Guidance for Industry 

and Review Staff 

Nonclinical Safety Evaluation of 

Reformulated Drug Products and 

Products Intended for Administration 

by an Alternate Route 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact (CDER) Paul Brown at 301-796-0856. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2008 

Pharmacology/Toxicology 

I:\7686dft.doc 

2/22/2008 
Guidance for Industry 

and Review Staff 

Nonclinical Safety Evaluation of 

Reformulated Drug Products and 

Products Intended for Administration 

by an Alternate Route 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2008 

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.......................................................................................................4

B. Route-Specific Considerations......................................................................................................4

1. Oral..................................................................................................................................................4

2. Dermal (Including Patches).............................................................................................................4

3. Intravenous ......................................................................................................................................5

4. Ocular ..............................................................................................................................................5

5. Otic...................................................................................................................................................5

6. Inhalation.........................................................................................................................................6

7. Intranasal.........................................................................................................................................6

8. Vaginal.............................................................................................................................................6

9. Rectal ...............................................................................................................................................6

10. Intraoral (Including Buccal or Lingual, or Periodontal) ...........................................................6

11. Intracavernosal or Intraurethral ................................................................................................7

12. Intravesicular (Intrabladder)......................................................................................................7

13. Extended Release Injected or Implanted Formulations ..............................................................7

14. Intrathecal or Epidural ...............................................................................................................7

15. Subcutaneous or Intramuscular..................................................................................................8
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

Guidance for Industry and Review Staff1 1 

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Nonclinical Safety Evaluation of Reformulated 

Drug Products and Products Intended for 

Administration by an Alternate Route 

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9 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

10 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

11 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

12 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

13 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

14 the appropriate number listed on the title page of this guidance. 

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I. INTRODUCTION 

This guidance provides recommendations regarding the nonclinical evaluation of a new 

formulation containing a previously approved drug substance and of a product proposed for use 

by an alternate route of administration for which the product was not previously approved. This 

guidance is intended for individuals or organizations 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 products containing previously approved drug 

substances and proposals for existing formulations to be used in a new route of administration. 

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 formulation containing a previously approved drug substance and 

provides nonclinical evaluation information for formulations intended for use by new routes of 

administration even if there is no change in the composition of the formulation. Although this 

situation does not represent a reformulation, it is appropriate in this case to reevaluate 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 or 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 

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 This guidance has been prepared by the Pharmacology/Toxicology Coordinating Committee in the Center for Drug 

Evaluation and Research (CDER) at the Food and Drug Administration. 

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listed drug.2 This guidance pertains to new formulations containing previously approved drug 

substances only and does not address the safety evaluation of excipients. For recommendations 

regarding nonclinical issues that apply to excipients, see the guidance for industry Nonclinical 

Studies for the Safety Evaluation of Pharmaceutical Excipients.

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The goals of this guidance are to: 

• Communicate to industry the FDA’s current thinking pertaining to safety data needed to 

support these drug products 

• Increase uniformity within CDER on recommendations for the nonclinical development of 

reformulated drug products and drugs being used by an alternate route 

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 

Generally, nonclinical data support use of a drug by a particular route and also reflect the 

planned duration of use. For example, antibiotics intended for short-term use generally do not 

have carcinogenicity studies. Much of the available nonclinical information used to support 

approval of the initial formulation can be used to support the safety of additional formulations, 

but this may not be sufficient to support such additional approvals because changes in the 

formulation could produce a new toxicity. This is particularly true if the drug’s route of 

administration is different, or the duration of use changes markedly. Therefore, additional 

nonclinical studies might be recommended to ensure that the toxicity of a new formulation is 

fully characterized. 

If the new formulation is to be used similarly to previous formulations, the need for further 

nonclinical data generally will be small. However, if the alternative formulation will be used in a 

substantially different way (e.g., new route, longer duration) then the need for additional 

nonclinical data becomes greater. Indeed, further nonclinical evaluation information for drugs to 

be used by new or alternate routes or greater duration 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 

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 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). 

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 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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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 generally 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 carcinogenicity data are recommended for new formulations 

indicated for long-term use or for the original formulation when newly proposed for long-term 

use. 

We recommend that the ICH guidance for industry M3 Nonclinical Safety Studies for the 

Conduct of Human Clinical Trials for Pharmaceuticals and the appropriate review division be 

consulted regarding when nonclinical data should be provided relative to clinical development. 

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 the systemic exposure 

obtained after administration of a proposed new formulation or of a previous formulation by a 

new route. Additional toxicity studies might be recommended if the available toxicity 

information is not sufficient to support the exposure measured with the new formulation or if a 

significantly different pattern of exposure results from the new formulation. 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 toxicity data, if 

any, are recommended. When comparing the PK/ADME of a new formulation with a previously 

approved formulation, it is important to examine the shape of the concentration/time curve and 

not just the total area under curve. For example, alterations in absorption or the dosing 

frequency can produce significantly different concentration/time profiles that might lead to 

different toxicological effects. Changes in the vehicle composition or form also can alter the PK 

of active ingredients. In some cases, PK/ADME for the new formulation 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. 

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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 relevant to proposed new routes might be deficient when a reformulation results in a 

change in the route of administration from the one previously used. Even reformulations that do 

not result in a change of route might still have some local toxic effects not previously observed 

since 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. 

A. Considerations for All Routes 

For all reformulations and all routes, depending on the route of administration, acute and repeat 

dose local toxicity studies with histological evaluation should be conducted either in one species 

(e.g., skin for dermal formulations or patches; lung for inhaled formulations; gastrointestinal for 

oral formulations; injection site for intravenous, subcutaneous, intraperitoneal, or intramuscular 

formulations; extended release injected or implanted formulations; intracavernosal or 

intraurethral; intrabladder) or in two species (e.g., ocular; intrathecal or epidural). 

B. Route-Specific Considerations 

In addition to the considerations for all routes listed in section 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 might not be critical for an 

adequate evaluation of a particular concern, if existing information is already sufficient. Similar 

recommendations can be considered for any route not mentioned here. 

1. Oral 

No studies are recommended in addition to the acute and repeat dose toxicity studies listed in 

section V.A. 

2. Dermal (Including Patches) 

• The delayed hypersensitivity potential of the new formulation should be evaluated. 

• Photoirritation should be evaluated if the new formulation absorbs ultraviolet or visible 

radiation (290 nm to 700 nm) and if the product is applied to sun-exposed skin. If the new 

formulation is a patch, then photoirritation should be considered if the patch is permeable to 

light and is applied to sun-exposed skin. (See the guidance for industry Photosafety Testing.) 

• If the new formulation contains an active ingredient that has not been used by the dermal 

route, the repeat dose local toxicity study mentioned earlier should be conducted in a 

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nonrodent species. This study should be of at least the same duration as clinical use (up to 9 

months) and include both local and systemic evaluation. 

• The skin dose from topically applied drug products can be orders of magnitude larger 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. 

• The photococarcinogenic potential should be evaluated if the new formulation is used 

chronically on sun-exposed skin. Evaluation of photococarcinogenicity generally is not 

recommended for patch products. (See the guidance for industry Photosafety Testing.) 

• Nonclinical dermal studies generally should be conducted with untreated control, vehicle 

control, and complete formulation groups. 

3. Intravenous 

• Compatibility with blood should be evaluated. 

4. Ocular 

• If the active ingredient has not been used by the ocular route, then toxicity studies in two 

species with complete eye and systemic evaluation for the appropriate duration should be 

carried out with the new formulation. In certain cases, studies in one most appropriate 

species may be adequate. Optimal design of these studies would include the evaluation of 

ocular and systemic PK. Ocular toxicity can be assessed using slit lamp biomicroscopy (with 

fluorescein staining), funduscopy, tonometry, and histopathology. Nonclinical ocular studies 

generally should be conducted with vehicle control and complete formulation groups. 

5. Otic 

• The dermal irritation and delayed contact hypersensitivity potential of the new formulation 

should be evaluated. 

• The ability of the drug 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 is expected to reach the middle or inner ear during clinical use, 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. 

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• If an active ingredient 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 in two species followed by up to a 6-month study in the most appropriate species with 

the new formulation for a chronically indicated drug. Optimal design of these studies for 

new formulations would include sham control, vehicle control, and complete formulation 

groups. 

• For drugs 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 and by the oral 

route (because intranasally administered drugs can be swallowed). 

8. Vaginal 

• The new formulation should be evaluated for delayed hypersensitivity. 

• Reproductive and developmental toxicity of the new formulation should be evaluated 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 acute and repeat dose 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 an active ingredient 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. Optimal design of these studies 

would include thorough gross and histopathological examination of the gastrointestinal tract. 

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• 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. As 

an alternative to this clinical approach, a 28-day nonclinical oral irritation study of the new 

formulation with a dosing frequency that meets or exceeds clinical frequency can be carried 

out. 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. 

11. Intracavernosal or Intraurethral 

• If an active ingredient 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. 

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 active ingredient has not been tested in an extended release formulation previously, but 

all inactive ingredients have been tested by this route, then a single dose 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, studies in two 

species by both the epidural route and the intrathecal route of administration are still 

recommended to understand the risks in case unintentional intrathecal delivery occurs in the 

clinical setting. 

• If the drug is under development for intrathecal route of administration only, nonclinical 

studies via the epidural route should not be necessary. 

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• 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 active ingredient. 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 levels, an evaluation of the neurotoxicity, including gross 

and histopathological analysis of the central nervous system, is strongly encouraged in all 

studies. 

• The evaluation of the PK of the new formulation should include analysis of the cerebrospinal 

fluid in addition to systemic levels of the drug. 

• The design of nonclinical studies should reproduce as closely as possible the intended 

clinical dosing regimen, taking into consideration the drug concentration, the volume to be 

administered, and the rate of infusion. 

15. Subcutaneous or Intramuscular 

No studies are recommended in addition to the acute and repeat dose toxicity studies listed in 

section V.A. 

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