As evidence continues to mount that some drugs metabolize differently based on age, sex, race, and other variables, the U.S. Food and Drug Administration is recommending actions with implications for certain pharmaceuticals and medical devices.

Published in July, the FDA’s Population Pharmacokinetics Guidance for Industry draft aims to increase safety and efficacy for pharmaceutical products. The draft guidance calls for sponsors of new drug and biologics license applications to apply population PK analysis, which is frequently used to guide drug development and inform recommendations on therapeutic individualization. This guidance also includes common applications of population PK analysis, the FDA’s current thinking on the data and model requirements needed to support regulatory decisions, recommendations to sponsors on drug labeling based on population PK analysis, and general expectations.

The FDA guidance documents do not establish legally enforceable responsibilities. However, once a draft guidance is published, a new wave of industry best practices usually begins to take form. Companies that fail to follow suit risk losing competitive ground.

Impetus For Change

This population PK movement is largely the result of increased scientific knowledge, data collection capabilities, and industry insight and does not intend to imply prior or present negligence on the part of drug and/or device manufacturers. Traditionally, studies often limited — and continue to limit — the breadth of trial subjects due to a variety of rational scientific and business factors. These include, but are not limited to, testing a desired result for a specific/relevant patient segment; the availability, vulnerability, and/or willingness of participants; and budgetary and time constraints.

Studying the effects of specific drugs and biologics on germane subpopulations could bring new information that leads to significant changes on drug dose and dosage frequency, use, and usage limitations for specific sub-populations, including a prominent boxed warning. Plus, genomics and proteomics are likely to drive even greater granularity of how drugs and biologics will be used in treatments. For example, as healthcare begins to incorporate personalized medicine into the mainstream, new discoveries will likely drive the need to account for treatment safety and efficacy for additional subpopulations.

Implications For Drug And Device Development

As a matter of practice, device companies today tend to assume a single population PK will be used long-term for a given drug and so design their devices, including software as a medical device, accordingly. For example, this is often true of calculation devices used to determine the appropriate drug dose for treatment of hemophilia, clostridium difficile, and diabetes. With an insulin calculator, for instance, the calculation of how much insulin is still in a person X amount of time after a dose is given includes consideration of the PK for insulin. Knowing how much insulin is on board helps prevent a patient from getting too much insulin and becoming severely hypoglycemic. These types of devices often incorporate specific PK from the drug labeling, usually deep within the product design and often hardcoded.

That means, if a pharmaceutical company makes any PK-related modifications or additions to a drug or biologic in response to the draft guidance, then any affiliated devices need to be modified to match. As a result, the likely new norm for device manufacturers will become creating flexible designs capable of 1) addressing multiple populations, and 2) mitigating associated risks. Keep in mind, design changes also could require new validation studies and/or new premarket notifications, e.g., 510(k) filings.

With this in mind, companies in the process of developing products that incorporate drug PK information may want to design algorithms to be updatable without having to change the software code itself. In this case, the company may be required to perform some level of validation on the update, but perhaps not a new premarket submission. In addition, it is possible — and some precedent exists — that if the only aspect being changed is the software algorithm, then the FDA might allow devices to be bundled into a single submission or limit the scope of the submission to a bench-level software validation. However, because manufacturers execute designs in different ways and drugs often use different risk profiles, FDA approval to bundle submissions is likely to be decided case by case. Again, more will become known as the draft guidance moves through public comment and finalization.

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Preparing For The ‘New Normal’

While many unknowns remain, life sciences companies are well advised to take proactive steps knowing the draft guidance signals change is underway. Moving forward, pharma/biopharma and medical device developers should work together, communicate clearly with one another, and continue to implement appropriate mechanisms to help ensure the safety and effectiveness of drugs and devices for patients.

For their part, pharma companies should put — and keep — processes in place to share relevant and timely information related to the draft guidance and resulting in-house developments with their medical technology partners.

Likewise, medical device developers should proactively monitor guidance updates, consult with their pharma partners to stay abreast of relevant product changes, and be prepared to adjust accordingly. For new products or products early in development, medtech companies should consider designing a flexible system that can react to changes in PK information. For legacy products or those far along in development, medtech companies should consider what changes might need to be made to business plans, e.g., launch and product update schedules, as well as budget and other resources.

About The Authors:

Scott Thiel is a director in Navigant’s healthcare and life sciences disputes, regulatory, compliance and investigations practice, leading the health information technology regulatory group. He has more than two decades of experience in the medical device industry, with expertise including product development, software and connectivity related to medical devices (including interfaces with consumer electronics), regulatory affairs, compliance, and quality system creation and remediation. He can be contacted at Scott.Thiel@navigant.com.

Liisa Eisenlohr is an associate director at Navigant within the Healthcare and Life Sciences Disputes, Regulatory, Compliance and Investigations practice, bringing more than 20 years of experience within the life sciences industry. Liisa’s broad skillset includes experience in various areas of medical affairs, regulatory affairs, compliance, health economics and outcomes research (HEOR), and clinical trial management. She has supported such projects as effective global clinical trial initiation and ongoing monitoring; creation of technical documents for regulatory submissions; and establishing post-marketing adverse event reporting systems. She can be contacted at Liisa.Eisenlohr@navigant.com.

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