU-

a) Orphan Drug Act of 1983-
  • It is a law passed in the United States designed to facilitate the development and commercialization of drugs to treat rare diseases, called Orphan Drugs.
  •  Orphan drug designation does not indicate that the therapeutic is either safe and effective or legal to manufacture and market in the United States.
Important features of Orphan Drug Act-
  • The companies developing Orphan Drugs have marketing exclusivity for 7 years.
  • The companies may get clinical trial tax incentives.
  • The companies may have reduced taxes from the federal government.
b)  Rare Diseases Act-
This legislation amended the Public Health Service Act to establish the Office of Rare Diseases in USA. It also increased funding for the development of treatments for patients with rare diseases.

c) REGULATION (EC) No 141/2000 of European Union-

Features of REGULATION (EC) No 141/2000-
  • This legislation lays down a Community procedure for the designation of medicinal products as orphan medicinal products.               
  •  It provides incentives for the research, development and placing on the market of designated orphan medicinal products.          
  •  It sets up a Committee for Orphan Medicinal Products (COMP) within the Agency
  • Orphan drug status granted by the European Commission gives marketing exclusivity in the EU for 10 years after approval
In addition to the United States and the European Union, legislation has been implemented by Japan, Singapore, and Australia which  have all passed legislation that offers subsidies and other incentives to encourage the development of drugs that treat orphan diseases.

IV.Some of the Organizations/offices of Regulatory Agencies associated with Orphan Drugs:

a)      FDA Office of Orphan Product Development (OOPD)-

The OOPD has following roles-
  • Evaluates scientific and clinical data submissions from sponsors to identify and designate products as promising for rare disease and to further advance scientific development of such promising medical products.
  • It provides incentives for sponsors to develop products for rare diseases.

b)       National Organization for Rare Disorders (NORD)-
  • It is a NGO based in USA, involved in providing information, advocacy, research, and patient services to help all patients and families affected by rare diseases.
  • It was involved in lobbying along with other organizations for passing Orphan Drug Act in USA.

C ) Committee for Orphan Medicinal Products (COMP)-
  • It is one of the scientific committee of EMA that is responsible for reviewing applications from people or companies seeking orphan medicinal product designation.
  • It is also responsible for advising the European Commission on the establishment and development of a policy on orphan medicinal products in the EU, and assists the Commission in drawing up detailed guidelines and liaising internationally on matters relating to orphan medicinal products

d)  European Organization for Rare Diseases (EURORDIS)-

It is an NGO based in Europe, dedicated towards improving quality of life of all people living with rare diseases in Europe.

V.Significant results due to passage of legislations in support of Orphan Drugs-
  • Many orphan drugs have been developed to treat rare diseases like Hodkins Lymphoma, congenital Factor XIII deficiency. glioma, multiple myeloma, cystic fibrosis,  phenylketonuria, snake venom poisoning, neoplastic meningitis etc.
  • Before enactment of ODA in USA, only 38 drugs were approved to treat orphan diseases. From the passage of the ODA in 1983 until May 2010, the FDA approved 353 orphan drugs and granted orphan designations to 2,116 compounds, which is a significant achievement.
  • Although the European Medicines Agency grants market access to its 27 member states, medicines only reach the market when each member state decides that its national health system will reimburse for the drug. For example, 35 orphan drugs reached the market in Belgium, 44 in the Netherlands, and 28 in Sweden in 2008. 35 such drugs reached the market in France and 23 in Italy in 2007.
Orphan Drugs Approved by the FDA in the year, 2011 (until November, 2011)-

Name of Drug
Adcetris(brentuximab vedotin)
For treatment of Hodgkin’s lymphoma and ALCL (systemic anaplastic large celllymphoma).
Anascorp(Centruroides [Scorpion] Immune F(ab’)2 [Equine])
For treatment of clinical signs of scorpion envenomation.
Caprelsa (vandetanib)
To treat adult patients with metastatic (late-stage ) medullary thyroid cancer who are ineligible for surgery and who have disease
that is growing or causing symptoms.
Corifact(Factor XIII Concentrate
For routine prophylactic treatment of congenital Factor XIII deficiency.
For treatment of acute attacks of a rare condition called hereditary angioedema (HAE) in people ages
18 years and older.
Xalkori (crizotinib) and companion genetic  test
To treat certain patients with late stage (locally advanced or metastatic), non-small cell lung
cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene.
Yervoy (ipilimumab)
To treat patients with metastatic melanoma (late-stage skin cancer).
Zelboraf (vemuranfenib)
with companion diagnostic
To treat patients with metastatic (late-stage) or unresected (cannot be removed by surgery) melanoma (skin cancer) in patients whose tumors express a gene mutation called BRAF V600E.
Nulojix (belatacept)
To prevent organ rejection in adult patients who have had a kidney transplant, in combination with
other immunosuppressants.
Spherusol(Coccidioides immitis
Spherule-Derived Skin Test Antigen)
For detection of delayed type hypersensitivity to C. immitis in individuals, 18-64 years of age,
with a history of pulmonary coccidioidomycosis

Keywords- Orphan Drugs, rare diseases, Orphan Drug Act of 1983, Rare Diseases Act, Regulation (EC) No 141/2000, OOPD, NORD, COMP, EURORDIS.