Combination products – A 5 point checklist for compliance approval

Posted: 08/01/2017

After a decade in development, products in a multi-billion dollar sector are falling at the last hurdle – under-the-gaze of the regulator

Combination products, or drug and device products, fuse a medical element (biologic) with that of a medical device (syringe, inhalers, injectors).

The market for these products is earmarked for growth with some sources stating that the industry is likely to hit US $115 billion by 2019.


The path to approval for these products is not simple. When concerning compliance requirements, these products emulate a “marriage between two partners with cultural differences”. Simply put, manufacturers struggle to execute meeting regulations for the products’ biologic and device simultaneously.

Leading the way

The EU and US markets are streets ahead in the combination products market, with the majority of drug-device products investigated and approved in these regions.

Dave Anderson, Roger Liu, J.Anand Subramony of AstraZeneca  state that although there has been “admirable cooperation between the industry and FDA in recent years”, stubborn review criteria have been  imposed on certain product design features.

Regulatory authorities are stepping in to improve the compliance gauntlet for these medicines to ensure both patient safety and product innovation is maintained.

The EU opened public consultation for a new concept paper to frame a quality guideline on drug and device products.

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Patient safety  

One key compliance stumbling block with these products is evidencing that patients “on average” will interact with the product safely. The device component adds another level of complexity to verifying patient adherence.

Manufacturers have fallen victim to delays because they failed to grasp that a lack of human factor testing can hold back product development. Often this realisation occurs too late in the product development cycle.

Richard Featherstone, human factors and usability practitioner, notes that the science and regulatory guidance behind testing human factors in combination products is not as advanced as testing in other areas of drug discovery.  

He maintains: “A complaint we hear often is that there is conflicting guidance from different reviewers within the same regulatory body. For example, one reviewer might request an untrained group to be included in a study, whilst a different reviewer might say that an untrained group is not required.”


What is required? A five point checklist

Tests must show that users can administer the drug and device product safely and effectively within the intended environment.  Data from testing must prove the performance of the product within simulations that replicate the intended environments for use.

  • Pharma firms should consider if they are testing the right users, this may include physicians.
  • Focus on the risks relating to how the product is used – and how it functions as a result. Do your instructions inform a previously untrained user enough so they can implement the dose effectively?
  • Digital tools are often paired with these devices to improve patient usability, thereby reducing the need for healthcare professionals to administer doses. 
  • It is useful to also evidence test peripheral items that support your product – this may entail a charging port or carrying case as they are part of the system as a whole.
  • As Featherstone points out,  medical authorities there is a range of experience within looking at human factors with drug devices. “In practice, this means that you will have to help the regulator by working hard to provide a clear, concise report with suitable references, and a scientific justification for your arguments, in particular, with regard to any residual use-related risks.

In the race to approval, compliance expectations are only going to rise. To steer clear of an emergency stop on their course towards market access, pharma firms would be wise to build comprehensive human factor testing into their development cycles before it is too late.  

Disclaimer: The notions expressed in this article shoudl not be taken as legal advice.
Posted: 08/01/2017

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