Advanced Prostate Cancer: 
Developing Gonadotropin-
Releasing Hormone 
Analogues 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Oncology Center of Excellence (OCE) 
 
May 2022 
Clinical/Medical 
   
Advanced Prostate Cancer: 
Developing Gonadotropin-
Releasing Hormone 
Analogues  
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Oncology Center of Excellence (OCE) 
 
May 2022 
Clinical/Medical 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................1 
III.  DEVELOPMENT PROGRAM ............................................................................2 
A.  Drug Product Development .............................................................................................. 2 
B.  Nonclinical Development .................................................................................................. 4 
C.  Registrational Trial Considerations ................................................................................ 5 
1. Trial Design ......................................................................................................................... 5 
2. Trial Population .................................................................................................................. 5 
3. Dose Selection ..................................................................................................................... 5 
4. Trial Procedures and Timing of Assessments ..................................................................... 5 
5. Pharmacokinetics and Pharmacodynamics ........................................................................ 7 
6. Efficacy Endpoints ............................................................................................................... 7 
7. Statistical Considerations .................................................................................................... 8 
D.  Labeling Recommendations ............................................................................................. 9 
APPENDIX .......................................................................................................................10 
 
 
  Contains Nonbinding Recommendations 
Advanced Prostate Cancer:  Developing  
Gonadotropin-Releasing Hormone Analogues 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
page. 
 
 
 
I.  INTRODUCTION 
 
This guidance describes the Food and Drug Administrations (FDAs) current recommendations 
regarding the overall development program to establish the effectiveness and safety of 
gonadotropin-releasing hormone (GnRH) analogues for treating advanced prostate cancer.   
 
The recommendations in section III.C., Registrational Trial Considerations, apply to drug 
product development programs for GnRH analogues in advanced prostate cancer for all dosage 
forms and routes of administration (e.g., tablets, capsules, injectable suspensions, injectable 
emulsions, subcutaneous implants). Other sections apply only to extended-release injectable 
dosage forms. 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited. The use of the word should in Agency 
guidance means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
GnRH analogues remain a mainstay for treating patients with prostate cancer. Both GnRH 
agonists and antagonists are intended to reduce testosterone (T) levels in the blood, a major 
driver of prostate cancer growth, but they achieve that goal through different mechanisms of 
action. GnRH agonists cause a transient surge in luteinizing hormone (LH) and T. This surge 
desensitizes the LH receptors and is followed by a sustained decrease in T levels. Patients whose 
LH receptors have not been fully desensitized may develop a second surge in T after doses 
 
1 This guidance has been prepared by the Division of Oncology 1 in the Center for Drug Evaluation and Research 
(CDER) at the Food and Drug Administration. 
1  Contains Nonbinding Recommendations 
subsequent to the first dose (subsequent doses). In contrast, GnRH antagonists bind to the GnRH 
receptor, suppressing production of LH and follicle-stimulating hormone (FSH) and the resultant 
production of T. GnRH antagonists direct suppression of LH and FSH avoid the transient T 
surges seen with the agonist products.2 
 
New drug applications (NDAs) for GnRH analogues typically rely, in part, on FDAs finding of 
safety and/or effectiveness for a previously approved GnRH analogue, and applicants submit 
these NDAs through the pathway described in section 505(b)(2) of the Federal Food, Drug, and 
Cosmetic Act. These 505(b)(2) applications rely on FDAs prior findings of safety and/or 
effectiveness and also generally include product-specific data from nonclinical general 
toxicology studies and a clinical trial. This guidance addresses the current regulatory 
requirements and provides recommendations for the approval of these drug products and the use 
of a standardized approach to trial design.  
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  Drug Product Development 
 
GnRH analogues typically contain a synthetic peptide similar to naturally occurring GnRH. The 
drug product is often marketed in the form of a polymer (such as freeze-dried powder 
(microspheres) that a provider must mix with a solvent in a prefilled syringe to be reconstituted 
into a suspension) in a single-dose delivery system for intramuscular administration. Chemistry, 
manufacturing, and controls (CMC) information for this peptide and the excipients and other 
components of the extended-release formulation can be provided within the application or as a 
cross reference to a drug master file. The CMC information submitted in the investigational new 
drug application (IND) during drug product development should follow relevant FDA guidance 
documents, including the following: 
 
  Guidance for industry Content and Format of Investigational New Drug Applications 
(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, 
Biotechnology-derived Products (November 1995)3 
 
  Guidance for industry INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, 
and Controls Information (May 2003) 
 
For drug products entering clinical trials, the drug product development program should be 
aligned with the following applicable International Council for Harmonisation (ICH) guidance 
documents: 
 
 
2 TN Clinton, SL Woldu, and GV Raj, 2017, Degarelix Versus Luteinizing Hormone-Releasing Hormone Agonists 
for the Treatment of Prostate Cancer, Expert Opin Pharmacother, 18(8): 825832; and LG Gormella, 2009, Effective 
Testosterone Suppression for Prostate Cancer: Is There a Best Castration Therapy?, Rev Urol, 11(2): 5260. 
 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
2  Contains Nonbinding Recommendations 
  Guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products 
(November 2003) 
 
  Guidance for industry Q1B Photostability Testing of New Drug Substances and Products 
(November 1996) 
 
  Guidance for industry Q2(R1) Validation of Analytical Procedures: Text and 
Methodology (November 2005) 
 
  Guidance for industry Q3A(R) Impurities in New Drug Substances (June 2008) 
 
  Guidance for industry Q3B(R2) Impurities in New Drug Products (August 2006) 
 
  Guidance for industry Q3C Impurities: Residual Solvents (December 1997) 
 
  Guidance for industry Q3D(R1) Elemental Impurities (March 2020) 
 
  Guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for 
New Drug Substances and New Drug Products: Chemical Substances (December 2000) 
 
Because the active ingredient is intended to be released over an extended period (e.g., 1 to 6 
months), ensuring adequate and continuous drug release is critical to successful development. 
During drug product development, sponsors should conduct in vitro tests to evaluate and 
characterize the quality and performance of the proposed drug products. Ideally, the in vitro 
drug-release characteristics should correspond to the in vivo drug-release performance, and the 
sponsor should select clinically relevant drug-release acceptance criteria to ensure consistent 
quality, efficacy, and safety. The sponsor can also use in vitro drug-release testing to evaluate 
changes in formulation (e.g., polymer and excipient selection) and the manufacturing process 
(e.g., equipment parameter changes) during drug product development and potential scale-ups. 
The in vitro drug-release tests are often used to monitor the quality of the drug product at release 
and over time, and the tests are intended to provide evidence that the drug product will perform 
consistently throughout its shelf life.  For drug products for which drug release is expected to 
occur over a long duration, developing an accelerated in vitro drug-release method is an option 
for drug release and stability testing. Sponsors should characterize in vitro drug release early in 
drug product development and should make it available at initial IND submission for FDA 
feedback.4   
 
When a delivery or mixing device is used, sponsors should describe the drug-delivery device and 
reference an approved or cleared device or device application. Sponsors should also ensure that 
the performance characteristics of the syringe are maintained throughout the shelf life. Sponsors 
should consider in-use testing. 
 
 
4 See the appendix for additional information. 
3  Contains Nonbinding Recommendations 
B.  Nonclinical Development 
 
Nonclinical development of anticancer pharmaceuticals is described in the following guidance 
documents: 
 
  ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals 
(March 2010) (ICH S9) 
 
  ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals: 
Questions and Answers (June 2018) 
 
  ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals (May 2012) (ICH S6(R1)) 
 
  Guidance for industry Oncology Pharmaceuticals: Reproductive Toxicity Testing and 
Labeling Recommendations (May 2019) 
 
Sponsors should include pharmacology studies supporting the proposed trial with the initial IND. 
It is important for sponsors to test the formulation in an animal model for dose finding and 
chemistry and manufacturing consistency before initiating clinical trials.5 In general, sponsors 
should provide nonclinical, general toxicology studies in rodents and nonrodents of up to 1 
months duration to support early clinical development, and they should provide studies of 3 
months duration to support pivotal registration trials. Safety pharmacology and toxicokinetic 
endpoints can be included in these studies rather than using stand-alone studies. The general 
toxicology studies should use a route of administration similar to the route of administration in 
the intended clinical trial and should follow the recommendations described in Table 1 of ICH 
S9. Consistent with ICH S6(R1), if the 1-month studies show a consistent toxicological profile, 
then a 3-month study in a single species may be sufficient. Because GnRH analogues are 
peptides with expected high specificity, secondary pharmacology studies are usually not 
warranted.   
 
Consistent with the FDA guidance on reproductive testing for oncology pharmaceuticals, no 
embryo-fetal toxicology study or other reproductive toxicology study is needed to support the 
indication of advanced prostate cancer (see ICH S9, ICH S6(R1), and guidance for industry 
Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations). 
Unless there are unnatural amino acids (i.e., amino acids not normally found in mammals) in the 
GnRH product, the sponsor does not need to evaluate genotoxicity or carcinogenicity. 
 
In general, it is not necessary to evaluate phototoxicity or immunotoxicity to support developing 
or marketing GnRH analogues to treat advanced prostate cancer.  
 
 
5 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
4  Contains Nonbinding Recommendations 
C.  Registrational Trial Considerations 
 
1.  Trial Design 
 
Single-arm trials using T levels as pharmacodynamic/response biomarkers are conducted to 
support the approval of GnRH analogues. These trials should demonstrate the following:  
 
  Attainment of a castrate (less than 50 nanogram (ng)/deciliter (dL)) T level 
 
  Maintenance of castrate T levels until the end of a dosing interval 
 
  Maintenance of castrate T levels immediately after subsequent doses of the study drug 
product 
 
To demonstrate these effects of the study drug product on T levels, the treatment period should 
be at least twice as long as the dosing interval.  For drug products that act over a relatively short 
period (e.g., 1 month), the treatment period should extend over several (three to four) dosing 
intervals.  
 
Sponsors should discuss with the division randomized designs intended to support comparative 
claims (efficacy and/or safety) among GnRH analogues.  
 
2.  Trial Population 
 
Participants enrolled in trials intended to support an indication for treating advanced prostate 
cancer should have normal T levels and either metastatic or biochemically recurrent disease. 
Sponsors could consider excluding participants with bone metastases in weight-bearing bone 
who are at risk for developing symptoms associated with T flare. We recommend that sponsors 
record information concerning the participants history of prostate cancer, including the date of 
diagnosis, current stage, extent of metastatic disease at baseline, and prior therapies. 
 
3.  Dose Selection  
 
The study drug product dose used in the clinical trial should be informed by nonclinical testing.  
Sponsors should consider using early dose-finding studies or enrolling participants at multiple 
dose levels in the registrational trial. The adequacy of data for the selected dose for the new drug 
product will be assessed based on one or more clinical trials that demonstrate an adequate bridge 
to support the ability to rely on the safety and effectiveness of the listed drug for the new drug 
product.  
 
4.  Trial Procedures and Timing of Assessments 
 
GnRH agonists are expected to achieve castrate T levels by Day 28, and T levels should be 
measured at this time. GnRH antagonists are expected to achieve more rapid development of 
castrate T levels than GnRH agonists. To document when castrate T levels occur, sponsors 
should consider weekly assessment of T levels until Day 28. Although the final analyses should 
5  Contains Nonbinding Recommendations 
use T levels assessed at a central laboratory, T levels should also be assessed at local laboratories 
so that participants who do not have castrate T levels (on or after Day 28) can be promptly 
removed from the trial for safety reasons. 
 
To ensure that castrate T levels are maintained over the dosing interval, sponsors developing 
GnRH agonists or antagonists should measure T levels before each dose of the study drug 
product. Sponsors could consider additional measurement of T levels at other time points, 
including the midpoint of the dosing interval, to help guide further drug product development if 
the predose level fails to show castrate T levels. 
 
To assess for potential T surges following subsequent doses of a GnRH agonist, sponsors should 
obtain T levels at 1 hour, 4 hours, and 3 days after subsequent doses in all trial participants and 
provide these results as supportive efficacy data. Sponsors could consider an additional T 
measurement between 3 and 7 days after the additional dose. Sponsors should justify and discuss 
the appropriateness of the timing of T-level assessments with FDA before initiating the study. 
 
We recommend that sponsors assess the effect of the study drug product on tumors by measuring 
prostate specific antigen at a central laboratory and reviewing bone scans and scans of known 
sites of disease (e.g., computed tomography (CT) scans). For participants with metastatic 
disease, tumor measurements would normally be obtained every 3 to 6 months during the 
treatment period, and we recommend that these results be included in the application database. 
 
Sponsors should collect information on the dates of use and dose of herbal medications and 
dietary supplements, if they were used, at trial entry and throughout the treatment period because 
some herbal or alternative medications may affect T levels. Sponsors should also provide 
participants with a list of medications that they should not use during the trial period. 
 
Adverse event collection should solicit events using open-ended questions and known adverse 
events for this class of drugs, such as hot flushes, breast pain, bone pain, difficulty sleeping, and 
injection site reactions. After collecting data on injection site reactions, sponsors should report 
all terms related to this concept (e.g., injection site swelling, redness, pain) under a single term. 
The incidence of injection site reactions has varied markedly between trials, and this may be 
related to a lack of uniformity in ascertainment and assessment. Sponsors should assess adverse 
events throughout the treatment period and for 30 days after the end of the dosing interval. For 
example, sponsors should assess adverse events for 4 months after the last dose of a 3-month 
formulation of a GnRH analogue. 
 
Safety monitoring should include measurement of hemoglobin A1C and a lipid panel at 
screening and at the end of treatment, at minimum. Multiple trials have demonstrated an 
association between GnRH agonist use and adverse effects on insulin sensitivity and 
dyslipidemia, which may increase the risk of cardiovascular disease.6 If the treatment period 
 
6 GN Levine, AV DAmico, P Berger, PE Clark, et al., 2010, Androgen-Deprivation Therapy in Prostate Cancer and 
Cardiovascular Risk: A Science Advisory From the American Heart Association, American Cancer Society, and 
American Urological Association: Endorsed by the American Society for Radiation Oncology, Circulation, 
121(6):83340, doi: 10.1161/CIRCULATIONAHA.109.192695. 
6  Contains Nonbinding Recommendations 
exceeds 1 year, these tests should be repeated annually. If the treatment period exceeds 2 years, 
bone density should also be measured at baseline and every 2 years. 
 
Before trial initiation, sponsors should discuss with the division the potential use of patient-
reported outcomes (PRO) to support labeling claims.7 
 
5.  Pharmacokinetics and Pharmacodynamics 
 
Plasma T levels have been used as pharmacodynamic/response biomarkers leading to traditional 
approval8 of GnRH analogues for advanced prostate cancer in the 505(b)(2) pathway. Therefore, 
a robust bioanalytical method for measuring plasma T levels is critically important. Sponsors 
should employ a fully validated bioanalytical assay for the analysis of plasma T levels.9 The 
bioanalytical methods used to measure plasma T levels should be accurate, precise, specific, 
sensitive, and reproducible.  
 
Given the use of a pharmacodynamic/response biomarker (i.e., T level) in the clinical trial to 
support approval, sponsors need not demonstrate pharmacokinetic (PK) bioequivalence of the 
proposed drug product to the listed drug on which the sponsor intends to rely in a proposed 
505(b)(2) application. However, sponsors should collect samples of the drug product and the 
listed drug in a pilot study or a subgroup within the registration trial to characterize the PK of the 
drug product relative to the listed drug. Characterizing the PK profile of the drug product can 
also illustrate the drug substance release from the drug product, estimate the accumulation 
potential of the drug substance after multiple doses, and describe the relationship between 
pharmacokinetics and plasma T cells for the drug product. 
 
6.  Efficacy Endpoints 
 
Plasma T level is used as a surrogate endpoint to assess the efficacy of GnRH analogues. A T 
level less than 50 ng/dL is considered castrate level. The timing of T-level assessments is 
discussed above. To accommodate T-level assessments at the end of a dosing interval, sponsors 
should extend the trial period for at least two dosing intervals for long-acting (3 to 6 months) 
formulations and three to four dosing intervals for short-acting (1 month) formulations.  
 
Assessing mean T levels would not provide an adequate measure of efficacy because averaging 
T levels will not reveal the participants who did not benefit (i.e., achieve castrate levels); 
 
7 See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims (December 2009) and the draft guidance for industry Core Patient-Reported Outcomes in 
Cancer Clinical Trials (June 2021). When final, this guidance will represent the FDAs current thinking on this 
topic. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
8 The term traditional approval denotes the longstanding route of drug product approval based on the demonstration 
of clinical benefit or an effect on a surrogate endpoint known to predict clinical benefit.  That term is distinguished 
from accelerated approval, which is associated with use of a surrogate endpoint or intermediate clinical endpoint that 
is reasonably likely to predict clinical benefit to support drug product approval. 
 
9 The guidance for industry Bioanalytical Method Validation (May 2018) provides recommendations on 
bioanalytical method validation. 
7  Contains Nonbinding Recommendations 
therefore, it is critical to show that a high percentage of participants achieved and maintained a T 
level less than 50 ng/dL. The percentage of participants who achieved and maintained a T level 
less than 20 ng/dL should also be included as a secondary endpoint and included in labeling. 
Particularly for randomized trials seeking to demonstrate a comparative benefit between two 
alternative GnRH analogues, PROs can be included as secondary endpoints. Sponsors should 
discuss their PRO assessment strategy with the FDA review division. 
 
7.  Statistical Considerations 
 
The primary analysis for the single-arm trial described above should be the calculation of the 
proportion of participants who achieve and maintain castrate T levels from Day 28 through the 
end of the treatment period. To demonstrate efficacy, the lower bound of the 95 percent 
confidence interval for this estimate should be greater than 90 percent (i.e., less than 10 percent 
treatment failures). The Kaplan-Meier method is recommended to calculate the estimate and its 
95 percent confidence interval. For this method, an event is defined as a treatment failure, which 
is a noncastrate T level (i.e., T level greater than or equal to 50 ng/dL) at any time from Day 28 
through the end of the treatment period. Although noncastrate T levels before Day 28 are not 
considered treatment failures, participants who fail to achieve a castrate T level at Day 28 should 
be considered to have an event at Day 28 in this analysis.   
 
The following recommendations for handling missing data after Day 28 in participants who 
successfully achieve a castrate T level by Day 28 should be considered when the Kaplan-Meier 
method is used: 
 
1)  Participants who leave the trial for reasons other than a noncastrate T level should be 
censored at their last T level assessment. 
 
2)  Participants with one or more consecutive missing T levels and a noncastrate T level after 
the missing time point should be considered to have had a treatment failure at the first 
missing time point.   
 
3)  Participants with castrate T levels immediately before and after a single missing T level 
should not be considered to have had a treatment failure or censored at the missing time 
point.  
 
4)  Participants with two or more consecutive missing T levels (across more than 1 day) and 
castrate T levels immediately before and after the missing time points should be censored 
at their last T level before the missing data.  
 
Sponsors should conduct a sensitivity analysis in which participants who leave the trial and 
participants with two or more consecutive missing T levels, regardless of T levels before and 
after those missing time points, are considered to have had treatment failures. Sponsors should 
plan for approaches to handle missing data in participants who have other types of missing 
patterns not captured above and should consider additional missing data sensitivity analyses. 
Sponsors also should conduct sensitivity analyses with different approaches for handling 
8  Contains Nonbinding Recommendations 
participants who received concomitant medications and herbal supplements that could possibly 
affect T levels. 
 
In determining the sample size of the trial, sponsors should anticipate and account for the 
possibility of participants leaving the trial prematurely. Sponsors should make every effort to 
avoid missing data. 
 
D.  Labeling Recommendations 
 
The CLINICAL STUDIES section of labeling should include a summary of the clinical study or 
studies that provide the primary support of effectiveness of the drug product.10 This section 
should provide information on the percentage of participants who achieved and maintained a 
castrate T level, which is necessary for demonstrating substantial effectiveness of a GnRH 
antagonist for the treatment of advanced prostate cancer.11 This section should also include the 
percentage of trial participants who achieved and maintained a T level less than 20 ng/dL during 
the treatment period. Additionally, if the applicant proposes to describe the time course of 
achieving castrate T levels, this information should be presented in this section as the percentage 
of participants treated with GnRH antagonists who achieved castrate levels at Day 14 or 21. 
Presenting mean T levels over time can be misleading because the mean value may mask a 
clinically important incidence of treatment failures; therefore, applicants should not include 
mean T level results in product labeling.   
 
 
10 See 21 CFR 201.57(c)(15) and the guidance for industry Clinical Studies Section of Labeling for Human 
Prescription Drug and Biological Products  Content and Format (January 2006).  
 
11 21 CFR 201.57(c)(2)(iv). 
9  Contains Nonbinding Recommendations 
APPENDIX 
 
The following are general comments regarding the in vitro drug-release method development, 
acceptance criteria, and data submission that applicants should provide in new drug applications. 
 
1. In Vitro Drug-Release Method Development Report 
 
a.  Provide a detailed description of the in vitro drug-release method being proposed to 
evaluate the drug product. Provide data to support that the selected in vitro drug-release 
method development parameters are the most appropriate for the proposed in vitro drug-
release method (e.g., testing apparatus, dialysis chamber, in vitro release medium 
conditions, temperature). An accelerated drug-release method can be developed for quality 
control purposes. The testing conditions used for each test should be clearly specified. The 
release profile should demonstrate complete drug release or a plateau (i.e., no increase 
over three consecutive time points). We recommend the use of at least six samples per 
testing variable during method development. 
 
b.  Provide complete in vitro drug-release profile data (individual, mean, standard deviation). 
The data should be reported as the cumulative percentage of drug released with time (the 
percentage is based on the drug products proposed labeling claim at different time 
points). 
 
c.  Submit data to support the discriminating ability of the selected in vitro drug-release 
method. In general, the testing should compare the in vitro drug-release profiles of the 
target drug product and proposed drug products that are intentionally manufactured with 
meaningful variations for the most relevant critical material attributes and process 
parameters (i.e., plus or minus 10 to 20 percent change to the specification ranges of these 
variables). 
 
d.  Provide supportive validation data for the in vitro drug-release method (i.e., method 
robustness, etc.) and analytical method (e.g., precision, accuracy, linearity, stability). 
 
e.  Provide a list of critical material attributes and critical process parameters affecting in 
vitro drug release. 
 
2. In Vitro Drug-Release Acceptance Criteria 
 
The complete in vitro drug-release profile data (e.g., 0.5, 1, and 6 hours, then 1, 2, 4, and 6 days, 
etc., n = 12) from clinical and registration/stability batches should be used for setting the in vitro 
drug-release acceptance criteria. Adequately validated and fully documented analytical methods 
should be used. FDA recommends a minimum of three time points to set the acceptance criteria 
(i.e., sampling time points and acceptance limits) for extended drug-release products from the 
lots used in the clinical trials and primary stability batches. These time points should cover the 
early, middle, and late stages of the drug-release profile.  The last time point should be where at 
least 80 percent of the drug product is released. If the maximum amount released is less than 80 
percent, the last time point should be the time when the plateau of the drug-release profile has 
10  Contains Nonbinding Recommendations 
been reached. In general, the selection of the drug-release acceptance criteria ranges is based on 
mean target value plus or minus 10 percent and greater than 80 percent for the last sampling time 
point. Wider criteria ranges may be acceptable if they are supported by an approved in vitroin 
vivo correlation or physiologically based pharmacokinetic model. 
 
3. Data Submission 
 
The complete in vitro drug-release profile data for the clinical and stability batches of the drug 
product should be presented in tabular and graphical formats. The tables and plots of mean and 
individual vessel data for the clinical and stability batches should include profile data at release 
(time-zero) and throughout the duration of stability testing under long-term storage conditions. 
11