Generic Biologics' Safety Questioned as Approval Process Stalls

The Biologics Price Competition and Innovation Act, quietly tucked into the health reform bill passed earlier this year, mandated the creation of an abbreviated approval process for follow-on biologic agents similar to the existing pathway for small-molecule drugs.

But 5 months later, the Food and Drug Administration has yet to work out just what that process will entail – and physicians have yet to be reassured that whatever emerges won’t cut corners on safety. And if the safety can be assured, the fruits of such a pathway could be life changing for some patients.

“Tremendously overpriced as they are, the available biologic drugs prevent so much human suffering and disability,” added Dr. Karen Kolba, who is a rheumatologist in solo private practice in Santa Maria, Calif.

“All of my patients would benefit. Those who cannot afford the copays because they are up to 30% of the drug cost would benefit. Those who have private insurance with low copays would benefit because their insurance companies will ultimately be paying out less to drug companies. And those with Medicare or Medicaid will benefit, as will all taxpayers, with lower drug costs.”

The Back Story

Unlike small-molecule generics, which gain approval through an abbreviated new drug application that does not require clinical trials, biologic drugs are vastly more complex – so complex, in fact, that their exact composition is not even known in some cases, according to the Merck Manual.

That is why, in the past, all new biologic drugs for which pharmaceutical companies seek approval in the United States have had to go through a complete new drug application process – including evaluation in animal studies and a full round of human clinical trials – before gaining approval.

The new Biologics Price Competition and Innovation Act (BPCIA) “aligns with the FDA’s long-standing policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing,” according to a statement by the FDA.

And the new law provides guidance on the intellectual property side of the issue. It grants 12 years of patent exclusivity for an original biologic drug, plus a hold on applications for generics until 4 years after the original’s approval. And once approved, the law states, the first generic will itself enjoy a 1-year period of exclusivity.

The Safety Debate

However, the BPCIA does not offer very much guidance on what the abbreviated approval process will entail, said Merrill Matthews, Ph.D., a medical ethicist and a resident scholar with the Institute for Policy Innovation, Lewisville, Tex., a conservative advocacy group that seeks “lower taxes, fewer regulations, and a smaller, less-intrusive government.” He also is the director of the Council for Affordable Health Insurance, a D.C.-based organization promoting free-market health insurance reforms.

The BPCIA “gives the FDA an awful lot of latitude and flexibility in the process of approving biosimilars, and though it requires biosimilars to demonstrate ‘similarity’ with their reference products, approval can be done without clinical trials,” he said at a July 19 press conference on Capitol Hill.

Indeed, the law reads: “An application submitted under this subsection shall include information demonstrating that ... the biological product is biosimilar to a reference product based upon data derived from ... analytical studies that demonstrate that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components.”

Gordon Johnston, vice president of regulatory science at the Generic Pharmaceutical Association, said he does not find the law to be clear. “The legislation could have been clearer, in our view, in ... defining terms such as ‘highly similar’ and ‘no clinically meaningful difference,’ ” he said in an interview. “For this reason, the process now under way of writing the legislation into regulations is critically important,” he added.

Dr. Kolba also pointed out that the new law would have done well to include at least some requirement that new generic products be entered in a registry to collect safety data. “This would be a much less expensive alternative to years of clinical trials, but ultimately assures us all that they are as safe as the branded products,” she said.?

Dr. Craig Kessler, professor of medicine and pathology at Georgetown University, Washington, agreed. “As a physician, I’m very much in favor of having biosimilars in the marketplace,” he said. “I think we owe it to society to try to reduce the cost of care.”

Nevertheless, “I don’t want to sacrifice patient safety for the decrease in the cost of care, because in the long run, the cost of care will actually be increased if we make the wrong decision.”

Added Rep. Michael C. Burgess (R-Tex.), a physician and also the chairman of the congressional Health Care Caucus, at the July press conference: “Can you really go through an abbreviated process with a drug that is just simply similar to the complex biologic that has already been introduced?

“My concern as a physician, first, always comes back to safety,” he said.

The Next Steps

To resolve these terms, and to figure out a pathway for biogeneric approval, the FDA has formed the Biosimilar Implementation Committee and placed at its head Dr. Janet Woodcock, who is also director of the Center for Drug Evaluation and Research. The new center will hold public meetings to solicit comment from stakeholders, experts, innovators, patients, and the public on some of the concerns surrounding biosimilar approval, according to Dr. Woodcock in a recent press release.

Mr. Johnston said that he expects a meeting to be held sometime by the end of 2010. However, the details remain vague. FDA spokesperson Karen Mahoney could not confirm that any meeting had been scheduled, and would not give any information on when physicians and patients could expect to see the first approvals of generic biologics.

“There are so many factors that will impact when biosimilar products will enter the market,” added Ms. Mahoney. “Therefore,?it is not reasonable to speculate.”

Added Rep. Burgess: “This is a difficult concept, and it does involve a lot of moving parts, and a lot of different contingencies. “For your average member of Congress – or even for your member of Congress with some background in health – it does become difficult to think about these things,” he added.

Dr. Kolba, meanwhile, offered some ideas about how to move forward – without generics.

“If the companies currently manufacturing biologic drugs and selling them at huge profits (having made back their research and development costs years ago) are truly concerned about the potential harm of generic biologics [to their market share,] they can simply decrease their prices to costs plus 10%. This would decrease the overall cost of the drugs by about 65%,” she said.

“At the new prices, generic drug makers will no longer be willing to enter the market, there will be no expensive lawsuits or advertising to pay for, and the 1% of the population with rheumatoid arthritis and other TNF [tumor necrosis factor]-driven diseases will be assured of safe and effective drugs.”

Dr. Kolba disclosed being a past consultant or speaker for the pharmaceutical companies Abbott, Amgen, Bristol-Myers Squibb, Genentech, and UCB. She is currently a principal investigator in clinical trials sponsored by Abbott, Amgen, Lilly, Pfizer, Sanofi-Aventis, and UCB. Dr. Craig Kessler has also disclosed consulting for and receiving research support from pharmaceutical companies including Amgen, Eisai, GlaxoSmithKline, and Sanofi-Aventis.

To view an online version of the July 19 press conference featuring Dr. Kessler, Dr. Matthews, and Congressman Burgess, visit http://health.burgess.house.gov/Blog/?postid=198224.

To view the entire text of the Biologics Price Competition and Innovation Act of 2009, visit www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf.

The Biologics Price Competition and Innovation Act, quietly tucked into the health reform bill passed earlier this year, mandated the creation of an abbreviated approval process for follow-on biologic agents similar to the existing pathway for small-molecule drugs.

But 5 months later, the Food and Drug Administration has yet to work out just what that process will entail – and physicians have yet to be reassured that whatever emerges won’t cut corners on safety. And if the safety can be assured, the fruits of such a pathway could be life changing for some patients.

“Tremendously overpriced as they are, the available biologic drugs prevent so much human suffering and disability,” added Dr. Karen Kolba, who is a rheumatologist in solo private practice in Santa Maria, Calif.

“All of my patients would benefit. Those who cannot afford the copays because they are up to 30% of the drug cost would benefit. Those who have private insurance with low copays would benefit because their insurance companies will ultimately be paying out less to drug companies. And those with Medicare or Medicaid will benefit, as will all taxpayers, with lower drug costs.”

The Back Story

Unlike small-molecule generics, which gain approval through an abbreviated new drug application that does not require clinical trials, biologic drugs are vastly more complex – so complex, in fact, that their exact composition is not even known in some cases, according to the Merck Manual.

That is why, in the past, all new biologic drugs for which pharmaceutical companies seek approval in the United States have had to go through a complete new drug application process – including evaluation in animal studies and a full round of human clinical trials – before gaining approval.

The new Biologics Price Competition and Innovation Act (BPCIA) “aligns with the FDA’s long-standing policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing,” according to a statement by the FDA.

And the new law provides guidance on the intellectual property side of the issue. It grants 12 years of patent exclusivity for an original biologic drug, plus a hold on applications for generics until 4 years after the original’s approval. And once approved, the law states, the first generic will itself enjoy a 1-year period of exclusivity.

The Safety Debate

However, the BPCIA does not offer very much guidance on what the abbreviated approval process will entail, said Merrill Matthews, Ph.D., a medical ethicist and a resident scholar with the Institute for Policy Innovation, Lewisville, Tex., a conservative advocacy group that seeks “lower taxes, fewer regulations, and a smaller, less-intrusive government.” He also is the director of the Council for Affordable Health Insurance, a D.C.-based organization promoting free-market health insurance reforms.

The BPCIA “gives the FDA an awful lot of latitude and flexibility in the process of approving biosimilars, and though it requires biosimilars to demonstrate ‘similarity’ with their reference products, approval can be done without clinical trials,” he said at a July 19 press conference on Capitol Hill.

Indeed, the law reads: “An application submitted under this subsection shall include information demonstrating that ... the biological product is biosimilar to a reference product based upon data derived from ... analytical studies that demonstrate that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components.”

Gordon Johnston, vice president of regulatory science at the Generic Pharmaceutical Association, said he does not find the law to be clear. “The legislation could have been clearer, in our view, in ... defining terms such as ‘highly similar’ and ‘no clinically meaningful difference,’ ” he said in an interview. “For this reason, the process now under way of writing the legislation into regulations is critically important,” he added.

Dr. Kolba also pointed out that the new law would have done well to include at least some requirement that new generic products be entered in a registry to collect safety data. “This would be a much less expensive alternative to years of clinical trials, but ultimately assures us all that they are as safe as the branded products,” she said.?

Dr. Craig Kessler, professor of medicine and pathology at Georgetown University, Washington, agreed. “As a physician, I’m very much in favor of having biosimilars in the marketplace,” he said. “I think we owe it to society to try to reduce the cost of care.”

Nevertheless, “I don’t want to sacrifice patient safety for the decrease in the cost of care, because in the long run, the cost of care will actually be increased if we make the wrong decision.”

Added Rep. Michael C. Burgess (R-Tex.), a physician and also the chairman of the congressional Health Care Caucus, at the July press conference: “Can you really go through an abbreviated process with a drug that is just simply similar to the complex biologic that has already been introduced?

“My concern as a physician, first, always comes back to safety,” he said.

The Next Steps

To resolve these terms, and to figure out a pathway for biogeneric approval, the FDA has formed the Biosimilar Implementation Committee and placed at its head Dr. Janet Woodcock, who is also director of the Center for Drug Evaluation and Research. The new center will hold public meetings to solicit comment from stakeholders, experts, innovators, patients, and the public on some of the concerns surrounding biosimilar approval, according to Dr. Woodcock in a recent press release.

Mr. Johnston said that he expects a meeting to be held sometime by the end of 2010. However, the details remain vague. FDA spokesperson Karen Mahoney could not confirm that any meeting had been scheduled, and would not give any information on when physicians and patients could expect to see the first approvals of generic biologics.

“There are so many factors that will impact when biosimilar products will enter the market,” added Ms. Mahoney. “Therefore,?it is not reasonable to speculate.”

Added Rep. Burgess: “This is a difficult concept, and it does involve a lot of moving parts, and a lot of different contingencies. “For your average member of Congress – or even for your member of Congress with some background in health – it does become difficult to think about these things,” he added.

Dr. Kolba, meanwhile, offered some ideas about how to move forward – without generics.

“If the companies currently manufacturing biologic drugs and selling them at huge profits (having made back their research and development costs years ago) are truly concerned about the potential harm of generic biologics [to their market share,] they can simply decrease their prices to costs plus 10%. This would decrease the overall cost of the drugs by about 65%,” she said.

“At the new prices, generic drug makers will no longer be willing to enter the market, there will be no expensive lawsuits or advertising to pay for, and the 1% of the population with rheumatoid arthritis and other TNF [tumor necrosis factor]-driven diseases will be assured of safe and effective drugs.”

Dr. Kolba disclosed being a past consultant or speaker for the pharmaceutical companies Abbott, Amgen, Bristol-Myers Squibb, Genentech, and UCB. She is currently a principal investigator in clinical trials sponsored by Abbott, Amgen, Lilly, Pfizer, Sanofi-Aventis, and UCB. Dr. Craig Kessler has also disclosed consulting for and receiving research support from pharmaceutical companies including Amgen, Eisai, GlaxoSmithKline, and Sanofi-Aventis.

To view an online version of the July 19 press conference featuring Dr. Kessler, Dr. Matthews, and Congressman Burgess, visit http://health.burgess.house.gov/Blog/?postid=198224.

To view the entire text of the Biologics Price Competition and Innovation Act of 2009, visit www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf.

The Biologics Price Competition and Innovation Act, quietly tucked into the health reform bill passed earlier this year, mandated the creation of an abbreviated approval process for follow-on biologic agents similar to the existing pathway for small-molecule drugs.

But 5 months later, the Food and Drug Administration has yet to work out just what that process will entail – and physicians have yet to be reassured that whatever emerges won’t cut corners on safety. And if the safety can be assured, the fruits of such a pathway could be life changing for some patients.

“Tremendously overpriced as they are, the available biologic drugs prevent so much human suffering and disability,” added Dr. Karen Kolba, who is a rheumatologist in solo private practice in Santa Maria, Calif.

“All of my patients would benefit. Those who cannot afford the copays because they are up to 30% of the drug cost would benefit. Those who have private insurance with low copays would benefit because their insurance companies will ultimately be paying out less to drug companies. And those with Medicare or Medicaid will benefit, as will all taxpayers, with lower drug costs.”

The Back Story

Unlike small-molecule generics, which gain approval through an abbreviated new drug application that does not require clinical trials, biologic drugs are vastly more complex – so complex, in fact, that their exact composition is not even known in some cases, according to the Merck Manual.

That is why, in the past, all new biologic drugs for which pharmaceutical companies seek approval in the United States have had to go through a complete new drug application process – including evaluation in animal studies and a full round of human clinical trials – before gaining approval.

The new Biologics Price Competition and Innovation Act (BPCIA) “aligns with the FDA’s long-standing policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing,” according to a statement by the FDA.

And the new law provides guidance on the intellectual property side of the issue. It grants 12 years of patent exclusivity for an original biologic drug, plus a hold on applications for generics until 4 years after the original’s approval. And once approved, the law states, the first generic will itself enjoy a 1-year period of exclusivity.

The Safety Debate

However, the BPCIA does not offer very much guidance on what the abbreviated approval process will entail, said Merrill Matthews, Ph.D., a medical ethicist and a resident scholar with the Institute for Policy Innovation, Lewisville, Tex., a conservative advocacy group that seeks “lower taxes, fewer regulations, and a smaller, less-intrusive government.” He also is the director of the Council for Affordable Health Insurance, a D.C.-based organization promoting free-market health insurance reforms.

The BPCIA “gives the FDA an awful lot of latitude and flexibility in the process of approving biosimilars, and though it requires biosimilars to demonstrate ‘similarity’ with their reference products, approval can be done without clinical trials,” he said at a July 19 press conference on Capitol Hill.

Indeed, the law reads: “An application submitted under this subsection shall include information demonstrating that ... the biological product is biosimilar to a reference product based upon data derived from ... analytical studies that demonstrate that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components.”

Gordon Johnston, vice president of regulatory science at the Generic Pharmaceutical Association, said he does not find the law to be clear. “The legislation could have been clearer, in our view, in ... defining terms such as ‘highly similar’ and ‘no clinically meaningful difference,’ ” he said in an interview. “For this reason, the process now under way of writing the legislation into regulations is critically important,” he added.

Dr. Kolba also pointed out that the new law would have done well to include at least some requirement that new generic products be entered in a registry to collect safety data. “This would be a much less expensive alternative to years of clinical trials, but ultimately assures us all that they are as safe as the branded products,” she said.?

Dr. Craig Kessler, professor of medicine and pathology at Georgetown University, Washington, agreed. “As a physician, I’m very much in favor of having biosimilars in the marketplace,” he said. “I think we owe it to society to try to reduce the cost of care.”

Nevertheless, “I don’t want to sacrifice patient safety for the decrease in the cost of care, because in the long run, the cost of care will actually be increased if we make the wrong decision.”

Added Rep. Michael C. Burgess (R-Tex.), a physician and also the chairman of the congressional Health Care Caucus, at the July press conference: “Can you really go through an abbreviated process with a drug that is just simply similar to the complex biologic that has already been introduced?

“My concern as a physician, first, always comes back to safety,” he said.

The Next Steps

To resolve these terms, and to figure out a pathway for biogeneric approval, the FDA has formed the Biosimilar Implementation Committee and placed at its head Dr. Janet Woodcock, who is also director of the Center for Drug Evaluation and Research. The new center will hold public meetings to solicit comment from stakeholders, experts, innovators, patients, and the public on some of the concerns surrounding biosimilar approval, according to Dr. Woodcock in a recent press release.

Mr. Johnston said that he expects a meeting to be held sometime by the end of 2010. However, the details remain vague. FDA spokesperson Karen Mahoney could not confirm that any meeting had been scheduled, and would not give any information on when physicians and patients could expect to see the first approvals of generic biologics.

“There are so many factors that will impact when biosimilar products will enter the market,” added Ms. Mahoney. “Therefore,?it is not reasonable to speculate.”

Added Rep. Burgess: “This is a difficult concept, and it does involve a lot of moving parts, and a lot of different contingencies. “For your average member of Congress – or even for your member of Congress with some background in health – it does become difficult to think about these things,” he added.

Dr. Kolba, meanwhile, offered some ideas about how to move forward – without generics.

“If the companies currently manufacturing biologic drugs and selling them at huge profits (having made back their research and development costs years ago) are truly concerned about the potential harm of generic biologics [to their market share,] they can simply decrease their prices to costs plus 10%. This would decrease the overall cost of the drugs by about 65%,” she said.

“At the new prices, generic drug makers will no longer be willing to enter the market, there will be no expensive lawsuits or advertising to pay for, and the 1% of the population with rheumatoid arthritis and other TNF [tumor necrosis factor]-driven diseases will be assured of safe and effective drugs.”

Dr. Kolba disclosed being a past consultant or speaker for the pharmaceutical companies Abbott, Amgen, Bristol-Myers Squibb, Genentech, and UCB. She is currently a principal investigator in clinical trials sponsored by Abbott, Amgen, Lilly, Pfizer, Sanofi-Aventis, and UCB. Dr. Craig Kessler has also disclosed consulting for and receiving research support from pharmaceutical companies including Amgen, Eisai, GlaxoSmithKline, and Sanofi-Aventis.

To view an online version of the July 19 press conference featuring Dr. Kessler, Dr. Matthews, and Congressman Burgess, visit http://health.burgess.house.gov/Blog/?postid=198224.

To view the entire text of the Biologics Price Competition and Innovation Act of 2009, visit www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf.