Originally Published MDDI March 2005

Coatings



Combination products face different, and often more difficult, hurdles to jump for FDA approval.

Phil Triolo

The potential benefit of coating an existing product with a drug or biologic to improve efficacy and increase profits is significant. The regulatory requirements and technical issues, however, can be daunting. For combination products—those that combine in some way a drug, device, or biologic—the development process can challenge the resources of even the largest medical device manufacturer.

An initial concern is which of FDA's centers will be primarily responsible for regulating the product. In addition, most device manufacturers have little or no experience working with the drug that will be included in the device or its coating. They not only have to decide how to select, possibly modify, and incorporate the drug into the product. They must also demonstrate its acceptable toxicity and shelf life and characterize its release into the body. In addition, coated combination products must often be shown to be safe and effective by conducting preclinical and, often, clinical evaluations.

In a previous article in MD&DI, I discussed the technical and regulatory requirements for coatings that do not contain a therapeutic drug or biologic.¹ Here, I will focus specifically on those products in which a therapeutic drug or biologic (agent) is incorporated in a coating (carrier) or attached to a device (platform) surface. I'll also explore the additional requirements for coatings that contain a therapeutic agent.

Who Will Be the Lead Center?

Primary regulatory jurisdiction for combination products can be assigned to either CDRH, the Center for Drug Evaluation and Research (CDER), or the Center for Biologics Evaluation and Research (CBER). Because device manufacturers are familiar with CDRH's PMA process, and the fees for reviewing such applications are lower than those for reviewing biologic or drug applications, device manufacturers generally prefer having CDRH as a lead center.

The Office of Combination Products (OCP) assigns the center that will have primary regulatory responsibility for a combination product. That decision is based on the product's primary mode of action, as defined in the proposed 21 CFR Part 3 (italics added):

Primary mode of action is the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall therapeutic effects of the combination product.²

The proposed rule also provides an algorithm for cases when the primary mode of action of a new combination product is unclear. It is prudent to discuss the specifics of complicated or unclear situations with OCP or with the center likely to review the product's PMA application.

A manufacturer can also send OCP a formal request for designation stating its case for assigning a product's review and regulatory responsibility to a particular lead center.³ The device's primary mode of action must be the first criterion used to make a lead center assignment.

Assignment of CDRH does not lessen the regulatory requirements for the agent component of the combination product. The review of agent information may be assigned to a consulting or collaborating CDER or CBER

reviewer if required expertise does not reside within CDRH. In the case of drug-eluting cardiovascular stents (DES), CDRH is the lead center, while CDER conducts consulting reviews.

The offices that review certain parts of the IDE and PMA applications for a DES include:

• Cardiovascular device: ODE (CDRH).
• Cardio-renal drug product: Office of New Drugs (CDER).
• New drug chemistry: Office of Pharmaceutical Science (CDER).
• Pharmaceutical evaluation: Office of Clinical Pharmacology and Biopharmaceutics (CDER).
• Mechanics and materials: Office of Science and Technology (CDRH).

Three of the five offices involved in the premarket review are located in CDER. The information they provide is influential, but final authority to approve the product always rests with the lead center.

The consulting center may have issues or questions that require the longest time for the manufacturer to address. For CDRH lead-center reviews, this is especially true if the device part of the combination product is already approved for an identical use. The agent's manufacture; rate of release from the carrier; stability, purity, quality, and potency; and safety and efficacy will require the most attention.

Design Verification

Design verification activities demonstrate whether product specifications are met. The performance of the platform, the carrier, and the agent must be verified. However, each of these elements can influence the performance and safety of the others, which complicates verification requirements.

The verification activities for the platform and carrier without an agent present were explained in the previous article.1 The additional consequences of applying the carrier and agent to the platform have to be considered when developing a combination product. The manufacturing process must not degrade (e.g., corrode if it is metallic, embrittle if it is polymeric, etc.) platform performance.

The agent has potentially minor effects on the performance of the carrier. Adhesion of the carrier to the platform is a concern and must be verified with the agent present. In addition, agent elution can create voids in the carrier and, if the voids are significant, can lead to unwanted or early carrier degradation. The carrier must be characterized with the agent present after it is exposed to final manufacturing process conditions. It must be characterized again after agent release if the release could significantly alter the carrier's properties.

Most design verification activities that are required for coated combination products but not for coated devices concern the agent and its release rate. A medical device manufacturer does not normally address agent manufacture, stability, and safety and efficacy issues. Doing so can be extremely expensive and time-consuming. It is a good idea, from a practical standpoint, to choose an agent that is approved for a similar intended use in the United States, and whose manufacturer is willing to share and discuss its drug master file (DMF) in support of an application.

Drug Development

It is usually not practical for device manufacturers to conduct a Phase I investigational new drug (IND) study for an agent to be used in a combination product. So, whenever possible, previously approved drugs are used. The partnering drug manufacturer is typically asked to provide the required safety information by allowing FDA to access its DMF.⁴ The usefulness of the information provided in the DMF depends on whether it is applicable to the drug when used in the coated product. Generally, the DMF can provide manufacturing information on the drug substance or product to satisfy chemistry, manufacturing, and control requirements.^5,6

Additionally, systemic toxicity information can usually be leveraged from the DMF. Fortunately, the total dose present in the coated combination product often is less than the amount known to produce a systemic toxic effect.

There are often differences in method of administration or intended use between the approved drug and the drug in the coated device. Therefore, additional data must be collected specifically for the drug in the combination product to supplement those in the DMF. The required information about the drug's safety and efficacy can be collected in design verification studies and preclinical and clinical investigations.

Release Profile

The agent's release profile is arguably the most important characteristic of a coated combination product. It is typically presented as a graph of the percentage of the agent that is released as a function of time.

The release profile is initially created in vitro under controlled conditions. Usually, the release medium is physiologically buffered saline (PBS) or bovine serum albumin maintained at 37°C and 7.4 pH. It may be necessary to add a small amount of surfactant or alcohol to enable the release of hydrophobic drugs, which may not be soluble in PBS. Also, the release medium should be continually agitated. Doing so facilitates creation of sink conditions and eliminates any boundary layers, which can hinder the agent's diffusion from the carrier.

In vitro release profile information can determine the effects of different agent and carrier characteristics on the release rate. It can be used to optimize agent and carrier properties and the amount of agent in the carrier during product development. During manufacturing, it serves as a quality control check to verify that the coating process is consistent from lot to lot.

However, the in vitro release rate is rarely the same as the in vivo release rate. The agitation provided by constant shaking facilitates removal of the released agent from the surface of the carrier. When the agent is released from the surface of an implanted device, it must diffuse into the surrounding biological fluid and then cross cell membranes. The agent's transport from the product surface may be slower in the biological environment than in vitro, reducing the release rate. In addition, an avascular fibrous capsule typically forms around implanted devices, further slowing the diffusion of agent into the surrounding tissue.

Therefore, the best way to estimate the release profile that will occur in patients is to perform release studies in a suitable animal model. The product should be implanted in its intended anatomical location, and agent release should be recorded as a function of time.

The concentration and quantities of agent released are so small they are difficult to measure, especially when dispersed in tissue. Therefore, the product is usually explanted at predetermined times, and the amount of agent remaining is measured. The agent lost from the product is assumed to have been released into the surrounding tissue.

The goal of product development activities is to produce a release profile that meets the physiologic requirements for the agent. That is, the agent released to the target tissue should be within the therapeutic window for the desired treatment time. The therapeutic window is the concentration of agent that falls between the minimum therapeutic concentration and the concentration known to have a toxic effect.

Generally, one of two mechanisms is used to control delivery from the carrier. Chemically controlled systems rely on the controlled degradation of the carrier or on ion-exchange mechanisms to release agent that is physically trapped or chemically or physically bound. In diffusion-controlled systems, agent release is controlled by a membrane at the carrier surface or by the characteristics of the tortuous path the agent must take to reach the target tissue.

The release profile can be controlled by a number of methods, including using different carriers or combinations of carriers. Altering the agent's solubility in the carrier or biological environment or its interaction with the carrier, modifying its concentration in the carrier, and changing coating thickness are other means of modifying the release profile. A pure polymeric overcoat onto the carrier loaded with the agent can serve as a rate-controlling membrane. However, the polymeric overcoat must be compatible with and adhere to the carrier; to achieve this, it is often composed of the carrier material itself, or a chemically similar material.

The analytical methods used to characterize the agent-and-carrier coating are numerous and specific to the delivery systems employed. The agent can either be dispersed or dissolved in the carrier. If dispersed, particle size and morphology are important characteristics that influence the release profile. Techniques such as scanning electron microscopy, atomic force microscopy, or confocal microscopy can confirm agent particle size uniformity and disper sion. X-ray or thermogravimetric analyses can verify the crystallinity of the agent and carrier.

When the agent's release depends on the carrier's degradation, the carrier properties (molecular weight, molecular-weight distribution, cross-link density, crystallinity, etc.) need to be tightly controlled. An FDA guidance document, although written for the testing of biodegradable polymer orthopedic devices, provides useful information for the characterization of any biodegradable system.⁷

Most polymers used as carriers are dissolved during manufacturing operations. The amount of solvent, as well as other manufacturing materials remaining in the product, must be controlled to levels known to be safe. Residual quantities must not have a significant effect on agent release rate or potency or product toxicity.

Biocompatibility and Toxicity

The biocompatibility requirements for a coated combination product are the same as those for a coated medical device and are identified in ISO 10993-1.⁸ Potential side effects, including known toxicities, can be documented if the drug has been the subject of previous animal or clinical investigations. If unknown, the agent's toxicity must be assessed to the extent required in a Phase I IND application before initiating a clinical trial for the device. Dose-ranging studies in preclinical evaluations can establish safety and justify evaluation of the agent in humans.

Stability and Shelf Life

The issue of drug stability is important for coated products. Sometimes, the processing required to incorporate the agent into the coating and to sterilize the finished device can degrade it. The agent must be physically dispersed or dissolved in the carrier, and the effects of solvation or physically manipulating the drug in the carrier must be evaluated. The results should demonstrate that the desired potency and concentration of the drug required to achieve the desired release profile have been achieved.

The International Committee on Harmonization and FDA documents suggest collecting stability data on at least 10 samples at numerous time points after product sterilization.^9,10 The number of samples or the number of time points when samples are evaluated can be decreased through an agreement with FDA. A reduction in sample requirements can reduce manufacturing and testing requirements while meeting the same safety and effectiveness requirements. However, there is an increased risk in the process, since the acceptable number of failed units is also reduced.

Methods Validation

It may be possible, and it is highly desirable, to use USP or other validated test methods to determine the purity and potency of the agent. However, such methods are not always relevant for the agent in a coated combination product. The agent may be chemically modified or present in solvents different from those used in the validated method, or in concentrations below the limits of detection of the instrumentation or method. In such cases, a new analytical method must be developed and validated to demonstrate its repeatability and reproducibility, sensitivity, and limits of detection. FDA has outlined recommendations for performing methods validation.¹¹

Pre-IDE-Submission Meetings

Pre-IDE-submission meetings are imperative for helping FDA understand the product and its development plan. They also inform the manufacturer of the agency's thoughts on its requirements for demonstrating that the combination product is safe and effective for its intended use.

Bringing experts to the meeting to discuss the specifics of the development program can facilitate communication, especially if new test technologies, methods, or clinical trial designs are involved.

For novel products, a pre-IDE meeting should be held as soon as the product design is well-defined, indications for use are documented, and the product development plan is created. However, it is important to schedule meetings with FDA when they are needed to clarify positions or receive concurrence on a plan of action. Specific proposals are most effective, because these can elicit comments that provide concrete guidance.^12,13

Preclinical Investigations

Preclinical animal tests should be performed to support the IDE. They can be used to optimize the agent delivery profile and establish the safety of the product so that clinical trials can begin. Often, animal models are well established for the medical conditions to be treated by the product. Such animal models should be used whenever practical.

Animal studies are used to gather required pharmacokinetic (absorption, distribution, metabolism, and excretion) and pharmacodynamic information for the agent released from the product. Safety data previously obtained for the drug when delivered systemically must be augmented with local toxicity data for the drug when delivered via the combination product. Dose-ranging studies should be performed as part of these local toxicity studies. Whenever possible, the studies should include deliberate administration of an overdose to ensure that toxic limits of the agent are quantified.

The desired local effects resulting from release and distribution of the agent into the volume of tissue surrounding the product must be demonstrated. A lack of systemic effect may be assumed if the total amount of agent present is below levels known to exert a clinical effect.

As always, FDA should be consulted before initiating preclinical studies and, if possible, should be asked to review protocols. All rationales for not performing suggested studies or for the use of historical data to supplement or replace data must be acceptable to the agency.

Clinical Evaluations

A random, controlled clinical trial is the standard way to assess clinical safety and effectiveness. Except size, there are no special requirements for a clinical trial of a coated combination product that are not applicable to a trial of an uncoated device. The trial must demonstrate a reasonable assurance of safety and efficacy of the constituent parts of the device and the agent. The coated product is typically compared with the noncoated device in the trial to demonstrate the improvement in safety or efficacy provided by the agent.

The size of the trial for a combination product is larger than that for an uncoated device. The increased size reflects concerns about the safety and efficacy of the agent parts. For example, in Johnson & Johnson's Cypher DES clinical trial, approximately 1100 patients were enrolled.1¹⁴ For a DES or other novel coated combination product, FDA recommends using independent core laboratories, clinical event committees, and an active data-safety-monitoring board.

FDA required the sponsor to perform a 5-year follow-up of patients enrolled in the DES study. The long follow-up period enabled an assessment of any long-term safety issues and a determination of the long-term efficacy of the product. Extensive guidance on device clinical trials is available from FDA's Web site, at www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfIDE/daIDEgd_print.cfm.

Manufacturing Requirements

Combination products are unique because manufacturers must meet two sets of quality system requirements. The quality system regulation (QSR) requirements apply to medical device manufacturing. Current good manufacturing practices (CGMP) requirements apply to drug and biologic manufacturing. To manufacture a combination product, FDA requires both systems to be considered during and after the joining of the device and agent parts.

For drug manufacturers that already meet the CGMP requirements, the QSR requirements to consider include design and purchasing controls and corrective and preventive actions. For device manufacturers that already meet the QSR requirements, the CGMP requirements of note are those for drug and container testing, drug stability, and the retention of samples. FDA identifies the specific requirements for consideration on its Web site.

Validation of the processes used to manufacture device and drug constituents must be completed before the combination product can be marketed. However, not all process validations need to be completed before initiating a clinical trial.^15,16
In addition, the labeling for a coated combination product must address device and agent issues. Final labeling requirements must be negotiated with FDA. Guidance on the labeling of combination products is being drafted by OCP.

Postmarketing Activities

The requirements for reporting adverse events for drugs and those for medical device reporting are not the same.^17,18 Different criteria are used to determine which events are reportable and how quickly FDA must be informed. It is possible to define a specific reporting system to be used for a coated combination product in the request for designation. It is logical to apply the medical device reporting (MDR) requirements to products whose lead center is CDRH, and the adverse event reporting system (AERS) requirements to products assigned to CDER. This has been the case for DES, where reports are submitted to CDRH in accordance with MDR requirements. CDRH then shares the data with CDER. Guidance on this subject is being drafted.

Current Coated Combination Products

A considerable number of coated combination products that are regulated as devices by CDRH have been successfully introduced to the marketplace. The products include heparinized intravascular catheters and cardiopulmonary bypass circuits, antimicrobial bone cements and intravascular and urinary catheters, and cardiac pacing leads with steroid-coated tips. Many of these products have been cleared under 510(k)s. CDRH often has the expertise to review many of these products in-house, eliminating the need for a consulting or collaborative review.

FDA's guidance documents for 510(k)s for coatings applied to intravascular catheters and urological catheters are particularly useful.^19,20 The information recommended for inclusion in premarket notifications for these coated combination products can serve as a basis for creating PMA applications for similar products.

Some manufacturers have noticed an increased regulatory scrutiny for devices with heparin coatings, including Joe Chinn, director of commercial regenerative technologies at SurModics Inc. (Eden Prairie, MN). Chinn says CDER's consultation for a heparin coating may result in additional premarket questions about the use of heparin in medical device coatings. “We anticipate more questions for device manufacturers concerning the amount of heparin released from coatings than in previous submissions,” he says. This is true even though the coatings and amounts released are fundamentally the same as those cleared in previous submissions.

Conclusion

The creation of OCP has, for the most part, cleared the path for determining regulatory jurisdiction for coated combination products. When regulated by CDRH, such products typically require a consulting review by CDER or CBER personnel. Manufacturers unfamiliar with the requirements for drugs or biologics should incorporate already-approved drugs or biologics into their coated products whenever possible. Partnering with a drug manufacturer to provide basic information on the agent's manufacture and safety profile can speed the development process.

Greater concerns exist for a coated combination product than for an uncoated device. These concerns mostly involve the safety of the agent when delivered to a small volume of tissue and its stability when manufactured into the final product. Ultimately, a clinical trial is typically required to demonstrate that the coated combination product is safe and efficacious and improves the performance or safety of the uncoated device.

References

1. Phil Triolo, “Using Risk Analysis to Develop Coated Medical Devices,” Medical Device & Diagnostic Industry 27, no. 1 (2005): 130–140.
2. Code of Federal Regulations, 21 CFR 3, Docket No. 2004N–0194, Federal Register, vol. 69, no. 89 [on-line] (Rockville, MD: FDA, 2004); available from Internet: www.fda.gov/OHRMS/DOCKETS/98fr/oc03366.pdf.
3. Code of Federal Regulations, 21 CFR 3.7.
4. Guideline for Drug Master Files [on-line] (Rockville, MD: FDA, CDRH, 1989); available from Internet: www.fda.gov/cder/
guidance/dmf.htm.
5. Draft Guidance: Drug Product Chemistry, Manufacturing, and Controls Information [on-line] (Rockville, MD: FDA, CDER, 2003); available from Internet: www.fda.gov/cder/guidance/
1215dft.pdf.
6. Draft Guidance: Drug Substance Chemistry, Manufacturing, and Controls Information [on-line] (Rockville, MD: FDA, CDER, 2004); available from Internet: www.fda.gov/cder/guidance/
3969DFT.doc.
7. Draft Guidance Document for Testing Biodegradable Polymer Implant Devices [on-line] (Rockville, MD: FDA, CDRH, 1996); available from Internet: www.fda.gov/cdrh/ode/odegr914.html.
8. ISO 10993-1, “Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing” (Geneva: International Organization for Standardization, 2003).
9. Guidance for Industry: Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products [on-line] (Rockville, MD: FDA, CDER, 2003); available from Internet: www.fda.gov/cder/guidance/4985fnl.pdf.
10. Draft Guidance: Stability Testing of Drug Substances and Drug Products [on-line] (Rockville, MD: FDA, CDER, 1998); available from Internet: www.fda.gov/cder/guidance/1707dft.pdf.
11. Draft Guidance: Analytical Procedures and Methods Validation: Chemistry, Manufacturing, and Controls Documentation [on-line] (Rockville, MD: FDA, CDER, 2000); available from Internet: www.fda.gov/cder/guidance/2396dft.htm.
12. IDE Guidance Memorandum D95-1, Goals and Initiatives for the IDE Program [on-line] (Rockville, MD: FDA, CDRH, 1995); available from Internet: www.fda.gov/cdrh/d951.html.
13. IDE Guidance Memorandum D99-1, Pre-IDE Program: Issues and Answers [on-line] (Rockville, MD: FDA, CDRH, 1999); available from Internet: www.fda.gov/cdrh/ode/d99-1.html.
14. Boam, Ashley, “Drug-Eluting Stents: Current Approach to Review” (presented at Workshop on Innovative Systems for Delivery of Drugs and Biologics: Scientific, Clinical, and Regulatory Challenges, July 8, 2003).
15. Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Premarket Approval [on-line] (Rockville, MD: FDA: Office of Regulatory Affairs, 1993); available from Internet: www.fda.gov/ora/compliance_ref/cpg/
cpgdrg/cpg490-100.html.
16. Quality System Information for Certain Premarket Application Reviews; Guidance for Industry and FDA Staff [on-line] (Rockville, MD: FDA, CDRH, 2003): available from Internet: www.fda.gov/
cdrh/comp/guidance/1140.html.
17. Adverse Event Reporting System (AERS) [on-line] (Rockville, MD: FDA, CDER, 2002); available from Internet: www.fda.gov/
cder/aers/default.htm.
18. Medical Device Reporting (MDR) [on-line] (Rockville, MD: FDA, CDRH, 2002); available from Internet: www.fda.gov/cdrh/mdr.
19. Guidance on Premarket Notification [510(k)] Submission for Short-Term and Long-Term Intravascular Catheters [on-line] (Rockville, MD: FDA, CDRH, 1995); available from Internet: www.fda.gov/cdrh/ode/824.pdf.
20. Guidance for the Content of Premarket Notifications for Conventional and Antimicrobial Foley Catheters [on-line] (Rockville, MD: FDA, CDRH, 1997); available from Internet: www.fda.
gov/cdrh/ode/oderp097.html.

Phil Triolo, PhD, RAC, is president of Phil Triolo and Associates LC (Salt Lake City), an organization that assists companies in developing new medical devices and combination products that meet regulatory requirements.

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