A Primer On Investigational Drug/Delivery Device Regulatory Requirements

By David Amor, MSBE, CQA, Medgineering

The device part of a drug/ delivery system submissions needs to comply to the device requirements for investigational devices – with a few other common sense considerations.

Combination drug/device delivery products are becoming the standard of care in many therapeutic areas. Accordingly, many pharmaceutical companies looking to supplement their R&D pipelines acquire innovative combination products being developed by medical device start-ups.

Most of these new technologies start as investigational products that need to be characterized for safety and efficacy before the U.S. Food and Drug Administration (FDA) will clear them for use in the United States. Although the FDA recently released the current Good Manufacturing Practice (cGMP) for combination products rule 21 CFR 4, as well as a corresponding guidance, a cloud of confusion persists surrounding investigational products: What are the requirements for drug/delivery devices used in clinical trials?

It’s All About The Classification

Drug/delivery devices are most commonly classified as combination products per 21 CFR 3.2 (e). Let’s use pen injectors as an example. Because the primary mode of action (PMOA) with pen injectors relates to the drug being delivered, regulatory applications/submissions are assigned with FDA’s Center for Drug Evaluation and Research (CDER) as the lead agency. As with most drugs, pen injectors would be submitted using a New Drug Application (NDA), or a scaled-down application equivalent (ex: 505(b)(2)) if predicates are being leveraged or claimed.

Still, while an NDA’s focal point is, well, a new drug, FDA also keeps a close eye on the device portion of any combination NDA submission — especially if the “newness” of the product is the device’s inclusion. In fact, although CDER acts as lead agency in an NDA, they usually outsource review of device testing and data to FDA’s Center for Devices and Radiological Health (CDRH) — the administration’s device experts. So, what should comprise the device portion of the submission?

I propose a basic, qualitative equation to address this question:

DHF_device = [DC + (FDA-G)] x [2(R_PC_P)]R_CC_RC

1. DHF_device = Design history file (DHF) — The device portion of a combination product submission, as mandated by 21 CFR 820.30
2. DC = Design control requirements — Design controls establish the minimum requirements for investigational devices.
3. FDA-G = FDA device-specific guidance — For example, if a company is working on a pen injector, they should be aware of, and follow, FDA Guidance for Industry and Staff: Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products.
4. R_P = Risk of product — Potential hazards, hazardous situations and harms associated with use of the product.
5. C_P = Complexity of product — This factor addresses technical complexity and scope of the product. More complex products will typically require additional DHF information, such as more thorough design inputs and a full spectrum of design outputs to fully characterize specifications.
6. R_C = Risk of company — This is a measure of regulators’ expectations of a company; it is assessed by reviewing size, products on the market, regulatory history, etc. For example: A company that is emerging from an FDA Form 483 or Warning Letter citation would be wise to ensure that future marketing applications are thorough.
7. C_RC = Complexity of regulatory climate — This factor is often overlooked when developing new products. Before a company develops and submits for approval a new drug-delivery device, it should review how competitors and similar products are performing on the market. If there are no competitors — as is the case with “revolutionary” first-gen products — consider any issues that plagued products with the same intended use, or products operating in the same therapy area. This analysis provides good insight into how regulators will assess your device.

Let’s review, in detail, each of the variables that device regulators will assess in your combination drug/delivery device submission:

DHF_device

In most cases, a drug delivery device using the NDA pathway will have to be evaluated just like a drug — in Phase I, Phase II, Phase III, and Phase IV clinical trials. Prior to initiating clinical trials, a manufacturer must submit what is called an Investigational New Device (IND), which the FDA reviews to ensure there are no inherent safety risks posed to trial enrollees.  Through these trials, the product is investigational.

Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products states that each constituent product of a combination product should follow its own rules for investigational devices. This means that the drug part is subject to requirements of 21 CFR 210/211, and the device portion is subject to the Investigational Device Exemption (IDE), specified in 21 CFR 812.

All GMPs are also exempt from clinical devices — except 21 CFR 820.30, most often known as “Design Controls.” Design control entails controlling and reviewing your design in progressive steps, each one reducing safety and efficacy risks, until a final product is verified, validated, and transferred to manufacturing.

Design control activities are documented in a design history file (DHF), which is why the first term of the equation represents the “device portion” of the combination product submission. This DHF will include all documented evidence that design requirements were fulfilled, risk was planned and controlled, the device was tested thoroughly and validated for its intended use, and the design was reviewed throughout the development process.

This naturally leads to the question, how much DHF documentation is enough? That’s what the rest of the terms in the equation explain.

DC (Design Control Requirements)

Design controls establish the minimum requirement for investigational devices (per 21 CFR 812). DC for combo submissions means:

1. Planning your design — Drug/delivery products should have a development plan that talks about the planned design activities, how and when the design will be reviewed, responsibilities for design (contractors, vendors, partners, etc.), and a description of the regulatory path.
2. Defining your device with design inputs — As a general rule, the more complexity and risk associated with the device, the more design inputs will be required to adequately characterize it. Design input documentation should cover key user needs and key interface requirements between the device and drug, particularly for delivery devices. Common requirements include extractables/leachables in a drug container, drug delivery volumes, and injection flow rates.
3. Specifying your design (design outputs) — Once your device is fully defined, prototypes, specifications, drawings, and other design outputs are required to demonstrate that design inputs are being fulfilled.
4. Verifying and validating your design (design verification) — Does the drug/delivery device meet its design inputs, and does the overall product successfully meet the intended use? Combination testing should be done as much as possible; this rules out potential adverse issues with the device and drug operating in concert in downstream clinical trials, or prior to commercialization. Human factors considerations are also key to combination product submissions. Use IEC 62366-1:2015 as guidance to ensure that use of the product is simple, intuitive, and devoid of major use errors that can compromise patient safety.
5. Reviewing your design — The whole intent of design control is to ensure that product design is constantly under control, and that design issues are discovered earlier in the development process — saving companies time and money, and preventing safety and efficacy issues in the field. Periodic reviews of the design with cross-functional teams — especially through the clinical trial stages — ensure that each time a product is to be used in a trial, the team is confident in its performance.

FDA-G (FDA Device-Specific Guidance)

For combination product submissions, FDA device-specific guidance helps further refine design control requirements, often detailing specific, necessary testing and features. For example, the pen injector industry guidance cited earlier describes the best materials for an injector, lists design features that should be considered, establishes performance testing requirements, and even specifies how the product should be sterilized. These guidance documents are the best place to start when trying to fulfill design control requirements.

R_P (Risk Of Product)

The burden of proof for most regulatory submissions is that a product must be safe and effective. Systematic identification, analysis, evaluation, and acceptance of risks is best done using EN ISO 14971:2012, an FDA consensus recognized standard. Hazards, hazardous situations, and harms attributed to drug/delivery products act as weighting factors to the depth and breadth of the DHF. As a general rule, if a product’s risk is foreseeably high, the design team should focus on defining and testing the product further (i.e., the DHF will be more substantial). With drug/delivery devices, particular emphasis should be placed on usability risks. The user interface often impacts whether the drug is delivered correctly, which could significantly impact the therapy effect.

C_P (Complexity Of Product)

Product complexity is a significant factor in the DHF equation because, as a rule, more complex devices require more planning, testing, and reviewing. Newer, more complex pen injectors include more components, materials, moving parts, and mechanisms than traditional piston syringes, which can be manufactured using fewer than a dozen parts. As such, it is wise to expect that newer injectors should be characterized and tested more rigorously, which translates to a more substantial DHF. It makes sense: De-risking a complicated product takes more time and effort, and in the quality and regulatory world, more time and effort means more documentation.

R_C (Risk Of Company)

Although this step is not as critical as other factors, always consider your company’s industry reputation (external) and record with regulators (internal). Activities should be scaled accordingly. As a practical example, if a company has been cited with multiple issues related to incomplete or missing requirements (design inputs), a subsequent submission should emphasize how those deficiencies have been addressed. A company’s size also contributes to regulator expectations. A large company should have a more robust and complex quality management system, capable of supporting full DHF development, versus an early stage start-up trying to get its first product to market.

C_RC (Complexity Of Regulatory Climate)

“Regulatory climate” is a nondescript term that can be used to describe trends in regulator activities and actions, particularly around a specific set of companies and/or products. Combination products have become a particular area of interest for the FDA, and rightfully so. When considering a drug/delivery product, take time to understand industry trends and hot topics concerning similar products. Attend conferences and learn from fellow manufacturers. Review the FDA website for adverse events related to drug/ delivery products (including the Manufacturer and User Facility Device Experience, or MAUDE, database), and ensure that you have assessed those same risks. Make sure to dedicate resources to market surveillance and vigilance, using what you learn to help guide your regulatory submission.

Requirements Only Will Get Stricter

The DHF equation describes a basic process for deriving the answer to “How much device information is enough?” for investigational drug/ delivery products. However, it should be noted that, as investigational combo products move through the progressively more challenging drug clinical trial phases, the depth and breadth of the DHF should correspondingly become more exhaustive. Changes should also be limited past Phase II, as the product must become more production equivalent (i.e., resembling the commercialized final product). Failure to settle on safe and effective design prior to NDA submission could lead to delays and additional testing requirements for companies.

Conclusion

Although the drug is usually the focal point in a drug/device delivery combination product, the FDA still expects to see the device being defined, tested, and characterized, even in investigational phases. A device’s DHF serves as objective evidence of device design being precisely controlled, and should be scaled according to the variables described herein. Regardless, decision-making surrounding regulatory strategies and paths for combination products should always be well documented and justifiable: If it isn’t documented, it didn’t happen!

About The Author

David Amor, MSBE, CQA is a medtech/biotech consultant and mobile health entrepreneur who founded Medgineering, a company focused on remote compliance, regulatory, and quality systems consulting for larger companies and start-ups. A graduate of the prestigious Innovation Fellows program at the University of Minnesota’s Medical Device Center, Amor was named a Top 40 Under 40 Medical Device Innovator in 2012 and a 35 Under 35 Entrepreneur in 2015 by Minnesota Business magazine. He co-founded and helped launch Remind Technologies, a Texas-based mobile health company developing a smartphone-based remote medication management system. He is also co-inventor on several issued utility patents and co-pioneered a disruptive e-consulting platform for the medtech and pharma industries called QuickConsult. Amor serves as an adjunct professor at St. Cloud State University (Maple Grove, MN) where he teaches courses on risk management and design control. The current focal points of his consulting practice are specializing in risk management, design controls, combination products, and mHealth. He can be reached at david@medgineering.com or at 786-546-1806.