Each year, different FDA divisions update their publication plans for new draft and final guidance documents that are long awaited by the drug development industry, particularly biopharma sponsors.

Clinical Trials Arena dives into the 2023 new and revised draft guidance agenda from the Center for Drug Evaluation and Research (CDER) to see what the agency has in store for clinical trial sponsors this year. In the document, CDER outlines that it is not “bound by this list of topics nor required to issue every guidance document on this list,” but it gives a good insight into upcoming directions and advices on shaping clinical development plans.

This year’s agenda carries over many planned draft guidances from last year, such as the decentralised clinical trial (DCT) document, which is anticipated to be released by the end of 2023. Also, the agency is looking at previously unguided areas such as psychedelic research, further explores master protocols, and aims to harmonise its existing guidance with international organisations. In addition, Clinical Trials Arena explores planned draft guidance on several indications and clinical trial designs.

Long-awaited DCT draft guidance

Hearing from colleagues at the FDA, Craig Lipset, co-founder and co-chairman of Decentralized Trials & Research Alliance (DTRA), says that the release of the DCT draft guidance has been a work in progress. This planned draft guidance has been on a list for a couple of years now; however, 2023 will finally be the year when it sees the light.

This was indicated in the Fiscal Year 2023 omnibus spending bill, which was signed into law by President Joe Biden in late December last year. The bill indicates that the DCT draft guidance must be released “not later than one year after the date of enactment of this Act.”

Lipset says that the FDA is likely to be inspired by already existing documents on DCTs, such as the published recommendations by the Clinical Trials Transformation Initiative (CTTI) in 2018 and the EMA’s recommendations paper in 2022. The CTTI’s recommendations were largely done together with the FDA and updated by the two organisations during the Covid-19 pandemic, he explains. Once the draft guidance is out, Lipset expects to see many organisations and companies pay close attention and share good feedback with the agency.

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While the Covid-19 pandemic accelerated the DCT adoption, now there is a risk to run into hesitation, concern, and fear among operators, Lipset notes. The eventual guidance will give more clarity around DCTs, reduce the perception of risk, and continue to sustain adoption, he adds.

Spotlight on psychedelic research

Amongst the newly added items, one draft guidance will look at psychedelics, called “Psychedelic Drugs: Considerations for Scientific Investigations.” Apart from Health Canada’s notice released last year, the FDA’s draft guidance is likely to be the first guideline document released by a regulatory agency.

Such guidance is very much needed in a field that has been expedited in the past few years. Albert Garcia-Romeu, PhD, assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, says that a decade ago there were only a few research laboratories working with psilocybin or MDMA. Now, there is a huge number of people starting to initiate trials investigating psychedelics.

Garcia-Romeu says that the FDA likely wants to standardise the research so everybody would at least do something similar. As a result, it will make the agency’s life easier, as many regulators who are looking at trial protocols may have never seen anything related to psychedelics before.

The draft guidance should include information regarding cardiovascular monitoring before administration and during drug effects, as well as screening for certain types of mental health conditions that should be exclusionary, Garcia-Romeu notes. The guidance might also explore drug interactions and clinical licensure requirements.

While this is a good initial step, the FDA should eventually look at different subclasses of psychedelics, as each substance has different considerations regarding safety and administration. “Ultimately, this guidance will help a lot of different people to do this work and make it easier and more transparent for starting it up and dosing safely,” he adds.

Further guidance on master protocols

Last year, the FDA released final guidance looking at oncology drug development using master protocols. In this year’s annual agenda plan, the agency added a draft guidance, “Master Protocols for Drug Development and Biological Product Development,” which is likely to cover non-oncology clinical trials.

This document would be very much welcomed, as master protocols are also taking off in other disease areas, says Dr Ben Saville, director and senior statistical scientist for Berry Consultants. He explains that the Covid-19 pandemic accelerated the industry’s interest in platform trials and now the consultancy receives calls regarding this approach every other week.

As for the content, the draft guidance is likely to cover data sharing issues, as in platform trials there might be challenges with data readout when different sponsors are participating in the trial. The agency should comment on shared placebos as such control offers tremendous efficacy gains. Also, Saville expects to see guidance on previous controls, also known as non-concurrently randomised control. He explains that a trial that uses only concurrent randomised controls throws away a lot of good information.

Saville hopes that the guidance will further accelerate clinical development into a future where almost all trials are using this approach. “Hopefully, it talks about the positives and the benefits they bring and not scare people away from pursuing platform trials,” he adds.

International harmonisation on adaptive trials

The FDA is also planning to further harmonise its guidance with regulators outside the US. The agency added a new item, “E20 Adaptive Clinical Trials,” which is currently being drafted by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). On its website, the FDA says that the agency implements all ICH Guidelines as FDA Guidance. The ICH final guidance is expected to be published in late 2024, according to the ICH work plan released last year.

Such international harmonisation between different organisations is very important, says Jay Park, PhD, scientific lead and founder at Core Clinical Sciences, a research consultancy. He explains that there can be competing or inconsistent advice when working across different geographic regulatory jurisdictions.

The ICH document is likely to be a complementary document and build on the existing guidance documents that the FDA and other regulatory agencies have done, Park says. The FDA released its final guidance on adaptive design clinical trials back in 2019. The ICH draft guidance is likely to cover Bayesian adaptive clinical trials. As there has been lots of excitement about using real-world data and/or external data, Park expects to see those concepts as well.

Also, Park hopes that the complementary ICH document and the planned draft of master protocols will help to demystify common misconceptions between the two approaches. He explains that it is common for people to associate adaptive trials as being a part of a master protocol. However, not all clinical trials that use master protocol framework act to use Bayesian statistics, nor do they have to use adaptive trial design.

Disease-specific draft guidance

The agency is also planning to develop many disease-specific draft guidance documents. Some of them have already been released in February, such as guidelines on drug development for early Lyme disease and neovascular age-related macular degeneration. Sponsors and other industry stakeholders can submit their comments until early April and late May, respectively.

While the FDA released its draft guidance on evaluating the safety of new type 2 diabetes drugs in 2020, this time the agency is looking at efficacy endpoints for clinical trials investigating antidiabetic drugs and biological products.

Pain indications also got a spotlight. A new addition to the agenda will look at drug development for preventive migraine treatment. The FDA released its final guidance on acute treatment back in 2018. Another planned draft guidance is focusing on chronic pain drug development. The agency had to withdraw its previous draft guidance on analgesic drugs as a response to the ongoing opioid epidemic.

Other notable plans for trial design

Under the Administrative/Procedural category, CDER also added planned draft guidance on institutional review board (IRB) review of individual patient expanded access requests. A similar final guidance was published in 2020, specifically looking at Covid-19 investigational drugs.

The agency also aims to provide key information and facilitate understanding of the informed consent process for FDA-regulated clinical investigations. In 2016, the FDA released final guidance on electronic informed consent, also known as eConsent. Clinical Trials Arena recently reported on the bumpy adoption road for this decentralisation tool.

While the FDA has several guidance documents looking at real-world data (RWD) and real-world evidence (RWE), the agency released its draft guidance on considerations for the design and conduct of externally controlled trials. Sponsors and industry stakeholders can provide their feedback until May. Clinical Trials Arena previously reported on the use of external control arms and recent trends and strategies in the RWD/RWE trial.

Another planned draft guidance under the same RWD/RWE category will look at using clinical practice data in randomised controlled trials for regulatory decision-making for drug and biological products. A similar guidance was released for medical devices in 2017.