Regulation for combination products and medical devices

Combination products are a combination of a drug or biological product or a medical device.

1. Regulation for combination products and medical devices

2. CONTENTS Combination products Medical devices History Request for designation process (RFD) Primary mode of action (PMOA) Preclinical evaluation Clinical evaluation cGMP for combination products General safety considerations References

3. COMBINATION PRODUCTS :- Combination products are a distinct group of therapeutic products that are made up by combining two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product with one another). The drugs, devices, and biological products included in combination products are referred to as “constituent parts” of the combination product. For example :- 1. metered dose inhaler 2. prefilled syringes 3. nicotine patches

4. Types of combination products :-

5. Examples of combination products :-

6. MEDICAL DEVICES:- Any tool, apparatus, implement, machine, appliance, implant, reagent for in vitro usage, software, material, or other like or related item that the producer intends to be used, either alone or in combination, for medical purposes is considered a medical device. Examples :- Single-use products such as catheters and syringes implantable (such as pacemakers and hip prostheses) imaging, such as CT and ultrasound scanners medical apparatus, such as hemodialysis machines, patient monitors, and anesthetic machines. software, frequently known as computer-aided diagnosis.

7. History :- The federal food and drug Act , which was passed in 1906 started the regulation of drugs ; however , the federal device act was passed in 1938 started the regulation of medical devices. In 1997 Food and drug administration modernization act (FDAMA) prohibited advertisement for unapproved uses of drugs and medical devices which lead to increase in warning letters to manufacturers. The US food and drug administration (FDA) has been regulating combination products since 1970.

8. The office of combination products(OCP) was established by FDA to regulate timely premarket reviewing of combination products according to Medical device user fee and Modernization act (MDUFMA). In 2013, FDA issued current good manufacturing practice requirements for combination products. FDA published Mode of action (MOA) and primary mode of action (PMOA). Every component part has a single MOA and significant MOA is PMOA. OCP designates audit responsibility to Center for biologics Evaluation and Research (CBER) , Center for drug Evaluation and Research (CDER) or Center for devices and radiological health (CDRH).

9. Request for designation process (RFD) :- Once a combination product has undergone formulation and pre-clinical testing, the device developer submits a Request for Designation (RFD) to OCP. The RFD describes crucial product parameters such as composition, pre-clinical study results, and potential indications. Identifying the primary mode of action (PMOA) is crucial in developing the RFD. The OCP classifies combination products using the PMOA and assigns them to the relevant lead review center for approval.

10. The three review centers specialize in drugs (CDER), devices (CDRH), and biologics (CBER), respectively. The OCP allocates a lead review center to regulate the regulatory pathway and decide the required type of investigative application based on the RFD's PMOA and their own review procedure. If the OCP qualifies a combination product as a medical device, the device developer can use the standard investigational device exemption (IDE) framework. Classification as a medication or biologic involves additional skills in the IND procedure, including managing phase I-III clinical studies.

11. Primary mode of action (PMOA) :- The PMOA is the means by which the products achieves its therapeutic efficacy. The PMOA of a combination product is the means by which the product is expected to deliver its greatest contribution to overall therapeutic activity. Com bination products that are based on PMOA of the medical devices are considered medical device-led combination products. In these products , the mechanisms to achieve the intended use are studied.

12. Preclinical evaluation :- The interactions between different components in combination products should be c onsidered initially. The addition of medicines to a device product can alter the original product's manufacturing process, storage conditions, indications, contraindications, and precautions. for example :- Heparin containing oxygenators could achieve anticoagulant action. Their drug loading techniques may have an action on the finished device’s mechanical and surface property. when an device is employed as a drug carrier , the production techniques , additives or storage conditions may affect drug release activity , drug release and overall product quality.

13. Clinical evaluation :- Before conducting clinical trials with combination medications, it is critical to clarify and comprehend their MOA and PMOA, anticipated efficacy, potential hazards, and adverse events. The goal of adding medicinal components to devices is often to improve product functionality or prevent adverse effects associated with their use. It is vital to establish the products' clinical risks and advantages. It is also vital to combine the performance characteristics and expected efficacy of combination goods in order to establish their science and the clinical design's suitability. for example :- Because of differences in the goals of clinical therapies, distinct drug-eluting stents may have different safety and efficacy evaluation result metrics.

14. cGMP for combination products :- The FD&C act considers drugs and devices to be adulterated if they are not manufactured in accordance with CGMP. The quality system regulation outlines GMP requirements for finished devices (21 CFR part 820) and CGMP regulations for all finished products (21 CFR part 211). The FDA publishes additional guidelines that may apply to one or more components of a combined product. The FDA acknowledges that many manufacturing sites follow one sort of current good manufacturing practice system. Essential Current Good Manufacturing Practice Provisions to Consider When Joining Along Co-packaged and Single-Entity Combination Products.

15. General Safety Considerations :- In combinations when one is a new molecular entity :- Conduct general toxicology of the NME:- Genetic toxicology, pharmacology, safety pharmacology, PK/ADME, general toxicology, Reproduction and developmental toxicology, carcinogenicity. Conduct 90-day bridging study with the combination in most appropriate species. In combinations of two or more new molecular entities. Pharmacology, safety pharmacology, PK/ADME, developmental toxicology, carcinogenicity. Conduct in 90 days

16. REFERENCES :- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637005/ https://www.lubrizol.com/-/media/Lubrizol/Health/Literature/Combination-Products-for-Medical-Developers.pdf file:///C:/Users/KUNNER%20SAAB/Downloads/ey-drug-device-combination-products-whitepaper%20(1).pdf https://www.jmcp.org/doi/pdf/10.18553/jmcp.2011.17.1.40 https://www.researchgate.net/publication/260877383_Combinational_products_A_regulatory_review Foote SB, Berlin RJ. Can Regulation Be as Innovative as Science and Technology? The FDA's Regulation of Combination Products. Minn. JL Sci. & Tech.. 2004;6:619. Tian J, Song X, Wang Y, Cheng M, Lu S, Xu W, Gao G, Sun L, Tang Z, Wang M, Zhang X. Regulatory perspectives of combination products. Bioactive Materials. 2022 Apr 1;10:492-503. Lauritsen KJ, Nguyen T. Combination products regulation at the FDA. Clinical Pharmacology & Therapeutics. 2009 May;85(5):468-70.