Patent Extension Policy for Paediatric Indications
Nelson, Richard E., McAdam-Marx, Carrie, Evans, Megan L., Ward, Robert, Campbell, Benjamin, Brixner, Diana, Lafleur, Joanne, Applied Health Economics and Health Policy
Children often experience the same conditions as adults, many of which can be treated with pharmaceuticals. Yet, it was estimated in 1999 that <25% of all drugs marketed in the US had a paediatric indication, meaning that they lacked data and product labelling on safety, efficacy and dosing in children. Because of this, physicians are often confronted with the dilemma of whether to prescribe a medication for a child 'off label' and possibly put the child at risk or to deny the child the potential benefits of off-label therapy.
In efforts to remedy this situation, the Food and Drug Administration Modernization Act of 1997 (FDAMA) included The Pediatric Exclusivity Provision, Section 505A, that provided a 6-month market exclusivity extension as an incentive for pharmaceutical manufacturers to conduct clinical trials in children as requested by the FDA. This provision was renewed in 2002 as the Best Pharmaceuticals for Children Act (BPCA) and again as the Pediatric Research Equity Act of 2007. Since the FDAMA was passed, 355 product labelling changes specific to children have been made.
By design, paediatric exclusivity generates a cost to society by delaying the entry of less expensive generic versions of the drug into the market. This extra 6 months of unchallenged revenue provides an incentive for manufacturers to generate paediatric drug data when these incentives are not provided by the market. In a 2001 Report to Congress, the FDA estimated that the cost to consumers over the next 20 years would be $US13.9 billion ($US695 million per year). Critics contend that these costs reflect a disproportionate benefit to manufacturers, whose additional profits from having 6 additional months of market exclusivity are far greater than the costs of conducting the trials. Improvements in children's healthcare by more accurate dosing and reductions in adverse drug effects have been postulated but have been much harder to measure. Furthermore, many medications that are used in children are multisource products (i.e. they are available generically) and therefore do not qualify for the Pediatric Exclusivity Provision. Because of this, there is little incentive for manufacturers to study these drugs in children. Instead, the BPCA established funding for a National Institutes of Health programme to contract for paediatric studies in off-patent products.
In this paper, we estimate the cost impact of the 6-month exclusivity extension policy on the Utah Medicaid drug programme. To do this, we selected three classes of drugs: selective serotonin reuptake inhibitors (SSRIs), HMG-CoA reductase inhibitors (statins) and ACE inhibitors (ACE-Is). These classes were selected for evaluation as they have the most representation on the list of products granted paediatric exclusivity and are top-selling drug classes in the Medicaid programme. SSRIs are commonly used in both adult and paediatric patients, and statins and ACE-Is are regularly used in adults but rarely used in children. Two drug classes that are often used in children, amphetamines/stimulants and sodium channel blocker anticonvulsants, were identified but not included in the analysis because of many factors that precluded our ability to accurately conduct a cost analysis. In the case of amphetamines/stimulants, methylphenidate and Adderall® were granted patent extensions through the Pediatric Exclusivity Provision, but neither could be included in the analysis. The patent for methylphenidate was overly complex because of various dosage forms and because the patent extension applies to the drug moiety in all dosage forms. Adderall® could not be included in the analysis because of product line extensions (e.g. Adderall XR® ) that captured much of the market share prior to the original product's patient expiration, leading to little generic shift. In the case of sodium channel blocker anticonvulsants, our analysis could not be conducted on the drug lamotrigine because of a legal battle that caused the first generic exclusivity to last 3 years rather than the typical 6 months.
Most would agree that an appropriate cost is justified to help ensure drugs used in children are safe, efficacious and dosed appropriately. However, there are currently few data that allow policy makers to evaluate this cost. The FDA released a report shortly after the FDAMA that projected the costs of paediatric exclusivity to society as a whole. Kesselheim et al. estimated the cost to Medicaid of delayed generic availability due to a variety of causes, one of which was paediatric exclusivity. However, the current study is the first to estimate the effect on prescription price of this patent extension policy within entire drug classes and to calculate the cost impact on a state Medicaid programme using patient-level claims data.
Our goal was to characterize the cost impact of the 6-month market exclusivity extension policy to the Utah Medicaid drug programme in the SSRI, statin and ACE-I classes. This was done by estimating the impact of the 6-month delay of generic entry on the reimbursement amount to Medicaid for a brand name drug and then comparing actual costs versus projected costs had the 6-month exclusivity extension not been granted. This analysis was conducted for the drugs that went off-patent and were granted patent extensions before 31 December 2008. The medications analysed included SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), statins (simvastatin, pravastatin and lovastatin) and ACE-Is (lisinopril, benazepril, enalapril, fosinopril and quinapril).
This study utilized Utah Medicaid prescription claims data from 1 January 1999 to 31 December 2009. The data contain the drug strength, quantity dispensed, price and days supplied for each prescription claim made to Utah Medicaid. From this dataset, we were able to extract the claims for all drugs in the selected classes.
Impact on Reimbursement Amount for Each Brand Name Drug
In evaluating the impact of the 6-month market exclusivity extension policy on the reimbursement amount to Medicaid for the brand name drug, we utilized a difference-in-difference technique, running separate regressions for each of the medications receiving the extension. In each case, the drug receiving the extension served as the experimental group while the other drugs served as the control group. The dependent variable in this difference-in-difference regression was the log-transformed prescription drug reimbursement amount. The key independent variables were an indicator for the particular brand of interest (each drug in its own regression), an indicator for whether the 6-month extension was currently in place for the drug of interest and the interaction between these two variables.
The difference-in-difference technique allows us to isolate the impact of this policy from a general time trend by comparing the difference in drug reimbursement amount before and after the 6-month exclusivity extension for the drug that received the extension with the difference in drug reimbursement amount before and after the 6-month extension for the drugs that did not receive the extension. The indicator for brand captures the difference in reimbursement amount between the drug affected by the extension policy and those not affected by it. The indicator for whether the prescription was filled during the 6-month extension period allows us to separate the effect that this particular time period had on Medicaid's reimbursement amount for this prescription drug. Finally, the coefficient on the interaction term indicates the percentage change in the reimbursement amount of the drug of interest as a result of the 6-month extension relative to other drugs within the same class.
Other co-variates in this regression included quantity of units in the prescription, strength, month of fill and the volume of sales for that particular drug relative to the entire class. The month of fill variable was included to control for the length of time that the drug had been available because the price manufacturers set for their drug often increases the longer the drug has been on the market. The relative volume variable was calculated by taking the ratio of the volume of prescriptions for the specific drug over the total volume of prescriptions for all drugs within the class during that particular month. This variable controlled for competitiveness of the class at the time of the prescription fill since the price of a drug is a function of competition from other drugs in the therapeutic class.
A separate regression of this sort was run for each of the 14 drugs of interest within the three chosen drug classes. In each case, the data were restricted to include only prescriptions that were filled during the 5 months before and 5 months after the month in which the 6-month market exclusivity extension began, for a total of 11 months. We did not include the sixth month after the initiation of the patent extension because the exclusivity extension would have ended sometime in the middle of this month, and therefore generic drugs would have entered and led to a decrease in the reimbursement amount to Medicaid for the brand name drug. Therefore, excluding this sixth month led to a cleaner identification of the effect of the patent extension on the brand name drug reimbursement amount.
Cost to Utah Medicaid
In calculating the cost of the policy to Utah Medicaid, it was necessary to calculate both the actual cost and the hypothetical cost had there been no extension policy. Figure 1 is useful in describing our method of calculation. This figure depicts the average adjusted monthly reimbursement amount (adjusted for number of units, strength and volume of sales relative to entire class) of brand name (Zocor® ) and generic simvastatin with the average reimbursement amount on the vertical axis and the month on the horizontal axis. The actual total cost for the 18-month analysis period was calculated by summing the reimbursement amounts for each prescription for the 6 months before (dashed black line in figure 1) and the 12 months after generic availability (dashed grey line in figure 1).
Fig. 1 Average price per prescription per month for Zocor® (brand name simvastatin) and generic simvastatin. [Figure omitted.]
The hypothetical cost was calculated after first finding the percentage difference between the brand name prescription price in the last several months of the 6-month extension and the generic prescription price in the first several months following exclusivity expiration for each drug. This percentage difference in Medicaid reimbursement amount is the gap between the end of the dashed black line and beginning of the dashed grey line. This was done using prescription fills for the brand and generic versions of the drug of interest from only the month in which the patent expired as well as the 2 months before and 2 months after the patent expiration, for a total of 5 months.
Using these data, we regressed the log-transformed reimbursement amount on an indicator for the brand name drug of interest, controlling for number of units, relative volume within the class and strength. This was used to estimate what the initial generic prescription reimbursement amount would have been (i.e. what the vertical distance between the end of the solid black line and beginning of the solid grey line would have been), which was then used to estimate what costs would have been in the 18 months following the original expiration date if the exclusivity extension had not been granted (solid grey line).
While figure 1 shows the cost impact calculation method for Zocor® and simvastatin, the same method was applied to all of the other study drugs. Medicaid rebates were assumed to be 15.1% for branded products and 11% for generics.[10-12]
The calculation of the cost impact of this policy requires several assumptions. The first is that the manufacturer's price of the brand name drug at the end of the original patent was the same whether the drug received the 6-month extension or not. The second is that the proportion of brand to generic utilization that occurred after generic entry was the same had generic entry happened 6 months earlier. This assumption is important because switching from brand to generic is often not instantaneous.
Table I shows the results from the estimation of the impact of the 6-month extension policy on prescription drug reimbursement amounts for each drug broken down by class. The coefficient indicates the percentage change in the dependent variable resulting from a one unit change in the independent variable corresponding to that particular coefficient. Therefore, the results from table I show that the 6-month extension for Zocor® resulted in a 19.0% (p < 0.001) increase in reimbursement amount over other statin drugs at the time. Likewise, the 6-month extension for Pravachol® and Mevacor® resulted in 4.5% (p < 0.001) and 6.1% (p < 0.001) increases in the reimbursement amount of these two drugs to Medicaid, respectively, relative to other statin drugs. The results of this analysis for ACE-Is and SSRIs are also shown in this table. For ACE-Is, the 6-month exclusivity extension did not result in a significant change in the reimbursement amount for Vasotec® , Privinil® or Accupril® , but the resultant increase in prescription reimbursement amount for the remaining drugs was significant and ranged from 3.1% (p < 0.001) for Zestril® to 14.8% (p < 0.001) for Monopril® . The patent extension led to significant reimbursement amount increases in all SSRIs except Luvox® (p = 0.836). These increases ranged from 3.3% (p < 0.001) for Paxil® to 17.1% (p < 0.001) for Zoloft® .
Table I. The effect of 6-month patent extension on prescription price[superscript] a[/superscript] [Table omitted.]
In order to calculate the cost impact of this policy, we first needed to estimate what the reimbursement amount of generic versions of these brand name drugs would have been had the 6-month extension not occurred. Results from the regression estimating the percentage reimbursement amount difference between the brand name drug just prior to generic entry and generic drug just after entry are presented in table II. The coefficient on the dummy variable 'patent expired' indicates this percentage difference, which ranged from 24.4% (p < 0.001) for enalapril to 3.8% (p = 0.0951) for pravastatin sodium.
Table II. The effect of patent expiration on drug reimbursement amount paid by Utah Medicaid[superscript] a[/superscript] [Table omitted.]
The percentage reimbursement amount differences were used in the calculation of the cost impact of this policy, the results of which are presented by drug class in table III. These results include the number of prescriptions filled as well as the total cost with and without the Medicaid rebate. In the calculation of actual cost, results are shown for both the 6-month extension period, during which the brand name drug was the only version available, and the first 12 months after the extension period, when the generic drug was available. In the hypothetical cost calculation, the cost of the total amount of prescriptions filled during the 18-month period following the patent expiration are presented along with what the cost would have been if this 18-month period had started around the original patent expiration rather than after the 6-month extension.
Table III. Calculation of actual cost, hypothetical cost if no 6-month exclusivity and cost difference ($US, year 2007 values): statins, ACE inhibitors (ACE-Is) and selective serotonin reuptake inhibitors (SSRIs) [Table omitted.]
The total costs taking into account the Medicaid rebate for prescriptions were $US1 198 458, $US2 862 675 and $US12 751 764 for statins, ACE-Is and SSRIs, respectively, during this 18-month time period (year 2007 values). The hypothetical costs for these three classes had there been no 6-month extension were $US1 010 774, $US2 494 977 and $US11 155 914, respectively, over the 18 months following the original patent expiration date. Finally, the differences between the actual costs and the hypothetical costs, i.e. the cost impact of the policy, were $US187 684, $US367 699 and $US1 595 851 for statins, ACE-Is and SSRIs, respectively. The total cost of this policy to Utah Medicaid for these three drug classes was $US2 151 234.
Table IV presents the 95% confidence intervals of the cost impacts. This confidence interval is derived from the regression results.
Table IV. Cost impact ($US, year 2007 values) of 6-month exclusivity: 95% confidence internal [Table omitted.]
Roughly 0.5% of the overall Medicaid population lives in Utah, a proportion that was relatively steady from 1997 through 2009.[13,14] Projecting the costs calculated here to the entire US Medicaid population yields costs of $US430.2 million, with upper and lower limits of $US475.2 million and $US370.6 million, respectively.
This is the first study to examine the cost of the Paediatric Exclusivity Provision from a payer's perspective within specific drug classes using patient-level claims data. It is also the first study to estimate the impact of this policy on the reimbursement amount of brand name prescription drugs to Medicaid. For the individual drugs that we examined, the percentage decrease in reimbursement amount resulting from market exclusivity expiration ranged from 24.4% (p < 0.001) for enalapril to 3.8% (p = 0.0951) for pravastatin sodium. Our findings also suggest that the cost impact on the three classes evaluated is substantial. The total cost to Utah Medicaid is estimated to be $US2.2 (95% CI 1.9, 2.4) million over the 18 months following the original patent expiration date. Projected out over the entire US Medicaid population, this cost is $US430.2 (95% CI 370.6, 475.2) million. In estimating the total cost of the Pediatric Exclusivity Provision to Medicaid, it would be necessary to perform a similar analysis for all drug classes. Costs for other classes may not be as high as for these medications because these are among the most frequently used in the Medicaid population. However, it is clear from this analysis that the 6-month extensions for medications undergoing paediatric studies have resulted in increased revenue for manufacturers and increased costs for society.
Our goal in conducting this analysis was not to criticize the policy of creating incentives for companies to collect information about the use of medications in children. Rather, it was simply to begin a dialogue about the current method for deciding how tax payer money is allocated to support these endeavours.
It is unclear how much the new information has impacted the frequency of use of the studied drugs or the improvement of clinical endpoints in paediatric patients. As with other medications studied through these incentive programmes, specific product dosing accuracy and medication safety are unknown until the studies are conducted. Li et al. found that 34% of studies conducted as a result of this regulation identified dosing or safety issues, which are hard to assess in monetary terms. The impact of this provision on the health of children treated specifically with drugs in the statin, ACE-I and SSRI classes has not been studied. Our Utah Medicaid data showed that 0.6% (82 of 14 857) of the patients receiving prescriptions for statins, 19.9% (20 141 of 101 112) receiving SSRIs and 2.7% (761 of 27 998) receiving ACE-Is were paediatric patients during the study period. Thus, the majority of patients utilizing these drugs were adults and therefore not able to benefit from the paediatric label changes that would result from increased studies in these drugs.
While it would be difficult to precisely assess the cost effectiveness of the Pediatric Exclusivity Provision due to challenges in determining the benefit of the labelling information obtained, a rough estimate is possible. Using a cost-effectiveness threshold of $US50 000 per QALY, we can use the costs obtained in this study to determine the QALY gains necessary for this policy to be cost effective. Using Utah Medicaid data from 1 January 1999 to 31 December 2009, these QALY gains would need to be 0.053 for statins, 0.010 for ACE-Is and 0.0014 for SSRIs. These numbers are far lower than the average reported QALY gain of 0.16 and 0.38 estimated for adolescent patients using fluoxetine or other SSRIs, respectively.[15,16] ACE-Is have more variable QALY gain estimates ranging from 0.014 to 0.694 across a variety of disease states in adults.[17-22] The highest estimate of QALY gains (0.694) for ACE-Is was found in the youngest population studied (aged 25-34 years) with diabetes. For that study, QALY gain estimates decreased dramatically as the study population aged. Finally, QALYs gained for statins were also highly variable and ranged between 0.023 and 0.229.[23-30] The youngest patients studied were aged 40 years and many of the results applied to secondary prevention only.
While these rough calculations suggest that the Paediatric Exclusivity Provision may be cost effective, there are several limitations to this estimation. First, the ratio described previously will vary over time, with both the numerator and denominator increasing at an unknown rate. Second, the equation cannot account for benefits derived from information that resulted in a paediatric contraindication or other limits to use.
The cost estimation presented in this paper is only one piece of the economic impact of these provisions. Our projection applies to the US Medicaid drug market, which represents only 20% of the total US population. The Pediatric Exclusivity Provision could also have a major impact globally; many countries honour patents from the US. In fact, through the Agreement on Trade Related Intellectual Property Rights, the World Trade Organization requires member countries to honour patents originating in all other member countries. Therefore, in delaying the entry of less expensive generic medications, this policy generates a cost beyond that reported in this study for US Medicaid. Prices of brand name drugs are considerably higher and prices of generic drugs are considerably lower in the US than other countries.[32,33] Although this smaller price gap would lead to lower costs attributable to this policy than in the US, more specific information on these prices would be required to get a more accurate idea of non-US costs. Conversely, the usage of pharmaceuticals subject to this policy by children in countries around the world also substantially increases the number of potential beneficiaries of this legislation.
The results of this study depend on the key assumptions outlined earlier. The first assumption, that the price of the brand name drug at the end of the original patent would have been the same whether the drug received the 6-month exclusivity or not, may not be plausible. It is possible that the manufacturers would have made different pricing decisions had they not been granted an extra 6 months of market exclusivity. However, there is no way to know precisely how the exclusivity extension affected pricing decisions for the individual products. Also, at least for Mevacor® , there is evidence to suggest that the patent extension was unexpected and, therefore, there would have been no difference in the manufacturer's price at the end of the original period of exclusivity had the extension not been granted. The second assumption, that patients would have followed the same pattern of generic drug consumption with or without the 6-month extension, seems more plausible. There is nothing to suggest that generic utilization patterns would change drastically in 6 months.
Additional assumptions were made for the Medicaid rebates of 15.1% for brand name drugs and 11% for generics used in our calculations. Each quarter, drug makers are required to pay Medicaid either 15.1% of the average manufacturer price (AMP) (the average price the drug maker receives that quarter for sales of that drug to wholesalers) or the difference between the AMP and the lowest price paid by any private buyer (this is referred to as the 'best price'), whichever is higher. In addition, further rebates are applied if the price of the drug in question rises faster than inflation. Thus, the rebate amounts depend on manufacturer-reported prescription prices but these are affected by volume discounts and other rebates, and the methods used to calculate the AMP and the best price vary considerably by manufacturer. The actual rebate, therefore, may vary over time depending on the distribution of prices for that particular drug and would be difficult to calculate given the proprietary nature of this price data. However, ignoring the rebate would inaccurately inflate the cost of the Paediatric Exclusivity Provision to Utah Medicaid. Therefore, it was necessary to assume a value of this rebate, knowing it would not be completely correct, in order to more closely approximate the true cost of this policy.
While 15.1% is the most commonly cited rebate amount for brand name drugs, one source suggests that this rebate may be as high as 31.4%. We performed a sensitivity analysis using this higher rebate amount and found the cost impact of the Pediatric Exclusivity Provision to be $US1 107 131 (95% CI 919 453, 1 364 346). This cost is roughly half of the cost estimated using the 15.1% rebate for brand name drugs, which suggests that these results are sensitive to this assumption.
The results from this study, obtained using data from Utah Medicaid, were used to project what the cost impact of this policy would be for the entire Medicaid programme. This may be problematic because individuals on Utah Medicaid may not be representative of individuals who receive and use Medicaid drug benefits in other states. One such example is that Utah residents have higher rates (twice the national average) of antidepressant use, which may overestimate the US Medicaid projected cost of the SSRI class.
The cost impact of the Paediatric Exclusivity Provision on one Medicaid programme for three drug classes was substantial. Intelligent dialogue is needed to evaluate whether the current method for allocating resources to the study of drugs in children is the most rational.
This study was funded by an Interdisciplinary Seed Grant from the University of Utah, Salt Lake City, UT, USA. BCC was previously employed by the University of Utah College of Pharmacy under a grant from Utah Medicaid to perform medication reviews. At the time of the work done on this paper, he was not in this position.
The authors have no conflicts of interest that are directly relevant to the content of this study.
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School of Medicine, University of Utah, Division of Epidemiology, Salt Lake City, Utah, USA
Correspondence: Dr Richard E. Nelson, School of Medicine, University of Utah, Division of Epidemiology, 500 Foothill Blvd, IDEAS Center 151, Salt Lake City, UT 84148, USA.
Questia, a part of Gale, Cengage Learning. www.questia.com
Publication information: Article title: Patent Extension Policy for Paediatric Indications. Contributors: Nelson, Richard E. - Author, McAdam-Marx, Carrie - Author, Evans, Megan L. - Author, Ward, Robert - Author, Campbell, Benjamin - Author, Brixner, Diana - Author, Lafleur, Joanne - Author. Journal title: Applied Health Economics and Health Policy. Volume: 9. Issue: 3 Publication date: May 2011. Page number: 171+. © Wolters Kluwer Health Adis International Jun 2009. Provided by ProQuest LLC. All Rights Reserved.