Originally Published MDDI May 2005
Many regulatory considerations may be unfamiliar to manufacturers pursuing market approval of combination products. Understanding and planning for these considerations can significantly affect FDA review and approval times.
Stuart Portnoy and Steven Koepke
|Table I. Differences in device and drug development and FDA regulation (click to enlarge).|
Products that combine a drug or biologic with a device, such as drug-eluting stents and drug-delivery systems, can offer valuable approaches for treating diseases. With the approval of Johnson & Johnson's Cypher drug-eluting stent in 2003 and Boston Scientific's Taxus drug-eluting stent in 2004, drug-device combination products have attracted significant medical and media attention.
Novel combination products are currently subject to intense regulatory scrutiny for the issues of safety and effectiveness they raise. A team of device and drug product reviewers at FDA is dedicated to evaluating such products. Beyond drug-eluting stents, combination products may include innovative drug-delivery systems, hemostatic sealants, photodynamic-therapy systems, gene-therapy systems, and products for many other investigational treatments.
This article discusses the preclinical testing requirements that have historically been required for drug-eluting stents. The requirements, though not uniformly or consistently applicable for other types of drug-device combination productions, may provide a good starting point for getting such products approved. Certain critical regulatory strategy considerations may be unfamiliar to many device and pharmaceutical manufacturers pursuing market approval of combination products. A later article will focus on drug testing requirements including chemistry, manufacturing, and controls, an equally important set of technical and regulatory considerations.
|Table II. Combination-product examples and FDA center jurisdiction (click to enlarge).|
An overarching consideration is awareness of the different clinical and scientific approaches at FDA's CDRH versus the Center for Drug Evaluation and Research (CDER). For example, consider a device manufacturer submitting its first drug-device combination product application to FDA. The manufacturer often fails to realize that CDER likely has different—and higher—expectations and testing performance standards than CDRH. Table I summarizes some of the differences between drugs and devices.
The sponsor of a new combination product should determine early in the product development process which FDA center will have the lead responsibility for reviewing the submission. By law, assignment of the lead center is made based on a determination of the product's primary mode of action (PMOA). Table II provides an informal guide to previously established combination-product jurisdictional determinations. For example, if the combination product contains a biologic component and a device, and if the biologic is responsible for the PMOA, the product will be regulated by the FDA Center for Biologics Evaluation and Research (CBER).
Determination of a combination product's PMOA establishes which center takes lead review responsibility. In most cases, the FDA center that assumes the lead review responsibility also will have jurisdictional responsibility (see Table III).
OCP and RFD
|Table III. Combination-product responsibilities of FDA centers (click to enlarge).|
Because of the growing number of combination-product applications, FDA recently established the Office of Combination Products (OCP), located in FDA's Office of the Commissioner. OCP serves many critical functions. It provides guidance to manufacturers pursuing development and market approval of combination products; it resolves jurisdictional and other issues that often arise during premarket review of combination products, especially novel therapies; and it arbitrates disputes between FDA and external stakeholders.
Manufacturers can submit to OCP a request for designation (RFD), which is a 60-day formal process for establishing which FDA center will have jurisdictional responsibilities. While the RFD is an important formal process, practically speaking, informal consultations can also be very helpful. The OCP staff is remarkably accessible by phone or e-mail to assist applicants with informal and nonbinding jurisdictional advice.
If a sponsor does request a formal RFD, OCP helps manufacturers during the 60-day RFD review period. Informal interactions leading up to the formal RFD submission can provide the sponsor with a critical opportunity to present and enhance its position beyond the written RFD submission.
OCP is open-minded and flexible about many complex issues regarding the regulation of combination products. So, stakeholders should seek contact with OCP staff as a valuable and often-informal resource for information and guidance.
|Table IV. CDRH and CDER combination-product review teams (click to enlarge).|
The ease of obtaining FDA approval for a drug-device combination product depends on the individual regulatory status of the drug and device components. In the case of drug-eluting stents, incorporating a previously approved drug into the combination product made market approval much easier than if the drug had been investigational. This was true even though the drug had a different intended use for the combination product compared with its original approved indication.
The greater difficulty of obtaining market approval with an investigational drug arises from CDER requirements for demonstrating drug safety. For example, the Taxus stent was approved in 2004 for use in preventing coronary artery restenosis. The active ingredient in the stent, paclitaxel, had already been approved for many years to treat cancer. FDA's prior approval of paclitaxel as chemotherapy was critical in facilitating approval of the paclitaxel-stent combination product, because the drug's safety was well established.
In approving Taxus, FDA evaluated safety and effectiveness results from a clinical trial that treated approximately 1000 patients. By contrast, if the drug had been investigational, the manufacturer would likely have been required to provide clinical data from perhaps as many as 2000 patients to adequately evaluate safety. Thus, the regulatory status of the drug will likely significantly affect the amount of safety data necessary to support FDA approval of a combination product.
Pre-IDE and Pre-IND Evaluation Processes
Combination products are typically subject to one of two different but parallel initial FDA evaluations: CDRH's investigational device exemption (IDE) and CDER's investigational new drug (IND) processes. However, they rarely require both. Depending on center jurisdiction, a sponsor must formally follow the IDE process for combination products regulated as medical devices or the IND process for products regulated as drugs. Regardless of jurisdiction, the sponsor typically needs to provide FDA with data to support both processes. For example, drug-eluting stents are regulated by CDRH as medical devices and therefore follow the pre-IDE process. However, the series of FDA submissions leading to product approval all involve some data specifically intended to be reviewed by CDRH (e.g., stent mechanical performed testing) and other data relevant to CDER review (e.g., CMC).
Once a sponsor is ready to freeze the design version of the combination product, the applicant should consider submitting a pre-IDE or a pre-IND application to FDA. These submissions are optional; while they are often desirable, they are not always necessary. For a combination product, the application typically includes the following information:
• Indicated disease and current treatments.
• Potential benefit of combination product.
• Product description.
• Proposed indications for use.
• Summary of preclinical testing. This should include tests already performed and those planned for the future.
• Summary of animal testing. Like preclinical testing, this should include tests already performed and those planned for the future.
• Summary of human clinical studies, if any were performed.
• Proposed investigational plan for clinical trials.
• Draft meeting agenda.
• List of questions to be discussed during the meeting and addressed by FDA.
Once a pre-IDE/IND application is submitted to the appropriate center, the sponsor should contact the branch chief or regulatory project manager, preferably by e-mail, to establish the date and time for the pre-IDE/IND meeting. Such meetings typically take place from 2 to 4 weeks after FDA receipt of the formal submission.
|Table V. Common preclinical testing inadequacies for combination-product submissions (click to enlarge).|
Although some pre-IDE/IND submissions are followed by written or phone communications, a face-to-face meeting follows many submissions. A pre-IDE/IND meeting, which lasts 1–2 hours, is usually the first face-to-face interaction between a new applicant and the FDA review team. Depending on the issues at hand, representatives of CDRH, CDER, or CBER (or any combination of the three), and OCP typically attend.
The applicant should be ready with a 30-minute PowerPoint presentation that summarizes key points from the submission and enumerates issues requiring FDA comment. It is critical to leave sufficient time to allow for FDA real-time feedback.
It is advisable to bring a well-respected expert to the meeting to address any relevant issues. For example, a physician could speak to relevant clinical trial design or practice-of-medicine issues. Similarly, a toxicologist or pharmacologist could discuss laboratory testing issues.
Finally, the most important issues to discuss at the pre-IDE/IND meeting include the following:
• Confirmation of jurisdictional determination.
• Preclinical testing requirements:
• Device testing—mechanical, electrical, etc. (as applicable).
• Drug testing—laboratory; chemistry, manufacturing, and controls (CMC); pharmacology; toxicology; etc.
• Animal studies.
• Clinical trial design issues.
All applicant attendees should take notes, but one person should be designated with the task of recording the official meeting minutes.
After the meeting, the applicant should produce consolidated minutes and send them to FDA by e-mail for possible revisions. Although neither completely foolproof nor legally binding, comprehensive meeting minutes can help to reveal any early misunderstandings between the sponsor and the agency. Table IV identifies FDA scientific reviewers and managers, many of whom would be expected to attend important meetings with the sponsor.
The CDRH and CDER teams outlined in Table IV evolved at FDA in 2000–2001, largely to meet the growing demand to review drug-eluting stent applications. CDER now has a dedicated combination-products team based in the Cardiorenal Drugs Division. The teams' mission is to ensure consistency and timeliness in reviewing these very complicated and lengthy submissions.
|Table VI. Clinical trial design parameters and data robustness (click to enlarge).|
FDA prefers to get a sense of how a product developed and evolved over time. For this reason, IDE/IND submissions should include reports of early animal studies, even though this is not strictly required by statute or regulation. Reports of early animal studies usually include those performed as a part of product development. These reports may even include studies that had negative or otherwise unfavorable results. Providing these early testing results to the agency helps establish the credibility of both the submission and the applicant. FDA usually understands that negative or unfavorable results often arise during early product development. Such results usually lead to improvements that provide a safer and more-effective product design.
For later-stage animal studies, applicants are required to provide comprehensive testing results using the final design version of the product. Applicants should discuss with FDA as early as possible the expected number of animals to be tested and the duration of follow-up. Before filing the pre-IDE/IND or IDE/IND submission, the applicant should consider submitting draft protocols of animal studies to FDA for its review and comment. In doing so, the sponsor may be able to obtain informal FDA agreement on study design parameters. A typical informal agreement might include number of animals, relevant end points, methods of evaluation, etc.
In reporting animal results to FDA, the sponsor should identify the definitive animal study that tested the final drug dose and device design. The objective of most animal studies is to provide preliminary evidence of product safety to support initiating a human clinical study. If, at the same time, the sponsor can also collect proof-of-concept results providing evidence of product effectiveness, that is certainly helpful.
In most cases, unfortunately, it is not feasible to obtain clinically meaningful effectiveness results in animals because the linkage to human pathophysiology is typically weak. For example, there is no known reliable animal species to model human atherosclerotic disease. However, some animal models, such as the New Zealand White and hypercholesterolemic rabbit models, do exhibit cellular features in common with human atherosclerosis. For example, inflammatory macrophages are common in both species from early onset to late progression of the disease.
Even when animal models do exist for certain diseases, there is often poor correlation between animal and human effectiveness parameters and study results. For combination products in particular, it is very difficult to reproduce the complex biological interactions between the drug and the local, regional, and systemic tissues that may be affected. Consequently, the sponsor should provide FDA with preliminary evidence of product safety based on the results from both acute and chronic animal studies. Typically, this information is ample to support initiating a human clinical study.
Rigorous in vivo pharmacokinetic (PK) studies, typically those in which live animals receive the intended dose, are very important to FDA. These studies are intended to quantify the duration of drug exposure. Drug concentrations should be measured at the local (tissue), regional (organ), and systemic levels in animal and human subjects. Generating PK data, even in animal models, can be difficult for combination products because they often use very small drug doses. The sponsor may need to develop highly sensitive analytical methods (at the microgram rather than milligram level of detection) to collect fitting PK data or to demonstrate that such studies are impractical.
In the case of very small drug doses, time-release profiles usually suffice to demonstrate safety for human trials. The profiles are typically collected in an appropriate animal model and reflect tissue drug levels and quantity of drug remaining on the device. In vitro PK studies of drug properties, such as rates of dissolution, have also been required for drug-eluting stent approval. These critical laboratory and animal studies can also serve as the basis for an in vivo–in vitro correlation (IVIVC). Finally, it is important to note that with drug-release technologies, it is not possible ethically to duplicate in vivo studies in humans because doing so requires removing the implant and surrounding tissue.
FDA is particularly interested in sponsors developing an IVIVC because this model can be very helpful in assessing changes in product performance as a result of design and/or manufacturing modifications. Once a combination product is approved, changes are likely to occur. Manufacturing and processing, product design and dimensions, drug formulation and excipients, and alternate drug dosing are all examples of possible changes. For these reasons, the establishment of a robust IVIVC model—one that is based on valid scientific evidence, highly reproducible results, and well-characterized testing methods—may prove critical to FDA approval of modifications to an approved drug-device combination product.
Dosing Studies in Animals
|Table VII. Requirements for FDA inspections (click to enlarge).|
Although FDA does not formally require dosing studies, the agency will likely address concerns about how a particular therapeutic dose was chosen. It is useful to identify a low dose that was shown to be subtherapeutic and a high dose shown to be toxic. In this manner, a target therapeutic dose believed to be both safe and efficacious can be identified. Ideally, a dosing study will establish an efficacy margin between the subtherapeutic dose and the therapeutic dose, and a safety margin between the therapeutic dose and the toxic dose.
Toxicity studies for a drug-eluting stent have included evaluating local, regional, and systemic effects. Studies have included follow-up evaluations at 1, 3, and 6 months to provide preliminary evidence of drug safety. This schedule might be typical for toxicity studies of a drug that already has FDA approval for a different intended use.
Additional animal toxicity and human Phase I studies might be expected, however, if the drug component is not already approved. An expected additional requirement would be completion of a Phase I IND study (initial human testing) in healthy volunteers intended to determine the no observed adverse effect level, or NOAEL.
However, it is important to remember that there are many different types of combination products and methods of administration. Toxicity studies should consider each combination product and mode of delivery. The testing typically needs to evaluate study questions that are particular to that product. For example, a permanent implant may require different testing data than a drug-device combination product that provides topical delivery of a drug.
In reporting animal toxicity testing results, an applicant should provide a summary of the experimental methods and results in the body of the submission. Full protocols, gross photographs, histologic photomicrographs, and detailed pathology reports should be attached as appendices. Clinical results from outside the United States can be very helpful in an IDE/IND submission, but typically these are not a substitute for favorable results from animal studies.
It is also important to recognize that, especially for combination products, some study end points can only be tested in an animal model. For example, local toxicity is assessed by examining tissue histology, which is typically not possible with human subjects.
Bench and Biocompatibility Testing
A sponsor studying a combination product is expected to perform a series of bench tests on the integrity of the device component of the investigational product. The sponsor must demonstrate that the drug and device do not chemically or physically interact adversely with each other. The sponsor must also determine the extent of particulate matter released from the product.
In addition, it is important for the sponsor to elucidate how applying a drug or biologic to the device may affect the device's fatigue and corrosion properties, coating integrity, durability, and any other relevant product-specific factors.
Many combination products are intended to be implanted permanently and come into contact with blood. In such cases, the applicant must perform biocompatibility testing to support initiating a human clinical study. Testing for blood-contacting implants typically includes findings of cytotoxicity, sensitization, acute toxicity, genotoxicity (mutagenicity), and hemocompatibility. Depending on the product, FDA may also require tests for chronic toxicity and carcinogenicity.
Applicants should discuss with FDA the extent of biocompatibility testing required. It is important to note that for some products, certain biocompatibility tests will be known to fail. For example, biocompatibility testing of a combination product containing a chemotherapeutic agent, such as paclitaxel, would be expected to be cytotoxic. As a result, it is likely that FDA would not require cytotoxicity testing under those circumstances.
Preclinical Testing Inadequacies
Table V lists common preclinical testing inadequacies for combination-product submissions. Ashley Boam, branch chief of the Interventional Cardiology Products Branch of FDA, summarizes FDA's expectation of preclinical data for submissions. “By the time a company is ready to do a clinical trial, the manufacturer should be able to characterize the actual product intended for study so that FDA will know how the results for the clinical trial apply to the commercially distributed product,” she says.
Designing a Clinical Trial
Clinical trial design can be a critical factor in collecting appropriate safety and effectiveness data to support product approval. Table VI summarizes the effects of important clinical trial design parameters on data robustness. Although it is preferable to use a clinical end point (e.g., mortality from atherosclerotic heart disease) rather than a surrogate end point (e.g., ability to decrease serum cholesterol), FDA realizes that doing so is not always feasible in the clinical setting. The sponsor and FDA should negotiate the details of clinical trial design to support FDA marketing approval of the combination product.
The preferred control group is an active control where patients are treated with a commercially available product. Less attractive is a placebo control, which usually raises ethical and enrollment, or feasibility, issues. The least-attractive control group is based on objective performance criteria, which are typically developed from historical data obtained from the clinical literature. A historical control is usually not acceptable for a novel therapy, which is likely to be the case for a drug-device combination product.
The choice of a control group can be illustrated in the design of clinical trials of drug-eluting stents. The Cypher and Taxus stents demonstrated superiority to bare-stent controls. Currently, manufacturers of new drug-eluting stents are designing clinical trials intended to demonstrate equivalence to commercially available drug-eluting stents, rather than superiority, to receive FDA approval.
A truly novel drug-device combination product will likely raise questions that the Office of Device Evaluation will take to an FDA advisory panel in a public meeting. In developing a clinical trial, sponsors should consider that FDA and the advisory panel might have differing views. FDA is typically conservative, preferring longer patient follow-up (e.g., as long as 1 year). An advisory panel might be satisfied with a shorter duration of follow-up.
Because panel members are clinicians, they are typically more aware than FDA of the challenges inherent in designing and monitoring clinical trials for extended periods of patient follow-up.
Areas where an FDA review team and an advisory panel may differ include risk-benefit analysis, clinical trial design, study end points, patient sample size, length of follow-up, clinical and statistical outcomes, and labeling claims. The current trend is for FDA advisory panels to require long-term (e.g., 5-year) postapproval follow-up. Postapproval follow-up could involve patients already enrolled and treated in the pivotal study, and it could also include enrolling new patients for a registry study in the postapproval setting.
Generating appropriate labeling for novel drug-device combination products is a unique challenge for both FDA and industry. An important precedent for product labeling was established with FDA's approval of the Cypher and Taxus stents. The instructions-for-use labeling for both products reflects a compromise with regard to the style and content of standard drug- and device-labeling requirements. For any novel combination product, FDA will be likely to take an active role, working closely with the applicant to develop product-appropriate labeling reflecting the relevant safety and effectiveness performance results.
FDA typically inspects manufacturing sites, animal testing sites, and select clinical study centers. These inspections are usually performed around the time that the marketing application is submitted, or during the subsequent review period. Table VII summarizes the information an applicant should provide to FDA in preparation for inspections.
FDA works closely with a sponsor to schedule the necessary manufacturing, animal, and study center inspections. FDA district offices may send one or more inspectors qualified in evaluating drug and device quality and manufacturing compliance. Although the sciences of manufacturing drugs and devices are very different, the quality control measures and documentation procedures are similar. This facilitates a relatively straightforward inspection of combination-product manufacturing facilities.
Lessons to Be Learned
To facilitate FDA approval of combination products, manufacturers need to appreciate the substantial differences in scientific expectations and cultural environments between CDRH and CDER. FDA's testing requirements for drugs are much more complex than its requirements for devices. Failure to address quality and process issues early during product development and validation testing will most likely result in regulatory setbacks that can ultimately interfere with successful marketing of a newly approved combination product. Given the high financial stakes of these products, it is critical for applicants to be sensitive to all of the regulatory strategy considerations described in this article.
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Stuart Portnoy is senior director of medical device consulting at PharmaNet Inc. (Washington, DC). Steven Koepke is president and founder of SRK Consulting LLC (Walkersville, MD).
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