FDA Searches for Clinical Trial Middle Ground at Biosimilar Hearing

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.