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7 Federal Laws and Regulations This chapter and the next discuss the issue of federal and state laws and regulations and the disincentives in developing new anti-addiction medications to the industry. This chapter includes a discussion of the drug-development process, focusing on the multiple interactions between the private sector and federal regulatory agencies, specifically the Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA), necessary to develop and bring to market an approved anti-addiction medication. This chapter also presents recommendations aimed at accelerating drug discovery and development by removing obstacles to the private sector. CREATION OF A DRUG BY THE PHARMACEUTICAL INDUSTRY More than 90 percent of new drugs are discovered by scientists in the pharmaceutical industry (Kaitin et al., 1993; PMA, 1993b). With rare exceptions, the remainder are derived from the work of academic or government scientists (Kaitin et al., 1993~. Even for drugs discovered outside the industry, a partnership or licensing agreement with a drug firm is ultimately necessary for development, manufacturing, and marketing. The process used by the pharmaceu- tical industry to turn a compound into an agent that can be used by patients (e.g., a tablet or an injectable medicine) can be divided into three stages (Figure 7.1~: discovery, development, and marketing (Knoop and Worden, 1988; Spilker and Cuatrecasas, 1990; Agersborg, 1993~. 154

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FEDERAL LA US AND REGULATIONS . 155 Drug discovery consists of a complex set of laboratory research activities, conducted mainly by chemists and pharmacologists (or molecular biologists in the case of the biotechnology industry), from which emerges a compound or a set of related compounds with a specified biological activity, e.g., inhibition of a key enzyme or receptor. The hope is that such a compound, when subjected to further testing (the process called drug development), will prove to be a useful therapeutic agent for a disease in which, e.g., that enzyme or receptor plays a role. New compounds are identified through such approaches as screening large numbers of compounds for the desired biological activity, optimizing molecular structures, using computer-assisted molecular modeling, and testing active compounds in animal models of the relevant disease, when such models exist (Spilker and Cuatrecasas, 1990; PMA, 1993a; Rapaka and Hawks, 1993~. Scientists engaged in drug discovery use the scientific techniques of basic biomedical research, but the goals of the enterprises are different. The purpose of basic research is to advance knowledge and to make it available to the scientific community at large. Basic research is usually funded by government and conducted by academic or government scientists, and its product is public information in written, visual or electronic form. In contrast, the purpose of drug discovery is to identify new substances of potential value in the treatment or prevention of disease. Drug discovery makes use of basic biomedical knowledge, but its end products are a new chemical entity and information on what it does; much of this information is considered proprietary, and new chemical entities are patentable as inventions. Drug discovery as an organized enterprise takes place almost exclusively in the pharmaceutical industry. When a new drug is discov- ered outside the pharmaceutical industry, it is usually a biotechnology product that is an outgrowth of basic research (an event that is likely to become more common) or a product of a collaborative government-industry or university- industry partnership. Drug development consists of studies on a potential new drug to determine what it does in humans, whether it is safe and effective for the treatment or prevention of a disease, and whether it is properly labeled. The studies include toxicity studies in animals and clinical studies in humans that are customarily divided into three phases: Phase I clinical trials in which healthy volunteers receive the drug, and tests are conducted to determine pharmacological information including absorption, blood concentrations, metabolism, initial side effects and, if possible, mechanism of action and efficacy. Phase II clinical trials involve several hundred patients in which evidence on efficacy and dose-response relationships are obtained.

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156 DEVELOPMENT OF MEDICATIONS Phase Ill clinical trials involve several hundred to several thousand patients in which efficacy and safety are demonstrated in hospital and outpatient settings. During drug development, the formulations to be marketed (e.g., tablets, capsules, injections) are also developed, and the manufacturing process is scaled up progressively and optimized (Figure 7.1) (Spilker and Cuatrecasas, 1990~. When a compound is ready for the first clinical study in humans (Phase b, it falls under the regulatory authority of FDA and an investigational new drug (IND) application is submitted to the agency. During the remainder of the drug- development period, there is extensive interaction with FDA that includes consultation on the development plan and protocols, the submission of data on serious and unexpected adverse events, and the submission of periodic reports. When the manufacturer has completed the drug-development program, all the information on the formulations, the manufacturing process and plant, toxicity in animals, and clinical effects in humans is submitted in a new drug application (NDA). An important document in the NDA is the proposed package insert, which states that the drug has been shown to be safe and effective and provides directions for use. The NDA is then reviewed by FDA, often with considerable interaction between the agency and the manufacturer; the process might include open review by an advisory committee. If all parts of the NDA are judged to meet the standards prescribed by federal law and regulations, it is approved. The final step in the creation of a new drug is marketing. This ordinarily lasts many years unless (as happens rarely) the drug must be withdrawn because of a safety problem. An important characteristic of the marketing period, not widely recognized by the public, is that new uses for a drug are often found after initial marketing as the result of serendipitous discovery by an astute clinician or planned studies by clinical investigators in new patient populations. Sometimes such a new use is more important medically than the use for which the drug was originally developed. The discovery of new uses after initial marketing has proved to be a particularly powerful route to innovation for psychoactive drugs, inasmuch as their effects are not easily predicted from animal models and must usually be identified and proved in humans. Indeed, most of the drugs now in use or in the later stages of evaluation by NIDA for the treatment of opiate or cocaine addiction were originally developed for other medical indications (Wes- son and Ling, 1991; NIDA, 1990~. The total cost of creating (discovering, developing, and marketing) a new drug has been analyzed in several studies (Wiggins, 1987; Grabowski and Vernon, 1990; DiMasi et al., 1991) and recently reviewed by the Office of Technology Assessment (OTA, 1993~. OTA concluded that "in 1990 dollars, the mean cash outlay required to bring a new drug to market (including the costs of failures along the way) was approximately $127 million for drugs first entering

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FEDERAL LA US AND REGULATIONS 157 human testing in the 1970s." If capitalized costs (the so-called "cost of time") and tax deductions are considered, the after-tax cost per marketed drug estimated by OTA was "somewhere between $140 and $194 million (in 1990 dollars)." A little more than half the total cost went to preclinical activities such as drug discovery, chemical synthesis, formulation development, and toxicology and the remainder went to clinical development. The mean time to create a successful drug was about 12 years. Corresponding figures for the biotechnology industry are not available. To assess the adequacy of the budget of the NIDA Medications Development Division (MDD), it is most useful to consider actual cash outlays by pharmaceu- tical companies, inasmuch as the capitalizing of expenditures and tax deductions do not apply to MDD. In this context, the cash outlay for Phase III studies of marketed drugs was estimated by DiMasi and co-workers (1991) to be $14.3 million in 1990 dollars; that figure was supported by OTA (1993~. Those costs r~r`^ri~ril`' romeo r~ni~llv_fz~ct~r then the rate of general inflation- during the 1 ~l)V1 ~1] 1 V ~- ~ ~ AM ~ } ^ ~ ~_^ ~ ~ _ _ _ 1980s and presumably continue to do so. On the basis of those figures and informal estimates given by the pharma- ceutical executives who met with the committee, the committee believes that $10~0 million is a reasonable estimate for the average cash outlay to develop a major new indication for an already-approved drug. The cash outlay for the full development of a new compound would presumably be near the industry average, i.e., in the range of $100-200 million. For a shared development pro- gram MDD in partnership with a private organization in which the govern- ment supported clinical development, the cash outlay of public funds would be about half the total cost. Individual pharmaceutical and biotechnology companies have continuing research programs searching for new psychoactive chemicals; some might also have marketed drugs that could be useful in treating one aspect or another of addiction in addition to their primary uses. Individual firms also have the technology for developing, manufacturing, and marketing such drugs. NIDA has research funds to support the development of improved animal models and screening techniques, an operating clinical investigator network, funds to support the clinical development of new drugs and new indications, and a relationship of trust with FDA. Given the enormous amounts of time and money required for pharmaceutical research and development, a collaborative approach between the government and the private sector that pulls complementary resources together appears to be highly desirable. Chapter 3, in its assessment of MDD, considered the interactions between the private sector and NIDA. The remainder of this chapter addresses the ways in which FDA and DEA interact with the private sector and provides committee recommendations to remove federal regulatory disincentives.

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FEDERAL LAWS AND REGULATIONS FOOD AND DRUG ADMINISTRATION 159 Complaints that the traditional FDA drug-approval process is too slow and discourages drug development are not new. In recent years, however, the tradi- tional process has undergone changes designed to expedite FDA review and to expand the use of experimental treatments under some circumstances. The User Fee Law was passed in 1991 to expedite review and approval of new drugs. In addition, the federal Food, Drug, and Cosmetic Act (FDCA) provides special incentives to manufacturers of particular categories of drugs. These incen- tives such as accelerated approval, treatment INDs, and orphan exclusivity are also available to manufacturers of new anti-addiction drugs. For example, LAAM (levo-alpha-acetylmethadol), which on July 9, 1993, became the first narcotic maintenance drug approved since methadone, was granted orphan exclusivity for use in the treatment of heroin addiction suitable for maintenance with opiate agonists. LAAM also was given an expedited final review by FDA (see LAAM case study in Chapter 84. The recent changes to the traditional drug-approval process might provide additional opportunities for encouraging and expediting the development of anti- addiction medications. Recent Initiatives to Expedite Availability of New Drugs Of particular importance is a series of initiatives intended to expedite the availability of drugs to treat serious and life-threatening diseases for which no adequate therapeutic alternatives exist. The acquired immune deficiency syndrome (AIDS) crisis was the driving force behind these efforts, but products intended to treat a variety of other conditions including drug addic- tion properly qualify for treatment under these initiatives. The first such initiative was the treatment-IND mechanism, established in 1987, which allows expanded access to some experimental treatments before they are approved. Under the treatment-IND regulations, FDA may approve the distribution of an investigational drug outside the context of controlled clinical trials to treat patients with serious or immediately life-threatening diseases for which no comparable or satisfactory alternative therapy is available [21 CFR 3 12.34a. For this purpose, FDA defines a disease, including a stage in the progression of a disease, to be immediately life-threatening if "there is a reasonable likelihood that death will occur within a matter of months" or "if premature death is likely without early treatment" [21 CFR 312.34(b)~3~(ii)~. Whether a disease or a particular stage of a disease is serious depends on "its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress to a more serious one" (FDA, 1992a). The standard for

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160 DEVELOPMENT OF MEDICATIONS FDA approval of a treatment IND in the case of a "life-threatening disease," in turn, is whether the "available scientific evidence, taken as a whole," provides a "reasonable basis" for concluding that the drug "may be effective for its intended use in the intended patient population" and would not expose patients to an "unreasonable and significant additional risk of illness and injury" t2 1 CFR 312.34(b)~3~(i)~. For a "serious disease," the standard is whether there is sufficient evidence of safety and effectiveness to support treatment use [21 CFR 312.34(b)~2~. Most of the customary IND procedural requirements apply to treatment INDs, including informed-consent requirements and prohibitions on proapproval promotion or other commercialization of experimental treatments (although companies normally may charge to cover costs) [21 CFR 312.34(c), 312.7(d)~2~. In addition, the drug sponsor is expected to continue conventional clinical trials and to pursue marketing approval of the drug with "due diligence" [21 CFR 312.34(b)(iv)~. Among the products that FDA has approved for treatment-IND status are drugs for the treatment of hairy-cell leukemia, AIDS and AIDS related conditions, Alzheimer's disease, multiple sclerosis, respiratory distress syndrome in infants, Gaucher's disease, obsessive-compulsive disorder, Parkinson's disease, and ovarian cancer (FDA, 1993c). Although the treatment-IND program was designed primarily for patients who could benefit from earlier access to promising experimental drugs, it theoretically offers potential benefits from a sponsor's perspective as well. It allows recovery of developmental costs earlier in the process than might otherwise be possible. It also offers the chance to familiarize patients, prescribers, and payers with a product earlier in the process, and this can facilitate the formal introduction and initial marketing of the product (as long as the sponsor keeps applicable restrictions on proapproval promotion and commercialization in mind). Given that drug addiction should qualify as a serious, and even a life-threatening, disease for treatment-IND purposes, The committee recommends that the FDA make the treatment-IND route available for anti-addiction medications. A second mechanism, known as parallel track, also extends the availability of investigational treatments. Although it is now limited to AIDS patients, parallel track might be adapted to a program tailored to meet the needs of drug- addicted patients in combating addiction. Under parallel track, "promising" investigational agents may be provided to AIDS patients who are not able to take standard therapy or for whom standard therapy is no longer effective and who are not able to participate in clinical trials (U.S. DHHS, 1992~. Parallel-track drugs are thus distributed entirely outside the controlled clinical-trial framework, although they must be under a study protocol and data on safety and side effects

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FEDERAL LA US AND REGULATIONS 161 must still be collected (U.S. DHHS, 1992~. The evidence of effectiveness needed for a parallel-track drug is less than that generally required for a treatment IND; the parallel-track standard is "promising evidence of efficacy" combined with evidence that the drug is "reasonably safe" (U.S. DHHS, 1992~. In reviewing a parallel-track proposal, FDA looks at such factors as evidence of a lack of satisfactory alternative therapy and the possible impact of the parallel-track study on the controlled trials that will be the primary source of evidence of the drug's efficacy (U.S. DHHS, 19921.' With its goals of reaching patients beyond the scope of standard therapy or conventional clinical trials, parallel track provides a prototype for expanding access to treatment to addicted patients, who share some general characteristics with AIDS patients. For example, it is often difficult to find drug-addicted individuals who qualify as subjects for controlled clinical trials. Both population groups include members who might take other drugs that confound the interpretation of controlled clinical trials. For AIDS patients, the issue is exposure to other treatments; for drug-addicted patients, the issue is polydrug use. In addition, as with AIDS, there can be important ethical and recruitment issues with respect to placebo (or no-treatment) controls. Furthermore, a parallel- track procedure that would reach addicted individuals who might otherwise fall outside the system (at least at the testing stage) might further the important public-policy goals of preventing and treating drug addiction. Therefore, The committee recommends that FDA include medications for drug addiction in the parallel-track mechanism. Another important development aimed at speeding the drug-approval process is FDA's accelerated-approval program. Adopted in its final forth in December 1992, accelerated approval is available for drugs that offer "meaningful therapeu- tic benefit compared to existing treatment" for "serious or life-threatening illnesses" and whose approval is to be based on evidence of the drug's effect "on a surrogate end point that reasonably suggests clinical benefit or . . . on a clinical 'In addition, some formal IND requirements do not necessarily apply, most notably supervision by an institutional review board. However, the parallel-track policy statement contemplates a national panel of"human subjects" to protect patients in parallel-track programs. At least in theory, individual patients seeking access to parallel-track treatments must satisfy a fairly detailed and stringent set of entry criteria designed to exclude patients who could take standard approved treatments.

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162 DEVELOPMENT OF MEDICATIONS end point other than survival or irreversible morbidity" (FDA, 1992b).2 Such approval will be conditioned on completion of postmarketing clinical studies to "verify and describe [the drug's] clinical benefit and to resolve remaining uncer- tainty about the relationship of the surrogate end point to clinical benefit" (21 CFR 314.51 0~. Drugs approved under the accelerated procedure are also subject to a streamlined procedure for withdrawal of approval, e.g., if a postmarketing clinical study fails to verify clinical benefit (21 CFR 314.530~. Thus, The committee recommends that, to the extent that a valid end point for the effectiveness of an anti-addiction medication might be established, accelerated approval be available. The committee is impressed that these newer administrative mechanisms for drug distribution under INDs and for more rapid approval are properly applicable to anti-addiction medications, but it notes that FDA has not included anti-addic tion medications in its public statements or written examples in the Federal Register related to these new policies. We encourage the commissioner of FDA to announce clearly (in public statements and the Federal Register) that treatment IND, parallel track, and accelerated approval are applicable to anti- addiction medications as an incentive to private investment in this field. Market Exclusivity and Orphan Drug Status Other potential sources of incentives for anti-addiction drug development are the various statutory exclusivity provisions. The 1984 Drug Price Competition and Patent Term Restoration Act (DPC-PTR Act, Public Law 98-417), which amended the FDCA, gives a sponsor of a drug that is a new chemical entity 5 years of market exclusivity after NDA approval, during which time no other sponsor may submit an abbreviated application for a generic version of the same drug [FDCA 505(c)~31(D)(ii), 505(j)~41(D)(ii)~. Manufacturers of drugs approved for a new indication are granted 3 years of exclusivity for the new indication if new clinical tests were "necessary" to support the approval [FDCA 505(c)~3~(D)(iv), 505(j)~4~(D)(iv)~. In addition, the DPC-PTR Act allows a Surrogate end points are clinical or laboratory measurements that correlate with patient benefit, such as CD4+ blood-cell counts as a basis for assessing the efficacy of AIDS drugs or reduction in blood pressure as a predictor of decreased mortality or morbidity due to hypertensive cardiovascular disease (e.g., stroke, heart failure, and myocardial infarction).

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FEDERAL LAWS AND REGULATIONS 163 manufacturer to obtain an extension to its patent term for a portion of the term lost while the product was in regulatory review if the sponsor pursued its market- ing application with due diligence (35 USC 156~. A separate basis for exclusivity is the Orphan Drug Act (Public Law 97-414, FDCA 525-528~. This law, enacted in 1983 and amended several times, is intended to encourage the development of drugs needed to treat rare diseases whose potential sales might not justify funding of the animal and clinical trials needed to bring products to approval. The standard for orphan status is whether a drug is intended to treat a "rare disease or condition," i.e., a disease or condition that affects fewer than 200,000 persons in the United States or that affects more than 200,000 but for which there is no reasonable expectation of recovering development costs from sales in the United States. To obtain orphan exclusivity, a sponsor must first request and obtain FDA designation of its drug as an orphan drug. The request, which must be filed before the sponsor submits its marketing application for the product and be granted before the marketing application is approved, must include a description of the rare disease or condition for which the drug is being investigated, the reasons why the drug is needed for the disease or condition, a description of the drug arid a discussion of its scientific rationale, and documentation of the rarity of the disease or condition within the meaning of the statute (21 CFR 3 16.201. A drug that has been designated an orphan is entitled to marketing exclusivity for 7 years abler approval, during which time FDA may not approve another sponsor's application for the same drug for the approved orphan indication, apart from specified exceptions.3 In addition to market exclusivity, an orphan-drug manufacturer may apply for special FDA orphan research grants and contracts and is eligible for tax credits for the costs of clinical trials conducted in the United States. Also, FDA, if asked, must provide the sponsor with written protocol recommendations, and the statute instructs FDA to encourage open-label studies so that patients needing the drug have access to it (FDCA 525, 528; 26 USC 44H). Several sponsors of anti-addiction drugs already have taken advantage of the orphan-drug provisions. For example, LAAM was granted orphan status for the treatment of heroin addicted patients suitable for maintenance on opiate agonists, as was Du Pont's Trexan~ (naltrexone) for maintenance of the opiate-free state in detoxified formerly opiate-addicted persons by blocking the effects of exogenously administered opiates (FDA, 1994~. In addition, Pharmavene Inc. Obtained an orphan-drug designation for its product butrylcholinesterase, which 3These exceptions include inability of an orphan-exclusivity holder to ensure a supply of the drug [FDCA 528(b)~1~] and demonstration by a second sponsor that its version of the product is clinically superior to the orphan-exclusivity holder's version [21 CFR 316.3(b)~13~(ii)].

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164 DEVELOPMENT OF MEDICATIONS is in testing for increasing the clearance of toxic blood concentrations of cocaine produced by a drug overdose (FDA, 1993a). Although the sponsors of LAAM took advantage of the provisions of the Orphan Drug Act, the fact that other manufacturers of anti-addiction drugs now in development have not obtained orphan status might indicate that additional incentives are needed. Legislation that would have granted orphan-drug incentives specifically to manufacturers of anti-addiction drugs was proposed in 1989 and 1990 but was not enacted [S. 171 1, 101st Cong., 1st Sess. (19891; S. 2649, 101st Cong., 2d Sess. (19901; S 2650, 101st Cong., 2d Sess. (19901~. This issue is further explored in Chapter 9 and a recommendation is made. FDA Guidelines on Evaluation of Anti-Addiction Drugs The FDA has written draft guidelines intended to assist manufacturers in developing new anti-addiction drugs (FDA, 1 992c). The draft document entitled "Guidelines for the Development and Evaluation of Drugs for the Treatment of Psychoactive Substance Use Disorders" is circulating within FDA and is not yet publicly available.4 The guidelines address such issues as appropriate clinical end points, clinical-trial methods, the use of adolescents in clinical trials (an important issue, given the age of the drug-addiction patient population), polydrug abuse, and the greater potential for abuse of prescription drugs by drug users than by the rest of the population (FDA, 1992c). Several of those issues require special mention. The question of appropriate clinical end points in establishing the effectiveness of anti-addiction drugs has long been debated for a number of reasons, including the nature of the patient population, the use of women and pregnant drug users in clinical trials, the ethics of using placebo or no-treatment controls, and the difficulties of measuring absti- nence and recidivism. In principle, the ideal clinical end point would be cessation of drug addiction without the need for maintenance therapy with a treatment drug. However, reduction in, rather than outright cessation of, use of the illegal drug in question might also be a suitable end point. Cessation or reduction, in turn, can be measured through biological tests, self-reporting of use, measure- ment of money spent on drugs, or a challenge test. Other possible end points might be: retention time in therapy, severity of dependence, withdrawal symptoms or drug-abuse toxicities, patient craving for the drug, illegal activities involvement related to drug use, employment or family status, and mortality or morbidity. 4The committee received a copy of the guidelines for developing and evaluating anti- addiction medications after the publication of the preliminary report (March 1994~.

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FEDERAL LAWS AND REGULATIONS 165 Another guideline issue concerns the evidence required for evaluation of the safety and effectiveness of anti-addiction drugs. For example, although LAAM had been the subject of over 20 studies from 1969 through the early 1980s, FDA required the completion of a "usage" study before approval (FDA, 1 993b). It was concerned about the application of LAAM to the current drug-addict population and whether the directions for use would ensure successful treatment, i.e., in methadone (now narcotic) treatment clinics (FDA, 1992d). The study was an uncontrolled "open-label" (unblinded) trial designed so that drug-addicted individuals were permitted to come in directly and participate. Efficacy was mea- sured by retention rate and "dirty urine" and safety by serious adverse reactions (FDA, 1992d). To resolve the ethical questions raised by a placebo control, the study used historical controls that were based on comparable data on methadone use (FDA, 1992d). Thus although FDA is likely to require some clinical information on "real-world" conditions of use for particular anti-addiction drugs, it appears to be flexible in accepting nontraditional trial designs to obtain such information. The committee is impressed that the guidelines on efficacy end points and approval requirements are valuable to drug sponsors in planning their drug- development programs. Clinical guidelines diminish the uncertainty faced by private sponsors and can serve as an incentive to develop anti-addiction medica- tions. Therefore, The committee recommends that FDA make publicly available the draft guidelines for developing and evaluating anti-addiction medications, seek open comment from the private sector and academic experts, and then complete and publish those guidelines in a timely way. DRUG ENFORCEMENT ADMINISTRATION Scheduling FDA's approval of an anti-addiction drug does not necessarily end the regulatory requirements for marketing the drug. If the drug is a narcotic itself or is subject to abuse, as are methadone and LAAM, it is subject to regulation as a controlled substance by DEA. For those drugs, there is another step before marketing can occur. When FDA reviews a new drug product with a potential for abuse, it must notify DEA (Controlled Substances Act 201(f); 21 USC 801(f); 21 CFR 314.104~. FDA requires that an NDA include a section assessing the drug product's abuse liability (FDA, 1990~. During the review process, FDA, with the assistance of the Drug Abuse Advisory Committee and input from

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166 DEVELOPMENT OF MEDICATIONS NIDA (FDA, 1985), makes a scheduling recommendation to DEA using the criteria outlined in the Controlled Substances Act [CSA 201 (b), (c); 21 USC 81 labs, (c)~.s Under the CSA, a drug with a potential for abuse is placed into one of five schedules, depending on the magnitude of the potential for abuse, whether the drug has accepted medical uses, and the extent to which abuse of the drug will lead to physical or psychological dependence.6 The restrictions arid requirements that apply depend on the schedule into which a particular drug product falls. Congress made the initial scheduling determinations in the statute; DEA has authority to make scheduling decisions for new drugs not covered in the statute and to reschedule drugs under some circumstances (CSA 201, 202; 21 USC 811, 812~. After receipt of FDA's recommendation, DEA makes its initial scheduling determination and publishes it as a proposed rule in the Federal Register, waits for comments, and then issues its final rule. This might occur before or after FDA approval. In the mid-1980s, FDA routinely issued NDA "approvable" letters for drugs proposed for scheduling. In 1986, FDA changed its policy regarding NDA approvals for drugs pending scheduling and issued final "approv- al" letters with the addition of a statement that the drug could not be marketed until it was scheduled by DEA. The result was that the "clock" measuring time before patent expiration, for DPC-PTR Act purposes, was started, even though the drug was not able to be marketed. Under current FDA policy, issuance of a 5The criteria include the scientific evidence of the drug's pharmacologic effect, if known; the state of scientific knowledge regarding the drug; the risk, if any, to the public health; the drug's psychic or physiologic dependence liability; whether it is an immediate precursor of a substance already controlled; the scientific and medical considerations involved in the drug's actual or relative potential for abuse; its history and current pattern of abuse; and the scope, duration, and significance of abuse. Specifically, a Schedule I drug has a high potential for abuse, has no accepted medical use in treatment in the United States, and there is a lack of accepted safety for use of the drug under medical supervision; a Schedule II drug has a high potential for abuse and has an accepted medical use in treatment in the United States or an accepted medical use with severe restrictions, and its abuse might lead to severe psychologic or physical dependence; a Schedule III drug has a lower potential for abuse than a Schedule I or II drug and has an accepted medical use in treatment in the United States, and its abuse might lead to moderate or low physical dependence or high psychologic dependence; a Schedule IV drug has a lower potential for abuse than a Schedule III drug and has an accepted medical use in treatment in the United States, and its abuse might lead to less physical or psychologic dependence than a Schedule III drug; and a Schedule V drug has a lower potential for abuse than a Schedule IV drug and has an accepted medical use in treatment in the United States, and its abuse might lead to less physical or psychologic abuse than a Schedule IV drug [CSA 202(b)~.

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FEDERAL LA US AND REGULATIONS 167 final approval letter seems to permit sale under the Food, Drug and Cosmetic Act without restriction, and no provision of the CSA applies to a drug that is not controlled under that Act. Drug manufacturers have complained about the delay in DEA scheduling. Typically, scheduling can take from several weeks up to 2 months after approval of an NDA by FDA. For example, in the case of LAAM, DEA published its proposed decision to transfer the product from Schedule I to Schedule II in April 1993, before the NDA was approved. A 30-day comment period was set, and the final rule was issued on August 18, 1993, about 5 weeks after the NDA was approved (DEA, 1993~. The lag at DEA, if it becomes substantial, has practical implications for anti-addiction drugs, with respect to lost marketing time. As stated above, pioneer drug manufacturers might be eligible for patent-term extension to allow them to recoup the time lost during regulatory review. In calculating the review period for controlled substances, however, FDA does not count the time lost after approval of an NDA through scheduling by DEA (FDA, 1988~; this time is unre- coverable by the manufacturer. The committee recommends that DEA review time be counted as part of the regulatory process for purposes of patent-term extension for controlled substances. To accomplish this, any of the following three options could be implemented: Amend the DPC-PTR Act. Concurrent DEA scheduling and FDA approval, in the final stages of drug review. Unilateral FDA reversion to its earlier policy of issuing NDA "approvable" letters for drugs proposed for scheduling. The committee has reviewed the issue of scheduling at the state level in Chapter 8 and offers an additional recommendation regarding this issue. Quotas If a drug is scheduled by DEA as a controlled substance, its manufacture is heavily regulated by DEA. Specifically, DEA must set aggregate and individual annual production quotas for Schedule I and II drugs (CSA 306; 21 USC 826), a process in which FDA also plays a role (21 CFR Part 1303~. In particu

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168 DEVELOPMENT OF MEDICA TIONS far, FDA must report to DEA the "results of studies and investigations of quanti- ties of narcotic drugs or other drugs subject to control under [the CSA], together with reserves of such drugs, that are necessary to supply the normal and emergency medical and scientific requirements of the United States . . . not later than the first of April of each year" [Public Health Service Act 302(a); 42 USC 242a. With FDA's recommendation in mind, DEA establishes yearly aggregate production quotas for each Schedule I and II drug to meet "the estimated medical, scientific, research, and industrial needs of the United States, for lawful export requirements, and for the establishment and maintenance of reserve stocks" [CSA 306(a); 21 USC 21 826(a)~. Although the purpose of the DEA quota system is to prevent inappropriate diversion of controlled substances, it also has the effect of restricting a manufact- urer's ability to manufacture and sell its product. Quotas may also affect manu- facturing costs, because optimal batch sizes may exceed quota limits. Further- more, the scheduling of a drug imposes substantial restrictions on the prescribing of the drug by physicians. Those factors combine to make the scheduling of a drug an important disincentive to developing a drug with addiction potential. Regulatory Authority Over Anti-Addiction Drugs In Development DEA's jurisdiction over a drug undergoing clinical investigation for an anti-addiction indication depends on whether the drug is a controlled substance. If the drug is a new chemical entity that has not been scheduled under the CSA, it is not necessarily under DEA jurisdiction at the clinical-trial stage, even though it might later be scheduled. FDA is not required to notify DEA about a new drug that is not yet (but that ultimately might be) scheduled until it receives an NDA for the drug, which will presumably be after clinical trials have been completed [CSA 201(f); 21 USC 811(f)~. However, FDA could apprise DEA of the drug at an earlier stage in the process if it thought that the drug had a potential for abuse, in which case it is possible that the drug could be scheduled while still in clinical trials or even earlier. If the investigational drug is already a controlled substance (as was LAAM), then it will by definition be subject to DEA jurisdic- tion while in clinical trials. Although holders of INDs for controlled substances are exempt from some DEA requirements that parallel FDA requirements, DEA still maintains substantial authority over the manufacture, distribution, and research use of controlled substances, subjecting researchers of new anti-addiction drugs to a dual regulatory scheme. The CSA and !)EA's regulations require that persons conducting clinical research with any controlled substance register with DEA [CSA 302(a)~1~; 21 USC 822 (a)(1); see also 21 CFR 1301.21, 1301.22(a), 1301.22(b)~5~], keep specific kinds of records [CSA 307(a),~b); 21 USC 827(a), (b)], and

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FEDERAL LAWS AND REGULATIONS 169 periodically report to DEA [CSA 307(d); 21 USC 827(d)]. Holders of INDs for controlled substances must register with DEA but are exempt from the CSA's recordkeeping requirements (CSA 307(c)(2)(A); 21 USC 827(c)(2~(A); see 21 CFR Part 1304~. In particular, 21 CFR 1304.03(e) provides that a DEA registrant operating under an IND who "maintains records in accordance with [the FDCA] is not required to keep records if he notifies [DEA] of the name, address, and registration number of the establishment maintaining such records." FDA requires, however, that a sponsor or investigator make its FDA-mandated records pertaining to shipment, delivery, receipt, and disposition of the drug available to DEA for inspection and copying at DEA's request [21 CFR 312.58(b)~. In addition, FDA regulations mandate that investigators and sponsors in clinical trials using controlled substances take special precautions, including storage of the drug in a secure place with limited access, to prevent theft or inappropriate diversion [21 CFR 312.69, 312.58(b)~. This regulation is consistent with Section 307(f) of the CSA, 21 USC 827(f), which requires FDA to promulgate rules to "insure the security and accountability of controlled substances" used in clinical investigations. There is, however, no corresponding exemption from the reporting require- ments under the CSA [CSA 307(d); 21 USC 827(d)~. In addition, because a DEA registration for research with controlled substances also authorizes the manufacture and distribution of such substances (within defined limits) t21 CFR 1301.22(b)~3) for Schedule I and (bus) for Schedules II-V] if a researcher engages in either activity, he or she must comply with the recordkeeping and reporting requirements for manufacturers and distributors [21 CFR 1304.03a. Thus, for example, the holder of an IND for a controlled substance that also manufactures it must report data on the acquisition and reduction ofthe substance from inventory monthly (unless it receives permission from DEA to report more or less often) and data on the status of year-end inventory annually if the con- trolled substance is in Schedule I or II, is a narcotic in Schedules III, IV, or V, or is a listed psychotropic substance in Schedule III or IV (21 CFR 1304.35~. In addition, DEA requires that protocols for research with Schedule I controlled substances be submitted to it for approval and requires researchers using Schedule I substances to identify in their registration applications the extent to which the research will also involve manufacture or importation (21 CFR 1301.32(a)~6), 1301.33~. This does not, however, apply to clinical investigations under an IND. In those cases, the sponsor need only submit to DEA a copy of its IND with a statement of the security provisions for storing and dispensing the drug to prevent inappropriate diversion [21 CFR 1301.33(b)~. In either case, FDA has the ultimate authority to approve the study, either under the provisions of the FDCA pertaining to INDs or, for research protocols not under an IND, under 21 CFR 1301.42, which requires DEA to forward applications for registration for research with Schedule I substances to FDA. In making its

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170 DEVELOPMENT OF MEDICATIONS determination as to the merits of the study under the latter provision, FDA must consult with DEA as to the adequacy of procedures to be taken to prevent inappropriate diversion (21 CFR 1301.42~. When art investigator warts to increase the amount of a Schedule I controlled substance that it has received approval to use, the sponsor first must submit a request to DEA, DEA then forwards the request to FDA, which may grant or deny the request, taking into account DEA's comments [21 CFR 1301.33(c)~. The practical consequence of this dual authority over clinical research, particularly in the light of the additional complication of multiple state laws patterned after the CSA (Chapter 8), is a clinical research environment for scheduled drugs that is extraordinarily bureaucratic Tom the procedural point of view arid unnecessarily difficult. That is especially true given the relatively small amounts of any controlled substance used in research; thus the consequences of diversion to public health would be small even if the diversion from research was substantial. The administrative effort required to cope with this complex system is discussed in Chapter 3. The difficulty of conducting clinical research is also cited in the private sector as an important deterrent to R&D investment (Chapter 9~. Even if the new drug under study is not scheduled, the comparative agent in positively controlled studies of the drug (which might well be the pivotal studies for FDA approval) could be a controlled substance like methadone; this would trigger the complex dual system of regulation. Finally, studies to optimize the dose or dose schedule of a new drug and to extend the use to new patient populations, such as pregnant women and adolescents, are typically done after marketing, which means after the drug is scheduled. All studies of this type are vastly more difficult on scheduled drugs and therefore, as a practical matter, tend not to be done. The committee recommends that action be taken to remove the adverse effects of DEA requirements, under the Controlled Substances Act (CSA), on clinical research investigations involving controlled substances, by holders of active FDA INDs, either by amending the CSA to exempt such investigations from applicable DEA regulations or by the alternative administrative and regulatory measures: . The development of a Memorandum of Understanding between FDA and DEA governing the matter of dual authority over clinical research to provide exemption from DEA reporting requirements. . DEA revision of 21 CFR 1301.33 and parallel regulations to provide that protocols, drug security, recordkeeping, production controls, reporting, and other requirements would be governed by

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FEDERAL LAWS AND REGULATIONS the Fl)A regulations and monitored by FDA. This would require parallel changes in FDA's IND regulations. 171 FDA's current provisions for control and recording the disposition of controlled substances under an IND should be adequate to address concerns of drug security and diversion. CONCLUSIONS Lee committee concludes that the complexities faced in the normal process of drug discovery and development are made even more daunting arid costly by the multitude of regulations arid clinical research constraints imposed by FDA and DEA in the development of anti-addiction medications. Thus, the committee has offered recommendations with the intent of easing the regulatory disincentiv- es to the pharmaceutical industry and expediting the availability of new phannacotherapies for heroin and cocaine addicts. REFERENCES Agersborg HPK. 1993. Characteristics of Development Candidates and Overview of Development Process. Presentation at the Pharmaceutical Manufacturers Association Basic Course on Drug Development. May 23-26, 1993, San Francisco. DEA (Drug Enforcement Administration). 1993. Schedules of controlled substances: transfer of levo-alpha-acetyl-methadol from Schedule I to Schedule II. August 18, 1993. Federal Register 58~158~:43795. DiMasi JA, Hansen RW, Grabowski HO, Lasagna L. 1991. Cost of innovation in the pharmaceutical industry. Journal of Health Economics 10: 107- 142. FDA (Food and Drug Administration). 1985. Memorandum of Understanding with National Institute on Drug Abuse. May 1, 1985. FDA (Food and Drug Administration). 1988. Patent Term Restoration regulations. March 7, 1988. Federal Register 53~44~:7298-7309. FDA (Food and Drug Administration). 1990. Draft Guidelines for Abuse Liability Assessment. July 20, 1990. Drug Abuse Advisory Committee. FDA (Food and Drug Administration). 1992a. New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval. Proposed Rule. April 15, 1992. Federal Register 57:13234. FDA (Food and Drug Administration). 1992b. New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval. Final Rule. December 11, 1992. 57 Federal Register 57:58942. FDA (Food and Drug Administration). 1992c. Drug Abuse Advisory Committee Transcript of Meeting No. 24, 9-30. December 10, 1992. FDA (Food and Drug Administration). 1992d. Summary Basis for Approval for LAAM, ADA #20-315, Medical Officer Review of LAAM Usage Study.

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172 DEVELOPAlENT OF MEDICATIONS FDA (Food and Drug Administration). 1993a. Approved Drug Products with Therapeutic Equivalent Evaluations, 13th ed. Section 3.6, Orphan Drug Product Designations. Washington, DC: U.S. Government Printing Office. FDA (Food and Drug Administration). 1993b. Levo-alpha-acetyl-methanol (LAAM) in maintenance: revision of conditions for use in the treatment of narcotic addiction. July 20, 1993. Federal Register 58: 3870~38711. FDA (Food and Drug Administration). 1993c. Treatment Investigational New Drugs Allowed to Proceed (June 22, 1987-Nov. 5, 1993~. FDA (Food and Drug Administration). 1994. Cumulative List of Orphan Product Designations and Approval. December 31, 1994. FDA Office of Orphan Products Development. Grabowski HG' Vernon JM.1990. Unpublished appendix to: A New Look at the Returns and Risks to Pharmaceutical R&D. Durham, NC: Duke University Department of Economics. As cited in: Office of Technology Assessment(OTA). 1993. Pharmaceu- tical R & D: Costs, Risks and Rewards. Washington, DC: Government Printing Office. OTA-H-522. Kaitin KI, Bryant NR, Lasagna L. 1993. The role of the research-based pharmaceutical industry in medical progress in the United States. Journal of Clinical Pharmacology 33:412~17. Knoop SJ, Worden DE. 1988. The pharmaceutical drug development process: an overview. Drug Information Journal 22:259-268. NIDA (National Institute on Drug Abuse). 1990. NIDA's Medications Development Program. NIDA Notes Summer:31. OTA (Office of Technology Assessment).1993. Pharmaceutical R & D: Costs, Risks and Rewards. Washington, DC: Government Printing Office. OTA-H-522. PMA (Pharmaceutical Manufacturers Association).1993a. Drug Discovery. Industry Issue Brief 26. Washington, DC: PMA. PMA (Pharmaceutical Manufacturers Association). 1993b. Federal-Industry Drug Research Collaboration. Industry Issue Brief 8. Washington, DC: PMA. Rapaka RS, Hawks RL, eds.1993. Medications Development: Drug Discovery, Databases, and Computer-Aided Drug Design. Rockville, MD: NIDA. NIDA Research Monograph 134. Spilker B. 1989. Multinational Drug Companies: Issues in Drug Discovery and Development. New York: Raven Press. Spilker B. Cuatrecasas P. 1990. Inside the Drug Industry. Barcelona: Prous Science. U.S. DHHS (U.S. Department of Health and Human Services, Public Health Service). 1992. Expanded Availability of Investigation New Drugs Through a Parallel Track Mechanism for People with AIDS and Other HIV-Related Disease. Parallel Track Policy Statement. April 15, 1992. Federal Register 57:13250. Wesson DR, Ling W. 1991. Medications in the treatment of addictive disease. Journal of Psychoactive Drugs 23:365-369. Wiggins SN. 1987. The Cost of Developing a New Drug. Washington, DC: Pharmaceuti- cal Manufacturers Association.