Combination products have been controversial topic since the introduction of 21 CFR part 4 in 2013. Combination products can consist of Drug & Device, Biologic & Device, or drug/Biologic. Most Drug and Biologic products requires Clinical trials that are divided into phase I, Phase IIa, Phase IIb and Phase III. During phase I clinical studies, the device may not be fully designed and it may not have full functionality. The main question is What Design controls and Design transfer activities are required for phase I clinical studies.
This is an interesting question, which brings another question to mind: would design transfer activities even have begun at phase I clinical studies? I ask because typically for drugs and biologics, transfer to manufacturing is not done during phase I, since low volumes are needed. Phase I studies are run with very small number of patients, which shouldn't really require manufacturing. If something does not even pass phase I, why would manufacturing even be considered?
Good discussion topic. I found this interesting link that provides a helpful visual on page 3 to understand where Phase I Clinical Studies would occur. As per the source, it shows that as part of the design validation, the clinical trials would be done after the validation tests and reports are completed. Also, the DDP, DID, DSD and design output (including the verification and review) must all be completed before sending the product into the validation stage.
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Design plans are just a plan. In fact, this is stated in both Clause 7.3.1 of the ISO Standards, and in Section 21 CFR 820.30b of the FDA QSR.Design control for 1st phase include the following 16 tasks:
Identification of the regulatory pathway based upon the device risk classification and applicable harmonized standards.
Development of a risk management plan
Approval of your design plan (1st design review)
Initial hazard identification
Documentation and approval of design inputs (2nd design review)
Risk control option analysis
Reiterative development of the product design
Risk analysis
Documentation and approval of design outputs (3rd design review)
Design verification and validation, and risk control verification
Clinical evaluation and risk/benefit analysis
Development of post-market surveillance plans with post-market risk management plan
Development of a draft Device Master Record(DMR) /TF Index
Commercial release (4th and final design review)
Regulatory approval and closure of the Design History File (DHF
Review lessons learned and initiate actions to improve the design process
Hi,
During the phase I clinical trials we can find out if the drug or medical device is safe to for people. In this initial phase of clinical trials small group of people is tested for couple of months. In most cases it is a group between 20 and 100 healthy volunteers who are receiving money for being part of the study. The study is intended to determine the effects of the device or the drug on people. During this phase the side effects when dosage is elevated are also recorded. On the average about 70% of devices and drugs is permitted to go to another phase.
Thanks
Phase 1 clinical studies are done on a small group of participants after the drug or treatment has been proved safe on animals. Doctors use this phase to establish a good dosage range as well as collect data on the effects of the drug or treatment and its safeness. Clinical studies are a part of the validation process in design controls. If a product fails to meet the design input requirements during the design validation effort, it will be necessary to revise the design or manufacturing processes. The purpose of design transfer is to ensure product designs are transferred into manufacturing specifications. There are no design transfer activities associated with phase 1 clinical studies because there are done on only a small population. The clinical studies need to advance to the later phases and be tested on more people before design transfer comes into play.
As a few others have mentioned, technical transfer activities are not completed until a company has fully developed the medical device/drug/combination product and its manufacturing process. This often doesn't occur until during or after Ph3 clinical trials (and often the timeline depends on how risk averse the company is, i.e. some companies start tech transfer before Ph3 trials are completed because they are THAT confident that the product will be successful). Often, the product made for Ph1 trials is not manufactured in a sustainable way since the patient count for those trials is often low. After successful a PH1 trial read-out, a company will start developing the final product/manufacturing process for eventual technical transfer.
- Laura Wehmeyer
Design transfer is an integral process in the early life of a product. It must be well executed, especially for complex medical devices. FDA's quality system regulation requires the manufacturer to complete the following steps in order to satisfactorily complete the design transfer process:
* ensuring the device design--configuration
* Transfer the product design into production methods and procedures
* Create a production environment that ensures the product complies with regulatory requirements and industry standards
The design control requirements are basic controls needed to ensure that the device being designed will perform as intended when produced for commercial distribution. The elements of design controls are - planning, input, output, review, verification, validation, transfer, design changes and design history file. Clinical trial is an important aspect of the design verification and validation process during the design and development of the device. Phase I clinical study aims at the safety and tolerance of the product. It is done on a small population. It is to determine preliminary safety, performing information and adverse effects. Clinical trials are a part of the design validation process. Before clinical trials; preclinical tests are done for for determination of safety, efficacy or performance in in-vitro and animal systems. These include biocompatibility tests designed to ensure biological safety of the materials and animal efficacy tests designed to evaluate effectiveness of the design in nonhuman systems.
I believe design control should be implemented in every step of the process from start to end of the product's life. It is important to numerically or for some cases observationally be able to determine how well you are doing in each step. Also, figuring out this process in advance may be beneficial towards applying it to future products. In addition, by having documents trials and progress of each step of the design process it will be easier in terms to troubleshoot if your device fails at some step. In addition, if any auditing organization comes to audit your company it is extremely easy to show that you have followed each step of the design process according to laws and standards. In addition, it will be easier to convince customers of safety and the accuracy of your products since you are able to answer any questions regarding the accuracy and error of any step of the design process.
In combination products design controls, the clinical trials takes place as three constituents - for drug constituent part, the device constituent part and the combination product as whole. The implication from each part help change the impact on the combination product as a whole and consequently changes in design control document. And the DHF must address all clinical trial issues resulting from the combination of the constituent parts.
