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ICH Offers New Guidance on Nonclinical Safety Testing for Pediatric Trials

January 28, 2019

Hoping to harmonize pediatric clinical trials globally, the ICH has issued new draft guidance urging drug sponsors to consider whether they need to conduct nonclinical safety experiments on drugs before moving on to pediatric trials.

The guideline, S11-Nonclinical Safety Testing in Support of Development of Pediatric Medicines, recommends taking an integrated, weight-of-evidence approach to nonclinical trials — considering pharmacology, pharmacokinetic, in vitro, in vivo animal and clinical safety data — to make sure that no single factor is considered in isolation.

Generally, nonclinical experiments won’t be necessary if “existing clinical data are considered sufficient to support pediatric use and/or if identified safety concerns can be clinically managed,” the ICH document states. Studies on young animals aren’t necessary to confirm organ toxicity if sponsors think that a given drug will affect juvenile organs the same way it effects adult organs.

The “most relevant safety and efficacy data for pediatric patients come from other pediatric subpopulations and adults exposed” to a given drug, the guideline says. But sponsors also should consider the youngest age of a drug’s intended patients and the duration of clinical treatment.

The draft document also offers advice on how to frame juvenile animal studies, with some suggestions for core endpoints.

Read the ICH draft guideline here: https://bit.ly/2S2MrCX.

FDA Guidance Advises Multi-Tiered Approach to Assessing Immunogenicity of Therapeutic Proteins
Sponsors should use a multi-tiered anti-drug antibody (ADA) testing approach when they develop and validate assays for assessing therapeutic protein product immunogenicity during clinical trials, the FDA recommends in a final guidance released last week.

In the multi-tiered approach, a sensitive screening assay designed to detect small levels of low- and high-affinity ADA is used to gain an understanding of the natural history of the ADA response, such as by minimizing wash steps.

Samples that test positive in the screening assay are then put through a confirmatory assay to validate that the ADAs are specific to the therapeutic protein product. For example, a competition assay could confirm an antibody specifically binds to the therapeutic protein product and show that the positive screening assay results were not actually caused by non-specific interactions of the test serum or detection reagent with other materials in the assay milieu.

Positive samples from the confirmatory assay should then be further characterized in other assays, such as titration and neutralization assays. Assays that detect cross-reactivity to other proteins, such as the corresponding endogenous protein, may be required, the guidance says, such as when the product belongs to a high homology protein family and it’s important to know how ADA will impact family members.

As a general principle, sponsors should use a risk-based approach to evaluate and manage immune responses and immunologically related adverse events for therapeutic protein products that affect their safety, efficacy, pharmacodynamics and pharmacokinetics, the guidance says.

You can read the final guidance here: https://bit.ly/2S2MrCX.

British Parliament Weighs New Brexit Clinical Trial Rules
The British Parliament is weighing legislation that would transfer drug regulatory authority back to its national regulator if the UK crashes out of the EU without a new treaty in place.

The legislation would give the Medicines & Healthcare Products Regulatory Agency top authority for drug regulation, including over clinical trials. Backers say the legislation will do little to disrupt the regulatory regime already in place under the EU; it merely changes the cop on the beat.

Trials would have to be authorized by MHRA but they’d still have to have “a favorable ethics opinion” and be conducted under good clinical practice rules.

Brexit has already disrupted the UK’s drug industry as the EU moves its drug regulatory headquarters from London to Amsterdam. But it also appears to have affected the clinical trials industry. An analysis last year found that the number of clinical trials had fallen 25 percent, on average, from the years before the Brexit vote.

The UK government has until March 29 to come up with some kind of new treaty arrangement with the EU.

EMA, FDA Warn Patients Off Lily’s Lartruvo After Failed Phase III Trial
European Union and U.S. regulators are warning the public off Eli Lilly’s Lartruvo after the drug failed a Phase III trial for its use against metastatic soft tissue sarcoma.

Lartruvo (olaratumab) had won accelerated approval from the FDA after a successful Phase II trial, but later announced that the injectable drug had proved ineffective. Last week, both the FDA and EMA issued statements urging doctors not to prescribe it for new patients and urged doctors to talk to patients who were already using the drug.

Lilly said in a statement that it was suspending promotion of the drug but that a global Phase II trial would continue. The company said it expects to write off between $70 million in $90 million in the failed trial.

WIRB-Copernicus Acquires Velos eResearch
The WIRB-Copernicus Group (WCG) has acquired Velos eResearch, the companies announced last week.

Velos offers a single technology platform that promises to bring together the administrative, financial and regulatory elements of clinical trials, making it easier for sponsors, sites and researchers to focus on the science of the trials.

WCG currently partners with 90 percent of the academic medical centers that conduct research in the US. Velos will continue to operate independently out of its Fremont, Calif. headquarters.