FDA underlines commitment to post-marketing drug testing

Critical Path is a broad initiative at the FDA involving all of its medical centres. The effort is aimed at catalysing the creation of a new generation of scientific tools to enable product sponsors to better predict and evaluate the safety and effectiveness of candidate products.

It also aims to make product development less risky and more efficient; and to enable individualisation of therapy to improve effectiveness and avoid side effects.

Our goal is to translate the science developed under this initiative into FDA guidance to scientists and product manufacturers in order to clarify the regulatory path for modernising approaches to bringing products to market.

Under Critical Path, we are working on long-term science development as well as near term improvements and modernisations in our own regulatory procedures to accommodate new scientific tools and approaches.

For example, we are launching a clinical trial collaboration to validate the use of positron emission tomography imaging as a surrogate endpoint for cancer therapies and we hope to expand this collaboration to include additional imaging technologies. And we recently announced other new initiatives such as a framework for conducting early studies with micro doses, as well as a safe harbour for the submission of pharmacogenomics data, which we hope to soon extend to other kinds of data submissions such as proteomic data.

At the same time, we are developing regulatory guidance for incorporating these new scientific tools into the development process. One such guidance, which should be out in draft form this year, addresses how product developers can seek approval for a new drug and a diagnostic test for guiding the targeted use of that therapy, all within the same registration trial.

But as we take steps to modernise the scientific tools that are used during drug development, we are also mindful to continue to take steps to modernise our own processes and approaches so that we are adopting modern management approaches and so that new scientific tools can become integrated into the registration process.

One way we can do this, for example, is to promulgate guidance on how scientists can use these new tools as part of the drug development process. We also want to continue to take steps to modernise our own internal approaches to evaluating the information we receive, and setting regulatory standards, whether it is through process improvements in our own work, through quality systems we adopt, or through technological improvements such as the incorporation of information technology to help us better evaluate the information we receive.


More phase four commitment

To these ends, we now have a new commitment to improve the process for collecting medical information as part of the so-called phase four trials or ‘post marketing commitments’ drug developers often undertake after drugs are approved.

Right now, sponsors often don’t complete these important studies, sometimes they argue because the trials were too hard to enroll, or the clinical environment changed and the questions they were seeking to answer were no longer relevant to the practice of medicine.

We fully intend to work with sponsors to make sure these important commitments get completed. We have recently been evaluating more of these incomplete post market commitments at our advisory committee meetings. The cancer division recently had one such meeting, where they reviewed eight post-market trials that were never brought to completion. We want to take opportunities to evaluate these trials after they are set in motion to make sure they are still clinically relevant, and focused on finding out the most important information.

If there are improvements we can make in the design of these trials, or if the practice of medicine has changed in a way that the questions these trials seek to answer are no longer as relevant, we want to know about it and see how we can make the design of these studies more focused around the most practical and important medical questions that doctors and patients ought to have answers to in order to safely and most effectively use a new medicine.


Lack of early discussion

Drug developers argue that one problem that sometimes gets in the way of designing the best trials is that FDA often does not have the opportunity to discuss the design of these trials until very late in the drug review process, often weeks and sometimes even days before the agency is expected to make a final decision to approve a new drug.

So there isn’t a lot of time for careful scientific discussion between FDA and drug developers about how to design optimal trials. With more scientific exchange, it may be possible to design better trials that will answer important questions with more accuracy and more certainty.

FDA is currently in the process of undertaking the first step in an effort to evaluate and perhaps improve how post marketing commitments are developed and implemented by the agency, and how we work collaboratively with scientists and drug developers to design optimal studies and to make sure they are brought to completion after new drugs are approved.

To begin, we will be contracting with an outside group to undertake a thorough evaluation of how these commitments get designed and implemented. We are currently negotiating the contract to undertake that study and should be ready to announce it shortly.

The objectives of this effort are to evaluate the consistency of the processes within divisions, across divisions, and across the different medical centres at FDA for requiring, requesting, facilitating, and reviewing post market commitments. We want to identify any obstacles that may result in these processes being less efficient or consistent than they ought to be.

Additional objectives include recommendations for, and assistance with implementation of standard policy and procedures for requesting post marketing commitments which reflect FDA’s best practices, and creation of a quality system for justifying, drafting, and reviewing post marketing commitments. This will include additional training for reviewers and management on the best way to design and implement post marketing commitments.

This contract is not intended to assess the tracking and monitoring systems for post marketing commitments. Instead, it is intended primarily to identify and improve the scientific decision-making process around the design of these important studies. Once the contract is announced, the evaluation is expected to take a full year. We believe the results of this analysis will lead to recommendations for how we can improve the process for designing and implementing post marketing commitments.

These studies are a vital part of evaluating the safety and effectiveness of new drugs as well as new devices. Even the largest and best-designed pre-market studies cannot reasonably answer all of the important questions patients and doctors have about medicines.

No reasonably sized clinical study can evaluate all of the subtle effects of medicines, including new indications for a medicine or the very rare size effects that may occur only once in tens of thousands of patients.

Continuing to evaluate drugs after they are approved – in post marketing trials as well as the routine collection of bottom line information from ordinary medical encounters – is an important part of ensuring their safety and learning new things about their benefits.

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