- Email: [email protected]
Does neurology need a faster FDA?
In Context
Does neurology need a faster FDA? The FDA’s neurology division has been reported as the slowest of all the agency’s divisions at approving new drugs. If this is true, the economic impact could be affecting drug innovation and ultimately patient care. But what, if anything, needs to be done? Adrian Burton investigates. A report published on April 7, 2014, by the Manhattan Institute shows the Division of Neurology Products of the US Food and Drugs Administration’s (FDA) Centre for Drug Evaluation and Research (CDER) to be the slowest of all the agency’s divisions at approving new drugs. The median approval time for this division is three times that of the fastest—the divisions of oncology and anti-viral products (around 600 days compared with about 200 days). The economic cost of such a lag could have a negative effect on drug innovation in the field, with serious repercussions on patient health. But is there really anything we need to fix? The report, by Joseph DiMasi, Christopher-Paul Milne (both of the Tufts Center for the Study of Drug Development, Boston, MA) and Alex Tabarrok (George Mason University, Fairfax, VA), does not seek to criticise any of the FDA’s CDER divisions, but simply to detect differences in approval times between them, and identify the possible causes for them, so that efficiency across the agency might be improved. Even so, the report can hardly be easy reading for
For the Manhattan Institute report see http://www. manhattan-institute.org/html/ fda_07.htm#.U2iH7KLQDCb For more on soaring development costs see http:// www.ft.com/intl/ cms/s/0/43580ab0-3cac-11e286a4-00144feabdc0. html#axzz32Qw9gkrr and
Steve A Johnson
http://www.forbes.com/sites/ matthewherper/2013/08/11/ how-the-staggering-cost-ofinventing-new-drugs-isshaping-the-future-of-medicine
Does the FDA’s Division of Neurology really lag behind others in reviewing drugs?
760
the FDA or for companies working on new neurological drugs at a time of soaring development costs. “Our results show that the most productive divisions approve drugs much faster than the slowest, but not because they have smaller workloads, more resources, lower task complexity, or because they cut corners in safety”, says DiMasi. “Indeed, the Oncology Division, the fastest of all, had the highest workload per staff member, while the Neurology Division, the slowest, had below average workloads. [Since] the complexity of new drug applications can vary across drugs and divisions, [we considered] differences in disease and drug characteristics by, for example, taking into account such factors as whether an advisory committee was involved, whether a clinical hold was placed on development of the drug, the issue of black box [safety] warnings, the number of post-marketing requirements, and clinical development time. [But even] after controlling for the numerous factors relating to a division’s resources and review burdens, the question remained: what accounts for differences in measured productivity between divisions like oncology and neurology?” The FDA, however, is not sure that the report reflects any variations in productivity, and holds that differences in disease and drug characteristics are indeed the reason for the discrepancies seen. “We agree that there are differences in the average time it takes to approve drugs across CDER’s different review divisions”, says FDA spokesperson Stephen King (Silver Spring, MD). “However, we believe that these differences are not an indicator of inconsistencies in [efficiency across
divisions but rather] a reflection of the different types of drugs and disease conditions, which also vary considerably.” King underscores that the oncology and anti-viral products divisions receive a high proportion of drugs designated for rapid, priority review—ie, drugs that might provide substantial improvements compared with existing or absent therapies. “Other FDA review divisions, because of their area of medical specialty, may receive [relatively few priority review drugs], and may also have a higher proportion of drugs that demonstrate modest efficacy in conditions for which there are many similarly effective treatment options, which may present a less clear benefit/risk balance”, continues King. “Given that there are very important differences in drug and disease characteristics [across review divisions], it is not at all surprising to [see some divisions take] longer. …The FDA is aware that similar patterns of times to approval [are] also observed for other regulatory agencies, which validates our view that these findings are more directly related to the drugs and disease area than differing efficiencies of divisions.” Outcome measures and trial endpoints for neurological diseases are more difficult to define than in oncology, which could make decisions about the benefit versus risk relationship of a neurological drug harder to reach. It would also be very hard to fully control for this difficulty in any comparison of approval times. Furthermore, neurology regulators might actually need more leaden feet. “Neurology medicines include a large number of treatments for chronic, slowly progressive conditions for which imminent mortality risk is often low, www.thelancet.com/neurology Vol 13 August 2014
In Context
the potential of the treatment to be fully curative is often low too, and the number of patients needed to treat to gain substantial benefits is often high”, explains Joel Hay, Professor of Pharmaceutical Economics and Policy at the University of Southern California (Los Angeles, CA). “This means that the risks must be given more weight since the benefits are unlikely to be dramatic while the treatment risks, particularly over the entire treatment population, may be considerable.” Oncology, however, lies at the other extreme. “Consider a patient with end-stage metastatic cancer and a median survival, given any available existing therapy, of only a few weeks”, continues Hay. “The incremental risk for the FDA approving a new therapy for such a patient is minimal, even if the new drug has serious or permanent side-effects, since the likelihood of long-term survival is very low without the new therapy. On the other hand, if the new drug [offers even a little] additional survival and/or quality of life, and has even a slight chance of providing [substantial improvement], the FDA (and patients) forego enormous potential benefits for every month that approval is delayed.” If the report is right, however, and productivity differences do exist, the economic benefits of applying the best work practices across the FDA could be huge. “On average, the Oncology Division is 60% faster at approving drugs than all the other divisions considered together”, explains Milne. “If that gap were just halved, the cost of bringing a new drug to the US market would be around $46 million lower. For the average 19 non-oncology drugs being approved each year, that’s an annual saving of $874 million. If you factor in $150 000 as a conservative value for each year of patient life gained, the annual value of the increase in life expectancy created would be $4 trillion.” Improvement in the Neurology Division would, of course, be associated with proportionally greater savings. Hay cautions, however, that www.thelancet.com/neurology Vol 13 August 2014
“$46 million is a drop in the bucket compared to the downside for drugs with unknown, potentially important risks being used by millions of patients.” The authors of the report also suggest that reduction of approval times, and therefore drug development costs, could see drug pipelines become fuller, provide clinicians with a wider choice of treatment options sooner, and ultimately improve patient care—a point large pharmaceutical companies might echo. Oddly, all those The Lancet Neurology contacted declined to comment; indeed, even PhRMA, a lobby for a group of US pharmaceutical interests, explained that they could make no statement. However, “time to approval is critical for small biotech companies developing neurological drugs”, says Javier Burgos, CEO of Neuron Bio (Granada, Spain), which is working on treatments for Alzheimer’s, Huntington’s, and Parkinson’s diseases, epilepsy, and Smith-Lemli-Opitz syndrome.
“What accounts for differences in measured productivity between divisions like Oncology and Neurology?” “Economically, small biotechs, which make a disproportionate contribution to innovative drugs, cannot reach the approval stage alone, and need to make co-development or licensing agreements with large pharmaceutical companies. If approval times were quicker, the latter would be happier about entering such agreements, the smaller developer would stand more chance of survival, and that would translate into more drugs in development.” Changes in the type of approval given could also help to ensure the survival of small developers. “Right now agencies like the FDA produce blanket safety and efficacy statements for the population as a whole”, says Burgos, “but the dawn of personalised medicine means we need to approve drugs for those people
who would benefit from them. That would increase our therapeutic arsenal, improve patient care, and certainly help developers survive to look for more drugs.” The large pharmaceutical companies contacted also declined to comment on whether delays in the approval of neurological drugs might make them less keen to develop drugs overall. However, “I think this is clearly true”, says Hay. “Manufacturers are now focusing on very expensive specialty and oncology drugs with prices in the $10 000s or more per treatment episode. Many of these drugs are not cost-effective, but since they are basically exempted from cost review with a rationale that these patients have no other options, they can generate very large revenues on a very small patient population base. This is becoming an ever more serious problem since drug research and development is being distorted into areas where the patient populations are relatively small and the societal and economic value of the treatments being developed is correspondingly also relatively small.” “Given the economic scenario, the results we provide, and the fact that the FDA is now approving fewer drugs across the board than 10 years ago, it would be highly valuable for the FDA to further examine its divisions’ differences in productivity”, concludes Tabarrok. “What might account for them? Could it be better management, a better ‘culture’ or smaller staff turnover? Are FDA staff in the oncology division better trained in oncology than those in neurology are trained in neurology? Could it be different rules or better communication with the pharmaceutical firms? We simply want to encourage the FDA to do a full process analysis to figure this out, since having the answer [might] speed drug approvals with no loss in safety— and that would be good for everyone.”
For more on small biotechs see Nat Rev Drug Discov 2010; 9: 867–82
Adrian Burton 761
Does neurology need a faster FDA? The FDA’s neurology division has been reported as the slowest of all the agency’s divisions at approving new drugs. If this is true, the economic impact could be affecting drug innovation and ultimately patient care. But what, if anything, needs to be done? Adrian Burton investigates. A report published on April 7, 2014, by the Manhattan Institute shows the Division of Neurology Products of the US Food and Drugs Administration’s (FDA) Centre for Drug Evaluation and Research (CDER) to be the slowest of all the agency’s divisions at approving new drugs. The median approval time for this division is three times that of the fastest—the divisions of oncology and anti-viral products (around 600 days compared with about 200 days). The economic cost of such a lag could have a negative effect on drug innovation in the field, with serious repercussions on patient health. But is there really anything we need to fix? The report, by Joseph DiMasi, Christopher-Paul Milne (both of the Tufts Center for the Study of Drug Development, Boston, MA) and Alex Tabarrok (George Mason University, Fairfax, VA), does not seek to criticise any of the FDA’s CDER divisions, but simply to detect differences in approval times between them, and identify the possible causes for them, so that efficiency across the agency might be improved. Even so, the report can hardly be easy reading for
For the Manhattan Institute report see http://www. manhattan-institute.org/html/ fda_07.htm#.U2iH7KLQDCb For more on soaring development costs see http:// www.ft.com/intl/ cms/s/0/43580ab0-3cac-11e286a4-00144feabdc0. html#axzz32Qw9gkrr and
Steve A Johnson
http://www.forbes.com/sites/ matthewherper/2013/08/11/ how-the-staggering-cost-ofinventing-new-drugs-isshaping-the-future-of-medicine
Does the FDA’s Division of Neurology really lag behind others in reviewing drugs?
760
the FDA or for companies working on new neurological drugs at a time of soaring development costs. “Our results show that the most productive divisions approve drugs much faster than the slowest, but not because they have smaller workloads, more resources, lower task complexity, or because they cut corners in safety”, says DiMasi. “Indeed, the Oncology Division, the fastest of all, had the highest workload per staff member, while the Neurology Division, the slowest, had below average workloads. [Since] the complexity of new drug applications can vary across drugs and divisions, [we considered] differences in disease and drug characteristics by, for example, taking into account such factors as whether an advisory committee was involved, whether a clinical hold was placed on development of the drug, the issue of black box [safety] warnings, the number of post-marketing requirements, and clinical development time. [But even] after controlling for the numerous factors relating to a division’s resources and review burdens, the question remained: what accounts for differences in measured productivity between divisions like oncology and neurology?” The FDA, however, is not sure that the report reflects any variations in productivity, and holds that differences in disease and drug characteristics are indeed the reason for the discrepancies seen. “We agree that there are differences in the average time it takes to approve drugs across CDER’s different review divisions”, says FDA spokesperson Stephen King (Silver Spring, MD). “However, we believe that these differences are not an indicator of inconsistencies in [efficiency across
divisions but rather] a reflection of the different types of drugs and disease conditions, which also vary considerably.” King underscores that the oncology and anti-viral products divisions receive a high proportion of drugs designated for rapid, priority review—ie, drugs that might provide substantial improvements compared with existing or absent therapies. “Other FDA review divisions, because of their area of medical specialty, may receive [relatively few priority review drugs], and may also have a higher proportion of drugs that demonstrate modest efficacy in conditions for which there are many similarly effective treatment options, which may present a less clear benefit/risk balance”, continues King. “Given that there are very important differences in drug and disease characteristics [across review divisions], it is not at all surprising to [see some divisions take] longer. …The FDA is aware that similar patterns of times to approval [are] also observed for other regulatory agencies, which validates our view that these findings are more directly related to the drugs and disease area than differing efficiencies of divisions.” Outcome measures and trial endpoints for neurological diseases are more difficult to define than in oncology, which could make decisions about the benefit versus risk relationship of a neurological drug harder to reach. It would also be very hard to fully control for this difficulty in any comparison of approval times. Furthermore, neurology regulators might actually need more leaden feet. “Neurology medicines include a large number of treatments for chronic, slowly progressive conditions for which imminent mortality risk is often low, www.thelancet.com/neurology Vol 13 August 2014
In Context
the potential of the treatment to be fully curative is often low too, and the number of patients needed to treat to gain substantial benefits is often high”, explains Joel Hay, Professor of Pharmaceutical Economics and Policy at the University of Southern California (Los Angeles, CA). “This means that the risks must be given more weight since the benefits are unlikely to be dramatic while the treatment risks, particularly over the entire treatment population, may be considerable.” Oncology, however, lies at the other extreme. “Consider a patient with end-stage metastatic cancer and a median survival, given any available existing therapy, of only a few weeks”, continues Hay. “The incremental risk for the FDA approving a new therapy for such a patient is minimal, even if the new drug has serious or permanent side-effects, since the likelihood of long-term survival is very low without the new therapy. On the other hand, if the new drug [offers even a little] additional survival and/or quality of life, and has even a slight chance of providing [substantial improvement], the FDA (and patients) forego enormous potential benefits for every month that approval is delayed.” If the report is right, however, and productivity differences do exist, the economic benefits of applying the best work practices across the FDA could be huge. “On average, the Oncology Division is 60% faster at approving drugs than all the other divisions considered together”, explains Milne. “If that gap were just halved, the cost of bringing a new drug to the US market would be around $46 million lower. For the average 19 non-oncology drugs being approved each year, that’s an annual saving of $874 million. If you factor in $150 000 as a conservative value for each year of patient life gained, the annual value of the increase in life expectancy created would be $4 trillion.” Improvement in the Neurology Division would, of course, be associated with proportionally greater savings. Hay cautions, however, that www.thelancet.com/neurology Vol 13 August 2014
“$46 million is a drop in the bucket compared to the downside for drugs with unknown, potentially important risks being used by millions of patients.” The authors of the report also suggest that reduction of approval times, and therefore drug development costs, could see drug pipelines become fuller, provide clinicians with a wider choice of treatment options sooner, and ultimately improve patient care—a point large pharmaceutical companies might echo. Oddly, all those The Lancet Neurology contacted declined to comment; indeed, even PhRMA, a lobby for a group of US pharmaceutical interests, explained that they could make no statement. However, “time to approval is critical for small biotech companies developing neurological drugs”, says Javier Burgos, CEO of Neuron Bio (Granada, Spain), which is working on treatments for Alzheimer’s, Huntington’s, and Parkinson’s diseases, epilepsy, and Smith-Lemli-Opitz syndrome.
“What accounts for differences in measured productivity between divisions like Oncology and Neurology?” “Economically, small biotechs, which make a disproportionate contribution to innovative drugs, cannot reach the approval stage alone, and need to make co-development or licensing agreements with large pharmaceutical companies. If approval times were quicker, the latter would be happier about entering such agreements, the smaller developer would stand more chance of survival, and that would translate into more drugs in development.” Changes in the type of approval given could also help to ensure the survival of small developers. “Right now agencies like the FDA produce blanket safety and efficacy statements for the population as a whole”, says Burgos, “but the dawn of personalised medicine means we need to approve drugs for those people
who would benefit from them. That would increase our therapeutic arsenal, improve patient care, and certainly help developers survive to look for more drugs.” The large pharmaceutical companies contacted also declined to comment on whether delays in the approval of neurological drugs might make them less keen to develop drugs overall. However, “I think this is clearly true”, says Hay. “Manufacturers are now focusing on very expensive specialty and oncology drugs with prices in the $10 000s or more per treatment episode. Many of these drugs are not cost-effective, but since they are basically exempted from cost review with a rationale that these patients have no other options, they can generate very large revenues on a very small patient population base. This is becoming an ever more serious problem since drug research and development is being distorted into areas where the patient populations are relatively small and the societal and economic value of the treatments being developed is correspondingly also relatively small.” “Given the economic scenario, the results we provide, and the fact that the FDA is now approving fewer drugs across the board than 10 years ago, it would be highly valuable for the FDA to further examine its divisions’ differences in productivity”, concludes Tabarrok. “What might account for them? Could it be better management, a better ‘culture’ or smaller staff turnover? Are FDA staff in the oncology division better trained in oncology than those in neurology are trained in neurology? Could it be different rules or better communication with the pharmaceutical firms? We simply want to encourage the FDA to do a full process analysis to figure this out, since having the answer [might] speed drug approvals with no loss in safety— and that would be good for everyone.”
For more on small biotechs see Nat Rev Drug Discov 2010; 9: 867–82
Adrian Burton 761