Guidance for Industry 

Bioequivalence 

Recommendations for 

Specific Products 

 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
 
June 2010 

OGD 
  
Guidance for Industry 

Bioequivalence 

Recommendations for 

Specific Products 

 
 
 
 
Additional copies are available from: 

 
Office of Communication 
 
Division of  Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Avenue, Bldg. 51, Room 2201 
 
Silver Spring, MD 20993-0002 
 
(Tel) 301-796-3400 
 
Internet:   http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
June 2010 

OGD 

  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 1 
 
A.   What Are BE Studies?...................................................................................................................1
  
B.   How Did the Agency Make This Information Available in the Past?.......................................2 
 
III.   PROCEDURES FOR MAKING RECOMMENDATIONS AVAILABLE................. 3
  
 
 
  Contains Nonbinding Recommendations 
 
1
 
Guidance for Industry  
 
Bioequivalence Recommendations for Specific Products 

 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations. If you want to discuss an alternative approach, contact the Office of Generic Drugs. 
 
 
 
I.   INTRODUCTION  
 
This guidance describes FDAs process for making available to the public FDA guidance on how 
to design bioequivalence (BE) studies for specific drug products to support abbreviated new drug 
applications (ANDAs). Under this process, applicants planning to carry out such studies in 
support of their ANDAs will be able to access BE study guidance on the FDA Web site,2 rather 
than having to request this information from the Agency and wait for the Agency to respond, as 
has been the case in the past. The FDA believes that making this information available on the 
Internet will streamline the guidance process, making it more efficient than the previous process.  
This process also will provide a meaningful opportunity for the public to consider and comment 
on BE study recommendations for specific drug products.   
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
 
II.   BACKGROUND 
 
A.  What Are BE Studies? 
 
To receive approval for an ANDA, an applicant generally must demonstrate, among other things, 
that its product has the same active ingredient, dosage form, strength, route of administration and 
conditions of use as the listed drug, and that the proposed drug product is bioequivalent to the 
                                                 
1  This guidance has been prepared by the Office of Generic Drugs in the Center for Drug  Evaluation and Research  
(CDER) at the  Food and Drug Administration. 
  
2  We  update guidance documents periodically.  To make sure you have the most recent version of a product-specific 
bioequivalence (BE) study  guidance, check the FDA Drugs guidance page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, Individual Product 
Bioequivalence Recommendations.    
  1
  Contains Nonbinding Recommendations 
 
reference listed drug (21 U.S.C. 355(j)(2)(A); 21 CFR 314.94(a)).  If a drug acts through 
absorption into the bloodstream, bioequivalent drug products are those that show no significant 
difference in the rate and extent of absorption of the therapeutic ingredient (21 U.S.C. 
355(j)(8)(B); 21 CFR 320.1(e)). For a drug that is not intended to be absorbed into the 
bloodstream, FDA may establish alternative methods to show bioequivalence that may be 
expected to detect a significant difference between the drug and the listed drug in safety and 
therapeutic effect (21 U.S.C. 355(j)(8)(C); 21 CFR 320.24).  BE studies are undertaken in 
support of ANDA submissions with the goal of demonstrating BE between a proposed generic 
drug product and its reference listed drug.  The regulations governing BE are provided at 21 CFR 
part 320. 
 
B.  How Did the Agency Make This Information Available in the Past?  
 
Previously, the Office of Generic Drugs (OGD) provided guidance on how to design BE studies 
for specific products only when asked for assistance by individual applicants.  We had 
determined that making recommendations to applicants about how to design BE studies would 
help the generic drug industry, the innovator drug industry, contract research organizations, 
academia, and others understand the Agencys expectations with regard to demonstrating 
bioequivalence. In most cases, the requested information was not available anywhere else, and, 
in some cases, OGD performed its own research before responding to an applicants request for 
product-specific information. In many cases, OGD responded to individual requests for 
information on BE studies in letter format after specific recommendations were prepared within 
the Center for Drug Evaluation and Research (CDER).  This meant that information about BE 
studies was only being provided to those specifically requesting such information.  In addition, 
the staff developing the recommendations and responding to requests for information have been 
the same individuals who are responsible for reviewing the BE data in ANDAs.  With the 
increase in the number of ANDA submissions and in the requests for BE information during the 
last few years, the process of providing BE recommendations has become extremely time-
consuming for the Agency.   
 
In October 2000, to help address this growing problem, FDA issued the guidance Bioavailability 
and Bioequivalence Studies for Orally Administered Drug Products  General Considerations,3  
which describes general recommendations for demonstrating bioequivalence.   These general 
recommendations were helpful, but many individuals have continued to seek assistance from the  
Agency in designing their product-specific BE studies, as certain drug products may raise BE 
issues not squarely addressed in more general guidance.  As a result, after exploring various 
mechanisms that would allow us to conserve our resources while responding to the needs of 
industry and other interested persons, OGD has developed a new approach to making guidance 
available on product-specific BE studies. As before, the Agency intends to develop BE  
recommendations based on its understanding of the characteristics of the listed drug, information 
derived from published literature, Agency research, and consultations within different offices in 
CDER as needed based upon the novelty or complexity of the BE considerations.  Once 
developed, the Agency intends to make BE recommendations for specific drug products 
available through the process described here. 
                                                 
3 The October 2000  guidance was finalized in March 2003  and is available on the FDA  Drugs guidance page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  2
  Contains Nonbinding Recommendations 
 
 
FDA is not required to publish draft or final product-specific BE recommendations before it 
approves an ANDA for the drug product. If the Agency determines that, as required by the 
statute and regulations (21 U.S.C. 355(j)(2); 21 CFR 314.94), an ANDA contains sufficient  
evidence that the proposed generic drug product is bioequivalent to its reference listed drug and 
the application meets the other requirements for approval, FDA will approve the ANDA.  In 
assessing whether an ANDA contains adequate evidence of BE, the Agency considers available 
relevant information, which may include information submitted by the public to dockets for 
citizen petitions and product-specific BE recommendations.   
 
 
III.   PROCEDURES FOR MAKING RECOMMENDATIONS AVAILABLE 
 
To streamline the process for making guidance available to the public on how to design product-
specific BE studies, the Agency intends to use the following process:  
 	  Product-specific BE recommendations will be developed and posted on the Internet on  
the FDA Drugs guidance page 
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/  
default.htm, Individual Product Bioequivalence Recommendations) in draft to facilitate 
public comment.  Users can also search for a specific product BE recommendation using 
the search tool on the guidance page. 
 	  Product-specific BE recommendations may contain differing amounts of detail and 
background information regarding the specific basis for the recommendations, depending 
upon the novelty and complexity of the scientific considerations. 
 	  Newly posted draft and final BE recommendations will be announced in the 

New/Revised/Withdrawn list, which is posted on the FDA Drugs guidance page.   

 	  The Agency will issue a notice in the  Federal Register (FR) announcing the availability 
on the FDA Web site of new and revised product-specific draft and final BE 
recommendations.  The notice will identify a comment period for the draft 
recommendations. 
 	  Comments on product-specific draft BE recommendations will be considered in 

developing final BE recommendations.   

 	  The BE recommendations will be revised as appropriate to ensure that the most up-to-
date BE information is available to the public. 
 
On occasion, the appropriate methodology for establishing bioequivalence for a specific drug 
product will be the subject of a citizen petition or other correspondence, and of a product-specific 
BE recommendation. This situation is particularly likely when the drug product raises novel or 
complex bioequivalence issues, as may be posed by certain topical and non-systemically 
absorbed products. When the same BE issue is under consideration in different contexts, the 
Agency will take into account the status of related matters in determining how to best address the 
scientific issues. This may involve, for example, coordinating the consideration of a pending 
citizen petition with the development and publication of a product-specific BE recommendation, 
  3
  Contains Nonbinding Recommendations 
 
or identifying in the notice of availability for the draft BE recommendation the docket number of 
a related citizen petition. 
  
  4