Nonclinical Safety Evaluation of 
Reformulated Drug Products 
and Products Intended for 
Administration by an Alternate 
Route 
Guidance for Industry and Review Staff 

 
Good Review Practice 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2015 

Pharmacology/Toxicology 

 
   
Nonclinical Safety Evaluation of 
Reformulated Drug Products 
and Products Intended for 
Administration by an Alternate 
Route 
Guidance for Industry and Review Staff 

 
Good Review Practice 
 
 
 
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  

Tel: 855-543-3784 or 301-796-3400;  Fax: 301-431-6353; Email:  druginfo@fda.hhs.gov  

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)
  
 
October 2015 

Pharmacology/Toxicology 

   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   GENERAL CONSIDERATIONS ................................................................................... 3 
 
IV.   SYSTEMIC TOXICITY CONSIDERATIONS ............................................................. 3 
 
V.   ROUTE OF ADMINISTRATION CONSIDERATIONS ............................................. 4 
 
A.   Considerations for All Routes of Administration ....................................................................... 4
  
B.   Route-Specific Considerations ...................................................................................................... 4
  
1.  Oral.................................................................................................................................................. 5
  
2.  Dermal (Including Patches) ............................................................................................................. 5
  
3.  Intravenous ...................................................................................................................................... 5
  
4.  Ocular .............................................................................................................................................. 5
  
5.  Otic................................................................................................................................................... 6 
 
6.  Inhalation ......................................................................................................................................... 6 
 
7.  Intranasal ......................................................................................................................................... 6 
 
8.  Vaginal ............................................................................................................................................. 7 
 
9.  Rectal ............................................................................................................................................... 7 
 
10.   Intraoral (Including Buccal or Lingual, or Periodontal) ............................................................ 7 
 
11.   Intracavernosal or Intraurethral ................................................................................................. 7
  
12.   Intravesicular (Intrabladder) ...................................................................................................... 8
  
13.   Extended Release Injected or Implanted Formulations  .............................................................. 8 
 
14.   Intrathecal or Epidural  ............................................................................................................... 8
  
15.   Subcutaneous or Intramuscular .................................................................................................. 9
  
  Contains Nonbinding Recommendations 
Nonclinical Safety Evaluation of Reformulated  

Drug Products and Products Intended for  

Administration by an Alternate Route 

1
 
Guidance for Industry and Review Staff
 
 
Good Review Practice 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not create 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 staff responsible for this guidance as listed on the title 
page. 
 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations for the nonclinical evaluation of previously approved 
drug substances when a new formulation or a new route of administration for a previously 
approved formulation is proposed by the sponsor.  This guidance is intended for sponsors and 
review staff in the Center for Drug Evaluation and Research (CDER) at the Food and Drug 
Administration (FDA) involved in the development and review of new formulations of 
previously approved drug substances and proposals for existing formulations to be used by a new 
route of administration. 
 
The goals of this guidance are to: 
 
	   Communicate to industry the FDAs current thinking pertaining to safety data needed to 
support approval of these drug products 
 
 	  Increase uniformity within CDER on recommendations for the nonclinical development of 
reformulated drug products and products being used by an alternate route 
 
This guidance assumes that the drug substance has already been used in an approved drug 
product. It outlines the nonclinical information generally recommended to support the 
development of a new product even if there is no change in the composition of the formulation.  
                                                 
1 This  guidance has been  prepared by the Pharmacology/Toxicology Coordinating Committee in the Center for Drug  
Evaluation and Research at the Food and Drug Administration.   
  1
  Contains Nonbinding Recommendations 
For example, the same formulation might be used by a new route, prompting a reevaluation of 
the toxicity information using considerations outlined in the guidance.   
 
This guidance does not absolve the sponsor from providing complete nonclinical information for 
a drug product, either directly (i.e., literature or study reports), through a right of reference to 
such information, or by relying on the finding of safety and effectiveness for a listed drug and 
establishing a clinical bridge to that listed drug.2    
 
This guidance does not fully address the complete safety evaluation that may be appropriate for 
excipients that are being used in a new formulation but that have not been previously used in 
FDA-approved products. The studies described in this guidance may help support the safety 
assessment of an excipient being used by a new route of administration.  For recommendations 
regarding nonclinical issues that apply to excipients that have not been previously used in FDA-
approved products, see the guidance for industry Nonclinical Studies for the Safety Evaluation of 
Pharmaceutical Excipients.3   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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. Although guidance documents do not legally bind FDA, review staff may depart 
from guidance documents only with appropriate justification and supervisory concurrence. 
 
 
II.  BACKGROUND 
 
Generally, nonclinical data support use of a drug product by a particular route and also reflect the 
planned duration of use. For example, carcinogenicity studies usually are not conducted to 
support approval of antibiotics intended for short-term use.  Much of the available nonclinical 
information used to support approval of an initial formulation can be used to support the safety 
of new formulations, but in some cases these data may not be sufficient to support additional 
approvals because changes in the formulation could produce a new toxicity or more commonly 
because the new formulation will be used in a different way.  This is particularly true if the drug 
products route of administration is different or the duration of use changes markedly.  In those 
cases, additional nonclinical studies might be recommended to ensure that the toxicity of a new 
formulation, as it is to be used, is fully characterized. 
 
                                                 
2 The term  listed drug is defined as a new drug  product that has an effective approval  under 505(c) of the act  for 
safety and effectiveness or  under 505(j) of the act, which has not  been withdrawn under section 505(e)(1) through 
(e)(5) or  (j)(5) of  the act,  and which has not been  withdrawn from sale for what FDA has determined as  reasons of 
safety or effectiveness (21 CFR 314.3). 
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
  2
  Contains Nonbinding Recommendations 
If the new formulation is to be used in a manner similar to previous formulations, the need for 
additional nonclinical data generally will be limited.  However, if the new formulation will be 
used in a substantially different way (e.g., new route, longer duration), the need for additional 
nonclinical data becomes greater and additional nonclinical information may be needed even if 
no change is made in the composition of the formulation.  For example, if a topical cream  
originally used on the skin will be used intravaginally, the safety database should be assessed to 
determine if this new route is safe  or if additional studies are needed. 
 
 
III.  GENERAL CONSIDERATIONS 
 
The recommendations provided in this guidance assume that the nonclinical evaluations of the 
previously approved drug products were adequate by current standards.  If this is not the case, 
and the change in formulation or route of administration triggers the need for additional studies, 
then additional nonclinical studies might be recommended to address any preexisting 
deficiencies.  
 
Sponsors should review available toxicity information to determine whether it supports the 
proposed clinical use of the new formulation or new route of administration.  This review should 
include considering whether additional data (e.g., chronic toxicity, carcinogenicity studies) are 
recommended for new products indicated for long-term use.  
 
We recommend that the ICH guidances for industry M3(R2) Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals or S9 
Nonclinical Evaluation for Anticancer Pharmaceuticals and the appropriate review division be 
consulted regarding the timing of submission of nonclinical data relative to clinical development.  
Toxicology studies used to support clinical use of a drug product should be conducted under the 
good laboratory practice regulations.4  
 
 
IV.  SYSTEMIC TOXICITY CONSIDERATIONS  
 
All routes of administration can result in systemic exposure.  Therefore, the adequacy of the 
available systemic toxicity information should be evaluated based on a comparison of the 
systemic exposure obtained after administration of a proposed new formulation to the systemic 
exposure with use of the previously approved formulation.  Changes in the formulation can alter 
the pharmacokinetics of an active ingredient.  Additional toxicity studies might be recommended 
if the available toxicity information is not sufficient to support the exposure associated with the 
new formulation or route or if a significantly different pattern of exposure results from the new 
formulation or route.   
 
An adequate evaluation of the pharmacokinetics and absorption, distribution, metabolism, and 
elimination (PK/ADME) of the drug substance is recommended for new formulations.  These 
data and any available human data can be helpful in determining what additional nonclinical 
                                                 
4 See 21 CFR part 58. 
  3
  Contains Nonbinding Recommendations 
toxicity data, if any, are recommended.  When comparing the PK/ADME of a new formulation 
or route with a previously approved product it is important to examine the shape of the 
concentration/time curve in addition to the total area under the curve.  For example, alterations in 
absorption or the dosing frequency can produce significantly different concentration/time  
profiles that might lead to different toxicological effects.  In some cases, PK/ADME for the new 
formulation or route might not be available.  In these cases, an assumption of 100 percent 
bioavailability from the proposed clinical dose might be used to judge the adequacy of available 
systemic toxicity information.  
 
 
V.  ROUTE OF ADMINISTRATION CONSIDERATIONS 
 
In addition to evaluating the adequacy of the available toxicity information, possible toxic effects 
relevant to the particular route of administration should be considered.  Information on toxic 
effects might be insufficient when there is a change in the route of administration with a new 
formulation.  Even reformulations that do not change the route of administration might have 
local toxic effects not previously observed, because new combinations of active and inactive 
ingredients can produce additive or new effects.  For example, two ingredients (active or 
inactive) that produce only mild irritation when used separately might produce more pronounced 
irritation when used together or one ingredient may alter the metabolism of another and 
consequently change its toxicity. 
 
A.  Considerations for All Routes of Administration 
 
For all drug product reformulations and for all drug products with new routes of administration, 
acute and/or repeat-dose toxicity studies with complete histological evaluation should be 
conducted using the clinical route of administration.  Acute studies may not be needed when 
repeat-dose studies are conducted. In general, durations of the toxicity studies should follow the 
recommendations outlined in ICH M3(R2) or ICH S9.  For a new formulation that will be used 
by the same route as the previously approved product, shorter duration toxicity studies than those 
outlined in ICH M3(R2) may be appropriate.  
 
If systemic exposure by a new route of administration is equivalent to or less than that of the 
approved route, histological evaluation may be limited to locally exposed tissues.  If there are 
insufficient data or a safety concern about any of the excipients in the formulation, the inclusion 
of a saline, water, or untreated control in the safety studies should be considered.  
 
B.  Route-Specific Considerations  
 
In addition to the considerations for all routes listed in sections IV. and V.A., the route-specific 
recommendations described in the following sections should be considered for all new  
formulations, whether they are proposed for a new route or the same route as a previous 
formulation.  Note that as with systemic toxicity, new studies may not be needed if existing 
information is already sufficient.  Similar recommendations can be considered for any route not 
mentioned here. 
 
  4
  Contains Nonbinding Recommendations 
1.  Oral 
 
No studies are recommended in addition to the toxicity studies listed in section V.A. 
 
2.  Dermal (Including Patches) 
 
 	  The potential for delayed hypersensitivity of the new formulation should be evaluated. 
 
 	  The potential for phototoxicity should be evaluated according to the principles outlined in the 
ICH guidance for industry S10 Photosafety Evaluation of Pharmaceuticals.   
 
 	  If the new formulation contains a drug substance that has not been evaluated for ocular 
irritation, then the potential of the topical drug product to induce irritation of the eyes if the 
eyes were inadvertently exposed to the product should be appropriately addressed.  The 
topical drug products ocular irritation potential should be evaluated through the use of 
appropriate in vitro or ex vivo methods.  The in vivo rabbit ocular irritation test method is no 
longer recommended for topical drug products.    
 
 	  If the new formulation contains a drug substance that has not been used by the dermal route, 
the repeat-dose local toxicity study mentioned earlier should be conducted in a nonrodent 
species (preferably minipig).  This study should be of the same  duration as clinical use (up to 
9 months for chronically used drugs) and include both local and systemic evaluation.  
  
 	  The skin dose from topically applied drug products can be orders of magnitude higher than 
the skin dose after systemic administration.  Therefore, a dermal carcinogenicity study might 
be recommended for drugs with a chronic indication even if systemic carcinogenicity studies 
are available.  However, a dermal carcinogenicity study might be waived if a chronic dermal 
study in an appropriate nonrodent species shows no preneoplastic effects and there are no 
other causes for concern (i.e., there are no genotoxicity signals and systemic carcinogenicity 
data show no concern.) 
 
 	  Dermal studies generally should be conducted with untreated control, vehicle control, and 
complete formulation groups. 
 
3.  Intravenous 
 
 	  Compatibility with blood (e.g., in vitro hemolysis, protein flocculation, platelet activation) 
should be evaluated. 
 
4.  Ocular 
 
 	  If the drug substance has not been previously administered by the proposed ocular route, then 
toxicity studies in two species with complete ocular and systemic evaluation for the 
appropriate duration should be carried out with the new formulation.  A study in a single 
most appropriate species may be adequate if the drug substance has been previously 
administered by the proposed ocular route.  Ocular toxicity can be assessed using slit lamp  
  5
  Contains Nonbinding Recommendations 
biomicroscopy (with and without fluorescein staining), funduscopy, tonometry, 
electroretinography, and histopathology. 
   
 	  Ocular studies generally should be conducted with vehicle control and complete clinical 
formulation groups.   
 
 	  These studies should include the evaluation of systemic exposure.  Ocular tissue distribution 
should also be assessed. 
 
5.  Otic 
 
 	  The dermal irritation and potential for delayed contact hypersensitivity of the new 
formulation should be evaluated. 
 
 	  The ability of the drug product to penetrate an intact tympanic membrane should be 
determined and the exposure to the middle and inner ears in an animal model should be 
estimated when this barrier is or is not intact.  
 
	   If the drug product is expected to reach the middle or inner ear during clinical use or is 
introduced directly to those regions, evaluation of the auditory brainstem response, as well as 
microscopy of relevant otic tissues, including a cytocochleogram, should be included in acute 
and/or repeat-dose studies conducted by intratympanic administration. 
 
6.  Inhalation 
 
	   If a drug substance in the new formulation has not been tested by inhalation, then inhalation 
toxicity studies should be conducted. These studies should consist of short-term studies (2 to 
4 weeks) in two species (at least one nonrodent) followed by up to a 6-month study in the 
most appropriate species with the new formulation for a chronically indicated drug.  Studies 
for new formulations should include sham (air) control, vehicle control, and complete 
formulation groups. 
 
	   For drug products administered chronically by inhalation, carcinogenicity studies by the oral 
route can be sufficient when no toxicity suggesting proliferative or preneoplastic changes is 
observed in chronic inhalation toxicity studies and when adequate local airway exposure by 
the oral route is demonstrated. 
 
7.  Intranasal 
 
	   The nonclinical studies carried out to support a new intranasal formulation generally should 
be similar to the studies for new formulations administered by inhalation.   
 
	   These studies should consist of short-term studies (2 to 4 weeks) in two species (at least one 
nonrodent) followed by up to a 6-month study in the most appropriate species with the new 
formulation for a chronically indicated drug product.  Studies for new formulations should 
include vehicle control and complete formulation groups.  Vehicle and complete formulation 
  6
  Contains Nonbinding Recommendations 
groups generally should be treated by the intranasal route (e.g., intranasal instillation) to 
maximize direct exposure of nasal tissues.  Histological assessment should include local 
tissues and potentially affected brain areas.  Inhalation studies may be adequate to assess 
intranasal safety if adequate local exposure can be demonstrated.  
 
 	  An inhalation study also may be recommended if the particle size (less than or equal to 5 
micrometers) results in lung deposition.  
 
8.  Vaginal 
 
 	  The new formulation should be evaluated for delayed hypersensitivity. 
 
 	  Reproductive and developmental toxicity of the new formulation should be evaluated by the 
vaginal route in one species if exposure in previous studies was inadequate to cover exposure 
from the vaginal route and the previous studies did not show a developmental risk. 
 
9.  Rectal 
 
No studies are recommended in addition to the toxicity studies listed in section V.A. 
 
10.  Intraoral (Including Buccal or Lingual, or Periodontal) 
 
This route applies to products intended to deliver the drug substance within the mouth.  The 
following recommendations should be considered for the intraoral route: 
 
 	  The possibility of accidental swallowing should be considered when comparing systemic 
exposure from the proposed new formulation with toxicokinetic data obtained using a 
different route or formulation.  Previously conducted oral studies to support an oral dosage 
form may be sufficient.  If the new formulation contains a drug substance not previously 
tested by oral administration, or if exposure associated with the new formulation is not 
qualified by data obtained previously, then toxicity studies conducted by the oral route (i.e., 
gavage, dietary, or drinking water) should be conducted.  Studies should include thorough 
gross and histopathological examination of the gastrointestinal tract.  
 
 	  An intraoral local tissue toxicity study in one species of the new formulation with a dosing 
frequency that meets or exceeds clinical frequency can be conducted.  If this study includes 
animals with abraded oral mucosa then an assessment of the effect of the drug on the healing 
of oral lesions is possible. Alternatively, frequent clinical monitoring of the oral cavity in 
early phases of clinical development can be used to ensure that excessive local irritation of  
the oral cavity does not occur in humans.   
 
11.  Intracavernosal or Intraurethral 
 
	   If a drug substance has not been tested for the effect on male fertility then the new 
formulation should be evaluated for its effect on male fertility in the most appropriate 
species.  
  7
  Contains Nonbinding Recommendations 
 
12.  Intravesicular (Intrabladder) 
 
	   Reproductive and developmental toxicity of the new formulation should be evaluated if 
exposure in previous studies was inadequate to cover exposure from the intravesicular 
(intrabladder) route and the previous studies did not show a developmental risk. 
 
13.  Extended Release Injected or Implanted Formulations 
 
	   If the drug substance has not been tested in an extended release formulation previously, but 
all inactive ingredients have been tested by this route, then a toxicity study of the proposed 
new formulation should be carried out in the most appropriate species.  The animals should 
be monitored for a period of time after administration sufficient to assess the entire duration 
of the extended release.  
 
	   The fate of any materials associated with the formulation (e.g., solid material from an  
implant) should be determined.  
 
14.  Intrathecal or Epidural 
 
	   If the drug substance has not been previously approved for use by either the intrathecal or 
epidural route of administration, toxicity studies in two species (at least one nonrodent) with 
the intended clinical formulation should be conducted.  
 
	   If the drug is under development for epidural route of administration only, the studies in two 
species should include dosing by both the epidural route and the intrathecal route of 
administration to understand the risks in case unintentional intrathecal delivery occurs in the 
clinical setting. 
 
	   If the drug product is under development for intrathecal route of administration only, 
nonclinical studies via the epidural route should not be necessary. 
 
	   Toxicity studies of a new formulation should be conducted in two species for the appropriate 
duration for a reformulation of a currently approved intrathecal or epidural drug product in 
which the new formulation contains a higher concentration of drug substance.  If one species 
has been determined to be the most sensitive species, sponsors should provide the review 
division with justification for use of a single species for evaluation.  
 
	   Because of the localized high drug product levels, an evaluation of the neurotoxicity, 
including behavioral observations and gross and histopathological analysis of the central 
nervous system, is strongly encouraged in all studies.  Such analysis may require special 
techniques and stains. 
 
	   The evaluation of the pharmacokinetics of the new formulation should include analysis of 
steady-state levels in the cerebrospinal fluid in addition to systemic levels of the drug 
substance. 
  8
  Contains Nonbinding Recommendations 
 
 	  The design of nonclinical studies should reproduce as closely as possible the intended 
clinical dosing regimen, taking into consideration the drug substance concentration, the 
volume to be administered, and the rate of infusion.   
 
15.  Subcutaneous or Intramuscular 
 
No studies are recommended in addition to the toxicity studies listed in section V.A. 
  9