Scheduling

The federal CSA places all substances into one of five schedules (Chapter 7). Placement is based on the substance's medical efficacy, safety, potential for abuse and diversion, and physical and psychological dependence liability; substances placed in one schedule can be rescheduled (21 USC § 811) as new information becomes available.

Although some states have adopted schedules identical to the federal schedules (basing their action on the uniform model developed by the National Conference of Commissioners on Uniform State Laws), some reschedule controlled substances independently of the federal government and more restrictively. The process of state scheduling of new drugs and revising the schedules of existing drugs occurs in three ways: automatic rescheduling, administrative rule-making, or, in many states, by new legislation. In any case, the process does not usually begin until a drug has been scheduled or rescheduled at the federal level (Chapter 7).

In many states (including Texas, Illinois, and New Jersey), the scheduling procedure is triggered automatically by a federal scheduling determination, and the medication is presumptively placed into the same schedule as the federal schedule. The entire process can be accomplished in about 30 days. In those states, however, public hearings can be held in case of objections, often slowing the process. In other states (including Pennsylvania, New York, California), there is no formal linkage between the state scheduling process and the federal process, nor is there any time limit on the state scheduling process. In those states, independent action by a state body (either a state regulatory agency or the state legislature) is necessary to begin the scheduling process.

States differ as to whether the legislature or a regulatory agency (or both) is primarily responsible for scheduling. For example, in South Carolina, Rhode Island, and Tennessee the scheduling determination is made by a regulatory agency (usually with an explicit provision for a legislative override); in New York and California, state legislative action is required. In other states (Iowa, Hawaii, Mississippi), the legislature and the state regulatory agencies are involved in the scheduling and rescheduling process.

Variations in the scheduling process can have a substantial effect on the marketing of a new medication. The fact that each state has its own scheduling mechanism creates a daunting set of tasks for prospective manufacturers. The potential for serious delay is real, particularly in states that require legislative action, because not all state legislatures meet in continuous session (for example, in 1994 only 38 state legislatures met in regular session). Such delays add a significant obstacle to pharmaceutical companies in calculating a return on the initial investment. In particular, the LAAM scheduling experience could dissuade companies as they consider developing portfolios of future anti-addiction medications (see LAAM case study below).

While state inactivity is rescheduling can result in long delays in moving a drug from schedule I (under state Controlled Substances Acts) to schedules II to V, this situation is brought about in part by the current federal policy of interpreting ''currently accepted medical use in treatment in the United States" (for purposes of scheduling under the Controlled Substances Act) as requiring NDA (new drug application) approval. A consequence of this policy is that the regulatory process at the federal level is prolonged for all newly approved drugs that are controlled substances (Chapter 7); this regulatory delay can become years when the rescheduling process requires both state and federal action and cannot begin until NDA approval, e.g., LAAM. The committee believes that the public health would be best served by an interpretation of the "currently accepted medical use" clause in the Controlled Substances Act that would recognize the use in humans under an IND (investigational new drug) and permit the scheduling process to begin at the time of NDA submission. The information required for scheduling a drug is already required to be in a self-contained section of the NDA. That section could be reviewed on a fast-track basis by the Food and Drug Administration (FDA), and a scheduling recommendation could be sent to the Drug Enforcement Administration (DEA) well ahead of NDA approval. Scheduling could be done contingent upon final FDA approval. That approach would permit states to reschedule schedule I drugs closer in time to final FDA approval, minimizing delays such as the one now affecting LAAM, and have no negative drug control implications. Furthermore, it would remove a significant regulatory disincentive at the federal level that affects all scheduled drugs, not just schedule I substances.

The committee recommends that the Office of National Drug Control Policy (ONDCP) direct DEA, in consultation with FDA and the National Institute on Drug Abuse (NIDA), to revise its policy on determining when a drug has a currently accepted medical use in treatment so that, for new therapeutic drugs that are also controlled substances, the process of scheduling can begin as soon as possible after submission of the NDA.

Each state is responsible for approving narcotic treatment programs and for monitoring those programs for compliance with state regulations. State treatment regulations must be at least as restrictive as federal regulations, but more stringent regulations are allowed. State approval of narcotic treatment programs is a prerequisite for federal approval, and individual states can recommend to the FDA that a program's approval be revoked for noncompliance [21 CFR § 291.505(h)(2)] (SAMHSA, 1992). ¹ Any new anti-addiction medication that is a narcotic will be required, under federal regulations, to be distributed through approved narcotic treatment programs. The states must not only schedule or reschedule the new medication, but they must also amend their treatment regulations to accommodate the new product before granting approval for its use in treatment.

Until recently, methadone was the only medication approved for use in narcotic treatment programs, and state regulations were written only for methadone maintenance treatment. Once a new anti-addiction medication receives FDA approval for the treatment of drug dependence, the states must amend their methadone regulations before it is used in a program. Thus, under the current regulatory landscape, there could be substantial delays before any newly approved anti-addiction medication actually reaches the patient population. In fact, not even methadone maintenance therapy is available in all states (SAMHSA, 1992).

A sample of state treatment regulations, discussed below, illustrates the complexities faced by pharmaceutical companies as they determine the feasibility of developing a new medication and the probability of success that a new anti-addiction medication will deliver an adequate return on investment.

Clinical Research

Clinical research with potential new medications follows a prescribed course outlined by the FDA's IND process, and clinical trials with medications that are not controlled substances may be conducted in any state with little or no added state regulation. However, additional regulatory steps often are required for clinical trials of controlled substances, which can add further costs and delay the development process. California, for example, requires that an investigator planning to conduct research on human subjects involving a Schedule I or II substance submit the protocol to the state's research advisory panel for approval (California Health & Safety Code § 11481; Research Advisory Panel, 1993). Approval is granted for 6 months, although the investigator may request permission to extend the study. Approved research programs are subject to inspection by panel members, staff, or hired consultants, and annual progress and final reports must be submitted to the panel (Research Advisory Panel, 1993)

New York similarly requires state approval of clinical research involving Schedule I substances, and state licenses are required for anyone engaging in research with a controlled substance generally (New York Public Health Law §§ 3324 to 3329; New York Compilation of Codes, Rules, and Regulations, Title 10 § 80.36). The state also imposes record-keeping requirements for researchers who study controlled substances (New York Public Health Law § 3329; New York Compilation of Codes, Rules, and Regulations, Title 10 § 80.37).

Federal Regulations

Although the federal regulations on narcotic addiction maintenance treatment (21 CFR § 291), originally included only methadone, those regulations were revised in 1989 to allow for the inclusion of other anti-addiction medications (Federal Register, 1989). In July 1993, concurrent with FDA's approval of the LAAM NDA, those treatment regulations were amended specifically to include LAAM (Federal Register, 1993). LAAM, like methadone, may be dispensed only by treatment programs approved by FDA, DEA, and designated state authorities (21 CFR § 291.505). The changes to the federal treatment regulations established a set of core standards (for such matters as patient evaluation and admission, medical and rehabilitative support services, and program sanctions) that could be applied to existing and future anti-addiction medications without requiring extensive additional rule-making. That framework preserved the opportunity to fine-tune such standards to account for the particulars of different medications (Federal Register, 1993).

In the case of LAAM, several specific restrictions on distribution were imposed to reflect the medication's characteristics as currently understood (Chapter 5). For example, the regulation prohibits take-home dosing, primarily because of LAAM's relatively lengthy time to peak effect: an uninformed patient or new user might become impatient and take illicit drugs in the interim, resulting in a potentially fatal overdose when the LAAM effect peaks [21 CFR § 291.505(k)(l)(iii); ORLAAM® package insert]. Also, the use of LAAM is prohibited in patients under 18 years of age, and strongly discouraged in pregnant women, in both cases because of an absence of relevant clinical data [21 CFR § 291.505(d)(l)(iii)(B), (d)(iv); ORLAAM® package insert].

State Regulations

In contrast to the well-coordinated regulatory effort devoted to LAAM at the federal level, the lack of coordination at the state level has seriously hampered LAAM's availability. Some of the obstacles include formulary approval and reimbursement for treatment costs (Chapter 5). The regulatory areas that pose the greatest problems, in addition to scheduling and rescheduling procedures, are the amendment of treatment regulations and the approval of treatment clinics.

Interim Actions

There are two interim steps federal agencies—the Office of National Drug Control Policy (ONDCP), NIDA, SAMHSA, FDA, and DEA—should take under existing authorities to ameliorate the delays, complexity, and lack of uniformity at the state level.

The committee recommends that federal agencies (ONDCP, NIDA, SAMHSA, FDA, and DEA) work more closely and actively with state regulatory authorities early in the drug development process to prepare the path for new anti-addiction medications. That recommendation can be implemented as follows:

• Identification of a regulatory point of contact in each state;
• Basic information could be given to the state contact early in the drug development process (preferably no later than the submission of an NDA) about the medication, with emphasis on characteristics that would be of most interest to state regulatory authorities (diversion potential, target populations, or any special characteristics that would affect how the drug would be dispensed, such as dosing frequency). To the extent that any of the information is proprietary and confidential, the developer's permission for such disclosure would have to be obtained.
• As the medication moves closer to FDA approval, federal agencies could ensure that the necessary state regulatory processes begin immediately after approval, or, if state regulations permit, even before—such as upon the issuance of an approvable letter.
• Federal agencies could work with the state contact, as the product moves through the state regulatory process, to correct any problems as they arise.

The committee recommends that ONDCP, in cooperation with FDA, DEA, SAMHSA, and NIDA, take an active role in compiling relevant information about state regulatory processes for anti-addiction medications that are categorized as narcotics and educating state regulators and pharmaceutical company representatives about the processes and their practical consequences. To implement that recommendation, the following steps may be taken:

• Conduct a comprehensive study of state laws and regulations pertinent to the development of anti-addiction medications that are controlled substances, and develop a step-by-step manual for pharmaceutical companies explaining the mechanisms involved in launching an anti-addiction medication.
• Establish and maintain on-line access to the comprehensive study, as well as to state regulatory information of a practical nature (for example, a directory of relevant state officials) to facilitate pharmaceutical company access.
• Sponsor nationwide or regional educational meetings for state authorities and clinic administrators to disseminate information about potential anti-addiction medications.

Long-Term Actions

Ultimately, close attention should be given to reforming the current patchwork of state regulations. The committee considered complete federal preemption of state controlled-substance laws and regulations insofar as those authorities affect the development of anti-addiction medications, but it concluded that such a proposal would go beyond what is strictly necessary and could be politically unrealistic. The committee does believe, however, that the initiative for reform must come from the federal government, and that it must involve some form of legislative change.

The committee recommends, on the basis of the comprehensive study recommended above, that ONDCP, in coordination with other relevant federal agencies, develop a series of specific actions encouraging states to reform their laws and regulations to facilitate the availability of new anti-addiction medications that are controlled substances. ² Those actions should give particular attention to:

• Modifying state laws and regulations for narcotic treatment programs to remove the need to reopen and amend the laws or regulations to accommodate each new product.
• Imposing specific deadlines for state regulatory action in response to FDA approval of a new anti-addiction medication that requires state action to be dispensed to patients.
• Developing flexible, alternative means of controlling the dispensing of anti-addiction narcotic medications that would avoid the ''methadone model" of individually approved treatment centers.

Finally, the committee urges that Congress, in cooperation with the National Conference of Commissioners on Uniform State Laws, draft legislation requiring states to implement needed changes, rather than preempt outright the relevant state laws or regulations. The legislation could establish regulatory benchmarks (such as the length of time allowed after FDA approval for the state to take legislative or other action; types of alternative dispensing controls). That legislation could be freestanding or as an amendment to NATA.

Clearly, if the federal government wishes to remove regulatory obstacles to the development of anti-addiction medications, significant changes in current policies, laws, and regulations are necessary.