Combination Products
- 1. Definition of Combination Product A combination product is defined as: a) A product composed 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 b) Two or more separate products packaged together in a single package or as a unit comprised of drug and device products, device and biological products or biological and drug products c) A drug, device or biological product packaged separately that according to investigational plan or processed labelling 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 d) Any investigational drug, device or biological product packaged separately that according to its proposed labelling 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 Some of the examples of combination products are: Drug or biologic with applicator/delivery device Drug/biologic combinations Radiopharmaceutical combined with biologic Monoclonal antibody combined with a chemotherapeutic drug Separate products that may constitute combination: Photodynamic therapy drug and laser/light source Diagnostic device requiring administration of a particular drug or biologic Drug requiring specific diagnostic device However, there are some examples of drug/device/biologic combinations that are not considered combination products. Some examples are: Drug/drug, device/device or biologic/biologic combinations such as: Fixed combination drug products Products comprised of two biologics, even if review responsibility shared between two separate divisions Most concomitant use of drugs, devices and biologics
- 2. General drug or biologic delivery devices ( e.g., unfilled syringe or infusion pump) not intended for use with specified drug or biologic product Combination Products and Canadian Regulations The following types of combination products were classified by the Therapeutic Products Classification Committee in accordance with the Policy on Drug/Medical Device Combination Products of October 1998. This list also includes products which are not combination products but where the classification of either drug or device was difficult to determine. Combination products that have been classified as drugs: Prefilled syringes Patches for transdermal drug delivery Implants whose primary purpose is to release a drug Wound dressings whose primary purpose is to deliver a drug Dental products impregnated with a drug whose primary purpose is to deliver a drug Red blood cell processing solutions Contrast media Peritoneal dialysis solutions Alcohol swabs Combination products that have been classified as devices: Drug coated devices such as catheters, shunt sensors or pacemaker leads Drug impregnated devices Wound dressings and surgical barriers containing an antimicrobial agent Wound dressings whose primary purpose is to act as a barrier to pathogens Blood bags containing anticoagulant or preservation solutions Bone cement containing antibiotic- novel bone void fillers, e.g., callogen matrix with bone morphogenic protein Injectable collagen Sodium hyaluronate nasal solutions Urea breath test ( accessory to device) Device for ex vivo photodynamic cell processing Combinations of drugs and devices to which this policy does not apply and which must comply with both the Food and Drug Regulations and the Medical Devices Regulations
- 3. Kits (e.g., epidural tray containing drugs and devices; first aid kit containing drugs and devices) Products for which neither set of regulations apply Organ preservation solutions Minimally manipulated tissue Up until 2006, the sponsors of drug/medical device combination products should have satisfied the requirements of two sets of regulations. The drug component of a combination product was to comply with the Food and Drug Regulations and the device component must comply with the Medical Devices Regulations. The Therapeutic Products Directorate (TPD) and the Biologics Genetic Therapies Directorate (BGTD) believed that the risks associated with a combination product can be managed appropriately under one set of regulations. This approach would harmonize regulatory requirements with both the United States and European Union and would assist in the development of mutual recognition agreements with those jurisdictions. With the announcement of a new policy in November 2005, the drug/device combination product classification decisions consider the principle mechanism of action by which the claimed effect or purpose of the product is achieved. The entire product will then be regulated under either the Food and Drug Regulations or the Medical Devices Regulations. This policy, which is effective as of March 1, 2006, provides an interim mechanism to address a gap in the current regulatory schemes. However, this policy does not apply to combinations of drugs and medical devices where the drug component and the device component can be used separately. Health Canada defines combination product as a therapeutic product that combines a drug component and a device component (which by themselves would be classified as a drug or a device), such that the distinctive nature of the drug component and device component is integrated in a singular product. According to the new policy, a combination product is subject to either the Medical Devices Regulations or the Food and Drug Regulations according to the principle mechanism of action by which the claimed effect or purpose is achieved. Where the principle mechanism of action is achieved by pharmacological, immunological or metabolic means, the combination product will be subject to the Food and Drug Regulations. Where the principle mechanism of action is assisted in that effect or purpose by pharmacological, immunological or metabolic means, the combination product is subject to the Medical Devices Regulations. However, both the principle and secondary components still meet the acceptable standards of safety, efficacy and quality. There are several requirements for this new policy:
- 4. The sponsor of a combination product may make a presentation to TPD or BGTD (as appropriate) for the purpose of classifying the product. The presentation may be in advance of the sponsor making a submission to support sale of product in Canada or to support investigational testing of the product in Canada The sponsor of a submission for a combination product not previously classified may present a written request for a classification decision to the relevant Bureau Director in advance of the submission filing providing the following information: Name of the product and identification of the device and drug components A summary of relevant data describing the mechanism of action of each component and the principal mechanism of action of the product, including composition, study design, measurements of efficacy in terms of structural, pharmacological, metabolic, immunologic and Absorption- Distribution- Metabolism- Elimination studies conducted, toxicity studies etc. A Screening Deficiency Notice will be issued by the receiving Bureau if a submission requiring a classification decision has not been supported by the classification request or the presented summary On receipt of a submission for a combination product, the classification of the product will be confirmed by using the three criteria identified in the Policy Statement. The receiving Bureau shall consult with other Bureaux affected for this purpose and where a decision cannot be reached or where there is no consensus among the Bureaux as to the classification, the submission will be referred to the Therapeutic Products Classification Committee (TPCC) for a final decision within 30 days of receipt The TPCC will classify the submission and notify the sponsor of the decision within 30 days of accepting the submission from the receiving Bureau The TPCC may request the sponsor to provide additional information with respect to the submission and may invite the sponsor to make a presentation to assist in its deliberations If the sponsor wishes to request a Reconsideration of the decision of the TPCC, a written Letter of Intent should be sent to the Director General within 30 days of receiving the notification of the decision of the TPCC. The request for Reconsideration will proceed in accordance with the procedure outlined in the Health Canada Guidance: Reconsideration of Final Decisions Issued for Human Drug Submissions The sponsor is required to attest in the application or submission for a license, Notice of Compliance, or Drug Identification Number, as the case may be, that the secondary component of the combination product meets acceptable standards of safety, efficacy and quality The review of submissions for the combination products will be undertaken according to the expertise required to assess the risk/benefit profile of the product. The review may be undertaken by one Bureau or a team of reviewers representing more than one Bureau Additional information to support the safety, efficacy or quality of either component of the combination product may be requested during the review period
- 5. Where a joint review of a combination product is conducted and the product is considered to be in compliance with the relevant Regulations, the Notice of Compliance will be signed by the Director General Submissions for combination products classified as drugs and regulated under the Food and Drug Regulations will be subject to any fees payable for drugs under regulations enacted for that purpose Submissions for combination products classified as devices and regulated under the Medical Devices Regulations will be subject to any fees payable for devices under regulations enacted for that purpose TPD will maintain a list of products that the TPCC considers subject to the Food and Drug Regulations or the Medical Devices Regulations for the guidance of the sponsors and Directorate staff A classification decision made for the purposes of investigational testing may change during the review phase of the submission on the basis of new information contained in the submission Combination Products and US Regulations Combination products (medical products that combine drugs, medical devices and/or biological products) are increasingly incorporating cutting-edge, novel technologies that hold great promise for advancing patient care. Drug eluting cardiovascular stents, that have the potential to reduce the need for surgery by preventing the restenosis that sometimes occur following stent implantation, and inhaled insulin are two breakthrough new products Congress first acknowledged the need for specific regulation on combination products in the Safe Medical Devices Act of 1990 (SMDA). To illustrate a procedure, we can look at a product such as the encapsulated dopaminergic cell. This product uses a device component to deliver a drug (dopamine) by means of a cellular mechanism. All three of the categories are included—drug, device, and biologic—so which center would regulate the product? In this case, FDA determined that the primary mode of action for the dopaminergic cells is in fact via a cellular mechanism; thus, CBER was granted primary jurisdiction over the product with consultation from CDRH for the device component. Although a product's primary mode of action determines which center has jurisdiction, the designated center could very well lack necessary information regarding components of the product that are outside its area of expertise. For example, while CBER could reliably analyze the cellular
- 6. component of the dopaminergic cells, could it be entrusted to accurately evaluate the drug and device aspects of the product? In response to this issue, SMDA created inter-center agreements among CBER, CDER, and CDRH. The agreements allowed the center with jurisdiction over a combination product to consult with the other centers regarding product components outside its specialty area. In the case of the dopaminergic cells, before making a decision about the product, CBER would consult with CDER about the drug component and with CDRH about the device component. Because the primary mode of action of the product is a cellular mechanism, CBER would retain jurisdiction and would ultimately make all decisions regarding marketing approval, but it would first enlist the expertise of the other two centers. The centers involved with combination device and biologic products are CBER and CDRH. When CBER has jurisdiction over a combination product, the inter-center agreement enables it to consult with CDRH regarding the safety, effectiveness, and durability of any device components of that product. Likewise, CDRH may consult CBER about the biologic components of combination products under its jurisdiction. Generally, combination products intended for direct therapeutic application will be regulated by CDRH. Products with components that collect, separate, or process blood or blood products, analogous products, or cellular biologics— including cellular and tissue implants, infused cells, and encapsulated cells of tissue—are regulated by CBER. Interactive wound-care products provide a useful illustration of how FDA currently regulates combination device and biologic products. Non-interactive wound-care products are regulated either by CDRH as devices (standard wound dressings), or, because they incorporate a drug, by CDER. However, the primary mechanism of interactive or biologically active wound dressings is not medicinal, but rather is achieved through a device or biologic component. These products serve as long-term skin substitutes or temporary synthetic skin and are intended to actively promote healing by interacting directly or indirectly with bodily tissues. Interactive wound dressings can be divided into a cellular products that seek to provide an enhanced environment for skin re-growth and cellular products that contain epidermal and/or dermal tissue. Examples of cellular interactive dressings include polymers or synthetic peptides linked with extracellular matrix constituents. Examples of cellular interactive dressings include products that contain allogeneic epithelial cells or fibroblasts cultured on biodegradable polymers and products that contain keratinocytes and fibroblasts that adhere to collagen substrates. These products meet both the definition of a device, since they work by mechanical mechanisms of action (e.g., they provide a macromolecular scaffold for tissue repair, and a biologic, since they contain biologic components (cells). In addition, interactive wound-care products that are considered to have a drug mechanism of action, and therefore would not be classified as wound dressings, may contain other biologic a cellular components, such as growth factors and enzymatic de-bridging agents.
- 7. On the other hand, CDRH was granted jurisdiction over Apligraf, a new interactive wound and burn dressing manufactured by Organogenesis (Canton, MA). Apligraf is an artificial skin graft used to treat serious skin ulcers caused by venous insufficiency. It is produced from bovine collagen, human keratinocytes, and fibroblasts derived from human infant foreskins. The dressing provides wound protection and fosters the growth of healthy new skin. Comprising a scaffold of cells on a collagen substrate, the product can be considered a cellular interactive wound dressing. Despite its cellular composition, however, FDA ruled that the device mechanism of the scaffold architecture constituted Apligraf's primary mode of action and determined that CDRH should regulate the product. Similarly, Dermagraft-TC (Advanced Tissue Sciences; La Jolla, CA), a dermal replacement wound dressing for use in plantar diabetic foot ulcers, is also being reviewed by CDRH but has not yet been approved. This product consists of neonatal dermal fibroblasts cultured in vitro onto a bio-absorbable mesh. When a combination product has a clearly definable primary mode of action, FDA can assign jurisdiction quickly, and the inter-center agreement system works as it should. Unfortunately, this is not always the case. It is often difficult for FDA to identify and agree on the primary mechanism at work in a new product, which sometimes results in lengthy disputes over jurisdiction and delays in marketing approval. If a sponsor suspects that a new combination product might cause debate over jurisdiction or the primary mode of action, the issue can often be resolved at the program level before such disputes begin. As soon as sufficient product information exists for the agency to make a regulatory designation, the manufacturer can contact the CDRH jurisdiction and device status expert or the CBER jurisdiction liaison (CBER ombudsman). Often, one or both of these representatives will expedite the decision-making process. If that approach fails, the sponsor can then make a formal request for product designation. The request (original and two copies) should not exceed 15 pages and should be filed prior to the submission of a premarket approval (PMA) application. All relevant sponsor information is required, along with a thorough description of the product, which should include: The product's classification, common name, and proprietary name. An indication of any component of the product that has already received or is not subject to premarket approval or an investigational exemption. The product's chemical, physical, or biological composition. The status of and brief reports on any developmental work, including animal testing. Descriptions of the manufacturing process. The sources of all components. The proposed use or indications of the product and a description of all known modes of action. The sponsor's identification of the primary mode of action and the basis for that determination. The schedule and duration of proposed use, and the dose and route of product administration. A description of any related products and their regulatory status. The sponsor's recommendation as to which center should have primary jurisdiction, with accompanying rationale for this recommendation.
- 8. The Office of Combination Products was established on December 24, 2002. The new Office of Combination Products (OCP) is part of the Office of the Commissioner and its responsibilities cover the entire regulatory life cycle of combination products, including jurisdiction decisions as well as timeliness and effectiveness of pre-market review and the consistency and appropriateness of post-market regulations. The primary regulatory responsibilities for, and oversight of, specific combination products still remains in one of three product centres: the Centre for Drug Evaluation and Research , the Centre for Biologics Evaluation and Research or the Centre for Devices and Radiological Health, to which they are assigned. The establishment of OCP is part of the FDA‘s implementation of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). The statutorily mandated functions of OCP are to: Promptly assign a centre with primary jurisdiction for a combination product Ensure the timely and effective pre-market review of combination products, by overseeing the timeliness of and coordinating reviews involving more than one centre Ensure the consistency and appropriateness of post-market regulations of combination products Resolve disputes regarding the timeliness of pre-market reviews of combination products Review and modify, revise ( or eliminate if appropriate) agreements, guidance documents or practises specific to assignment of combination products Submit annual reports to Congress on the activities and impact of the Office In addition, OCP assumes and continues the functions of the Combination Products Programme established earlier in 2002 within the Office of Ombudsman. These functions include: working with the centers to develop guidance and/or regulations to clarify the agency‘s regulations of combination products serving as a focal point for combination products issues for internal and external stakeholders Some of recent examples of combination products approvals are: Transdermal patch for treatment of Parkinson‘s disease Absorbable collagen sponge with genetically engineered human protein Device-biological product gel for surgical hemostasis Transdermal patch for attention deficit hyperactive disorder Transdermal patch for depression Inhaled Insulin combination product for diabetes Dental bone grafting material with growth factor Surgical mesh with antibiotic coating Dermal iontophoresis system Methylaminolevulinate cream with halogen light source Paclitaxel-eluting coronary stent system
- 9. FluMistTM influenza virus vaccine, live, intranasal Demagraft human fibroblast-derived dermal substitute Glucose monitor/ insulin pump Sirolimus-eluting coronary stent Lumbar tapered fusion device with genetically engineered human protein Peginterferon alfa-2a in combination with Ribavirin Fibrin sealant On May 6, 2004, FDA combined efforts with the Department of Health and Human Services to propose a ruling designed to simplify the definition of primary mode of action. The purpose of this ruling is: To codify the definition of primary mode of action (PMOA), the criterion the agency has used for more than a decade when assigning combination products to a particular centre within the agency for review To simplify the assignment process by providing a defined framework that sponsors may use when recommending and/or considering the PMOA Traditionally, FDA has required sponsors submitting a request for assignment of a combination product to identify the PMOA of the product and recommend a centre within FDA to take the lead in the process review. Under the proposal, the ―primary mode of action‖ would be defined as ―the single mode of action (e.g., drug, device, biological product) of a combination product that provides the most important therapeutic action of the combination product‖. This is the mode of action that is expected to make the greatest contribution to the overall therapeutic effects of the combination product. 21 CFR Part 3 defines ―mode of action‖ and ―primary mode of action‖ as follows: ―Mode of action would be defined as ‗‗the means by which a product achieves a therapeutic effect.‘‘ For purposes of this definition, ‗‗therapeutic‘‘ effect or action includes any effect or action of the combination product intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body. Products may have a drug, biological product, or device mode of action. Because combination products are comprised of more than one type of regulated article (biological product, device, or drug), and each constituent part contributes a biological product, device, or drug mode of action, combination products will typically have more than one mode of action. 1. A constituent part has a biological product mode of action if it acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure
- 10. of a disease or condition of human beings, as described in section 351(a) of the Public Health Service Act. 2. A constituent part has a device mode of action if it meets the definition of device contained in section 201(h)(1) to (h)(3) of the act (21 U.S.C.321(h)(1) to (h)(3)), it does not have a biological product mode of action, and it does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and is not dependent upon being metabolized for the achievement of its primary intended purposes. 3. A constituent part has a drug mode of action if it meets the definition of drug contained in section 201(g)(1) of the act and it does not have a biological product or device mode of action. b. Primary mode of action would be defined as ‗‗the single mode of action of a combination product that provides the most important therapeutic action of the combination product.‘‘ This would be the mode of action that is expected to make the greatest contribution to the overall therapeutic effects of the combination product. As with ‗‗mode of action,‘‘ for purposes of PMOA, ‗‗therapeutic‘‘ effect or action includes any effect or action of the combination product intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body.‖ Some of the examples that utilize application of proposed definitions are as follows: a) Conventional drug-eluting stent—a vascular stent provides a mechanical scaffold to keep a vessel open while a drug is slowly released from the stent to prevent the build-up of new tissue that would re-occlude the artery. PMOA Analysis—Which Mode of Action Provides the Most Important Therapeutic Action of the Combination Product? In this case, the product has two modes of action. One action of the vascular stent is to provide a physical scaffold to be implanted in a coronary artery to improve the resultant arterial luminal diameter following angioplasty. Another action of the product is the drug action, with the intended effect of reducing the incidence of restenosis and the need for target lesion revascularization. Assignment of Lead Agency Component: Center for Devices and Radiological Health (CDRH)—The product‘s PMOA is attributable to the device component‘s function of physically maintaining vessel lumen patency, while the drug plays a secondary role in reducing restenosis caused by the proliferative response to the stent implantation, augmenting the safety and/ or effectiveness of the uncoated stent. Accordingly, FDA would assign the product to CDRH for premarket review and regulation because the device component provides the most important therapeutic action of the product. It is unnecessary to proceed to the assignment algorithm because it is possible to determine which mode of action provides the most important therapeutic action of this particular combination product.
- 11. b) Drug eluting disc—a surgically implanted disc contains a drug that is slowly released for prolonged, local delivery of chemotherapeutic agents. PMOA Analysis—Which Mode of Action Provides the Most Important Therapeutic Action of the Combination Product? In this case, the product has two modes of action. This product has a device mode of action because it is surgically implanted in the body and is designed for controlled drug release, thus affecting the structure of the body and treating disease. Another mode of action is the drug action, with the intended effect of preventing tumor recurrence at the implant site. Assignment of Lead Agency Component: Center for Drug Evaluation and Research (CDER)—Though the product has a device mode of action, the product‘s PMOA is attributable to the drug component‘s function of preventing tumor recurrence at the implant site. Accordingly, we would assign the product to CDER for premarket review and regulation because the drug component provides the most important therapeutic action of the product. It is unnecessary to proceed to the assignment algorithm because it is possible to determine which mode of action provides the most important therapeutic action of this particular product. c) Contact lens combined with drug to treat glaucoma—in this case, a contact lens is placed in the eye to correct vision. The contact lens also contains a drug to treat glaucoma that will be delivered from the lens to the eye. PMOA Analysis—Which Mode of Action Provides the Most Important Therapeutic Action of the Combination Product? This product has two modes of action. One action of the product is the device action, to correct vision. Another action of the product is a drug action, to treat glaucoma. Though administration through a contact lens is not necessary for the drug‘s delivery, the combination product allows a patient requiring vision correction to receive glaucoma treatment without having to undertake a more complicated daily drug regimen. Here, both actions of the product are independent, and neither appears to be subordinate to the other. Because it is not possible to determine which mode of action provides the greatest contribution to the overall therapeutic effects of the combination product, it is necessary to apply the assignment algorithm. In certain cases, it is not possible for either FDA or the product sponsor to determine, at the time a request for assignment is submitted, which mode of action of a combination product provides the most important therapeutic action. In those cases, the agency would assign the combination product to the FDA centre that regulates other combination products presenting similar questions of safety and effectiveness with regard to the combination product as a whole. When there is no other combination product that present similar questions of safety and effectiveness, the agency would assign the combination product to the agency component with the most expertise to evaluate the most significant safety and effectiveness questions presented by the combination product.
- 12. Device makers are attracted to combination products for a variety of reasons, described as follows: By providing multiple and complementary modes of action, these combination products have the potential to offer greater therapeutic benefits than drugs or devices acting alone The products improve the overall quality of care by enhancing acceptance and functional life of implantable devices. Products such as pacing leads and glucose sensors could benefit from biocompatibility and a lower risk of inflammation and foreign-body responses, which can impede the function of devices They enable health care providers to treat diseases with localized drug delivery. Combination products offer an effective and safe alternative FDA‘s Office of Combination Products reported that 40 requests for designation (RFD) were submitted in 2005, a 25% increase over 2004. The regulatory regimes that apply to drugs and devices differ in fundamental ways. One major difference is that drugs take much longer to reach the market. From the time a drug enters preclinical studies to the time FDA approves a new drug application (NDA), 10 years or more elapse. Drug companies are accustomed to such long-term planning; device companies are not. Another aspect to consider is that the probability of success for drugs is much lower than that of devices. If a drug is already marketed and only an NDA supplement is needed (e.g., approval for a new intended use), these differential factors diminish but they do not vanish. Another difference is that once approved, drugs can remain on the market for decades unchanged. Meanwhile, rapidly advancing technology and continuing product modifications characterize the device industry. The integration of drug, biologic and device development requires the merging of the engineering, chemical and biological fields. This merger introduces new technical and organizational challenges to product development. Regulatory concerns include how the product will be regulated because the biologic and the device components have different marketing applications, regulations and post-market reporting requirements, because ―one-size-fits-all‖ approach does not work for combination products. For example, one of the biggest design and manufacturing challenges for drug enhanced devices is ensuring adequate sterility and shelf life of the drug on a device. Coating can flake off or the product can deposit too much drug into the body, both of which reduce efficacy and create a safety risk for end-users. To manage such problems, manufacturers must perform more product and process characterization earlier in the development cycle. And these processes must be supported by robust analytical and physical methods to establish a fundamental understanding of the relationship between process parameters, design inputs and product stability. There are still no specific regulations or regulatory submissions that are unique to combination products. The Office of Combination Products (OCP) is responsible for prompt assignment of a new combination product to the lead FDA review centre, which may be the Centre for Drug Evaluation and Research (CDER), the Centre for Biologics Evaluation and Research (CBER) or
- 13. the Centre for Devices and Radiological Health (CDRH). Drug eluting stents are regulated as devices while pre-filled syringes are regulated as drug. The responsibility of regulation becomes less clear when the product is of a new type. OCP has paved the way for companies to establish standardized and compliant development processes by recognizing the overlap between quality systems regulations (QSR) and current good manufacturing practices (cGMPs). It is still unclear how companies should manage differences across various regulatory agencies for annual reporting, safety monitoring and adverse event reporting. In addition, companies must properly estimate the incremental costs and timelines that are needed to develop, manufacture and meet compliance requirements for combination products. OCP responds to an RFD within 60 days. Lack of planning can lengthen the approval process. First, the companies need to decide what the product is. Should it consist of a device and drug sold separately with cross labelling, or should it be sold together in a box or as a single unit comprising drug and device? Second, the company should define the product‘s intended use. Sometimes, the intended use cannot be determined until after the clinical trials have been completed and the product‘s utility is better understood. Third, the parties need to agree how they want the product to be regulated. Companies also need to assess the potential effect of regulatory classification on reimbursement. The entire clinical and regulatory program, as well as time to market and clinical costs, will be dramatically affected if the goal is to have the product regulated as a drug instead of a device. Forth, the parties need to agree on who will control the process of determining regulatory status, including submission of an RFD. Firms should also consider how to address the potential follow-up issues, such as who will attend FDA-requested conferences to answer RFD questions or who will participate in telephone calls with OCP. The biological product regulations, 21 CFR Parts 600-680, may also apply to the manufacture of drugs that are also biological products along with the drug CGMP provisions. They also may apply along with the QS regulations to the manufacture of devices that are also biological products. There is considerable overlap in the CGMP and QS regulations, and for the most part the overlap is apparent. For example, both establish requirements for management, organization, and personnel; both require documentation and record keeping; and both allow flexibility in application to the manufacture of particular products. FDA considers the cGMP and the QS regulations to be similar, and they are meant to achieve the same goals. Nonetheless, FDA recognizes that each set of regulations is somewhat different because each is tailored to the characteristics of the types of products for which they were designed (i.e., CGMP for drugs or biological products, QS regulation for devices). Each set of regulations contains certain express/specific requirements that may be only more generally described in the other regulation. Typically, these express/specific requirements are related to the unique characteristics of a drug, device, or biological product. For example:
- 14. Calculating the yield and stability of a drug constituent part: The CGMP regulation has specific requirements for the calculation of yield (21 CFR 211.103) and for ensuring stability of the drug product (21 CFR 211.166). Under the QS regulation, for a combination product with a drug constituent part, yield and stability requirements would be incorporated more generally as part of the design validation provisions (21 CFR 820.30(g)). Corrective and preventive action (CAPA): The QS regulation has detailed CAPA requirements (21 CFR 820.100), while CAPA principles are more generally identified in the CGMP regulation as part of Production Record Review (21 CFR 211.192). FDA recognizes that many manufacturing facilities operate under one type of current good manufacturing practice system (i.e., either that described by the QS or CGMP regulation). As noted above, FDA recognizes that there is considerable overlap between the QS and CGMP regulations. It should generally not be necessary for manufacturers who make combination products that are produced as a single entity or are co-packaged to maintain two separate manufacturing systems to ensure compliance with both sets of regulations during and after joining the constituents together. FDA believes that compliance with both sets of regulations during and after joining these types of combination products can generally be achieved by using either the CGMP or QS regulations, e.g., by using the current good manufacturing practice system already operating at a manufacturing facility, as described below. During and after joining these types of combination products together, FDA believes that compliance with both sets of regulations can generally be achieved by following one set because under a more general requirement in one set of regulations, it will be possible to develop and implement a practice that complies with a more specific requirement in the other set of regulations. To ensure consistent and appropriate current good manufacturing practice, FDA recommends that manufacturers of these types of combination products assess how best to comply with both sets of regulations, during and after joining the constituent parts together, by carefully considering the requirements of the CGMP and QS regulations in relation to the constituent parts, and the combination product(s) they manufacture. According to an industrial statistics, the following conclusions were summarized in a bulletin: ―…an estimated 30% of new products under development are ―combo products‖ – involving medical devices embedded with pharmaceutical or biologics components. But for manufacturers, along with these exciting new opportunities, the convergence of drugs/biologics and devices also brings a host of regulatory challenges.‖ The combination products market is estimated at $5.9B in 2004, and will continue to grow at a compound annual rate of 10% through 2009. By 2009, the market is expected to reach approximately $9.5B worldwide with a majority of these revenues from drug- eluting stents and steroid-eluting electrodes. ―Combination products have the regulatory flexibility to apply the most appropriate regulation to a combination product by tailoring the approach to taking pieces of drug regulation, pieces of device regulation, or biologics, as appropriate.‖
- 15. Cardiovascular related combination product revenues will account for approximately 88% of worldwide sales in 2009. A majority of these revenues will be due to drug-eluting stent sales while steroid eluting electrode and water-jet device revenues account for the remainder Combination Products in Australia The product regulators within TGA are: Office of Devices, Blood and Tissues Prescription medicines Non-prescription (OTC) medicines Complementary medicines Biologicals TGA also has expert advisory committees: Medical Devices Advisory Committee (MDEC) Australian Drug Evaluation Committee (ADEC) Medicines Evaluation Committee (MEC) Complementary Medicines Evaluation Committee (CMEC) Biologicals (cellular therapies) Committee- proposed! With regard to life cycle approach, the TGA framework is divided into: Special Access Schemes for experimental products Clinical trial assessment Pre-market conformity assessment Post-market surveillance/monitoring Enforcement The combination products are regulated in accordance with principal intended purpose and mode of action by appropriate product regulator. Classification as device or medicine (or biological) is determined in accordance with definitions in legislation, and is regulated as device or medicine in accordance with the determined classification. For the borderline products, an internal committee decides on its regulation path. TGA defines medical devices as:
- 16. any instrument, apparatus, implement, machine, appliance, implant, software, material or other similar or related article, including any in vitro diagnostic device, intended by the person under whose name it is or is to be supplied, to be used, alone or in combination, for human beings for the specific purpose of one or more of the following: diagnosis, prevention, monitoring, treatment or alleviation of disease; diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap; investigation, replacement, modification, or support of the anatomy or of a physiological process; supporting or sustaining life; control of conception; disinfection of medical devices; providing information for medical purposes by means of in vitro examination of specimens derived from the human body; and that does not achieve its primary intended action in or on the human body by pharmacological, immunological or metabolic means, but may be assisted in its function by such means. TGA defines medicines as: therapeutic goods that are represented to achieve, or are likely to achieve, their principal intended action by pharmacological, chemical, immunological or metabolic means in or on the body of a human or animal; and any other therapeutic goods declared by the Secretary, by a notice published in the Gazette, not to be medical devices. For example, IUD releasing hormone is regulated as a medicine since primary purpose is to deliver the medicine. The device aspects of it may be referred to device program and it is expected that the manufacturer of the device component holds evidence to show compliance with Essential Principles, but device certification is not normally required. Some examples of combination products are: Non-prescription medicine: gingival retraction cords containing an antiseptic Complementary medicine: salt pipe (contains salt solution from a Transylvanian cave for inhalation) Biological: collagen matrix to be used as a base for the growth of autologous cartilage cells for re-implantation A substance that is incorporated in a device, that if used separately would be a medicine and is intended to act on a patient in a way that is secondary to the device, is Class III (highest risk).
- 17. Such devices that incorporate medicinal substance, are subject to conformity assessment by the TGA: The safety and quality of the medicine must be verified in accordance with the requirements for medicines The secondary action must be verified having regard to the intended purpose of the device Examples of devices incorporating a medicine are: Drug eluting stents Drapes incorporating an iodoform Catheters coated with albumin or antibiotics Dressings impregnated with silver Orthopaedic implants incorporating antibiotics Applications for such devices come into the devices program by electronic lodgement. The manufacturer must have a conformity certificate from the TGA after the conformity assessment process that is conducted within the device program. Extend of assessment depends upon the TGA‘s knowledge of the medicine and its manufacturer. The evaluation of the medicinal component is referred to the relevant medicines regulator, if required which is done parallel with the device assessment. Final decision rests with the device program which issues conformity assessment certification. Algorithm for referral to medicines evaluator is based on: Is it already included in the ARTG for that manufacturer? Is it a generic- known substance and new manufacturer? Is the use in the device consistent with the approved use as a medicine? The more the medicinal substance, its use and its manufacturer are known to the TGA, less requirements for evaluation or consideration by an expert committee outside the device program are needed. For substances that would normally be a prescription medicine: A new chemical entity will go through the full drug evaluation process, including consideration by the ADEC prior to consideration by MDEC
- 18. A medicine already on the ARTG, but from a new manufacturer, will be treated as a new generic drug and an evaluation of the Drug Master File is required (covering toxicology and pharmaceutical chemistry aspects) An approved medicine for which the device application involves a new indication, will undergo clinical assessment within the device program and the application will be referred to the drug evaluation area for pharmaceutical chemistry aspects The process summary for devices incorporating a medicine is: Application for conformity assessment to the device regulator Assessment by devices program (with referral to medicines regulator for advice- may go to ADEC, MEC or CMEC) Consideration by MDEC Device regulator issues conformity assessment certificate to manufacturer, if approval is recommended Common problems about the compliance of medicinal products are: Must meet all regulatory requirements applicable to the medicine Requires agreement of medicine manufacturer Access to DMFs Evidence of GMP compliance Device manufacturer‘s QMS must take into account the medicine supplier Pharmaceutical chemistry issues Control and release specifications Uniformity Elution characteristics Clinical evidence MDEC is concerned about the lack of clinical evidence specific to the device/medicine combination product o Number of patients o Endpoints for trials Post-market review of DES Expert working Group on cardiac devices Need for tracking/ extended follow-up Regulation of device/biological combinations To be addressed in time by new framework Device component not a medical device in its own right
- 19. Australia is a member of Global Harmonization Task Force (GHTF) and the priorities worked on ad-hoc group related to combination products are: Guidelines on process Work to develop links in the global context Guidelines for device manufacturers on content of dossiers Combination Products in Europe Convergent solutions are offering products that are less invasive, less painful, more patient- specific, more convenient, and sometimes more affordable. Naturally, the high costs associated with hospital procedures and prolonged drug therapies are prompting for more affordable, cost- effective alternatives, such as combination products. The European combination-product market is the second largest in the world, preceded by the United States and followed by Japan. The European regulatory tradition is built around the perceived differences between pharmaceutical products and medical devices. These are substantive differences, mostly involving the mechanism of action. In Europe, the Medical Device Directive (MDD) regulations provide guidance for gaining marketing approval through the declaration of conformance process. Ultimately, achieving the right to bear the CE mark designates a device as marketable in Europe. The extent of the requirements for CE marking depends on the product‘s classification. The FDA and MDD regulations are similar, but American companies face additional work to develop documentation that is not necessarily required by the FDA when it comes to CE marking. Under EU regulations, a country with strict rules cannot enforce them if the other countries have more liberal rules. While European countries have a common set of rules, they each have their own authorities to handle approval of combination products, and they operate on different timetables. A combination product typically will have an unpredictable road ahead for regulatory approval in each EU country. Placing medical devices on the market is not subject to a formal authorization, as is the case with pharmaceutical products. Devices are classified based on a number of rules described in the
- 20. Medical Devices Directive, which builds on the concept of a risk-based approach related to the device‘s duration of use, invasiveness, and associated hazards. In addition, there are special rules for specific types of devices; e.g., those containing animal tissues, blood bags, and those incorporating a medicinal product (drug or biologic). Class III devices present the highest risks and are subject to the most stringent assessment and third-party certification. There are three types of medical devices incorporated into combination products: Devices for the administration of medicines (e.g., empty single-use syringes and reusable spoons or droppers). These items are regulated by the medical device regulations. Devices that combine with a medicinal product to form a single, integral product designed to be used exclusively in the combination—e.g., prefilled syringes. These products are not reusable and are subject to Directive 65/65/EEC in the EU. In addition, the relevant essential requirements of Annex 1 of Medical Devices Directive 93/42/EEC apply to safety- and performance-related features of such devices. This means that the combination is assessed by the drug regulatory authorities, and the device also needs to meet the essential requirements of the Medical Devices Directive. This is usually satisfied by the use of a CE mark. Devices incorporating a substance, which, if used separately, may be considered a medicinal product. In addition, the substance (the drug) is liable to act upon the body with action ancillary to that of the device. In this case, the medical device assessment authority (notified body) assesses the combination product, and the drug information is sent by the notified body to a drug regulatory authority for assessment of that specific section. The drug regulatory authority must verify the safety, efficacy, and usefulness of the drug. Also, gaining a CE mark for a device-containing combination product means that it can be sold freely anywhere in the European Economic Area (i.e., the 15 EU countries plus Iceland, and Norway). In general, EU authorization (CE marking) for medical devices is deemed easier to obtain than FDA approval. This is mainly because clinical efficacy requirements, while playing a part, are not necessarily as rigorous as those in the United States. Companies can usually get their medical products on the market faster in Europe than in the United States, although for drug-device combinations, the EU pharmaceutical regulatory bodies will scrutinize the drug portion as thoroughly as FDA would. Drug/device combination products‘ assessment rules are set out in Medical Device Guidelines issued by the European Commission. The principles of regulations are relatively simple and clear. The first issue is to decide whether the device is a free-standing device that can be used to deliver several different medicinal products. An example would be a syringe pump. These are
- 21. clearly medical devices and are regulated as such through the ―New Approach‖ Medical Device Directive (93/42 EC). If the device is not freestanding, and is sold as an integral part of a product, then the fundamental issue is the claimed primary mode of action of the product. If the primary mode of action is through pharmacological or immunological means, then the product is regulated as a medicine. If the primary mode of action is through physical means (as defined in the Medical Device Directive) then the product is regulated as a medical device. An example for this, would be an implant releasing a medicinal substance. In such cases, the medical device must be assessed and comply with the medical device requirements, but this assessment takes place either before or alongside the assessment of the medicinal product. Such devices are becoming increasingly complex and will require pharmaceutical regulatory authorities to have considerable device assessment skills available to them. In the United Kingdom, the Medicines Control Agency would currently seek advice from the Medical Devices Agency (on June 13, 2002, it was announced that these two agencies will be merged into a single executive agency of the Department of Health effective April 2003). Alternatively, a manufacturer may expedite matters by using an already approved (CE marked) medical device. The second scenario is when the primary action is mechanical. Such products would include drug-coated catheters and drug-eluting coronary stents. Here, the primary action is that of the stent scaffold maintaining the patency of the coronary blood vessel. The medicine is added to reduce the risk of restenosis of the vessel. Thus, the action of the medicine is secondary to the primary mechanical action of the product. In such circumstances, the notified bodies that are responsible for evaluating and then granting the CE Certificate must seek the opinion of a pharmaceutical regulatory authority. The latter is required to consider the quality of the medicinal product and its safety (covering issues such as biocompatibility, toxicology and local toxicity). In addition, the regulatory authority must consider the rationale for the medicine and the evidence supporting its use in the product. If the medicine was licensed through the European centralized procedure then, the manufacturer might seek an opinion from the European Agency for the Evaluation of Medicinal Products (EMEA). If the drug/device combination uses a stable blood product or a product derived from human blood, under the terms of the new directive, the notified body must seek an opinion from the
- 22. EMEA. Under the directive the EMEA, through the expertise available to it, must consider the quality, safety, and "usefulness" of the secondary blood product. However, if there are doubts, it is perhaps beneficial for a manufacturer to send adverse event reports to both authorities. This is particularly important if the manufacturer is using a CE marked product, since there may be implications for the product outside the use of the particular combination. It may also be necessary to increase the flow of information between the two regulatory sectors. In vitro diagnostics are now regulated as medical devices. This directive came into force in June 2000 with a transition period until the end of 2003. By that time, all such devices must be assessed and certified by an appropriate notified body. Member States have adopted common technical specifications that products are evaluated by and manufacturers must comply with. Drug/device combination will require increasing collaboration and cooperation between the medicines and devices regulatory systems. Such collaboration is now being put in place. This will be important in allowing these new products to be developed while at the same time ensuring the safety of patients. It will also be important to evolve new guidelines to determine the clinical data requirements for such products. Depending upon the eventual regulatory route, this seems to be an area that might usefully be taken up either by the International Conference on Harmonization (ICH) or by the Global Harmonization Task Force (the medical device equivalent of ICH). Do EU Decisions Influence FDA? During the review process, FDA will evaluate information from a wide variety of sources, including, in some cases, decisions of other regulatory bodies. FDA is in no way bound by the decision of any other regulatory body; however, the rationale used to reach that decision may be informative for FDA. Both EU and U.S. regulatory bodies are independent bodies that make decisions based on their respective criteria. Although conditions have improved for cross-regional cooperation in the past few years, partly as a result of the ICH process for drugs. Combination Products in Japan
- 23. There is no specific definition for combination products in legal terms. A product consisted, comprised oｒcombined of a drug and a medical device in the following way is regarded as a so- called combination product. Physically/chemically combined like drug eluting stents, heparin-coated catheter , drug pre-filled syringe, drug-eluting patches co-packaged like surgical kit containing catheters, rubbing alcohol etc Separate ―cross labelled‖ products are not recognized as combination products, like drug for photodynamic therapy and laser A combination product is judged as a drug or a medical device by the primary mode of action of each product on case by case basis. Following three divisions/office of MHLW are involved in such judgement: Licensing and Evaluation Division Medical Devices Evaluation Office Compliance and Narcotics Division In case the product is judged as a pharmaceutical, Office of New Drug division of PMDA leads for its review. If the product is judged as a medical device, Office of Medical Devices division of PMDA leads for its review. Both offices co-operate with each other in review process. There is no unique type of marketing application for combination products: A combination product judged as a drug is a subject of drug SHONIN application and a combination product judged as a medical device is a subject of device SHONIN application. A single SHONIN application (drug or medical device) is sufficient for a final decision about a combination product. There is no special requirement for GMP/QMS or PMS for combination products. A combination product judged as a drug is a subject of drug‘s GMP and PMS and a combination product judged as a medical device is a subject of device‘s QMS and PMS.
- 24. Some examples of combination products are: Drug-eluting stents Stents coated by drug-containing polymer regulated as a medical device reviewed by a medical device team of PMDA Drug-prefilled syringe drug already filled in syringe regulated as a drug reviewed by a drug team of PMDA A normal syringe is certificated by third party certification Device coated with drug Heparin-coated catheter device Hydroxyapatite artificial bone with BMP device? Drug with device for delivering system Drug-eluting contact lens drug? Drug-eluting transdermal patch drug Gelatine sponge with BMP drug? Iontophoresissystem with a drug reservoir In case of disposable system in which a reservoir is pre-filled with a drug and cannot be re-filled, the whole system is judged as a drug In case of non-disposable system in which a reservoir can be re-filled with a drug repeatedly, and iontophores is system and a drug is distributed separately, the system is a medical device and a drug is regulated as a drug Following points should be considered: Primary mode of action Separate distribution Approval times typically are 12 months for PMA (efficacy plus safety) devices compared to six months in the United States; approval times for 510(k) devices, which relates to efficacy only, take three months in the United States compared to four months in Japan, six months in China and six to eight months in Korea. It should be noted that the time required to gain approval is lengthened not only by the process, but also for administrative reasons—the MHLW is perceived to be both understaffed and carrying a backlog of applications. The impact of these delays and lengthy processes is that new products offering better patient care are not being marketed as quickly as possible.
- 25. The Japanese regulatory process was revised in 2005 to accommodate combination products, biologics and medical devices, and to allow third-party review for approval. This process is in line with changes implemented at the FDA and in the European Union. However, these processes and systems are still new and will require a period of adjustment. Ultimately, these regulatory improvements will lead to a more efficient approval process but will require that manufacturers remain patient while longstanding practices are supplanted by new review methods. References: 1. Examples of Combination Products, www.fda.gov/cdrh/oivd/presentations/041905- torress-cabassa_files/textonly/slide5. . . . . . 2. Not Combination Products, www.fda.gov/cdrh/oivd/presentations/041905- torress- cabassa_files/textonly/slide6. . . . . . 3. Drug/Medical Device Combination Products, Health Canada, www.hc-sc.gc.ca/dhp- mps/prodpharma/applic-demande/pol/combo_mixte_pol_200. . . . . 4. Policy on Drug/Medical Device Combination Products- Decisions, Health Canada, www.hc-sc.gc.ca/dhp- mps/prodpharma/applic-demande/pol/combo_mixte_dec_pol. . . . 5. Definition of a Combination Product, US Food and Drug Administration, www.fda.gov/ oc/combination/definition.htlm 6. This Week in FDA History, US Food and Drug Administration, www.fda.gov/ contennial/this_week/52_dec_24_dec_31.htlm 7. FDA Establishes Office of Combination Products, US Food and Drug Administration- FDA News, www.fda.gov/bbs/topics/NEWS/2002/NEW00862.htlm 8. Overview of the Office of Combination Products, US Food and Drug Administration, www.fda.gov/oc/combination/overview.htlm
- 26. 9. ―State of the Union: Drug-Device Combinations”, Gibbs J., Medical Device Link, www.devicelink.com/mddi/archieve/06/11/009.htlm 10. ―Combination Medical Products: Capitalizing on Convergence‖, Cramer C, Rastogi S., Medical Device Link, www.devicelink.com/mddi/archieve/07/01/009.htlm 11. FDA Proposes Rule on ―Combination‖ Products, US Food and Drug Administration, www.fda.gov/bbs/topics/ANSWERS/2004/ANS01288.htlm 12. Recent Examples of Combination Product Approvals, US Food and Drug Administration, www.fda.gov/oc/combination/approvals.htlm 13. ―Combination Vaccines for Childhood Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP), and the American Academy of Family Physicians (AAFP)‖, Committee of Infectious Diseases, American Academy of Pediatrics, Vol. 103, No. 5, May 1999, pp 1064-1077 14. ―Definition of Primary Mode of Action of a Combination Product‖, 21 CFR Part 3, US Food and Drug Administration, Department of Health and Human Services, Docket No. 2004N-0194 15. ―Guidance to Industry and FDA: Current Good Manufacturing Practice for Combination Products‖, Draft Guidance, US Food and Drug Administration, Department of Health and Human Services, September 2004, www.fda.gov/oc/combination/OCLove1dft.htlm 16. ―Combination Devices‖, Segal S.A., Medical Device Link, www.devicelink.com/ mddi/archieve/99/01/016.htlm 17. ―Regulation of Combination Products: FDA Employee Perspectives‖, US Food and Drug Administration, Combination Products Program, Office of the Ombudsman, Office of the Commissioner, October 2002 18. ―Challenges of Drug/Device Combination Products‖, Wu, D. G., AAPS Workshop on Pharmaceutical Stability Testing to Support Global Markets, September 10-12, 2007 19. ―Industry Statistics‖, www.pharmameddevice.com/App/homepage.cfm?appname= 100485&linked=2329. . . . .
- 27. 20. ―FDA Regulation of Combination Products‖, Gross M., Part 15 Public Hearing, November 15, 2002 21. ―An Overview of Recent Developments in the European Regulation of Medicine/Medical Device Combination Products‖, Jefferys D. B., Drug Information Journal, 2003 22. ―Lost in Translation?‖, Sullivan J., Elbaek H., Medical Product Outsourcing, April 2007, www.mpo-mag.com/articles/2007/04/lost-in-translation 23. ―Regulation of Combination Products- the Australian Approach‖, Tang S., Medical Devices Assessment Section, Office of Devices, Blood and Tissue, TGA, 2007 24. ―Combination Products Regulation in Japan‖, Tawaragi T., Office of Medical Devices Evaluation, Pharmaceuticals and Food Safety Bureau, Ministry of Health, Labour and Welfare in Japan 25. ―Combination products are changing the life sciences industry‖, Ludvig, S., 2007, www.deloitte.com/dtt/press_release/0,1014,sid%253D12850%2526cid%253D163415,00. html 26. ―The ascendance of combination products‖, Langer R., Shmulewitz, A., Nature Biotechnology 24, 2006, pp 277 – 280, http://www.nature.com/ nbt/journal/ v24/n3/ full/nbt0306-277b.html 27. ―Australian Medical Devices Guidance Document Number 35‖, Australian Government, Department of Health and Ageing, TGA, November 2005 28. ―Getting Started with a Combination Product Part II: European Regulations‖, Sall, B. S., Lassoff P., Babbitt B., Medical Device Link, www.devicelink.com/ mddi/archieve/ 03/04/019.htlm