estimate is based on our analysis of  IMS data (Ref. 10). Total consumption of albuterol MDIs has fluctuated around  approximately 50 million MDIs annually over the last several years (Ref. 11).  Based on retail sales, we estimate approximately 96 percent of albuterol MDIs  sold were generic MDIs or branded MDIs relabeled and sold as generic (Ref. 10)  (all containing CFCs), suggesting a total market for generic albuterol MDIs of  approximately 48 million MDIs.

  IMS provides data on average retail prices  for marketers of albuterol MDIs for each of three payer types (cash customers,  Medicaid recipients, and patients covered by other third-party payers), and the  proportion of each marketer’s sales to each payer type. As described in table 3  of this document, the weighted average (across all payer types) of retail  prescription price for generic albuterol CFC MDIs during the first half of 2004  was about $13.50 per MDI, the weighted average retail prescription price for  branded versions of albuterol CFC MDIs was about $38.90 per MDI, and the  weighted average retail prescription price for albuterol HFA MDIs was about  $39.50 per MDI.

TABLE 3.—SUMMARY OF CURRENT RETAIL PRICES FOR ALBUTEROL CFC AND HFA MDIS 1

Payer Type

Generic Market

      Share (percent)

Albuterol CFC MDI Prices

Albuterol HFA

      MDI Prices

Price Premium: HFA MDI Price

      Relative to Generic Price

Estimated

      Units

      (millions) 2

Generics

Weighted Average

      Branded Products

Weighted

      Average

Dollars per

      MDI

Percent

Cash

97.0

$19.13

$45.90

$46.32

$27.19

142

5.2

Medicaid 3

97.3

$15.61

$37.10

$41.14

$25.53

164

8.7

Third-party

95.4

$12.03

$37.75

$38.60

$26.57

221

31.4

Total Market

96.0

$13.53

$38.87

$39.47

$25.94

192

45.3

1 Source:  (Ref. 10)

  2 These  estimates reflect retail sales of generic albuterol MDIs, excluding sales at  Internet and mail-order pharmacies.

  3 Medicaid prices do not reflect rebates given directly  to States by drug companies.

  We estimate albuterol CFC MDIs are  responsible for roughly 1,200 metric tons of CFC emissions annually. Each  albuterol CFC MDI contains about 21 grams of CFCs. 14 The  estimated 48 million albuterol CFC MDIs sold annually therefore contain about  1,000 metric tons of CFCs. Adding an additional 20 percent to account for use  in production, unusable batches, and other factors (as manufacturers typically
  do in the process of requesting  essential-use allocations of CFCs for manufacturing) brings the total emissions  to about 1,200 metric tons. To the extent that CFCs used in the production  process are reclaimed and destroyed, this estimate overstates expected  emissions reductions.

D. Benefits and Costs of the Final Rule

  The benefits and costs of a government  action are conventionally estimated relative to a baseline scenario that in  this case is a description of the production, use, and access to albuterol MDIs  in the absence of this rule. In this section we first describe such a baseline
  and then present our analysis of the  benefits of the final rule. Next we turn to the costs of the rule and to an  analysis of the effects on the Medicare and Medicaid programs.

  1. Baseline Conditions

  We developed baseline estimates of  future conditions to estimate the economic effects of prohibiting marketing of  albuterol CFC MDIs after December 31, 2008. It is standard practice to use, as  a baseline, the state of the world absent the rulemaking in question, or where  this implements a legislative requirement, the world absent the statute.

  For the baseline in this analysis, we  assume that access to CFC propellants, and therefore to albuterol CFC MDIs,  continues indefinitely. This assumption focuses our analysis on the impact of  removing less expensive generic albuterol CFC MDIs from the market, until the  date that competition from generic albuterol HFA MDIs lowers prices. As stated  previously in this document, we have identified listed patents on the HFA  technology with expiration dates of 2009, 2010, 2014, 2015, and December 2017.  In performing our analysis, we make two different sets of assumptions. First,  we perform an evaluation based on the assumption that generic versions of  albuterol HFA MDIS will come on the market after patents expire in 2010.  Second, we perform an evaluation based on the assumption that generic albuterol  HFA MDIs will come on the market after the last listed patent expires in 2017.  Without this rule, U.S.  commitments to the Montreal Protocol could limit future access to CFCs and,  therefore, inexpensive generic albuterol CFC MDIs. This observation suggests an  alternative baseline where Parties to the Montreal Protocol stop approving  nominations for the use of CFCs in albuterol MDIs at a particular date. While  the Parties could theoretically take such action for calendar year 2008, it  would be speculative on our part to assume that they would take such action for  that specific date or any other. As a result, we do not pursue a quantitative  analysis with such alternative baselines.

  Throughout our analysis, we assume that  future prices for albuterol CFC and HFA MDIs do not change from current levels.  This assumption overstates prices to the extent that competition from new  entrants reduces future albuterol HFA MDI prices. We assume, however, that  competition among the albuterol HFA MDI manufacturers will leave prices roughly  stable and note that one manufacturer has pledged to freeze prices until at  least the beginning of 2008.

  Throughout this analysis, we assume  that sufficient inventories of CFCs are available to meet demand up to December  31, 2008, and that albuterol HFA MDIs available on and after December 31, 2008,  will be adequate to meet demand. In calculating the present value of increased  expenditures, we discount expected future increases in expenditures by both 7  percent and 3 percent annually for each year after 2005.

  2. Benefits of the Final Rule

  The benefits of the final rule include  environmental and public health
  improvements from protecting  stratospheric ozone by reducing CFC emissions. Benefits also include  expectations of increased returns on investments in environmentally friendly  technology, reduced risk of unexpected disruption of supply of albuterol MDIs,  and continued international cooperation to comply with the spirit of the  Montreal Protocol, thereby potentially reducing future emissions of ODS  throughout the world.

  a. Reduced  CFC emissions. Market withdrawal of albuterol CFC  MDIs will reduce emissions by approximately 1,200 metric tons of CFCs per year.  We have reviewed current CFC inventories and believe currently available  quantities are likely to be sufficient to supply the albuterol CFC MDI market for  approximately 12 months. Nominations for new CFC production are generally  approved by the Parties to the Montreal Protocol 2 years in advance. The final  rule bans marketing of albuterol CFCs after December 31, 2008. There is  considerable uncertainty with respect to the amount of inventories that will be  available in the future, but we anticipate that utilization of existing  inventory will allow the United    States to avoid requesting a 2008 exemption,  or to significantly reduce the amount requested. Therefore, we estimate the  final regulation will reduce CFC use by 1,200 metric tons per year after the  end of 2008, a benefit that will continue beyond the evaluation period.

  In an evaluation of its program to  administer the Clean Air Act, EPA has estimated that the benefits of  controlling ODSs under the Montreal Protocol are the equivalent of $6 trillion  in current dollars. However, EPA’s report provides no information on the total  tons of reduced emissions or the incremental value per ton of reduced emissions.  EPA derived its benefits estimates from a baseline that included continued  increases in emissions in the absence of the Montreal Protocol. We have  searched for authoritative scientific research that quantifies the marginal  economic benefit of incremental emission reductions under the Montreal  Protocol, but have found none conducted during the last 10 years. As a result,  we are unable to quantify the environmental and human health benefits of  reduced ODS emissions from this regulation. Such benefits, in any event, were  apparently included in EPA’s earlier estimate of benefits.

  As a share of total global emissions,  the reduction associated with the elimination of albuterol CFC MDIs represents  only a small fraction of 1 percent. Current allocations of CFCs for albuterol  MDIs account for about 0.1

  percent of the total 1986 global  consumption of CFCs (Ref. 5). Furthermore, current U.S. CFC emissions from MDIs  represent a much smaller, but unknown share of the total emissions reduction  associated with EPA’s estimate of $6 trillion in benefits because that estimate  reflects future emissions growth that has not occurred.

  Although the direct benefits of this  regulation are small relative to the overall benefits of the Montreal Protocol,  we believe the reduced exposure to UV–B radiation that will result from these  reduced emissions will help protect public health. However, we are unable to  assess or quantify specific reductions in future skin cancers and cataracts  associated with these reduced emissions.

  b. Returns  on investment for environmental technology.  Establishing a phaseout date prior to the expiration of patents on albuterol  HFA MDIs not only rewards the developers of the HFA technology, but also serves  as a signal to other potential developers of ozone-safe technologies. In  particular, such a phaseout date would preserve expectations that the  government protects incentives to research and develop ozone-safe technologies.

  Newly developed technologies to avoid  ODS emissions have resulted in more environmentally ‘‘friendly’’ air  conditioners, refrigerants, solvents, and propellants, but only after  significant investments. Several manufacturers have claimed development costs  that total between $250 million and $400 million to develop HFA MDIs and new  propellant-free devices for the global market (Ref. 11).

  These investments have resulted in  several innovative products in addition to albuterol HFA MDIs. For example,  breath-activated delivery systems, dose counters, dry powder inhalers, and  mini-nebulizers have also been successfully marketed. This technology could  also affect other drugs used for the treatment of asthma and COPD because of  the likelihood that, eventually, CFCs will not be available for any drug use.  To compare the effect of alternative phaseout dates on these returns to  investment, we compare the ratio of the present value of increased revenues  expected to accrue to innovative firms from a December 31, 2008, phaseout date  and the present value of the future revenue stream of alternative phaseout dates,  using both 7 percent and 3 percent annual discount rates. This ratio can  provide a basis for relative assessments of the returns to investors for  alternative phaseout dates. We present estimates of this ratio in a later  discussion of alternatives.

  Returns on investment are very  sensitive to the current market prices in the United States. The pharmaceutical  markets of other Parties to the Montreal Protocol operate with implicit or  explicit price controls. These controls have depressed the potential returns to  technological innovation. For example, in 2003, the ex-manufacturer prices (the  prices of the drugs when they leave the production facilities) of the albuterol  HFA MDIs most widely sold in France, Germany, and the United Kingdom ranged  between roughly $3.30 and $6.40; in the United States these prices were in the  neighborhood of $29 to $30. 15

  c. International  cooperation. The advantages of selecting a date  that maintains international cooperation are substantial because the Montreal  Protocol, like most international environmental treaties, relies primarily on a  system of national self-enforcement, although it also includes a mechanism to  address noncompliance. In addition, compliance with its directives is subject  to differences in national implementation procedures. Economically  less-developed nations, which have slower phaseout schedules than developed  nations, have emphasized that progress in eliminating ODSs in developing  nations is affected by observed progress by developed nations, such as the United States.  If we had adopted a later phaseout date, other Parties could attempt to delay  their own control measures.

  3. Costs of the Final Rule

  The effects of the final rule include  increased spending for needed albuterol medication. The social costs of the  final rule include the lost benefits of albuterol use that may result from the  price increase. We discuss the increased spending and then the social costs in  turn.

  In the absence of this regulation, we  would expect 430 million generic albuterol MDIs to be sold during the entire  period between December 31, 2008, and December 2017, when the last patent  listed in the Orange Book for an albuterol HFA MDI will expire. Of these, 96  million would be sold before 2010, an earlier date when generics might arrive.  These figures are based on the estimate that approximately 96 percent (Ref. 10)  of the approximately 50 million albuterol MDIs sold per year (Ref. 11) are  generic, suggesting thata about 48 million generic albuterol MDIs  are sold annually.

  With this regulation, patients who  would have used generic albuterol CFC MDIs are expected generally to switch to  albuterol HFA MDIs. We estimated in section V.C.6 of this document a weighted  average price difference at retail pharmacies (across all payer types) of about  $26 between these products. If this difference can be applied to future  transactions involving 48 million generic albuterol MDIs annually (less the 2  million free samples promised by GSK and decreased demand of 300,000 to 900,000  MDIs resulting from price increases—as calculated later in this analysis), then  increased expenditures from consumers and private or public third-party payers  would reach about $1.2 billion per year. This estimate is based, in part, on  estimated increases in Medicaid prices that do not take into account rebates  given directly to States by drug companies. To the extent that such rebates are  larger for branded albuterol MDIs, which are more expensive, the increased  expenditures are overestimated.

  The present value of these increased  expenditures in 2005 is about $6.2 billion using a 7 percent annual discount  rate and $8.3 billion using a 3 percent annual discount rate. In estimating  this increased spending, we focus on the period between December 31, 2008, and  December 2017, when the last patent listed in the Orange Book will expire. We  also ignore the fact that after a VENTOLIN HFA MDI is first used, it expires  much more quickly than a PROVENTIL HFA MDI or albuterol CFC MDIs. Although this  change in the usable life of some MDIs may affect the quantity consumed, we are  unable to quantify the magnitude of such an effect.

  These increased expenditures represent  primarily transfers from consumers and third-party payers, including State and  Federal Governments, to branded pharmaceutical manufacturers; they are,  therefore, not net costs to society. Because these estimates are based on average  retail prices, they include additional spending that will go to parties other  than innovative manufacturers, such as distributors and retail pharmacies. We  estimate that about 11 percent of this increase—about $130 million annually—may  be paid by uninsured customers ($130 million) (Ref. 10). We derive these  estimates assuming increased spending is the product of the number of albuterol  MDIs sold for cash and the difference between the average price for generic  albuterol
  MDIs and the simple mean of the prices  for albuterol HFA MDIs. We estimate that 5 million generic albuterol MDIs are  sold to uninsured patients annually and that retail cash prices for albuterol  MDIs will rise by about $27 per MDI (details of these estimates follow later in  this section of the document.) Taking in to account savings from coupons and  free samples, uninsured albuterol users would therefore spend about $120  million more each year. 16

  According to MEPS, private nongroup and  uninsured individuals used, on average, 3.3 albuterol prescriptions per year  (Ref. 12). Based on IMS data, we estimate the average albuterol prescription is  for 1.2 MDIs (Ref. 10). The average uninsured, or underinsured, albuterol user  would therefore use about 4 MDIs/year. Based on these figures, we estimate that  a population of uninsured albuterol users of about 1.25 million 17 would  pay, on average, $95 more per year for albuterol. 18 This  estimate does not take in to account the reduced use of albuterol MDIs among  the uninsured that may result from higher prices or the extent to which quicker  expiration of some HFA albuterol MDIs, relative to CFC MDIs, will increase  albuterol MDI demand and expenditures. In the future, some fraction of these  cash payers will likely be covered by Medicare (Ref. 10).

  We expect price increases resulting  from market withdrawal of less expensive generic albuterol MDIs will reduce  albuterol use by several hundred thousand MDIs annually (as explained below),  although there is substantial uncertainty about these estimates. The impact of  this reduction on health outcomes is too uncertain to quantify given available  data. Some patients, however, respond to price increases for medications for  chronic conditions in ways that may adversely affect their health. A recent  article found that:

  ***copayment increases led to increased  use of emergency department visits and hospital days for the sentinel  conditions of diabetes, asthma, and gastric acid disorder: predicted annual  emergency department visits increased by 17 percent and hospital days by 10  percent when copayments doubled * * *.

  However, the article proceeds to  characterize these results as ‘‘not definitive.’’ (Ref. 4) This finding
  suggests that increased prices for  albuterol may lead to some adverse public health effects among the populations  that would face increased prices. This evidence is insufficient to permit us to  quantify any adverse public health effects. We use expected reductions in  albuterol MDI purchases as a surrogate measure of the impact.

  Our approach to estimating the effects  of the rule assumes that the primary effect of an elimination of albuterol CFC  MDIs from the market would be an increase in the average price of albuterol  MDIs. Given the price increase expected from the elimination of generics and  existing estimates of market responses to price increases, we have projected  how the quantity of albuterol MDIs consumed may decline as a result of this  rule. As in the 2004 proposed rule, we assume that the reduction in the use of  albuterol MDIs attributable to this rule can be calculated as the product of  the sensitivity of use with respect to the price increase, the baseline use of  albuterol MDIs among price—sensitive patients, and the price increase in  percentage terms. We discuss these in turn.

  We have no information about how  consumers react to increases in the price of MDIs per se or to increases in the  price of ‘‘rescue’’ types of MDIs, such as albuterol, in particular. Economists  have researched the response of consumers to higher insurance copayments for  drugs in general. The results appear to indicate price elasticities in the  range of -.1 to -.2, meaning that a 10 percent increase in insurance copayments  appears to lead to a reduction in the number of prescriptions of between 1 and  2 percent (Ref. 13). Some researchers have reported estimates of price  elasticities as great as -.3 for asthma drugs (Ref. 4), but the authors report  that there is wide variance based on the availability of over-the-counter  substitutes. For example, for drugs with no over-the-counter substitute—a set  that presumably includes albuterol—the reported price elasticity was -.15. 19 We  have used price elasticities of between -.05 and -.15 to estimate the potential  effect of price increases on demand. We recognize that elasticity estimates  derived from insurance copayment studies may not be specifically applicable to the  effects of average retail
  price increases on uninsured patients’  demand for albuterol.

  To derive an estimate of the number of  albuterol MDIs not sold as a result of this rule, we need an estimate of the  baseline use of albuterol MDI sales by price-sensitive consumers. From data on  retail sales by payer type from the first half of 2004, we find about 5 million  generic albuterol MDIs are sold to uninsured patients annually. This estimate  includes sales to people over age 65 not covered by Medicaid who we expect will  be covered by Medicare in the future, but it excludes mail order and Internet  sales and sales through hospitals and nursing homes. Alternatively, if  uninsured individuals under age 65 use albuterol MDIs in proportion to their  share of the population (roughly 15 percent) (Ref. 14), then roughly 7 million  of 46 million generic albuterol MDIs would be sold to the uninsured (46 million  = 48 million generic albuterol MDIs - 2 million free samples).

  Finally, to estimate the price increase  from this rule, we first assess IMS data, which indicate that cash payers paid,  on average, $19.10 for generic albuterol MDIs and $46.30 for albuterol HFA  MDIs, a difference that would suggest a price increase of $27.20 per MDI, or  142 percent. However, alternative assumptions about the future market share of  different albuterol HFA MDI manufacturers would result in a smaller price  increase—130 percent. These estimated price differences faced by cash payers  are only a proxy for price differences faced by uninsured patients, because  some people with insurance may pay cash, and some uninsured patients may buy  drugs from mail-order and Internet pharmacies.

  We believe that estimates of the recent  price premium for albuterol HFA MDIs may be a reasonable approximation of the  price increase anticipated from this rule, at least to the extent that patent  protection and the more costly criteria for FDA approval of albuterol HFA MDIs  substantially curb competition. At least one listed patent is expected to  expire in December 2017. While increased competition from new patented  albuterol HFA MDIs may reduce future albuterol HFA MDI prices, such reduction  may be small until generic albuterol MDIs are reintroduced into the market.  Apart from any patents, marketing of new albuterol HFA MDIs before the patents  expire requires FDA approval of a completed NDA. After the patents expire, FDA  can approve generic albuterol HFA MDIs by the abbreviated new drug application  (ANDA) process. The NDA process is more complicated, expensive, and time  consuming than the
  ANDA process by which new generic drugs  are brought to market. This NDA requirement constitutes a barrier to entry in  the market that will tend to further limit competition until the patents expire  as compared to markets where generic drugs can be marketed. Finally, as noted  previously in this document, one manufacturer has also announced a voluntary  price freeze on its albuterol HFA MDI until 2008.

  We combine different measures of price  elasticities (-.05 to -.15), the size of the uninsured generic albuterol MDI  market (5 to 7 million MDIs), and estimated price increases (130 percent to 140  percent) to estimate the impact of price increases on use. For example,  assuming a price elasticity of .15 and 6 million generic albuterol MDIs sold to  the uninsured annually, a 130 percent price increase would reduce demand for  albuterol MDIs from the uninsured by about 1.2 million MDIs annually (6 million  x -.15 elasticity x 130 percent price increase = 1,200,000 MDIs). These  preliminary estimates do not take into account offsetting increases in  consumption from changes in promotional efforts already announced by GSK. We  also note that the elasticity estimates are based on relatively small price  changes and may not be applicable to large price changes such as these.

  Manufacturers have announced programs  to distribute free samples and coupons to mitigate any adverse effect of higher  prices on utilization. For example, GSK has committed to provide 2 million  albuterol HFA MDIs each year to physician offices in expectation that they  would be distributed to patients in need (2003P–0029/CR1, p. 7). In addition,  GSK has committed to annually providing 3 million coupons worth $10 each in  rebates for VENTOLIN HFA to any patient. Both GSK and Schering currently  operate outreach programs that assist patients to obtain needed medications,  but we are unable to assess how many albuterol MDI users are currently helped  by these programs or how many more would be helped in the future.

  Free samples and coupons help mitigate  adverse impacts on uninsured patients only to the extent that they are  distributed to physicians and other health care professionals who then give  them to uninsured individuals. 20 To  assess how free samples and coupons might affect albuterol MDI use, we  conducted a thorough review of the relevant peer-reviewed literature and
  found two pertinent articles. One found  that, while 54 percent of the free samples were actually distributed to  patients, only 9 percent of the patients who received free samples were  uninsured (Ref. 15). These data suggest that 4.8 percent of the free samples  were actually distributed to uninsured patients. Assuming this estimate is  applicable to the albuterol HFA MDIs distributed by the GSK program, then about  96,000 albuterol HFA MDIs per year would reach the uninsured. The second  article estimated that 71 percent of free samples were given to patients (Ref.  16). As an upper bound, assuming all samples are distributed to patients and  that the uninsured receive them in proportion to their share of the population,  approximately 300,000 MDIs (15 percent of 2 million) would reach the uninsured  each year.

  We expect coupons will do relatively  little to improve access to albuterol among the uninsured. If 150,000 (5  percent (Ref. 15)) to 450,000 (15 percent) of the 3 million coupons reach  uninsured patients each year and 100 percent of them are redeemed, this would  increase albuterol MDI consumption by roughly 2,000 to 15,000 MDIs per year,  based on the range of price elasticities considered.

  Taking into account the offsetting  effect of free samples and coupons, we focus on a range of 300,000 to 900,000  fewer albuterol MDIs sold each year as a result of increased prices stemming  from removal of generic albuterol MDIs from the market. This assessment does  not take into account Schering’s and GSK’s patient assistance programs designed  to provide free or low cost drugs to low-income patients as we are unable to  assess how many albuterol MDI users are currently helped by these programs or  how many more would be helped in the future. Over the course of the evaluation  period, this would equal between 2.7 million and 8.1 million fewer albuterol  MDIs sold. We recognize that due to varying measures of the size of the generic  albuterol MDI market for the uninsured, uncertainty about the magnitude of  price increases, consumers’ response, and the impact of free samples and  coupons, and other factors, the true impact of the rule could fall outside this  range.

  4. Effects on Medicare and Medicaid

In  order to apportion the possible spending increases described previously in this  document to the Medicaid and Medicare programs, FDA and the Centers for  Medicare & Medicaid Services (CMS) have analyzed

  utilization data related to Medicaid  and Medicare, as well as Medicaid program

  spending data. As explained in this  section of the document, these data suggest that, were this rule in effect in  2003, Medicaid spending (including spending by States) would have increased by  approximately $100 million for that year. In addition (based on 2001  utilization and 2004 prices), it would have increased drug spending on Medicare  beneficiaries by roughly $240 million, although this estimate includes  copayments and coinsurance paid by individuals and may be too low because the  estimate does not take into account increases in utilization associated with  the increase in insurance coverage. These data yield the very rough estimate  that the rule would increase Medicare and Medicaid spending by $340 million  annually relative to a situation where access to generic albuterol CFC MDIs  continued.

  a. Medicaid.  Medicaid spending on albuterol MDIs would have been higher by roughly $100  million in 2003—after taking into account rebates from drug companies—if  albuterol CFC MDIs were not available. CMS estimates that 58 percent of this  amount would be paid by the Federal Government and 42 percent by States.

  Deriving this cost estimate required  making some adjustments to available data. Our point of departure is the State Drug Utilization Data, available at http://www.cms.hhs.gov/medicaid/drugs/ drug5.asp for 2003. These data on utilization  and spending on drugs paid for by the Medicaid program suggest that State  reimbursements under Medicaid would have been approximately $127 million higher  in 2003 if no albuterol CFC MDIs were available (that is, if only albuterol HFA  MDIs were available). This estimate assumes substitutes for all albuterol CFC  MDIs were purchased at the weighted average price of albuterol HFA MDIs.  However, it does not take into account the effect of the rebates from drug companies  to States and the Federal Government. CMS estimates that Medicaid program  rebates constitute roughly 20 percent of gross spending on prescription drugs  under the Medicaid program, suggesting that Medicaid spending on albuterol MDIs  after rebates would have been roughly $100 million higher in 2003 if albuterol  CFC MDIs were not available. It is important to note that this is a rough  estimate, as rebates for a specific drug may differ from the 20 percent  estimate. Incomplete data for 2004 suggest that comparable estimates for 2004  are higher but we believe that these are not reliable because of the  incompleteness of the data.

  b. Medicare.  Our analysis of the impacts of this rule on Medicare addresses: (1) The total  utilization of albuterol MDIs, (2) the likely price increase, and (3) the  aggregate spending increase.

  CMS estimates that noninstitutionalized  Medicare beneficiaries not eligible for Medicaid drug coverage filled about 8  million prescriptions for albuterol MDIs (including VENTOLIN and PROVENTIL) in  2001, based on the Medicare Current Beneficiary Survey (MCBS) and with an  adjustment for under-reporting for aggregate analysis purposes. As noted in  this section of the document, this estimate is based on Medicare beneficiaries’  self-reported outpatient prescription drug utilization, including prescriptions  filled at both retail and mail order pharmacies. In addition, the adjustment  for underreporting is normally used for aggregate use or spending data in MCBS  and may not necessarily reflect actual underreporting for albuterol.

  This analysis used data from the 2001  MCBS, a continuous, multipurpose survey of a nationally representative sample  of Medicare beneficiaries. The survey is focused on health care use, cost, and  sources of payment. No ‘‘paid claims’’ data on use of albuterol MDIs exist  because Medicare will pay for albuterol MDIs only after the implementation of  the new Medicare outpatient prescription drug benefit in January 2006. MCBS is  the largest nationally representative set of data available on prescription  drug utilization and spending by Medicare beneficiaries. The MCBS data have  been used by both CMS’s Office of the Actuary and the Congressional Budget  Office to prepare estimates related to the new Medicare prescription drug benefit.  However, because the data are self-reported, there are considerable  limitations, most notably underreporting. CMS has studied the underreporting in  the survey and has developed methods to adjust the data. For purposes of the  estimates done for the Medicare drug benefit, the data on drug spending are  analyzed in the aggregate (that is, for large collections of drugs). Estimates  of individual drug product utilization and spending, however, may be even more  vulnerable to the limitations inherent in self-reported utilization data.

  A reliable assessment of impacts must  avoid double counting of people who are eligible for both Medicaid and  Medicare. With the implementation of the new Medicare prescription drug  benefit, payment for outpatient prescription drugs on behalf of
  Medicare beneficiaries who are also  eligible for prescription drug benefits under Medicaid will be moved from the  Medicaid program to the Medicare program. For purposes of this analysis, this  population of dually eligible beneficiaries (that is, Medicare beneficiaries  also eligible for full-benefits under Medicaid) is excluded from the analysis  of the MCBS data, since their albuterol MDI utilization is captured within the  Medicaid data. Approximately half of total Medicaid prescription drug spending  is for this dually eligible population. However, the proportion will vary based  on the type of drug involved. It is worth noting that albuterol MDIs are used  to treat asthma in both the aged and disabled in the Medicare/Medicaid dually  eligible population, as well as to treat asthma in children, who make up a  large share of Medicaid beneficiaries.

For purposes of this analysis, we  assess only data for the time periods for which data are available and we do  not make projections for future years. As was noted in the impact analysis for  the proposed rule on the Medicare prescription drug benefit (69 FR 46632,  August 3, 2004), there is considerable uncertainty in making estimates when  there is no program experience from prior years. This uncertainty is  exacerbated in the context of making estimates related to a particular drug.  For example, in the context of preparing aggregate estimates for the Medicare  drug benefit, CMS makes assumptions about how increased coverage induces  greater utilization and, based on the National Health Expenditures, projects  growth in per capita drug spending. But making such calculations for a specific  individual drug would be difficult and not likely reliable. Furthermore, in the  case of albuterol MDIs, the drug is subject to large annual fluctuations in  demand per user and size of population
using the drug due to the nature of the  conditions being treated, such as asthma where acute episodes may vary by  environmental factors (for example, allergies), prevalence of infectious  diseases (for example, colds), and seasonal weather conditions (for example,  temperature-related bronchial conditions). In addition, analyzing the effect on  Medicare of a change related to one drug is further complicated, for example,  by the need to consider the interactions with beneficiary cost-sharing in the  context of the Medicare drug benefit design and the availability of additional  low-income subsidies for certain populations. Also, the introduction of an  albuterol HFA MDI from IVAX is expected to increase competition in the market  to some extent, potentially dampening anticipated price increases in part. Our  estimates, therefore, apply only to past years.

  We believe that prices paid by private  insurers offer a potentially reasonable approximation of prices negotiated in  the context of a privately administered risk-based insurance program such as  the new Medicare Part D drug plans. Using proprietary data from IMS Health, we  determined that prices for patients with third-party insurance were on average  about $30 more per prescription for albuterol HFA MDIs than for albuterol CFC  MDIs, according to IMS’s National Prescription Audit for the first half of 2004  (Ref. 10). This price estimate reflects transactions in U.S. retail  pharmacies, excluding Internet and mail-order sales. It also reflects both  payments by insurers and copayments or coinsurance payments by patients. We  calculate the average price per prescription for the albuterol HFA MDIs and the  albuterol CFC MDIs, respectively, as the weighted average of the price per  prescription of different firms’ products, where the weights are
  the firms’ shares of the total  albuterol MDIs sold. Price differences per prescription are larger than price  differences per MDI, because some prescriptions are for more than one MDI.

  Given this estimate of the price  difference that would have existed without CFC albuterol MDIs, spending by, and  on behalf of, Medicare beneficiaries without Medicaid drug coverage could have  been roughly $240 million more in order to fill the 8 million prescriptions  estimated to have been filled in 2001 (based on the MCBS data). This estimate  is quite approximate because it relies on an estimate of albuterol MDI  prescriptions from 2001 and estimates of prescription price differences from the  first half of 2004. In addition, albuterol MDI use may grow as the Medicare  drug benefit reduces the cost to individuals of using albuterol MDIs.

E. Alternative Phaseout Dates

  In developing this rule, we considered  removing the essential-use designation for ODSs in albuterol MDIs for different  dates between 12 months after issuance of a final rule and December 31, 2009.  As shown previously in this document, earlier removal would increase consumer  expenditures while increasing environmental benefits. A later date would reduce  the potential health effect from reduced access, but also reduce the  environmental benefit and potentially put at risk international cooperation. We  also considered and rejected small business exemptions as inconsistent with  international commitments.

  Table 4 of this document shows the  effects of selecting December 31, 2005, as the effective date, and Table 5 of  this document shows the effects if we had selected December 31, 2009 (assuming  continued availability of CFCs).

TABLE  4.—EFFECTS OF PHASEOUT AS OF DECEMBER 31, 2005

Number    of

      Affected    of

      Albuterol    MDIs

      (millions)

Increased    Expenditures for Albuterol MDIs Present Value in 2005 (billions)

Possible

      Reduction    in

      MDI    Use

      (millions)

Reduced    Aggregate

      CFC    Emissions

      Related    to Phaseout

      (metric    tons)

Relative    Return on Investment to New

      Technology    (return for 12/31/08 phaseout = 1)

3-percent

      discount    rate

7-percent

      discount    rate

3-percent

      discount    rate

7-percent

      discount    rate

576

$11.6

$9.3

3.6    to 9.8

14,400

1.4

1.5

TABLE 5.—EFFECTS OF PHASEOUT AS OF DECEMBER 31, 2009

Number    of

      Affected    of

      Albuterol    MDIs

      (millions)

Increased    Expenditures for Albuterol MDIs Present Value in 2005 (billions)

Possible

      Reduction    in MDI Use

      (millions)

Reduced    Aggregate

      CFC    Emissions

      Related    to Phaseout

      (metric    tons)

Relative    Return on Investment to New

      Technology    (return for 12/31/08 phaseout = 1)

3-percent

      discount    rate

7-percent

      discount    rate

3-percent

      discount    rate

7-percent

      discount    rate

384

$7.3

$5.3

2.4    to 7.2

8,400

.88

.85

F. Sensitivity Analyses

We have conducted a sensitivity analysis to address how key sources of  uncertainty  may affect our estimates. Our key focus is the  effect of alternative dates when generic competition for albuterol HFA MDIs may begin. In Table 6 of this document, we present estimates assuming that generic   competition arrives in 2015.

TABLE 6.—EFFECTS OF PHASEOUT ON DECEMBER 31, 2008—ASSUMING  GENERIC ENTRY IN 2015

Number    of

      Affected    of

      Albuterol    MDIs

      (millions)

Increased    Expenditures for Albuterol MDIs Present Value in 2005 (billions)

Possible

      Reduction    in MDI Use

    (millions)

Reduced    Aggregate

      Emissions

      Related    to Phaseout

    (metric    tons)

Relative    Return on  Investment to New Technology    (return for 12/31/08 phaseout with generic entry in 017 = 1)

3-percent

      discount    rate

7-percent

    discount    rate

3-percent

    discount    rate

7-percent

    discount    rate

336

$6.7

$5.2

2.1    to 5.6

8,400

.81

.84

  This analysis suggests that the  eventual date that generic competition arrives will have a substantial effect  on the total reduction in albuterol MDI use and the aggregate reductions in CFC  emissions. Further analysis of the arrival of generic competition would require  an evaluation of the legal merits of the different patents, but such an  evaluation is beyond the expertise of FDA.

G. Small Business Impact

  Current HHS guidance (Ref. 17) suggests  that a 3 to 5 percent impact on total costs or revenues of small entities could  constitute a significant regulatory impact. We lack the data to certify that  this final rule will not have a significant economic impact on a substantial  number of small entities. Therefore, this analysis, together with other  relevant sections of this document, serves as FDA’s Regulatory Flexibility  Analysis, as required under the Regulatory Flexibility Act.

  1. Affected Sector and Nature of  Impacts

  The affected industry sector includes  manufacturers of pharmaceutical products (NAICS 32514). We obtained data on  this industry from the 1997 Economic Census and estimated revenues per  establishment. Although other economic measures, such as profitability, may  provide preferable alternatives to revenues as a basis for estimating the  significance of regulatory
  impacts, we do not believe it would  change the results of this analysis.

  The impact of this rule on generic  manufacturers is the lost revenues currently generated by sales of generic  albuterol CFC MDIs. While ‘‘lost revenues’’ are an imperfect measure, because  production resources could be shifted to alternative markets, they provide a  measure that suggests the magnitude of the impact.

  The Small Business Administration (SBA)  has defined as small any entity in this industry with fewer than 750 employees.  According to Census data, 84 percent of the industry is considered small. The  average annual revenue for a small entity is $26.6 million per entity. However,  the agency does not have revenue information specific to the affected entities.  According to retail sales in the first half of 2004, of the 22.7 million  generic or relabeled annual prescriptions for albuterol, approximately 63  percent (14.3 million MDIs) were distributed by Schering, a large firm, under  the Warrick label. Six different companies marketed the other
  8.4 million albuterol MDIs, with three  companies accounting for over 99 percent of these 8.4 million (Ref. 10).  According to data collected by the Congressional Budget Office (Ref. 18), the  value of shipments from manufacturers of generic drug products accounts for  approximately 35 percent of the retail price of the product. If so, revenue  from 1.7 million albuterol MDIs

  would approximate $8.0 million per year  (1.7 million prescriptions X $13.50 per generic prescription X 35 percent).  Because we lack company-specific revenue data, we are unable to estimate the  impact of this rule on these small entities. To the extent that generic  albuterol HFA MDIs might become available prior to the removal of the  essential-use designation, any impact on small entities would be mitigated.

  2. Outreach

  The Montreal Protocol and Clean Air Act  have been in place for more than a decade. Manufacturers of albuterol CFC MDIs  have long known that CFCs would eventually lose their essential-use  designations for this purpose. During the proposal stage of this rulemaking, we  specifically solicited comments on the impact on small entities. No comments  were received that explicitly addressed this issue.

H. Conclusion

  This final rule could result in  increased health care expenditures of about $1.2 billion for each year between  the removal of the essential-use designation and reintroduction of generic  competition at patent expiration. Taking into account GSK’s commitment to  provide free samples and coupons, we estimate that higher prices due to the  elimination of generic competition will reduce the number of MDIs sold by  between 300,000 and
  900,000 per year. This estimate does  not take into account Schering’s and GSK’s patient assistance programs designed  to provide free or low cost drugs to low-income patients as we are unable to  assess how many albuterol MDI users are currently helped by these programs or  how many more would be helped in the future. In addition, each year without  using CFCs in albuterol MDIs will reduce atmospheric emissions of ODSs by 1,200  metric tons and provide increased investment returns for environmentally  friendly technology that may induce further gains. Removal of the essential-use  designation is consistent with FDA’s role in determining the essentiality of  MDIs under section 601 of the Clean Air Act, and also meets U.S.  obligations under international agreements. Finally, we lack the data to certify  that this final rule will not have a significant economic impact on a  substantial number of small entities.

VI. The Paperwork Reduction Act of 1995

  This final rule contains no collections  of information. Therefore, clearance by the Office of Management and Budget  under the Paperwork Reduction Act of 1995 is not required.

VII. Federalism

  We have analyzed this final rule in  accordance with the principles set forth in Executive Order 13132. We have  determined that the rule does not contain policies that have substantial direct  effects on the States, on the relationship between the National Government and  the States, or on the distribution of power and responsibilities among the  various levels of government. While this rule may result in States increasing  spending for albuterol MDIs in programs such as Medicaid, the increased  spending is not a substantial direct compliance cost, as the term is used in  Executive Order 13132. Accordingly, we have concluded that the rule does not  contain policies that have federalism implications as defined in the Executive  order and, consequently, a federalism summary impact statement is not required.

VIII. References

  The following references have been  placed on display in the Division of
  Dockets Management (see ADDRESSES) and may  be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday.

  1. U.S. Food and Drug Administration,  ‘‘Guidance for Industry: Integration of Dose-Counting Mechanisms into MDI Drug  Products,’’ March 2003.

  2. Penick, T. B. et al., ‘‘Accuracy of  Float Testing for Metered-Dose Inhaler Canisters,’’ Journal  of the American Pharmaceutical Association,  42:582, July/August 2002.

3.    Craig-McFeely, P. M. et al., ‘‘Prospective  Observational Cohort Safety Study to Monitor the Introduction of a Non-CFC  Formulation of Salbutamol with HFA 134a in England,’’ International  Journal of Clinical Pharmacology and Therapeutics,  41:67–76, 2003.

4.    Goldman, D. P. et al., ‘‘Pharmacy Benefits and  the Use of Drugs by the Chronically Ill,’’ The  Journal of the American Medical Association,  291:2344–2350, 2349, May 19, 2004.

5.  United Nations Environmental Programme,  ‘‘Production and Consumption of Ozone-Depleting Substances 1986–2000,’’ 2002.

6.   U.S. Environmental Protection Agency, ‘‘The  Benefits and Costs of the Clean Air Act: 1990–2010’’ (http://www.epa.gov/air/  sect812/copy99.html).

7.    Mannino, D. M. et al., ‘‘Chronic Obstructive  Pulmonary Disease Surveillance—United States, 1971–2000,’’ Morbidity  and Mortality Weekly Report, 51(SS06):1–16,  August 2, 2002.

8.    American Lung Association, ‘‘Trends in Asthma  Morbidity and Mortality,’’ Epidemiology & Statistics Unit, Research and  Scientific Affairs, April 2004.

9.  Mannino, D. M. et al., ‘‘Surveillance for  Asthma—United States, 1980–1999,’’ Morbidity  and Mortality Weekly Report, 51(SS01):1–13,  March 29, 2002.

10.   Analysis completed by FDA based on information  provided by IMS Health, IMS National Prescription AuditTM,  2004; IMS Health, IMS MIDASTM,  Q1/2004—Q2/2004. These data can be purchased from IMS Health. Please send all  inquiries to: IMS Health, Attn: Brian Palumbo, Account Manager, 660 West  Germantown Pike, Plymouth Meeting, PA 19462.

11.   Rozek, R. P., and E. R. Bishko, ‘‘Economics  Issues Raised in the FDA’s Proposed Rule on Removing the Essential-Use  Designation for Albuterol MDIs,’’ National Economic Research Associates, August  13, 2004 (FDA Docket No. 2003P– 0029/C25).

12.   Agency for Healthcare Research and Quality,  ‘‘Albuterol Inhalers: Prescriptions per User, Price per Prescription and  Expenditure Given Use,’’ spreadsheet prepared at FDA’s request for this  rulemaking, 2004.

13.  Ringel, J. S. et al., ‘‘The Elasticity of  Demand for Health Care,’’ National Defense Research Institute, Rand Health,  2002.

14.   U.S. Census Bureau, ‘‘Income, Poverty, and  Health Insurance Coverage in the United States: 2003,’’ Current  Population Reports, U.S.  Department of Commerce, pp. 14–15, August 2004.

15.   Morelli, D., and M. R. Koenigsberg, ‘‘Sample  Medication Dispensing in a Residency Practice,’’ Journal  of Family Practice, 34(1):42–48, 1992.

16.   Peterson, M. C. et al., ‘‘Disposition of  Pharmaceutical Samples from a Private Medical Clinic,’’ Journal  of the American Pharmacists Association,  44(3):397–398, 2004.

17.   U.S. Department of Health & Human Services,  ‘‘Guidance on Proper Consideration of Small Entities in Rulemakings of the U.S. Department  of Health and Human Services,’’ May 2003.

18.   Congressional Budget Office, ‘‘How Increased  Competition from Generic Drugs Has Affected Prices and Returns in the  Pharmaceutical Industry,’’ July 1998.

List of Subjects in 21 CFR Part 2

  Administrative practice and procedure,  Cosmetics, Devices, Drugs, Foods.

 Therefore,  under the Federal Food, Drug, and Cosmetic Act and the Clean Air Act and under  authority delegated to the Commissioner of Food and Drugs, after consultation  with the Administrator of the Environmental Protection Agency, 21 CFR part 2 is  amended as follows:

PART 2—GENERAL ADMINISTRATIVE  RULINGS AND DECISIONS

 1.  The authority citation for 21 CFR part 2 continues to read as follows:

Authority: 15  U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342, 343, 346a, 348, 351, 352, 355,  360b, 361, 362, 371, 372, 374; 42 U.S.C. 7671 et  seq.

Section 2.125 [Amended]

 2.  Section 2.125 is amended by removing and reserving paragraph (e)(2)(i).

  Dated: March 29, 2005.

Jeffrey Shuren,

  Assistant Commissioner for Policy.

  [FR Doc. 05–6599 Filed 3–31–05; 8:45  am]

  BILLING CODE 4160–01–S

Footnotes

 1 FDA has  verified all Web site addresses cited in this document, but FDA is not  responsible for any subsequent changes to the Web sites after this document has  published in the Federal Register.

  2 The  summary descriptions of the Montreal Protocol and decisions of parties to the  Montreal Protocol contained in this document are presented here to help you  understand the background of the action we are taking. These descriptions are  not intended to be formal statements of policy regarding the Montreal Protocol.  Decisions by the parties to the Montreal Protocol are cited in this document in  the conventional format of ‘‘Decision IV/2,’’ which refers to the second  decision recorded in the Report of the Fourth Meeting of the parties to the  Montreal Protocol on Substances That Deplete the Ozone Layer. Reports of meetings  of the parties to the Montreal Protocol may be found on the United Nations  Environment Programme’s Web site at http://www.unep.org/ozone/mop/mopreports.shtml.

  3 Production  of CFCs in economically less-developed countries is being phased out and is  scheduled to end by January 1, 2010. See Article 2a of the Montreal Protocol.

4 The  Open-Ended Working Group (OEWG) was established in 1989 at the first meeting of  the Parties to the Montreal Protocol held in Helsinki. The OEWG, among other duties,  considers proposals for amendments and adjustments to the Montreal Protocol and  prepares consolidated reports based on the reports of various scientific, technical,  and economic panels. These proposals and reports may subsequently be acted on  by a meeting of the Parties to the Montreal Protocol.

 5 In  conformance with Decision IV/2, EPA issued regulations accelerating the  complete phaseout of CFCs, with exceptions for essential uses, to January 1,  1996 (58 FR 65018, December 10, 1993).

6 Fran Du  Melle, Executive Vice President of the American Lung Association, submitted a  citizen petition on behalf of the U.S. Stakeholders Group on MDI Transition on  January 29, 2003 (Docket No. 2003P–0029/CP1) (Stakeholders’ petition). The  Stakeholders’ petition requested that we initiate rulemaking to remove the  essential-use designation of albuterol MDIs. Several comments were submitted in  response to the petition. All of the opinions and information in those  comments, with one exception (see comment 39 of this document), were also  contained in testimony at the PADAC meeting or in comments on the proposed  rule. In nearly every case, parties submitting comments on the petition also  testified at the PADAC meeting, submitted comments on the proposed rule, or  both. Accordingly, with the exception of comment 39 of this document, we will  not be directly responding in this document to the Stakeholders’ petition or  the comments on the petition.

7 An  ‘‘approvable letter’’ is a written communication to an applicant from FDA  stating that we will approve the NDA if specific additional information or  material is submitted or specific conditions are met. An approvable letter does  not constitute approval of any part of an NDA and does not permit marketing of  the drug that is the subject of the NDA (21 CFR 314.3).

  8 Levalbuterol  tartrate is the tartrate salt of levalbuterol, the single R-enantiomer of  albuterol, which is the active ingredient in both CFC and HFA MDIs as a racemic  mixture of the two stereoisomers (R and S) at a 1:1 ratio. We have not  determined whether we will, in the future, consider products whose active  ingredient is a stereoisomer to be alternatives to drug products whose active  ingredient is the corresponding racemic mixture.

9 We are  only aware of one report in our MedWatch system of an allergic reaction  attributed to the very small amounts of ethanol contained in PROVENTIL HFA.  VENTOLIN HFA, which does not contain ethanol, should be considered for asthma  and COPD patients who may be sensitive to ethanol. MedWatch is the FDA safety  information and adverse event reporting program, which allows health care  professionals and consumers to report serious problems that they suspect are  associated with the drugs and medical devices they prescribe, dispense, or use.

10 Although  the prices derived from IMS data give us much greater assurance than the prices  found on drugstore.com that the numbers we use accurately reflect market  prices, in the case of albuterol MDIs the differences in prices are not very  significant. The drugstore.com price for generic albuterol CFC MDIs is $13.99,  while the weighted average retail price derived from IMS data is approximately  $13.50. The drugstore.com prices for VENTOLIN HFA and PROVENTIL HFA are $39.61  and $38.99 respectively, while the weighted average retail price derived from  IMS data for albuterol HFA MDIs is $39.50. The drugstore.com prices are those  posted on February 10, 2005. See section V.C.6 of this document for more  information on the prices derived from IMS data.

 11 While  PROVENTIL HFA and VENTOLIN HFA can be substituted for albuterol CFC MDIs, they  are not therapeutic equivalents to albuterol CFC MDIs, or to each other, as  that term is defined in the Orange Book. There are minor differences between  the formulations of VENTOLIN HFA and PROVENTIL HFA that might be significant  for some small patient subpopulations (see our response to comment 28 of this  document), but for the vast majority of patients these differences should not  be significant.

  12 Since  publication of the 2004 proposed rule, two patents that expire in 2017 have  been listed in the Orange Book for VENTOLIN HFA.

13 The ozone  depleting potentials of CFC–11 and CFC–12 are  equal. See http://www.epa.gov/ozone/  ods.html.

 14 CFC MDI  manufacturers disclose the CFC content of their MDIs to EPA as part of the  process of requesting essential-use allocations; however, the CFC content of  any particular MDI is considered confidential business information and may not  be disclosed without the manufacturer’s consent.

15 Analysis  completed by FDA based on information provided by IMS Health, IMS MIDASTM,  United States, Germany, France and the United Kingdom, 2003.

16 (5  million MDIs - 300,000 free sample MDIs) x ($25/MDI) - (450,000 coupons) x  ($10) = $117,500,000. Here, we assume coupons and free samples reach uninsured  albuterol users in proportion to estimates of the uninsured fraction of the  overall population (15 percent).

  17 (5  million MDIs) / 4 MDIs per uninsured user = 1.25 million uninsured users.

  18 ($117,500,000)  / (1.25 million uninsured users) = $94.00 per uninsured user.

19 Some  patients may view PRIMATENE, an epinephrine MDI available over the counter, as  a substitute for prescription albuterol MDIs. If this view is widespread, the  decline in albuterol MDI use may be greater than that estimated here. However,  insofar as PRIMATENE is effective in treating asthma, the adverse health  effects would not be greater. We lack data to evaluate patients’ willingness to  substitute PRIMATENE for albuterol MDIs.

20 We found  no information addressing how pharmaceutical companies distribute free samples  among physicians and clinics, but assume that GSK will not systematically  channel free samples away from low-income areas.


[Federal Register: October 12, 2010 (Volume 75, Number 196)]
[Rules and Regulations]
[Page 62468]
[DOCID:fr12oc10-9]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 522

[Docket No. FDA-2010-N-0002]

Implantation and Injectable Dosage Form New Animal Drugs;
Ceftiofur Crystalline Free Acid

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; technical amendment.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the animal
drug regulations to reflect approval of a supplemental new animal drug
application (NADA) filed by Pharmacia & Upjohn Co., a Division of
Pfizer, Inc. The supplemental NADA provides for veterinary prescription
use of ceftiofur crystalline free acid suspension in swine, by
intramuscular injection, for the control of swine respiratory disease
(SRD) in groups of pigs where SRD has been diagnosed.

DATES: This rule is effective October 12, 2010.

FOR FURTHER INFORMATION CONTACT:  Cindy L. Burnsteel, Center for
Veterinary Medicine (HFV-130), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855,<PHONE_NUMBER>, e-mail:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Pharmacia & Upjohn Co., a Division of
Pfizer, Inc., 235 East 42d St., New York, NY 10017, filed a supplement
to NADA 141 235 for EXCEDE (ceftiofur crystalline free acid) for Swine
Sterile Suspension. The supplemental NADA provides for the veterinary
prescription use of ceftiofur crystalline free acid suspension in
swine, by intramuscular injection, for the control of SRD associated
with Actinobacillus pleuropneumoniae, Pasteurella multocida,
Haemophilus parasuis, and Streptococcus suis in groups of pigs where
SRD has been diagnosed. The application is approved as of September 15,
2010, and the regulations are amended in 21 CFR 522.313a to reflect the
approval. In addition, the regulations are amended to specify which
strength of two approved formulations is approved for use in horses.
This is being done to improve the accuracy of the regulations.
    In accordance with the freedom of information provisions of 21 CFR
part 20 and 21 CFR 514.11(e)(2)(ii), a summary of safety and
effectiveness data and information submitted to support approval of
this application may be seen in the Division of Dockets Management
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852, between 9 a.m. and 4 p.m., Monday through Friday.
    Under section 512(c)(2)(F)(iii) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(iii)), this approval qualifies
for 3 years of marketing exclusivity beginning on the date of approval.
    The agency has determined under 21 CFR 25.33 that this action is of
a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
    This rule does not meet the definition of ``rule'' in 5 U.S.C.
804(3)(A) because it is a rule of ``particular applicability.''
Therefore, it is not subject to the congressional review requirements
in 5 U.S.C. 801-808.

List of Subjects in 21 CFR Part 522

    Animal drugs.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs and
redelegated to the Center for Veterinary Medicine, 21 CFR part 522 is
amended as follows:

PART 522--IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS

0
1. The authority citation for 21 CFR part 522 continues to read as
follows:

    Authority: 21 U.S.C. 360b.

0
2. In Sec.  522.313a, add a second sentence to paragraph (e)(1)(ii) and
revise paragraph (e)(3) to read as follows:

Sec.  522.313a  Ceftiofur crystalline free acid.

* * * * *
    (e) * * *
    (1) * * *
    (ii) * * * For the control of SRD associated with A.
pleuropneumoniae, P. multocida, H. parasuis, and S. suis in groups of
pigs where SRD has been diagnosed.
* * * * *
    (3) Horses. The formulation described in paragraph (a)(2) of this
section is used as follows:
    (i) Amount. Two intramuscular injections, 4 days apart, at a dose
of 3.0 mg/lb (6.6 mg/kg) body weight.
    (ii) Indications for use. For the treatment of lower respiratory
tract infections in horses caused by susceptible strains of
Streptococcus equi ssp. zooepidemicus.
    (iii) Limitations. Do not use in horses intended for human
consumption.

    Dated: October 5, 2010.
Bernadette Dunham,
Director, Center for Veterinary Medicine.
[FR Doc. 2010-25527 Filed 10-8-10; 8:45 am]
BILLING CODE 4160-01-P


[Federal Register: February 22, 2010 (Volume 75, Number 34)]
[Notices]
[Page 7606-7608]
[DOCID:fr22fe10-64]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-1996-N-0006] (formerly Docket No. 1996N-0277)

Safety and Efficacy Review for Additional Ingredients in Over-
the-Counter Drug Products for Human Use; Request for Environmental
Impact Data and Information

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Request for data and information.

-----------------------------------------------------------------------

SUMMARY:  We (Food and Drug Administration (FDA)) are requesting data
and information regarding the potential environmental impact of
amending over-the-counter (OTC) drug monographs to include certain
active ingredients not previously marketed in the United States or
marketed in the United States under approved applications after the OTC
drug review began in 1972. Thirteen active ingredients have been found
eligible for potential inclusion in OTC drug monographs based on time
and extent applications (TEAs). We are currently evaluating the safety
and effectiveness of these ingredients.

DATES:  Submit data, information, and general comments by May 24, 2010.

ADDRESSES:  Submit electronic or written data, information, and general
comments in response to this document. Submit electronic comments to
http://regulations.gov. Submit written comments to the Division of
Dockets Management HFA-305), 5630 Fishers Lane, rm. 1061, Rockville, MD
20852.

FOR FURTHER INFORMATION CONTACT:  Michael L. Koenig, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, rm. 5411, Silver Spring, MD 20993-0002, 301-
796-2090.

SUPPLEMENTARY INFORMATION:

I. Ingredients Affected by This Notice

    We are currently evaluating the safety and effectiveness of 13
active ingredients found eligible for possible addition to an OTC drug
monograph via the TEA process described in 21 CFR 330.14. The
ingredients under review are shown in table 1 of this document:

    Table 1.--List of active ingredients found eligible for possible
                    addition to an OTC drug monograph
------------------------------------------------------------------------
 Active Ingredient      Monograph        Docket No.       Eligibility
------------------------------------------------------------------------
Amiloxate           Sunscreen          FDA-2003-N-019  July 11, 2003, 68
                                        6               FR 41386
------------------------------------------------------------------------
Bemotrizinol        Sunscreen          FDA-2005-N-045  December 5, 2005,
                                        3               70 FR 72449
------------------------------------------------------------------------
Bisoctrizole        Sunscreen          FDA-2005-N-045  December 5, 2005,
                                        3               70 FR 72449
------------------------------------------------------------------------
Climbazole          Dandruff           FDA-2005-N-002  December 5, 2005,
                                        1               70 FR 72448
------------------------------------------------------------------------
Diethylhexyl        Sunscreen          FDA-2006-O-031  July 26, 2006, 71
 butamido triazone                      4               FR 42405
------------------------------------------------------------------------
Ecamsule\1\         Sunscreen          FDA-2008-N-047  September 12,
                                        4               2008, 73 FR
                                                        53029
------------------------------------------------------------------------
Enzacamene          Sunscreen          FDA-2003-N-019  July 11, 2003, 68
                                        6               FR 41386
------------------------------------------------------------------------
Octyl triazone      Sunscreen          FDA-2003-N-019  July 11, 2003, 68
                                        6               FR 41386
------------------------------------------------------------------------
Piroctone olamine   Dandruff           FDA-2004-N-003  February 18,
                                        7               2004, 69 FR 7652
------------------------------------------------------------------------
Sodium picosulfate  Laxative           FDA-2006-O-005  June 22, 2006, 71
                                        7               FR 35917
------------------------------------------------------------------------
Sodium shale oil    Dandruff           FDA-2009-N-014  April 7, 2009, 74
 sulfonate                              6               FR 15741
------------------------------------------------------------------------
Triclosan           Acne               FDA-2005-N-045  December 5, 2005,
                                        4               70 FR 72447
------------------------------------------------------------------------
Triclosan\1\        Antigingivitis/    FDA-1981-N-001  July 6, 2004, 69
                     Antiplaque         5               FR 40640
------------------------------------------------------------------------
\1\ These ingredients are marketed under approved new drug applications
  (NDAs).

    When our initial assessment of safety and effectiveness data for
any of these ingredients is complete, we will prepare a proposed rule
describing our conclusions, which may include a proposal to add the
ingredient to an OTC drug monograph. Such an action would be subject to
the National Environmental Policy Act of 1969 (NEPA). In order to
comply with NEPA, we need data and information regarding the potential
environmental impact if these ingredients are included in an OTC drug
monograph, especially if this results in their use in drug products
marketed in the United States for the first time (see section II of
this document). We did not previously request such data and information
for these 13 active ingredients. Therefore, we are requesting such data
at this time. We cannot publish proposed rules for any of these 13
active ingredients until we receive this data and information.

II. Data Being Requested

    As stated in 21 CFR 25.1, FDA regulations must comply with NEPA. To
comply with NEPA, an environmental assessment (EA) of agency actions is
required unless we determine that a categorical exclusion is warranted.
Many actions on OTC drug monographs have been categorically excluded
from the NEPA requirement for an EA under Sec.  25.31(a) (21 CFR
25.31(a)), because, for active ingredients already marketed in the
United States, the actions generally have not resulted in increased use
of active ingredient. However, if we amend a monograph to include a new
generally recognized as safe and effective (GRASE) active ingredient
not previously marketed in the United States, this exclusion would not
apply because our action would increase the use of the active
ingredient. This situation may occur for active ingredients found
eligible for inclusion in an OTC drug monograph under the TEA process
on the basis of foreign marketing experience.
    Active ingredients found eligible for potential inclusion in an OTC
drug monograph under the TEA process might qualify for the categorical
exclusions provided under Sec.  25.31(b) or (c). These exclusions allow
for active ingredients that will not exceed 1 part per billion (ppb) (1
microgram per liter) in the aquatic environment or active ingredients
that naturally occur in the environment and do not alter significantly
the concentration or distribution of the ingredient, its metabolites,
or degradation products in the environment.
    In order to determine whether any of the active ingredients found
eligible for potential inclusion in an OTC monograph meet the
requirements for any categorical exclusion, including Sec.  25.31(b) or
(c), or to prepare an EA, we need additional data and information. To
assist the agency, we are requesting any information that would support
the application of any categorical exclusion, or that would support the
preparation of an EA, if necessary.
    To estimate the expected introductory concentration of an
ingredient or ingredients in the aquatic environment for purposes of
Sec.  25.31(b), please refer to section III of the CDER Guidance on
Environmental Assessment of Human Drug and Biologic Applications (CDER
EA Guidance Document). This guidance document can be viewed at http://
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm070561.pdf.
    To complete an EA, we need information similar to that specified in
section IV of the CDER EA Guidance Document (pages 9-27). We request
that a submitter segregate any data or information that the submitter
believes is protected from disclosure by 18 U.S.C. 1905 or 21 U.S.C.
331(j) or 360j(c). If such data or information is included in the
submission, we request that the submitter summarize the information, to
the extent possible, for public disclosure (see 21 CFR 25.50 and
25.51(a)).

III. Submission of Data

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic data, information, and general
comments. Submit a single copy of electronic data, information, and
general comments or two paper copies of any mailed data, information,
and general comments, except that individuals may submit one paper
copy. Data, information, and

general comments are to be identified with the docket number found in
brackets in the heading of this document. Received data, information,
and general comments may be seen in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: February 15, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-3319 Filed 2-19-10; 8:45 am]
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[Federal Register Volume 83, Number 237 (Tuesday, December 11, 2018)]
[Notices]
[Pages 63639-63640]
[FR Doc No: 2018-26732]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OECA-2014-0062; FRL-9986-60-OEI]

Information Collection Request Submitted to OMB for Review and
Approval; Comment Request; NESHAP for Pesticide Active Ingredient
Production (Renewal)

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Environmental Protection Agency (EPA) has submitted an
information collection request (ICR), NESHAP for Pesticide Active
Ingredient Production (EPA ICR No. 1807.09, OMB Control No. 2060-0370),
to the Office of Management and Budget (OMB) for review and approval in
accordance with the Paperwork Reduction Act. This is a proposed
extension of the ICR, which is currently approved through December 31,
2018. Public comments were previously requested, via the Federal
Register, on June 29, 2017 during a 60-day comment period. This notice
allows for an additional 30 days for public comments. A fuller
description of the ICR is given below, including its estimated burden
and cost to the public. An agency may neither conduct nor sponsor, and
a person is not required to respond to, a collection of information
unless it displays a currently valid OMB control number.

DATES: Additional comments may be submitted on or before January 10,
2019.

ADDRESSES: Submit your comments, referencing Docket ID Number EPA-HQ-
OECA-2014-0062 to: (1) EPA online using www.regulations.gov (our
preferred method), or by email to<EMAIL_ADDRESS>or by mail to:
EPA Docket Center, Environmental Protection Agency, Mail Code 28221T,
1200 Pennsylvania Ave. NW, Washington, DC 20460; and (2) OMB via email
to<EMAIL_ADDRESS>Address comments to OMB Desk Officer
for EPA.
    EPA's policy is that all comments received will be included in the
public docket without change including any personal information
provided, unless the comment includes profanity, threats, information
claimed to be Confidential Business Information (CBI), or other
information whose disclosure is restricted by statute.

FOR FURTHER INFORMATION CONTACT: Patrick Yellin, Monitoring,
Assistance, and Media Programs Division, Office of Compliance, Mail
Code 2227A, Environmental Protection Agency, 1200 Pennsylvania Ave. NW,
Washington, DC 20460; telephone number:<PHONE_NUMBER>; fax number:
(202) 564-0050; email address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Supporting documents, which explain in
detail the information that the EPA will be collecting, are available
in the public docket for this ICR. The docket can be viewed either
online at www.regulations.gov or in person at the EPA Docket Center,
WJC West, Room 3334, 1301 Constitution Ave. NW, Washington, DC. The
telephone number for the Docket Center is<PHONE_NUMBER>. For additional
information about EPA's public docket, visit: http://www.epa.gov/dockets.
    Abstract: The National Emission Standards for Hazardous Air
Pollutants (NESHAP) for Pesticide Active Ingredient Production (40 CFR
part 63, subpart MMM) apply to existing and new facilities engaged in
the production of pesticide active ingredients (PAIs) that emit HAPs.
New facilities include those that commenced construction, modification
or reconstruction after the date of proposal.
    In general, all NESHAP standards require initial notifications,
performance tests, and periodic reports by the owners/operators of the
affected facilities. They are also required to maintain records of the
occurrence and duration of any startup, shutdown, or malfunction in the
operation of an affected facility, or any period during which the
monitoring system is inoperative. These notifications, reports, and
records are essential in determining

compliance with 40 CFR part 63, subpart MMM.
    Form numbers: None.
    Respondents/affected entities: Owners and operators of pesticides
active ingredient production operations.
    Respondent's obligation to respond: Mandatory (40 CFR part 63,
subpart MMM).
    Estimated number of respondents: 18.
    Frequency of response: Initially, quarterly, and semiannually.
    Total estimated burden: 12,100 hours (per year). Burden is defined
at 5 CFR 1320.3(b).
    Total estimated cost: $1,350,000 (per year), which includes $26,500
in annualized capital/startup and/or operation & maintenance costs.
    Changes in the estimates: There is a decrease in the total capital/
startup cost and O&M cost due to a correction. This ICR corrects an
error in the capital/startup cost calculation in the previous ICR, as
existing sources are not expected to incur capital/startup costs
associated with purchasing PRD electronic indicators. There is also a
small adjustment increase in the estimated labor hours due to a change
in assumption. This ICR assumes all existing sources will take some
time to re-familiarize with the regulations each year.

Courtney Kerwin,
Director, Regulatory Support Division.
[FR Doc. 2018-26732 Filed 12-10-18; 8:45 am]
BILLING CODE 6560-50-P


[Federal Register Volume 85, Number 187 (Friday, September 25, 2020)]
[Notices]
[Page 60504]
[FR Doc No: 2020-21296]

-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

Sunshine Act Meetings

TIME AND DATE: 3:15 p.m. on Tuesday, September 29, 2020.

PLACE: The meeting will be held via remote means and/or at the
Commission's headquarters, 100 F Street NE, Washington, DC 20549.

STATUS: This meeting will be closed to the public.

MATTERS TO BE CONSIDERED: Commissioners, Counsel to the Commissioners,
the Secretary to the Commission, and recording secretaries will attend
the closed meeting. Certain staff members who have an interest in the
matters also may be present.
    In the event that the time, date, or location of this meeting
changes, an announcement of the change, along with the new time, date,
and/or place of the meeting will be posted on the Commission's website
at https://www.sec.gov.
    The General Counsel of the Commission, or his designee, has
certified that, in his opinion, one or more of the exemptions set forth
in 5 U.S.C. 552b(c)(3), (5), (6), (7), (8), 9(B) and (10) and 17 CFR
200.402(a)(3), (a)(5), (a)(6), (a)(7), (a)(8), (a)(9)(ii) and (a)(10),
permit consideration of the scheduled matters at the closed meeting.
    The subject matter of the closed meeting will consist of the
following topic:
    Institution and settlement of injunctive actions;
    Institution and settlement of administrative proceedings;
    Resolution of litigation claims; and
    Other matters relating to enforcement proceedings.
    At times, changes in Commission priorities require alterations in
the scheduling of meeting agenda items that may consist of
adjudicatory, examination, litigation, or regulatory matters.

CONTACT PERSON FOR MORE INFORMATION: For further information; please
contact Vanessa A. Countryman from the Office of the Secretary at (202)
551-5400.

     Dated: September 22, 2020.
Vanessa A. Countryman,
Secretary.
[FR Doc. 2020-21296 Filed 9-23-20; 11:15 am]
BILLING CODE 8011-01-P


[Federal Register Volume 78, Number 176 (Wednesday, September 11, 2013)]
[Proposed Rules]
[Page 55671]
[FR Doc No: 2013-22015]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 1140

[Docket No. FDA-2013-N-0521]

Menthol in Cigarettes, Tobacco Products; Request for Comments;
Extension of Comment Period

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking; extension of comment
period.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is extending the
comment period for the advance notice of proposed rulemaking (ANPRM)
that appeared in the Federal Register of July 24, 2013 (78 FR 44484).
In the ANPRM, FDA requested comments, including comments on FDA's
preliminary evaluation, and data, research, or other information that
may inform regulatory actions that FDA might take with respect to
menthol in cigarettes. The Agency is taking this action in response to
requests for an extension to allow interested persons additional time
to submit comments.

DATES: FDA is extending the comment period on the ANPRM. Submit either
electronic or written comments by November 22, 2013.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2013-
N-0521, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name
and Docket No. FDA-2013-N-0521 for this rulemaking. All comments
received may be posted without change to http://www.regulations.gov,
including any personal information provided. For additional information
on submitting comments, see the ``Comments'' heading of the
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Lauren Berkowitz or Annette L.
Marthaler, Center for Tobacco Products, Food and Drug Administration,
9200 Corporate Blvd., Rockville, MD 20850-3229,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of July 24, 2013 (78 FR 44484), FDA
published an ANPRM with a 60-day comment period to request comments on
FDA's preliminary evaluation, and data, research, or other information
that may inform regulatory actions FDA might take with respect to
menthol in cigarettes.
    The Agency has received comments requesting a 60-day extension of
the comment period for the ANPRM. These comments convey concern that
the current 60-day comment period does not allow sufficient time to
develop meaningful or thoughtful responses to questions raised in the
ANPRM. FDA has also received comments opposing an extension of the
current comment period on the grounds that ample time has been given to
comment on the issues raised in the ANPRM.
    FDA has considered the requests and is extending the comment period
for the ANPRM for 60 days, until November 22, 2013. The Agency believes
that a 60-day extension allows adequate time for interested persons to
submit comments without significantly delaying any potential regulatory
action on these important issues.

II. Request for Comments

    Interested persons may submit either electronic comments regarding
this document to http://www.regulations.gov or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

    Dated: September 4, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-22015 Filed 9-10-13; 8:45 am]
BILLING CODE 4160-01-P