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Regulatory Policy May Not Stop Comparative Efficacy Trials


Manufacturers, not regulators, may be the holdouts when it comes to eliminating comparative clinical efficacy trials, according to experts interviewed by The Center for Biosimilars®.

The way Sarfaraz K. Niazi, PhD, looks at it, doing comparative efficacy studies in humans to confirm that a biosimilar candidate is equivalent to a reference product is, in most cases, a complete waste of time. But many biosimilar companies still do these studies. The reason? The comparative clinical data may have little value in getting regulators to approve their products, despite helping with future marketing.

“Clinicians don’t understand all the steps to establish biosimilarity. They want to see clinical data,” said Niazi, an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, and a founder of biosimilars companies.

Regulatory authorities in the United States and Europe may not require clinical efficacy studies if they feel satisfied that other evidence presented by biosimilar developers is adequate to make the case for approval. Niazi argues that if earlier-phase pharmacodynamic (PD) and pharmacokinetic (PK) studies haven’t provided the needed evidence, it probably isn’t a good idea to proceed with in-human efficacy trials.

Copying the Bigger Companies

So many large companies have been doing these costly comparative trials that smaller companies may falsely believe it’s incumbent upon them to carry out these trials also, he says.

“Unfortunately, the larger companies do this to support their marketing efforts and not their scientific efforts. And that has caused a significant drawback for smaller companies, who begin to think that this is the norm—this is how we need to do the work,” Niazi said.

European Union regulatory authorities follow a stepwise approach to biosimilar approval that involves comparative quality studies based on functional and analytical attributes of the drug candidates, followed by comparative nonclinical studies concerning pharmacodynamics and toxicology. Only then do biosimilar developers move on to comparative clinical studies, which include PK and PD analysis, and potentially efficacy, safety, and immunogenicity studies.

However, European regulators state, “The aim of studies in humans is not to demonstrate safety and efficacy in patients, as these have already been established for the reference medicine.”

“Residual Uncertainty” Is the Trigger

In the United States, the key for doing additional studies is whether there is “residual uncertainty” that the product is equivalent to its reference drug. Niazi contends that biosimilar developers would be hard put to discover any specific requirement for “clinical efficacy” trials in FDA biosimilar guidance.

“The FDA can require additional studies [not necessarily clinical efficacy]. The onus is on the FDA to define what is residual uncertainty. Unless you get that answer, you should not be eager to do an efficacy study,” he said.

Arguments such as these have been behind increasing calls lately to do away with comparative clinical efficacy testing for biosimilars. In September 2020, the International Generic and Biosimilar Medicines Association publicly called for regulatory authorities to scale back any requests for efficacy testing on the assumption that other forms of testing can provide more exact and convincing evidence of biosimilarity.

In October 2020, the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) issued draft guidance indicating that these trials are unnecessary in most cases. The draft document was supported by a recent position paper from members of the MHRA contending that biosimilarity can usually be demonstrated by analytical testing and a PK trial. Exceptional cases only should be the measure for whether comparative efficacy trials are necessary, they argued.

“In my opinion, clinical efficacy studies do not give you the confidence that the product is bioequivalent,” Niazi said. One reason is that the margins for efficacy outcomes in a human trial are, to some degree, arbitrary. Should the margins for biosimilar performance be within 10% of reference product performance or 40%? he asks. Niazi said he has seen margins set at both those extremes for biosimilars that have been approved by regulatory authorities, from the United States to India.

These tests are not exact. “If you have to do a clinical efficacy study, you’ve already lost the game,” because such a study is not going to provide the evidence you need to demonstrate biosimilarity, he said.

The “Least Powerful” Measurement Tool

The issue is also intriguing to Paul Cornes, BM, BCH, MA, MRCP, FRCR, a UK-based oncologist who was part of the team that developed and presented evidence to the FDA's Oncologic Advisory Drugs Committee for the first successfully approved US biosimilar. Cornes recently lectured on clinical efficacy testing before the UK Royal Pharmaceutical Society.

“The UK position is just the same as the US one at a scientific level, and follows on from many statements given by both the FDA and European Medicines Agency that clinical comparative trials are the least powerful steps for determining biosimilarity and that they may not always be needed,” Cornes said.

The essential point to discover in qualifying a biosimilar is whether it is identical to the reference product to the point of not having any meaningful differences, and that requires highly sensitive testing. “In many instances, a [PD] end point will be a far better measure of potential difference than a clinical one,” he said.

Providing an example, Cornes said, “We use trastuzumab because it increases 5-year overall survival with high-risk, HER2-positive breast cancer by 5% better than chemotherapy alone. Pharmacologically, it does this by killing HER2-positive overexpressing cancer cells, which we can see in neoadjuvant treatment or in treating metastatic breast cancer where the effect is greater than 20% better than chemotherapy alone. So, a trial with the [PD] end point of breast cancer shrinkage is 4 times more likely to discover a meaningful difference between the 2 drugs than a clinical end point trial.”

The same applies to evaluating biosimilarity for insulin products, he said. An evaluation of “serial serum glucose levels over time is likely to be more sensitive than waiting to compare the clinical effects of diabetes to declare themselves.”

Looking at it another way, Cornes said, there are multiple anti-inflammatory biologics brands for rheumatoid disease, and in a study, The National Institute for Health and Care Excellence of Great Britain found that each of these drugs produced a similar response in patients in terms of arthritis control and toxicity events. “If you cannot clinically differentiate different drugs, how can you hope to clinically differentiate different versions of the same drug?” he asked.

The United Kingdom, which in January 2021 will make independent regulatory approval decisions about drugs following the country’s exit from the European Union, is “reasonable” in its recent draft guidance that places less emphasis on the importance of comparative efficacy trials, said Nancy Globus, PharmD, vice president of regulatory affairs at the Accreditation Council for Medical Affairs.

The Wrong Framework for Biosimilars

“If the overall sentiment of the industry and the regulators is to increase patient access to these products, then let’s make it a little easier for the manufacturers so that they do not necessarily have to comply with a framework that may not have been designed with these types of molecules in mind.” Such studies may be more suitable for generics, which are simple molecules, Globus said.

Another downside to comparative efficacy trials is that they require large patient populations to achieve statistical significance and they are costly. A recent study indicated that these comparative efficacy trials are costing more than pivotal trials for originator drugs. “That is just completely contrary to the whole reason why manufacturers are trying to get biosimilar products to market,” she added. “If the whole point is not to spend the same amount of time and money that the innovator did, doing them just to check a box strikes me as a little bit ridiculous.”

Cornes agreed, adding that other issues are also important to consider when it comes to comparing biosimilars with reference products. When changes are made in the manufacturing process, it’s easy for different batches of the same reference product to differ from one another. These changes “are often recorded to show greater differences in critical attributes than would be permitted for biosimilars,” he said.

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