Alan S Oberlender, MSPharm, CPh1 P O Box 1256 Summerfield, FL 34491 15 October 2012 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD 20852 Re: Docket Number FDA-2012-N-0548 (In the hope of informing, in particular, the HHS Secretary's upcoming scheduling recommendation2 for analgesic and antitussive hydrocodone combination drug-products) Distinguished Members, Drug Safety and Risk Management Advisory Committee: I welcome this opportunity to offer my thoughts, those of a pharmacist practicing for several years in the community, on the above-referenced matter. I am sensitive to the fact that you each face a painstaking burden to arrive at an equitable, scientifically defensible and practically sensible public policy with respect, on the one hand, to the ready availability, and, on the other, to appropriate drug control of the hydrocodone drug-product group under review. The burden before you is obviously substantial and consequential. Accordingly, it involves, at least thus far in the long, ongoing question of hydrocodone combination product (HCCP) scheduling, an either-or choice: whether, based on the pharmacoepidemiological and other scientific or related evidence presented, either to up-schedule the drug-product-group to C-II, or to keep the drug-group in C-III. This dichotomy might lead many of you to perceive, I would suppose, an uncomfortable dilemma at best, rather than an easy, cut-and-dried choice. Either choice, you might see, is problematic with respect to the striking interplay between the competing demands of the public health (needed access to acute or chronic pain treatment) and the public safety (needed drug control): Either up-schedule the drug-product group to C-II and in theory promote the public safety, but, as a consequence, adversely impact, to a measured, great extent, 1) the ready availability of the medications to the reliefneeding public, and 2) vital administrative resources in medical and pharmacy settings, leading to likely lesser quality in acute and chronic pain care, and so adversely affect the 1 MS in Pharmacy (Pharmaceutical Outcomes & Policy; Pharmacy Regulation & Policy track – University of Florida); Consultant Pharmacist licensure, State of Florida 2 Requested by DEA administratively; and, in lieu of an earlier but defeated motion by WV Senator Joe Manchin to amend the CSA by up-scheduling hydrocodone combination drug-products to C-II, mandated, rather, by recent statute – Title XI, Subtitle C, § 1139 of FDASIA (Pub L 112-144) – and so, legislatively as well.

1

public health; or, better assure the public health by meeting the preceding needs in keeping the drug group in C-III, but, as a result, impliedly ignore the sheer ravage of the prescription drug epidemic,3 thereby continuing the individually and societally degrading effects of diversion, misuse, abuse, addiction, and poisoning by drug overdosage associated with the current C-III scheme, and so diminish public safety. Need this be the case, either way? I show instead, below, a third regulatory alternative. In avoiding the necessary consequences of such an either-or regulatory dichotomy, I propose a new controlled substance schedule, III-S,4 to legally frame the HCCPs in question – the “S” standing for Special – intermediate between and incorporating the statutorily prescribed operations and functions of prescriptions for schedule II- and schedule III-listed substances. By any honest and reasonable analysis, and informed by current medico- and pharmacolegal notions on the all-important central principle of balance, this regulatory category or scheme is, arguably more than others, one in which these drug-products actually belong. A key premise of this assertion is that hydrocodone per se has remained listed in DEA's schedule II.5 Were a DEA schedule III-S 3 See, eg, CESAR Fax, National treatment admissions for opiates other than heroin continue to increase [and] now surpass cocaine and methamphetamine, 21:30, July 31, 2012; NCHS, Drug poisoning deaths in the United States, 1980—2008 (Poisoning is now the leading cause of death from injuries in the United States, and nearly 9 out of 10 poisoning deaths are caused by drugs), № 81, Dec, 2011; CDC Press Release, Prescription painkiller overdoses at epidemic levels [and k]ill more Americans than heroin and cocaine combined, 1 Nov 2011; and Paulozzi LJ, Jones CM, et al, Vital signs: overdoses of prescription opioid pain relievers – United States, 1999—2008, MMWR, 60(43), 1487-1492, 4 Nov 2011. 4 The emphasized suffix “-S” and its meaning are arbitrary and not necessarily final and certain if the concept and function of the new schedule turns out “to have legs”. A C-II.5, in mixing styles, might appear flip, while a C-2.5 might be seen to defy the category-designation Congress originally set down in the CSA; a C-II.V, however, might prove practically too confusing and troublesome. So C-III-S, or whatever might be more fitting and effective, remains open to style-improvement. At the same time, any expansion of the long-used set of enumerated schedules – I through V – by a whole Roman integer – to C-VI – is not contemplated here. 5 21 CFR § 1308.12(b)(1)(vi). Following the wanton murder of four bystanders during an HCCP-related armed robbery of a Medford, Long Island, NY, pharmacy in June, 2011, the state legislature moved to enact, among other drug control-strengthening provisions, the up-scheduling of HCCPs to the state's schedule II. http://longislandreport.org/news/david-laffer-shootings-motivate-prescription-drug-legislation/11419. Andrew Kolodny, MD, a leading NY addiction psychiatrist and a noted critic of the current federal C-III assignment for the HCCPs, in commenting on the state legislation, pending at the time, is quoted as saying: “The bill will correct a mistake made 40 years ago[,] before we knew that hydrocodone was as potent as morphine and as addictive as oxycodone and heroin. Because of this simple mistake, drugs like Vicodin and Norco are readily available in high school classrooms, college dorm rooms, and in our medicine chests at home. Putting these drugs into the same category as Percocet and OxyContin, where they belong, will decrease inappropriate exposure. Less people will become addicted. Lives will be saved.” Id. The NY drug legislation, now approved and known broadly, along with its amendments, as I-STOP!, received support as a bill from, among other noteworthy interests, The Pharmacists Society of the State of New York and The American Society of Addiction Medicine. Id. Will NY's legislation and professional motions be a sign of legislative things to come in your state and others'? If so, and if history and professional prudence in these regards are reliable guides to predict future events, that would not bode well for far too many pain patients, whose quality of care and inextricably

2

actually instituted6, a prima facie basis would likely exist – thanks to the schedule's special structure and favorably expected prescribing, dispensing, and regulatory processes for medicine and pharmacy alike – to overcome the unhappy administrative or societal results that arguably would ensue or continue to ensue after instituting one or re-instituting the other of the two presently posited, so-called only available regulatory options. The institution of schedule III-S (or whatever else it might be titled), instead, would likely lead overall to closer-to-optimal policy-outcomes in terms of satisfying both public safety and public health requirements under applicable law and its congressional intent. A comprehensive outline of the proposed controlled substance schedule III-S's key features is provided next; after which, I summarize and conclude. In borrowing from the statutory and related regulatory structure, function, and congressional intent of schedules II and III, as codified in the United States Code (USC) and the Code of Federal Regulations (CFR), a schedule III-S would, in the case of the present narcotic drugproduct group, have essentially two casts, according to its envisioned statutory authority and regulation: adequate provision for both 1) short-term narcotic therapy and 2) long-term narcotic therapy. Throughout this section, I reference current law from both codes. 1) a) Similar to the sense in which a prescription for a substance listed in schedule III (and schedule IV) may be transmitted orally by the prescriber to the pharmacist,7 a substance listed in schedule III-S may be transmitted orally– but in this case by the prescriber only, not his or her agent – with strict limitations, as stated in paragraphs b) and c), below. b) Somewhat similar to the sense in which a prescription for a substance listed in schedule II may be transmitted orally by a prescriber to a pharmacist only in the event and for the applicable duration of an emergency situation and period,8 a prescription for a substance listed in schedule III-S may be transmitted orally by phone only by the prescriber but without

related lives would likely suffer wholesale degradation. Such and more is the argument of those interests groups at the national level, including patient-advocacy, medicine, and community pharmacy, who today urge and have successfully achieved (see fn 2, p 1) the priority of the public health advantage in keeping HCCPs in C-III. And theirs, clarion public safety calls such as Andrew Kolodny's notwithstanding, is certainly a compelling one for both ethical- and business-minded practitioners alike. This proposal argues for the acceptance of a distinct and different, a middle ground. It is designed to lead to real-world outcomes that, at all events, might reasonably preempt legislative or administrative upscheduling to C-II. Such preemption would seem plausible because, in light of the currently declared national epidemic, this proposal takes the apparent need for more effective drug control quite seriously. Despite patients' human or legal rights to access treatment for either acute or chronic pain in a wholly reasonable and proper manner, the medical need for narcotics is necessarily part of a bigger, far more complex, societal whole. In addition to being holistic in nature, the proposal is, more specifically, pragmatic toward its objectives. 6 Amending the CSA, ultimately at the appropriate codified locations in § 812 of 21 USC would, of course, be required to enable subsequent and necessary rule-making. 7 21 USC § 829(b) and 21 CFR § 1306.21(a). 8 21 CFR § 1306.11(d).

3

the followup need for any finalizing, written Rx9 and only up to a quantity of 60 pharmaceutical formula-units (PFUs)10 of solid, oral dosage-forms, or 450 mL of an oral solution (elixir), ie, 30 PFUs of 15 mL each, for pain. Quantities of antitussive hydrocodone combination drug-products, depending on the particular drug-product in question, may in no event exceed 30 PFUs of either solid (individual tablets or capsules) or liquid (150 mL; or, say, 50 mL, in the event Tussionex® is prescribed) oral dosage forms. The above numbers of PFUs for pain, or their equivalents for cough, are thus limited to a maximum 5-day, ie, 120-hour course of the FDA-approved dosage for either acute pain or cough. c) Similar to the sense in which a prescription for a substance listed in schedule II is not refillable,11 an orally transmitted prescription for a substance listed in schedule III-S is therefore not refillable. 2) Similar to the sense in which a written prescription for a substance listed in schedule II is not refillable,12 a written prescription for a substance listed in schedule III-S and issued for an appropriate treatment period (so deemed by the prescriber) that is longer than an acute, ie, 5-day, period, as outlined above, and for that extended period deemed necessary to treat moderate to moderately severe pain – a) Is, up to a 30-day supply, not refillable; however – b) Similar to the sense in which a prescription for a substance listed in schedule II may be multiply issued over a period not to exceed 90 days from the issue-date;13 and similar to the sense in which a prescription for a substance listed in schedule III (or IV) is formally valid for up to 6 months, if authorized by the prescriber, such a prescription being fillable for up to 6 times, ie, filled initially and refilled up to 5 times, from its issue-date14 – so a prescription for a substance listed in schedule III-S may also be multiply issued, but for up to 180 days, rather than 90 days, from its issue-date – 9 21 CFR § 1306.11(d)(4). 10 Borrowing the term formula-unit from chemistry and adapting it to our purposes here, each pharmaceutical formula-unit or PFU, if you will, is the actual or physical drug-product that holds in each tablet, capsule, or exact number of milliliters the active ingredient(s) and strength(s) stated on the drug-product-container's label. In the case of such an HCCP; if, say, each tablet contains, according to its container's label, hydrocodone bitartrate 7.5 mg and acetaminophen 300 mg; then 1 such tablet constitutes 1 PFU. Now a dosage-unit may be comprised of more than 1 PFU inasmuch as a prescribed dose is not necessarily identical to a single PFU: A prescriber's written direction to a pharmacist to have the patient read “Take 3 tablets by mouth every morning and every evening, 12 hours apart” on her prescription label indicates that each dosage-unit prescribed equals 3 PFUs of the tablet-strength involved; so yes, each particular dosage-unit equals a prescribed, given dose. Likewise, a prescribed, individual oral dose of methadone 40 mg (for pain) would be duly comprised of either 4 PFUs of the methadone 10-mg tablet or 8 PFUs of the methadone 5-mg tablet. Recall the clinical axiom, patients, not drugs, have doses, and the authoritative point here crystallizes even further in the mind. Cipolle R. Drugs don't have doses – people have doses. DICP (Ann Pharmacotherapy) 1986; 20:881-2. 11 21 USC § 829(a) and 21 CFR § 1306.12(a) 12 Id. 13 21 USC § 829(a) and 21 CFR § 1306.12(b)(1)-(2). 14 21 USC § 829(b) and 21 CFR § 1306.22(a).

4

i) with a 30-day supply for each of up to 6 multiply issued prescriptions on the same date, with, say, 5 of the prescriptions (if a total of 6) being serially-dated as to successive 30-day intervals from the constantly stated issue-date, with a “Do not fill until _______” or like proviso on each successive multiply issued Rx – ii) the first prescription in the series being fillable as early as but in no instance earlier than 27 days from the date the last prescription in the previous series, if applicable, in fact, was filled and delivered to or for the ultimate consumer, and that – iii) an objectively based, good-faith judgment shall be applied by the pharmacist in the event the prescription record reflects the need to manage a theoretical accumulation of PFUs resulting from such an earlier-than-30-day fill. Any such overage of PFUs acquired and maintained by the patient in this manner shall be observed by the pharmacist, directly or indirectly – ie, via either the same pharmacy's prescription records or, say, the accessing of a PDMP's file for the given patient – and applied to the first prescription of a possibly newly written set of multiply issued prescriptions with respect to the new set's initial fill-date, or a single written prescription Rx. This exception notwithstanding, – iv) no patient's prescription record may reflect a series of 2 or more 27-day intervals between dispensations over a 180-day period; however up to 2 non-serial dispensations of a 27-day interval are permitted over the same 180-day period. The pharmacist's enabling of any early dispensations outside the limits of this provision and those of paragraphs ii) and iii), above, for such an occasional 27-day interval dispensing exception is therefore expressly prohibited. Consequently, patients may not otherwise obtain any surplus amount for their possession of any unlawfully, untimely dispensed substance listed in schedule III-S. 3) Dissimilar to the basic statutory authority15 and specific regulation16 governing partial refills of prescription substances listed in schedule III (and IV and V), but similar to the statutory requirement17 and specific regulation18 prohibiting any refills, including partial refills of prescriptions substances listed in schedule II – except when a prescribed quantity of a C-II substance cannot be met due to temporary outage but eventual restorage of the substance within 72 hours from the time of dispensing the initial partial-fill quantity,19 or where provided specially for those patients in LTCFs or under duly recognized hospice care20 – a written or orally transmitted prescription for a substance listed in schedule III-S under ordinary conditions, meaning, under none of the aforementioned exceptional facts and circumstances, shall not be partially filled; however, a 1-time, lesser quantity may be dispensed if deemed necessary unilaterally by the patient or the patient's representative. 15 16 17 18 19 20

21 USC § 829(b). 21 CFR § 13006.23(a)-(c). 21 USC § 829(a). 21 CFR § 1306.12(a). 21 CFR § 1306.13(a). 21 CFR § 1306.13(b).

5

4) Pharmacists shall duly meet and uphold the law's intent to implement a maximum 30-day dispensing limit corresponding to any single written, and a maximum 5-day dispensing limit corresponding to any orally transmitted prescription for a substance listed in schedule III-S – including the various special accommodations provided above,21 for the sake of reasonable and just care requiring narcotic therapy for those in such need. Summary. The addition of a therapeutic amount of acetaminophen to “not more than 15 milligrams of . . . dihydrocodeinone (hydrocodone) . . . per dosage-unit [sic]”22 has, over time, resulted in a far higher level of misuse, abuse, diversion, addiction, or poisoning, non-fatal and fatal alike due to overdosage, than the overseeing federal agencies originally envisioned for this combination drug-product. Arguably, then, in hindsight, these products may have been assigned incorrectly to schedule III.23 This is strongly suggested by the fact of HCCPs' consistently high rank over the years among non-heroin opioid substances used nonmedically to fuel the prescription drug epidemic currently plaguing our nation.24 Tasked at this juncture to decide between the interests expressed by essentially two competing policy-camps, you thus face those who, under the banner of public safety, urge the up-scheduling of HCCPs to schedule II at the clear risk of lessening the quality of the public health versus those who, quite to the contrary and carrying the banner of public health, insist that regulating authorities keep the same drug-products in schedule III while seeming to settle on the status quo with respect to the national epidemic, ie, the public safety. If only both choices were freer of the weighty yoke placed on their regulatory schemes by the law of unintended consequences as their results are played out in real-world events. Put another way, if only both of these options were more balanced in terms of their outcomes. Perhaps the burden of an either-or type of choice between the so-called only available regulatory options need not be borne. The availability of an alternate, harmonized, middle regulatory ground, pursuant to appropriate statutory amendment, may, if indeed it has legs, prove to be the right – balanced and just – option in the present matter. Conclusion. The medico- and pharmacolegal central principle of balance has been the guiding rail in this effort for the Committee to adopt and recommend the proposed controlled substance schedule, III-S. If this schedule holds anything worth commenting about once more, then perhaps pointing out its purpose to meet the deepest and truest, balanced intent of the CSA's original and amending authors would be apt. To bring the central principle of balance to bear on the inherently tense and conflicting issues of necessary access to care requiring controlled drugs and, therewith, necessary drug control, the following view is proffered. The principle of balance represents a dual imperative of governments to establish a system of 21 22 23 24

¶¶ 2) b) ii)-iv), 3) 21 CFR § 1308(e)(1)(iv). Id. See references cited at fn 3, above, p 2.

6

controls to prevent abuse, trafficking, and diversion of narcotic drugs while, at the same, ensuring their medical availability . . . Governments must take steps to ensure the adequate availability of opioids for medical and scientific purposes. These steps include . . . allowing [practitioners] to prescribe [opioids] according to the individual medical needs of the patients, and ensuring that a sufficient supply of opioids is available to meet medical demand . . . [While] a system of controls is necessary to prevent abuse, trafficking, and diversion . . . , [the principle of balance requires that the system of controls] not interfere with [opioids'] legitimate medical use and patient care . . .25

Thus, so much depends on good regulatory policy. In the related words of Lars Noah, “Providing more refined regulatory options may allow for a more sensible resolution of the perennial tension between patient access and drug diversion.”26 In the present context, blunt category-cries such as C-II! or C-III! may misdirect vital resources to select an inadequate regulatory structure. The adoption of a proposed, more fitting and appropriate regulatory scheme has been argued here – a pragmatic structure enabling and entailing suitable, workable processes. If adopted, more sensible policy outcomes would be anticipated.27 And yet, the balance so much sought in the desired processes and outcomes will be realized and appreciated only if and when the arguably resolved tension between patient access and drug control translates into a satisfactorily functional and minimally frictional regime fulfilling the care and treatment demanded by and deemed medically necessary for both acute and chronic pain patients. Continuously demonstrated, ie, empirical balance is key. And so if, in the end, schedule III-S should tie to something truly concise and simple to make its mark, then it just may be what Menalaos, King of Sparta, said to young Telemachos, son of resourceful Odysseus: “In all things,” the king averred, “balance is better.”28 Respectfully,

(E-signed) _________________________________ Alan S Oberlender, MSPharm, CPh 25 Emphasis supplied. Wisconsin Pain and Policy Studies Group (WPPSG), Achieving Balance in Federal and State Pain Policy: A Guide to Evaluation, 2008, 5th ed; available at: www.painpolicywisc.edu , Achieving Balance Reports, at 20 of pdf. 26 Noah L, Challenges in the Federal Regulation of Pain Management Technologies, J Law, Med & Ethics (2003), 31:55-74, 56. 27 Donabedian A, The Definition of Quality and Approaches to its Assessment, excerpted in Furrow BR, Greaney TL, et al, Health Law: Cases, Materials, and Problems, 5th ed (St Paul, MN: Thomas-West), 2004, at 21. 28 Lattimore R, trans, The Odyssey of Homer (New York: Harper Perennial), 1965 (rpt 1991), at 227 (XV: 71).

7

8