Originally Published MX September/October 2004
BUSINESS PLANNING & TECHNOLOGY DEVELOPMENT
Trials and TribulationsConducting clinical trials for combination products will lead manufacturers into a whole new world.
Peter Adams, Alan Davies, Eduardo March, William K. Sietsema
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Development of therapeutic products containing a drug and medical device in combination has blurred the traditional demarcation that exists between the two. While drug-device combinations have existed for some time (e.g., catheters coated with heparin and bone cements containing antibiotics), new device systems capable of delivering drugs in a controlled manner are entering the market (e.g., drug-eluting stents for the treatment of cardiovascular disease). It is anticipated that the number of such products, utilizing well-known medicinals in combination with novel drug-delivery systems, will grow significantly in the coming years. This growth will in turn be accompanied by increasing difficulties in determining the path for approval by regulatory agencies.
Drugs versus Devices
In general, a medicinal product (i.e., a drug) achieves its principal intended action through pharmacological, immunological, or metabolic means, while a device achieves its intended action by means of a physical attribute, such as a mechanical action or acting as a physical barrier.
Europe. Full definitions for European medicinal products and medical devices are found in Directive 2001/83/EC and Council Directive 93/42/EEC (the Medical Devices Directives), respectively.1, 2 According to the Medical Devices Directives, devices may incorporate substances considered to be medicinal products for the purpose of assisting the functioning of the device. This is specifically addressed in Article 1 (Section 4) of this directive. To determine which of the two directives is applicable to a combination product, the following two criteria need to be examined.
- The intended purpose of the product and how it is presented.
- The method by which the principal intended action is achieved.
If the primary function of the product does not rely on the pharmacological effect of the medicine, it is classified as a device. If the product's function relies primarily on the pharmacological effect of the active ingredient, it is classified as a medicine.
A single-use, prefilled disposable injection device is classified as a medicinal product; a drug-delivery pump or syringe is a device. However, for a kit comprising an insulin pen and insulin cartridges, the pen is classified a device and the insulin is defined as a medicinal product. A bone cement, with or without an antibiotic, is a device. A similar presentation required to deliver an antibiotic for the treatment of bone infections, however, is classified as a medicinal product. If the device and the medicinal product form a single integral product—intended for use in that presentation and not for reuse—that product is classified as a medicinal product (e.g., an aerosol and drug product). However, a nebulizer on its own can be reused and is classified as a device.
Guidance is available from the European Commission and should be consulted when determining which of the directives applies.3 It is important that further discussion and guidance be obtained from the notified body and the relevant competent authority at the time of compilation of the medical device technical file.
United States. In the United States, the term "combination product" is defined by FDA as a product containing a combination of a drug, device, or biological product produced as the following. 4
- A single entity.
- Two or more separate products (e.g., a drug and device) packaged together as a unit.
As with the European regulations, the categorization of the product is based on the primary mode of action, defined as the single action expected to deliver the most important therapeutic effect of the product.
FDA's Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), and Center for Drug Evaluation and Research (CDER) have in the past categorized products and taken lead review and regulatory responsibility on the basis of existing memorandums of understanding (MOUs) between the centers, which were implemented in October 1991.5,6
In December 2002, FDA established the Office of Combination Products to determine how combination products should be handled by the agency's three review centers. It is expected that the Office of Combination Products will continue to refer to and use the MOU between the centers as a framework for assigning appropriate review center(s) lead responsibility for product reviews and more timely preapproval reviews. Primary responsibility for postmarket regulatory activities such as inspections and compliance will remain within each center.
The MOU between CDER and CDRH assigns products into three categories, including the following.
- Products for which CDRH has lead review responsibility and market approval authority.
- Products for which CDER has lead responsibility and authority.
- Combination products with separate entities in which the review and approval authority would be shared.
CDRH has lead responsibility and market approval authority for devices or device kits that incorporate a drug component and are intended primarily to fulfill a device function; and for liquids, gases, or solids intended as implants, components, parts, or accessories to devices. Examples of such products include bone cement with microbial agent; cardiac pacemakers with steroid-coated tips; collagen implants for aesthetic use; dyes for tissues to enhance absorption of laser light; injectable silicone, collagen, and Teflon products; and spray-on dressings not containing a drug component. Intercenter consultation is required if the device has direct contact with the body.
CDER has lead responsibility and market approval authority for devices with the primary action of delivering or aiding in the delivery of a drug and for combination products incorporating a drug with a device component that are intended primarily to have a drug function. Examples of these products include nebulizers; prefilled syringes; glucose monitors linked to an insulin pump; transdermal patches; skin-prep pads with an antimicrobial agent; and surgical scrub brushes with an antimicrobial agent.
For situations in which drugs and devices are separate entities, FDA assigns the lead to CDRH when the device technology predominates and to CDER when the drug action predominates. Device and drug combinations are regulated as separate entities when the primary purpose of the device is to deliver or aid in the delivery of a drug, but is marketed without it; or when the device is used concomitantly with a drug to directly activate or augment its effectiveness.
In situations in which a device is intended for use with a drug already on the market, CDRH is the lead review center. For a new chemical entity for which labeling does not allow the user to substitute a generic marketed device, CDER is the lead review center. For a drug and drug-delivery device that are developed for use together, either CDRH or CDER will lead the review depending on whether the primary mode of action and development studies are primarily device-based or drug-based, respectively. Some examples are infusion pumps for implantation, iontophoretic drug-delivery devices, and nebulizers.
If the drug has been approved for another use and the developmental studies of the device technology predominate, CDRH will be the lead review center. Accordingly, if the device has been approved for another use and the developmental studies of the drug action predominate, CDER will be the lead review center. If neither the drug nor the device are approved and the product labeling creates a combination product, the Office of Combination Products will assign the lead center based on the component with the primary mode of action. (The Office of Combination Products maintains a Web site for current information on its initiatives and activities.7)
The approval process or pathway for a combination product will depend on its primary mode of action and the type of market approval authority deemed applicable by the agency. For combination products that are regulated by either CDRH or CDER under the agency's medical device authorities, the approval and clearance processes typical of medical devices will be applied. Those products deemed Class II devices will receive FDA review and clearance through the premarket notification (510(k)) procedures. On the other hand, products deemed Class III devices will need to follow the more substantive process demonstrating safety and effectiveness through the premarket approval process.
For combination products regulated by CDER under the drug and device authorities, the combination product will be subject to the new drug approval process requirements as well as any appropriate medical device authorities, such as FDA's quality system regulation.
There are instances when combination products have separate entities that are regulated separately, or are intended to process a drug into a finished package form. For these types of drug-device combinations, the agency's lead center will apply both drug and device regulations.
Clinical Endpoints and Trial Designs
Classical drug development today requires recruitment of more than 4000 patients into a drug development program at a cost of approximately $700 million for a duration of seven years. Classical device development programs require a few dozen patients, if any, depending on the device classification and regulatory requirements. Even for Class III products and implantable devices, where device failure is potentially catastrophic for the patient, studies typically involve fewer than 100 patients.
One issue that a drug or device company must address when seeking registration of a combination drug-device product is whether the product requires a drug-development strategy or a device approach. This is always a resource-dependent, critical question. Drug and device companies have different backgrounds and often different philosophies. For example, very large drug companies support dozens of products in the marketplace and launch two or three new products each year. In contrast, even medium-sized device companies may support hundreds or even thousands of products and launch new products daily. The large support cast of biological scientists and physicians behind every drug company launch does not usually exist in a device company, where products tend to be supported by engineers and material scientists. In determining clinical trial requirements, the following questions must be considered.
- Does CDRH or CDER have lead responsibility? What studies does CDRH require? These are likely to relate to risks of device failure and the potential consequences of failure. What studies does CDER require? These are likely to relate to the classic quality, safety, and efficacy questions evaluated in drug-development programs.
- What label claims are sought? If claims relate to a better delivery of a product—for example, a better syringe design for a prefilled syringe—then studies might not be necessary. If claims relate to improvement in patient outcome as a result of superior administration of a drug—such as a reduction in restenosis using drug-eluting coronary artery stents—then the program may require studying thousands of patients over several years.
Study design is dependent on the answers to these questions. Label claims for device products tend to be local and related to the local effects of the product—the syringe delivers the drug with more accuracy, ease, or speed. Label claims for drugs tend to be generalized and relate to the whole person—reduced incidence of disease, faster cure rates, or reduced complication rates. Device claims relate to engineering questions and solutions, while drug claims more often relate to efficacy, safety, and patient outcomes.
It is the efficacy, safety, and patient outcome claims that drive drug clinical research programs.8 Questions related to defining the primary and secondary objectives, population to be studied, and number of subjects in each population and the steps needed to ensure the right outcomes (such as, "How is the cure to be defined and measured?") are evaluated. The safety of a drug is quoted in terms of adverse-event rates per 100, 1000, or 10,000 subjects in a specified population. Thus a common adverse event will be characterized as occurring in one in 100 subjects. A general rule of thumb is that the drug needs to be studied in approximately 4000 subjects to characterize safety in a manner sufficient to receive regulatory authority approval. Additional studies will be required to characterize safety in special populations, such as the elderly or children.
Drugs are not able to make claims unless they are studied in the specific population for which the label is being claimed. In a similar manner, efficacy data are usually quoted as rates of success. So, a new drug may have a 5 or 20% improvement rate, or cure an additional 5 or 20% of the population under study.
Clearly the randomized, controlled study is the linchpin of drug development. It is necessary to make claims based on the performance of the drug relative to competitors and placebo. The judgment in clinical drug development rests on determining study design that is appropriate for the disease and drug under consideration. Programs for a common, nonfatal condition such as upper respiratory tract infection will differ from those required for a rare lethal disease for which no cure exists, such as many oncology studies.
Device studies are based on engineering principles and rely on quality manufacturing programs that demonstrate adequate fail-safe procedures and satisfactory checks and balances in production.
For drug studies, the objectives are formulated in terms of making comparisons between two or more treatment groups (e.g., between a new treatment and placebo; between a new treatment and an established treatment; or between two different doses of the same therapy). Whatever the comparison, the study examines either a parallel group or a crossover group. In a parallel group study, different patients are assigned (usually by some means of randomization) to each of one of the study groups. In a crossover study, each patient receives two or more treatments under study (usually assigned in a randomized order: Treatment A then Treatment B for one patient and vice versa for another patient). Study design choice is based on population, disease, and drug considerations. A disease that is not stable (e.g., Alzheimer's disease or most infectious diseases) is not suitable for a crossover design, but a chronic condition such as hypertension may be suitable because the natural variation within patients is minor.
Selected endpoints and study design will influence the label. If a drug is only studied in adult females, it is unlikely that a label will be allowed to claim efficacy in males, children, or the elderly. Short-term studies are unlikely to allow a label claim for long-term treatment of a chronic condition. For example, a three-week study would be insufficient to allow a label claim for chronic treatment of hypertension, but it would allow a claim for treatment of acute upper respiratory tract infection.
Clinical trials are designed to minimize variation in study endpoints. Attempts are made to study homogeneous populations as much as is practical to obtain better clarity of the true treatment effects. Bias is also reduced by the use of blinding and randomization techniques. Some of these techniques are complex and require sophisticated statistical methods to design, and elaborate procedures for various countries and cultures.
The relativistic, holistic, and biologically based approach to drug development is at odds with the absolute, localized, and engineering approach to device development. The challenge of combined drug-device development is to recognize that within and between companies there are cultural differences that are further stretched by differences in approach to drug and device development.9 Senior management needs to address these differences early on in the development process and appoint team members and project leaders who are sympathetic to the differing approaches of the two disciplines and will set clear goals for the project. In some cases, a clinical research organization may be useful in shaping product development programs (see sidebar).
Obstacles and Opportunities
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| Figure 1. Typical timelines for development of drugs, devices, and combination products. Hatched areas show variable timing. Typical device development time can range from 6 months to 4 years, whereas for drug development, timing can range from 5 to 8 years. Development times for drug-device combination products can be as rapid as 6 months or as long as 8 years, depending on whether the combination product is regulated more as a device or as a drug. (click to enlarge) |
Unrealistic expectations related to study timing are common in the development of combination drug-device products. Device companies are accustomed to small studies that are generally run by close-knit groups of investigators using tightly selected populations. These trials can often be conducted quickly with minimal expense. In contrast, drug studies are generally conducted in larger, less closely controlled populations with more (geographically and culturally) diverse investigators. It would be dangerous to extrapolate recruitment rates of small device trials to predict recruitment in a large drug trial. The lengthy setup and recruitment timelines for drug trials often frustrate drug-device teams because they demonstrate a lack of understanding of the bureaucracy that has evolved surrounding drug trials. Perhaps drug developers could learn something from device developers on how to design and manage an efficient study (see Figure 1).
Whether for drug, device, or drug-device combinations, successful development requires enthusiastic and committed support from senior management to ensure sufficient allocation of resources to a project. Lack of such support will pose a serious obstacle. Any development project needs a strong champion who can ruthlessly acquire resources and break down barriers, allowing the project team to move ahead in an unrestricted environment.
When two companies join forces to develop a drug-device combination, there can be conflict that hampers progress. For example, which company has the final word on clinical trial designs? Where will the trials be conducted? How are expenses for the clinical trials shared? And which company takes the lead in interacting with regulatory agencies and assembling the package for approval? The project team will be able to move more swiftly if these types of issues don't distract it, and a strong champion will be able to resolve these problems behind the scenes.
Registration failure is always a possibility in any program and much of the planning process is directed toward preventing such an outcome. When failure does occur, it most often is because the desired label claims are not supported by clinical evidence. This can be disastrous if a large, multimillion-dollar clinical program was conducted for registration. And, if the development team has exhausted the last of its corporate resources, that could mean the end of the company or venture. While no one can guarantee the outcome of a clinical study, the likelihood of success can be improved by conducting pilot studies with the drug-device combination, using the results to construct a statistical model on which the pivotal studies are based. These pilot studies will also uncover any operational difficulties that may be encountered in a large pivotal trial. They essentially become a "practice run" for the real thing.
Another reason for failure is mismatched expectations between developers and regulators. This is a common occurrence and can also be disastrous. Fortunately, there is an easy solution to this. Meet early and often with the regulatory agencies that will be reviewing and approving the product. Most agencies welcome the opportunity to review development plans and provide guidance on meeting their expectations for a robust registration package.
Registration for a combination drug-device product requires a balance between quality data and claims and the cost of time and money for running very large studies. Sometimes companies, or indeed authorities, misjudge the balance, but with thoughtful planning, flexibility, and frequent communication, the barriers can be overcome, leading to a successful registration.
References
Peter Adams, PhD, is a senior regulatory affairs consultant; Alan Davies, MD, MRCP, is European medical director; and William K. Sietsema, PhD, is vice president for clinical development at Kendle International Inc., a global clinical research organization headquartered in Cincinnati. Eduardo March is a senior consultant at AAC Consulting Group Inc. (Rockville, MD), a subsidiary of Kendle.
Illustration by ROB COLVIN.
Copyright ©2004 MX
