Contains Nonbinding Recommendations 

Guidance for Industry 

and FDA Staff: 

Early Development 

Considerations for Innovative 

Combination Products 

For questions regarding this document, contact: 

Patricia Y. Love, MD, Office of Combination Products, at 301-427-1934. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

Office of Combination Products 

September 2006 
Contains Nonbinding Recommendations 

Guidance for Industry 

and FDA Staff 

Early Development 

Considerations for Innovative 

Combination Products 

Additional copies are available from: 

Office of Combination Products, HFG-3 

Office of the Commissioner 

Food and Drug Administration 

15800 Crabbs Branch Way, Suite 200 

Rockville, MD 20855 

(Tel) 301-427-1934 

(Fax) 301-427-1935 

http://www.fda.gov/oc/combination

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

Office of Combination Products (OCP) 

September 2006 
Contains Nonbinding Recommendations 

Public Comment 

Written comments and suggestions may be submitted at any time for Agency consideration to the 

Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 

1061, (HFA-305), Rockville, MD 20852. Submit electronic comments to 

http://www.fda.gov/dockets/ecomments. When submitting comments, please refer to the exact 

title of this guidance document. Comments may not be acted upon by the Agency until the 

document is next revised or updated. 
Contains Nonbinding Recommendations

TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

A. Definition ........................................................................................................................... 3

B. How are combination products regulated? .................................................................... 3

III. GENERAL DEVELOPMENT CONSIDERATIONS................................................... 5

IV. CURRENTLY MARKETED PRODUCT CONSIDERATIONS ................................ 6

V. PERSPECTIVES BY CONSTITUENT PART.............................................................. 7

A. Device constituent considerations.................................................................................... 7

B. Drug and biological product constituent considerations............................................... 8

VI. ADDITIONAL PERSPECTIVES ................................................................................. 10

A. Clinical Investigation...................................................................................................... 10

B. Manufacturing considerations....................................................................................... 11

C. Reliance on information not developed by the applicant............................................ 12

VII. EARLY INTERACTION AND COMMUNICATION WITH FDA.......................... 12

A. Where may I obtain additional information?............................................................... 13
Guidance for Industry and FDA Staff1 1 

2 

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4 

Early Development Considerations for 

Innovative Combination Products 

5 This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

6 does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

7 You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

8 and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

9 implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

10 number listed on the title page of this guidance. 

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I. INTRODUCTION 

This document provides guidance to industry and FDA staff on developmental considerations for 

innovative products that combine devices, drugs and/or biological products. It is intended to 

provide a context for initial discussions on the type of scientific and technical information that 

may be necessary for investigational or marketing applications for these combination products. 

This guidance focuses on combination products as defined under 21 CFR 3.2(e). The concepts 

may also be useful for the co-development of devices, drugs, and biological products that are 

used concomitantly but which do not meet the regulatory definition of a combination product. 

This information supplements existing guidance documents developed by the Center for 

Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health 

(CDRH), the Center for Drug Evaluation and Research (CDER), and the Office of Combination 

Products (OCP). 

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. 

1

 This guidance has been prepared by the Center for Devices and Radiological Health, the Center for Biologics 

Evaluation and Research, the Center for Drug Evaluation and Research, and the Office of Combination Products in 

the Office of the Commissioner at the Food and Drug Administration. 
Contains Nonbinding Recommendations

29 II. BACKGROUND 

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FDA recognizes that innovative technologies may raise a spectrum of scientific and technical 

development issues. Combination products are increasingly incorporating cutting edge, novel 

technologies that hold great promise for advancing patient care. Innovative drug, biological 

product, device combinations have the potential to make treatments safer, more effective, or 

more convenient or acceptable to patients. For example, drug-eluting cardiovascular stents may 

reduce the need for repeated surgery by helping to prevent the restenosis that may occur after 

stent implantation. Drug and biologic products can be used in combination to potentially 

enhance the safety and/or effectiveness of either product used alone. Proteins incorporated into 

novel orthopedic implants may facilitate the regeneration of bone required to permanently 

stabilize the implants. Drug-device inhalation systems provide a new route of insulin delivery 

that may decrease the need for insulin injections. Genomic-based diagnostic devices may be 

used to help determine whether certain patients are suitable candidates for a drug or biological 

product, or at risk for certain types of adverse events.2

 

During an FDA workshop entitled, “Innovative Systems for Delivery of Drugs and Biologics: 

Scientific, Clinical and Regulatory Challenges,” industry and academic stakeholders requested 

that FDA provide guidance for the development of innovative technology that may challenge 

existing approaches.3 For example, what pre-clinical or animal studies are appropriate to begin 

human studies, or what types of clinical trial designs may be appropriate? Further, FDA 

recognizes that combination product development may raise a number of Critical Path4

challenges to progress from a novel concept to an innovative marketed product. 

Some of these developmental challenges may not be readily apparent. For example, although a 

combination product may be comprised of an already approved drug and an already approved 

device, new scientific and technical issues may emerge when the drug and device are combined 

or used together. New methodologies may need to be developed for manufacturing, evaluation 

of preclinical safety in targeted areas of the body, or clinical trial design to establish safety and 

effectiveness. 

FDA websites contain a wide variety of guidance documents for the development and testing of 

drugs, devices, and biological products. These address drugs, devices, or biological products as 

individual products, but few guidance documents currently address the scientific and technical 

issues to consider when combining drug, device, and/or biological product constituent parts as a 

combination product.. 

FDA believes it is important to address the scientific and technical issues raised by innovative 

combination products in order to develop efficient, appropriate techniques and methods to ensure 

the safety, effectiveness, and quality of the combination product. 

2

 Drug-pharmacogenomic test pairings may be considered combination products, depending how the products are 

intended for use and labeled. FDA is developing separate guidance for the co-development of drug and genomicbased diagnostic devices, and these types of products are not specifically addressed in this document. 

3

 A summary of the workshop is available at http://www.fda.gov/oc/combination/workshop070803.html. 

A transcript is available at http://www.fda.gov/ohrms/dockets/dockets/03n0203/03n0203.htm. 4

 See The Critical Path to New Medical Products at http://www.fda.gov/oc/initiatives/criticalpath/.

2
Contains Nonbinding Recommendations

64 A. Definition 

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As defined in 21 CFR 3.2(e), a combination product is a product comprised of any combination 

of a drug and a device, a biological product and a device, a drug and a biological product, or a 

drug, device, and a biological product. This includes: 

• “A product comprised of two or more regulated components; i.e., drug/device, 

biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or 

otherwise combined or mixed and produced as a single entity; 

• Two or more separate products packaged together in a single package or as a unit and 

comprised of drug and device products, device and biological products, or biological and 

drug products; 

• A drug, device, or biological product packaged separately that according to its 

investigational plan or proposed labeling is intended for use only with an approved 

individually specified drug, device, or biological product where both are required to 

achieve the intended use, indication, or effect and where upon approval of the proposed 

product the labeling of the approved product would need to be changed; e.g., to reflect a 

change in intended use, dosage form, strength, route of administration, or significant 

change in dose; or 

• Any investigational drug, device, or biological product packaged separately that 

according to its proposed labeling is for use only with another individually specified 

investigational drug, device, or biological product where both are required to achieve the 

intended use, indication, or effect.” 

For purposes of this guidance, a constituent part of a combination product is an article in a 

combination product that can be distinguished by its regulatory identity as a drug, device, or 

biological product, as defined in section 21 U.S.C. 321, Federal Food, Drug, and Cosmetic Act 

(Act), and 42 U.S.C. 252 (i), Public Health Service Act, and as set forth in 21 CFR 3.2(k). For 

example, a device coated or impregnated with a drug has two constituent parts, the device 

constituent and the drug constituent. For simplicity, the concepts in this guidance are described 

in the context of a combination product composed of two constituent parts. These concepts are 

also relevant for combination products with more than two constituent parts. 

B. How are combination products regulated? 

FDA’s Office of Combination Products (OCP) was established in 2002 as required by the 

Medical Device User Fee and Modernization Act of 2002. As set forth in section 503(g) of the 

Act, OCP is responsible for the prompt assignment of a lead Agency center that will have 

primary jurisdiction for the review and regulation of a combination product; ensuring timely and 

effective premarket review by overseeing the timeliness of and coordinating reviews involving 

more than one agency center; ensuring consistent and appropriate postmarket regulation of 

combination products; and resolving disputes regarding the timeliness of combination product 

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Contains Nonbinding Recommendations

review. OCP also works with agency centers to develop guidance and regulations to make the 

regulation of combination products as clear, consistent, and predictable as possible. 

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Under section 503(g)(1) of the Act, a combination product is assigned to a center with primary 

jurisdiction, or a lead center, based on a determination of the primary mode of action (PMOA) of 

the combination product. PMOA is defined as “the single mode of action of a combination 

product that provides the most important therapeutic action of the combination product.” For 

example, if the PMOA of a device-biologic combination product were attributable to its 

biological product constituent, the Agency component responsible for premarket review of that 

biological product would have primary jurisdiction for the combination product. The final 

regulation also includes an assignment algorithm that the Agency will use when the most 

important therapeutic action of a combination product cannot be determined with reasonable 

certainty.5 

A combination product is assigned to one of the Agency’s three human medical product Centers: 

CBER, CDER, or CDRH. The lead center has oversight responsibility for the review and 

regulation of the combination product. The lead center often consults or collaborates with other 

agency components and OCP, as appropriate, to identify and evaluate the information needed for 

a regulatory submission (e.g., investigational application or marketing authorization). 

In streamlining the review of combination products, FDA established a Standard Operating 

Procedure for the Intercenter Consultative and Collaborative Review Process.6 The document 

provides the policies and procedures for FDA staff to follow when requesting, receiving, 

handling, processing, and tracking formal consultative and collaborative reviews of combination 

products, devices, drugs and biologics. The objectives of the SOP are to ensure timely and 

effective intercenter communication on combination products, as well as the timeliness and 

consistency of intercenter consultations and collaborations. 

This guidance describes general information on developmental considerations for products that 

combine devices, drugs, and/or biological products. Although details on the regulatory processes 

described in this section are beyond the scope of this guidance document, FDA encourages 

developers to contact OCP for assistance in determining the assignment of a lead center when 

jurisdiction is unclear or in dispute, the number and type of marketing applications7

, the 

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 See final rule for Definition of the Primary Mode of Action of a Combination Product, published August 25, 2005, 

Federal Register, http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf 6

See Intercenter Consultative/Collaborative Review Process at 

http://www.fda.gov/oc/combination/consultative.html. 7

 For most combination products, a single marketing application is sufficient for the product’s approval, clearance or 

licensure. In some cases, however, a sponsor may choose to submit two marketing applications for a combination 

product when one application would suffice. For example, a sponsor may choose to submit two applications in 

order to receive some benefit that accrues only from approval under a particular type of application (e.g., new drug 

product exclusivity, orphan status, or proprietary data protection when two firms are involved). In other cases, FDA 

may determine that two marketing applications are necessary. For example, when one of the individual constituent 

parts of a combination product is already approved for another use, and where the labeling of the already approved 

product will need to be changed to reflect its new intended use in the combination product, FDA may determine that 

two applications are necessary if the labeling of the already approved product is subject to legal requirements 

different from those that will apply to the combination product. FDA encourages applicants who are uncertain as to 

whether a single or multiple marketing applications should be submitted for a combination product to discuss the 

issue with the lead reviewing Division and/or OCP. Information about the applicable time frames is provided in the 

4
Contains Nonbinding Recommendations

premarket review process, and the postmarket regulations such as adverse event reporting or 

good manufacturing practice requirements that may be appropriate for a combination product. 

OCP will work with the agency Centers as appropriate to facilitate a response. Additional 

information on combination product regulation, guidance, and process is available on OCP’s 

website.

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8 

III. GENERAL DEVELOPMENT CONSIDERATIONS 

As with other medical products, combination product development typically focuses on the 

scientific and technical issues raised by the particular product being developed. For a 

combination product, these scientific/technical issues will ordinarily reflect the combination 

product itself as well as its constituent parts. When combining products such as drugs or 

biologics and devices that are customarily developed using different regulatory paradigms, 

certain critical developmental issues, such as the interaction of the drug/biologic and device 

constituents, may not be readily apparent. Further, because of the breadth, innovation and 

complexity of combination products, there is no single developmental paradigm appropriate for 

all combination products. 

Existing guidance documents are generally excellent starting points for considering the types of 

issues raised by the constituent parts of a combination product, but often they will need 

adaptation to fully address the combined nature of a combination product. For example, 

guidance for preclinical evaluation of drugs/biologics differs from the preclinical/non-clinical 

studies conducted for devices. When developing a combination product, it is likely that neither 

isolated approach would fully address the relevant preclinical development questions for both 

constituents as well as for the combination product as a whole. Instead, FDA recommends that 

developers consider the scientific and technical issues raised by the combination product and its 

constituents and propose an approach that appropriately addresses these issues without requiring 

duplicative or redundant studies. 

In many circumstances, the development considerations depend on the type of combination 

product. When the combination product is comprised of constituents that are chemically, 

physically or otherwise combined or mixed and produced as a single entity, developers should 

consider and, as appropriate, evaluate the potential for a broad range of drug/biologic/device 

interactions. For example, for a drug eluting stent, the mechanical attributes of the polymer 

coating system that contains the drug substance are important for stent deployment, drug release, 

biocompatibility, and stability. For some combination products, the constituents may have 

synergistic effects that should be evaluated. In the context of these studies, it is appropriate to 

discuss approaches to avoid duplication/redundancy and to develop strategies to streamline the 

overlapping aspects of development. 

Innovative new technology may also challenge existing approaches for product development. 

For example, a new device used to deliver a drug/biologic to a new area of the body that was 

guidance document “Submission and Resolution of Formal Disputes Regarding the Timeliness of Premarket Review 

of a Combination Product,” available at http://www.fda.gov/oc/combination/dispute.pdf. 8

 See OCP’s website at http://www.fda.gov/oc/combination. 

5
Contains Nonbinding Recommendations

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previously inaccessible might make it necessary to develop new methods to determine the effect 

of such localized/targeted delivery, particularly when it results in higher exposure to that target 

than when the drug is systemically administered. Likewise, innovative technologies such as 

nanotechnology or live cellular products may lead to the development of new manufacturing 

methodologies or unique safety issues not associated with products manufactured in other ways. 

The following sections describe general principles to consider when developing information to 

demonstrate the safety and effectiveness of a combination product and its constituent parts. We 

recommend that combination product developers particularly consider the preclinical and nonclinical testing that should be conducted for their product, and how such testing may be 

influenced by the interaction of the constituent parts, and any prior approval/clearance of a 

constituent part. FDA believes that the general principles described in this guidance document 

would assist developers in providing the appropriate data to help establish the safety and 

effectiveness of innovative combination products. Consideration of these issues in the context of 

existing guidance documents may lead to a more targeted and efficient development pathway for 

the combination product. 

IV. CURRENTLY MARKETED PRODUCT CONSIDERATIONS 

Prior FDA approval and/or clearance of a particular constituent part of a combination product is 

often an excellent starting point for considering the appropriate data to establish safety and 

effectiveness for its use in a combination product. FDA recommends that developers fully 

consider what is already established about a constituent part; i.e., what existing information and 

data are available, to avoid duplication and ensure a more timely and efficient development 

process. Throughout the development process, however, it is critical to recognize that it is the 

combination product that is being developed for approval/clearance, not just the constituent part. 

While this prior information is often very helpful, developers should recognize that additional 

data and information may be necessary to address the scientific and technical issues raised by the 

new use of the constituent in the combination product. These issues may be raised by combining 

the constituent parts or by new uses for the constituent in the combination product, such as a new 

indication for use, a different target population, a new route of administration, or by different 

local or systemic exposure profiles once the products are combined. For example, developers 

should consider: 

 Are the constituent parts already approved for an indication? 

 Is the indication for a given constituent part similar to that proposed for the combination 

product? 

 Does the combination product broaden the indication or intended target population 

beyond that of the approved constituent part? 

 Does the combination product expose the patient to a new route of administration or a 

new local or systemic exposure profile for an existing indication? 

 Is the drug formulation different than that used in the already approved drug? 

 Does the device design need to be modified for the new use? 

 Is the device constituent used in an area of the body that is different than its existing 

approval? 

6
Contains Nonbinding Recommendations

 Are the device and drug constituents chemically, physically, or otherwise combined into 

a single entity? 

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271 • Changes in the stability or activity of a drug constituent when used together with an energy 

272 emitting device. 

 Does the device function as a delivery system, a method to prepare a final dosage form, 

and/or does it provide active therapeutic benefit? 

 Is there any other change in design or formulation that may affect the safety/effectiveness 

of any existing constituent part or the combination product as a whole? 

 Is a marketed device being proposed for use with a drug constituent that is a new 

molecular entity? 

 Is a marketed drug being proposed for use with a complex new device? 

As illustrated in the following sections, FDA recommends that the developmental studies should 

take into account these questions as appropriate for the constituent parts alone and for the 

finished combination product. FDA furthermore recommends that these issues be considered in 

the context of the proposed indication. 

V. PERSPECTIVES BY CONSTITUENT PART 

A. Device constituent considerations 

For new device constituent parts, some safety and/or effectiveness testing of the device alone 

may be necessary before or along with the studies to establish the safety and effectiveness of the 

combination product as a whole. For device constituent parts that are already approved/cleared 

for another purpose, the extent of preclinical testing largely would focus on the new use of the 

device constituent as part of the combination product. For example, if a combination product 

incorporates an indwelling, intravenous drug delivery catheter for a new use for long-term, drug 

delivery in the brain, new biocompatibility studies may be necessary to establish the safety of the 

device materials for placement in neural tissues. New engineering or functional testing may also 

be necessary to establish the suitability of the device design to the new environment in which it 

will be used. 

Consideration should also be given to the potential interaction (desired or undesired) between the 

device and the drug/biological constituents. For example, it may be appropriate to conduct 

studies to evaluate the potential for the following: 

• Leachables/extractables of the device materials into the drug/biologic substance or final 

combination product; 

• Changes in stability of the drug constituent when delivered by the device or when used as a 

coating on the device; 

• Drug adhesion/absorption to the device materials that could change the delivered dose; 

• Presence of inactive breakdown products or manufacturing residues from device manufacture 

that may affect safety, or device actions that could change the drug performance 

characteristics at the time of use; or 

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Contains Nonbinding Recommendations

273 Likewise, similar consideration should be given to the effects a drug or biological product may 

274 have on the device constituent. For example, the material properties of a delivery catheter may 

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be adversely affected by some drug/biologic products but not others. 

CDRH has an active program of evaluating and recognizing consensus standards.9 For many 

combination products, it may be appropriate to use these existing cons

device constituents of a combination product, including the standard test methods. For others, 

particularly those that are innovative, it may be appropriate to adapt these standards, or it may 

necessary to develop new methodologies. Because of the range of combination products and 

developmental strategies, developers are encouraged to seek early discussions with FDA when 

exploring the application of standards to candidate constituent parts and when alternative 

methodologies or approaches are being developed. 

B. Drug and biological product constit

W w molecular entity (NME) is a constituent part of a combination p

to what information is necessary to characterize the safety and eff c

NME when used in the combination product. Generally this begins with a consideration of the 

NME alone; e.g., the preclinical information necessary to begin the initial studies in human 

subjects of the NME and the information needed for combination of the NME and the device 

constituent. For example, certain conventional pharmacology and toxicology studies may be 

necessary to establish the safety profile of the NME alone (e.g., genotoxicity, mutagenicity, 

immunotoxicity, and local tolerance) before beginning clinical investigation of the combinatio

product.11 It is also important to consider the timing to initiate any necessary reproductive and

carcinogenicity studies; these types of studies are generally conducted after beginning the 

clinical investigation, and they are generally submitted in the marketing application for the 

product. 

When the combination product contains a drug/biologic constituent that is already approved

another u

or understood safety, effectiveness, and/or dosing requirements posed by the new combination. 

The following are examples of when additional preclinical or clinical safety information or new 

clinical studies may be appropriate for the drug/biologic constituent and/or the combination 

product: 

1. Approved drug or biological product with a change in formulation, strength, route of

ad

2. New dosage (e.g., absolute dose, dosing duration, dosing regimen, or total exposure); 

9

 See consensus standards recognized by FDA 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. 10 For purposes of this discussion, the term drug applies to drug and most biological product constituent parts. 

11See Guidance to Industry: Format and Content of Non-clinical Pharmacology/Toxicology Section of an 

Application at http://www.fda.gov/cder/guidance/index.htm. General pharmacology-toxicology guidances may also 

be found at this location. 

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312 3. New patient population, (e.g., pediatric, geriatric, pregnant or nursing women, or change 

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316 egardless of the approval status of the drug/biologic constituent, the marketing application 

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329 ther possible considerations when devising a development plan for a product incorporating a 

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in disease or disease status); or 

Change in approved indication. 

R

should contain appropriate data to establish the overall safety and effectiveness of the propos

new dosing regimen or indication as proposed in the combination product. For a combination 

product with a drug or biological product constituent that is already approved, it may be possib

to tailor the pre-clinical development program to address safety questions posed by the new route 

or method of delivery, or the change in indication or population. The goal of these studies would 

be to evaluate changes that may result in a different extent or distribution of drug constituent 

exposure.

12 To the extent that the combination product permits local or systemic drug exposu

that is greater than that occurring with approved dosing regimens, additional safety studies may 

also be needed to address the higher doses. New studies may be appropriate to evaluate the 

local/regional toxicity of a drug/device combination product administered directly to targeted

tissue. 

O

drug/biologic constituent include: 

strength, route of administration, dosing, population or other factors that may alter the 

extent or time course of systemic exposure. These studies might be used to determine 

drug release kinetics such as release rate, local peak concentrations of the drug, local 

distribution and systemic bioavailability (Cmax, Tmax, etc.). 

Dose ranging or dose finding studies13 in humans may be ap

adjustments for safety/effectiveness when therapy is targeted to a local site. 

Acute and repeat dose toxicity studies using the new route of administration 

delivery may be appropriate to determine the NOAEL (no observed adverse effect level) 

and toxicity profile of the combination product. Typically, these studies would evaluate 

the intended clinical formulation and dosing regimen/frequency that will closely 

approximate its use in clinical settings. 

Special safety studies may be appropriate

e.g., hepatotoxicity, QT prolongation, special populations. 

Specific safety monitoring in the clinical study may be appro

novel aspects presented by the combination product; e.g., local toxicity for a new route o

administration.14 

12 See Guidance to Industry: Exposure-Response Relationships - Study Design, Data Analysis, and Regulatory 

Applications at http://www.fda.gov/cder/guidance/5341fnl.doc. 13 See ICH E4 Dose-Response Information to Support Drug Registration at 

http://www.fda.gov/cder/guidance/iche4.pdf. 14 See ICH E1A: The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term 

Treatment of Non-Life-Threatening Conditions at http://www.fda.gov/cder/guidance/iche1a.pdf.

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In some instances, developers may be able to provide relevant information from the literature or 

may rely on prior agency findings to address these issues. When this is not possible, then 

additional studies may be necessary. 

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VI. ADDITIONAL PERSPECTIVES 

A. Clinical Investigation 

For most combination products, one investigational application (Investigational New Drug (IND) 

or Investigational Device Exemption (IDE) application) is submitted for the clinical investigation 

of the combination product as a whole. Generally, the regulatory guidance for INDs and IDEs 

provides substantial flexibility in considering how to address the issues posed by a particular 

product. Two such guidance documents that may be of interest to combination product 

developers are: (1) Exploratory IND Studies, which provides an alternative for exploring 

candidate products during research and development prior to selecting the composition for 

further development,15 and (2) guidance on changes that may occur during investigational 

development of a device.16 

Clinical development questions frequently arise about trial design, sample size, statistical 

methods, clinical endpoints, appropriate number of clinical studies, and appropriate 

indications/claims. We recommend that you consider the science and technology of the 

combination product when determining sample size, use of statistical approaches, surrogate 

endpoints, techniques to measure drug levels in areas not typically accessible, or techniques to 

evaluate drug-device interactions. Although these issues are beyond the scope of this guidance, 

FDA encourages developers to seek early discussion with the Agency around these concerns. 

For certain combination products that include a device constituent part, it may be necessary to 

evaluate the human factors of device use on the safety and effectiveness of the combination 

product. Such studies would evaluate how users operate the system in realistic, stressful 

conditions. In many cases, these studies include an assessment of all components and 

accessories necessary to operate and properly maintain the device; e.g., controls, displays, 

software, logic of operation, labels, instructions, analysis of critical tasks, use error hazard and 

risk analysis. We recommend that human factors evaluations take place early in the combination 

product development process to identify design features that may need modification before 

conducting the key studies to establish the safety and effectiveness of the combination product. 

15See Guidance to Industry and Reviewers: Exploratory IND Studies at 

http://www.fda.gov/cder/guidance/7086fnl.pdf. 16 See Guidance to Industry: Changes or Modifications During the Conduct of a Clinical Investigation at 

http://www.fda.gov/cdrh/ode/guidance/1337.pdf

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387 B. Manufacturing considerations 

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Manufacturing, scale-up, and quality management17 are important considerations during the 

development of a combination product. Manufacturing methodologies affect both premarket 

development and postmarket regulation. FDA encourages consideration of the manufacturing 

issues posed by the scientific and technical aspects of the drug, biological product, and device 

constituent parts, and of the combination product as a whole. FDA also encourages developers 

to carefully consider the effect of the manufacturing methods on the interaction of the constituent 

parts. For example, the stability of a combination product as a whole may be different than that 

of the separate constituent parts. Certain drug or biological product constituent parts may be 

altered or destroyed by terminal sterilization techniques. For constituent parts that use aseptic 

manufacturing techniques, developers are encouraged to implement manufacturing techniques to 

ensure aseptic control for the combination product. 

During premarket investigation, once the preclinical and clinical studies begin, any potential 

change in the manufacturing process for the drug, biologic, or device constituents or for the 

combination product may affect the safety or effectiveness of the combination product as a 

whole. For example, changes in concentration, inactive ingredients, software, or in the methods 

to combine two constituent parts, could affect the performance characteristics of the combination 

product. When applying cellular constituent parts to a device, the performance characteristics 

may vary with the time and methods used for cellular incubation before application to the device 

constituent. Additionally, the applicable device constituent design controls would consider 

anticipated manufacturing changes during investigational development. In order to address such 

manufacturing considerations, it may be necessary to develop new manufacturing techniques, inprocess testing, testing specifications, and other characterization methods to assess changes in 

the constituent parts and for the combination product as a whole. For certain developmental 

changes, additional bridging studies (in vitro, preclinical, or clinical) may be appropriate. 

In addition to considering manufacturing changes that may occur during premarket development, 

FDA also recommends early consideration of anticipated postmarket manufacturing changes for 

the combination product or its constituent parts. FDA encourages manufacturers to establish 

arrangements with the manufacturers of constituent parts to maintain sufficient awareness of 

manufacturing changes in constituent parts that may occur during the premarket or postmarket 

period. Such awareness could help to ensure continued safety and effectiveness of the 

combination product by ensuring that the potential impact of a manufacturing change is 

evaluated in a manner appropriate for the stage of combination product development. As 

appropriate, these postmarket manufacturing changes may require careful review, validation and 

prior approval before marketing. For some products, it may be helpful to develop post-approval 

change protocols for further discussion with the Agency. 

17 FDA’s current thinking about good manufacturing practices for combination products is described in “Draft 

Guidance for Industry and FDA Staff: Current Good Manufacturing Practice for Combination Products,” available 

at http://www.fda.gov/oc/combination/OCLove1dft.html. FDA intends to propose current good manufacturing 

practice regulations for combination products; see the April 24, 2006 Federal Register (71 FR 22565). 

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427 C. Reliance on information not developed by the applicant 

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Investigational or marketing applications often contain trade secret or confidential commercial 

information. In some instances, developers may wish to provide all necessary information in one 

marketing application. However, for combination products being developed by more than one 

manufacturer, there may be a desire to provide necessary information to FDA while maintaining 

the confidentiality of each manufacturer’s intellectual property. This can be accomplished by the 

application holder submitting to FDA a letter of authorized cross reference from the owner of the 

referenced material. This letter would grant FDA permission to consider the referenced material 

in its review of the current application. In general, the referenced information may be available 

from two sources: 

1. Existing application: An existing investigational application (IND or IDE) or an 

existing marketing application (NDA, BLA, PMA or 510(k)) may provide 

information relevant to a new developer’s application. In some instances, the 

application being cross referenced may be under co-review for use in the combination 

product. In other instances, the cross-referenced application may be approved for 

other purposes, but may have information relevant to the new use. 

2. Master file: Master files provide an administrative method to submit confidential 

information to FDA when an appropriate investigational or marketing application for 

the constituent is not available. A master file is not a substitute for an investigational 

or marketing application. FDA neither approves nor disapproves master files; rather, 

information in a master file is considered in the context of a particular investigational 

or marketing application. It should be recognized that the information in a master file 

may be sufficient to support a marketing application for one product, while additional 

information may be necessary to support its use in another product. For example, this 

may occur when specific issues raised by the new use of a constituent are not 

addressed in the master file. Such information could be provided by supplementing 

the existing master file, or by providing the necessary information in the application 

under review. More information on drug master files may be found in 21 CFR 

314.420 or at http://www.fda.gov/cder/dmf/index.htm. More information on device 

master files is available at 

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VII. EARLY INTERACTION AND COMMUNICATION WITH FDA 

FDA strongly encourages early communication and discussion between developers, FDA review 

components and, as appropriate, OCP. Early dialogue allows developers to obtain initial 

feedback on the kinds of preclinical and clinical testing that may be necessary. Such 

communication may identify critical issues for product development and help to ensure an 

efficient development and approval process. Further, early and frequent communication 

provides the opportunity for FDA to establish its intercenter review team and to develop the 

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appropriate scientific expertise to facilitate timely and efficient reviews of any future 

submissions. 

CBER, CDER and CDRH provide guidance on milestone/collaboration meetings throughout the 

development process and submission of investigational and marketing applications. Preinvestigational (pre-IND and pre-IDE) meetings are particularly useful for discussing innovative 

combination products. Pre-marketing application meetings are also helpful to discuss application 

content, as well as the sequence and timing of modular applications or when more than one 

marketing application will be submitted for the combination product. Guidance on how to 

arrange developmental meetings can be obtained on the CDER,18 CBER19 and CDRH20

websites. 

The lead center should be contacted to schedule meetings in accordance with the procedures and 

milestones applicable to the lead center. We encourage developers to request participation from 

relevant review components from both the lead and consulting Centers, where appropriate. In 

addition, OCP is available formally or informally to address jurisdictional, developmental, 

premarket review, and postmarket concerns. 

A. Where may I obtain additional information? 

OCP is available as a resource to developers and review staff throughout the lifecycle 

(assignment, development, premarket review and postmarket regulation) of a combination 

product. The Office can be reached at (301) 427-1934 or by email at combination@fda.gov. In 

addition, the Office maintains an updated list of FDA guidance documents that developers may 

find helpful in the development of their products. The guidance is available at the Office’s 

Internet Website at 

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In addition each center maintains a guidance webpage that provides comprehensive information 

on the types of constituents regulated in the center. The CDER Guidance webpage is accessible 

502 at http://www.fda.gov/cder/guidance/index.htm. The CDRH Guidance web page is accessible at 

503 http://www.fda.gov/cdrh/guidance.html and the device advice webpage is assessable at 

504 http://www.fda.gov/cdrh/devadvice/. The CBER Guidance web page is accessible at 

505 http://www.fda.gov/cber/guidelines.htm. 

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18 See http://www.fda.gov/cder/guidance/3683fnl.pdf. 19 See http://www.fda.gov/cber/gdlns/ind052501.htm. 20 See http://www.fda.gov/cdrh/devadvice/ide/print/approval.html , and, Early Collaboration Meetings Under the FDA 

Modernization Act, Final Guidance for Industry and CDRH Staff; http://www.fda.gov/cdrh/ode/guidance/310.html

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