The National Institute on Drug Abuse (NIDA) has the lead governmental role in developing New Chemical Entities (NCEs) into chemotherapeutic agents for the treatment of drug abuse. The Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) and its sister agency the National Institutes of Health (NIH) jointly share the difficult task of developing agents of little commercial value that are termed orphan drugs. NIDA has identified several substances as being both safe and efficacious in the treatment of opioid abuse. We focus on the process involved in transforming an NCE, EN-1639A (naltrexone), into a chemotherapeutic agent with a New Drug Application (NDA) approved by the Food and Drug Administration (FDA). In addition, specific data that were collected during delays in this process are presented, and the use of this data base to facilitate the NDA process is discussed.

 

In order to place these clinical data on naltrexone in a proper perspective, it is necessary to present (1) an overview of the FDA process, (2) an historical perspective of narcotic antagonists, and (3) a discussion of factors contributing to the delay of the scheduled Phase III studies, and the resultant implication.

 

THE FOOD AND DRUG ADMINISTRATION

The FDA is mandated to review preclinical and clinical material developed on new chemical entities to determine whether or not they will be safe and efficacious agents in the treatment of recognized medical conditions. A comprehensive set of preclinical and clinical guidelines has been developed and implemented as a result of experiences with other chemotherapeutic agents, including the ill-fated thalidomide experience.

 

There are four types of preclinical studies which must be conducted. One requirement is that these investigations must include data derived from at least two different animal species. Furthermore, it is required that control and experimental groups of sufficient size be used to permit statistical evaluation of the results. Four categories of preclinical investigations include:

 

1. Short term toxicity studies to determine LD-50s, effects on food and water intake, gross behavior, mortality, and other relevant information.

2. Two-year carcinogenicity studies with observations of gross behavior, and gross and microscopic tissue examinations.

3. Two-year chronic toxicity studies with metabolic; enzymatic, growth, and development examinations.

4. Reproduction and teratology studies:

(a) Study of fertility and general reproductive performance—Emphasis is on the effects of a given drug on gonadal function, estrous cycles, mating behavior, conception rates, and the early stages of gestation.

(b) Teratological study—Emphasis is on determining whether a drug has a potential for embryotoxicity and/or teratogenicity;drug administration is restricted to the period of organogenesis.

(c) Perinatal and postnatal study—Emphasis is on the effects of a drug administered during the last trimester of pregnancy and the period of lactation.

 

There are three clinical phases in the development of an NDA. These are:

 

Phase I: Pharmacology studies are used to determine toxicity, metabolism, absorption, and elimination, and other pharmacological actions; preferred route of administration, and safe dosage range are also studied. These studies involve a small number of persons and are conducted under carefully controlled circumstances by persons trained in clinical pharmacology. Approximately 20 to 80 healthy, male volunteer subjects participate in this phase which lasts approximately 9-12 months.

 

Phase II: Initial clinical trials are conducted on a limited number of patients to evaluate the agent and its effectiveness in the prevention or treatment of a specific disease. Additional pharmacological studies performed concurrently on animals may be necessary to further evaluate safety. The closely monitored human clinical trials designed to demonstrate efficacy and relative safety generally involve between 100 and 200 patients. This phase takes approximately two years to complete.

 

Phase III: Proposals for this phase involving extensive clinical trials are in order if the information obtained in the first two phases demonstrates reasonable assurance of safety and effectiveness, or suggests that the drug may have a potential value outweighing possible hazards. The Phase III studies are intended to assess the drug's safety, effectiveness, and most desirable dosage in treating a specific disease in a large group of subjects. These studies may vary considerably with respect to extent but are in any case carefully monitored. They usually do not exceed three years in total length.

 

The FDA is regularly provided with updated reports on the progress of each phase. If the continuation of the studies appears to present an unwarranted hazard to the patients/subjects, the sponsor may be requested to modify or discontinue clinical testing until further preclinical work has been done (Tocus, 1976).

 

HISTORICAL PERSPECTIVE ON NARCOTIC ANTAGONISTS

 

Wikler's work with narcotic antagonists during the 1960s (Wilder, 1965) was further pursued by Martin et al (1967) at NIDA's Addiction Research Center,'Lexington, Kentucky. It was demonstrated that narcotic antagonists could be effectively used to block the euphoria and dependence producing properties of opioids. Most significantly, these chemotherapeutic agents did not have pronounced behavioral effects as was the case with methadone, did not produce either physical or psychological dependence, and thus could be characterized as having no abuse liability.

 

The current theories of blockade of opioids by the narcotic antagonists are based on the physical mechanism of competitive inhibition. Antagonists occupy the same receptor sites as agonists but have little or no intrinsic activity at those sites. The optimal characteristics of narcotic antagonists should include the following properties (Julius, 1976):

 

1. Ability to antagonize the euphoria produced by the opioids;

2. Absent or low agonist effects, especially unpleasant effects;

3. Do not cause physical dependence;

4. Tolerance to the antagonistic actions does not develop;

5. Absence of serious side effects and toxicity with acute and chronic use;

6. Easily administered, preferably by the oral route;

7. Duration of action sufficient to require daily or less frequent administration;

8. Absent (or low) abuse potential;

9. Reversible effects, in case of medical emergency;

10. High potency to allow administration of small amounts in a biodegradable vehicle;

11. Easily available and relatively inexpensive;

12. High level of patient acceptance.

 

In the search for a chemical entity possessing these characteristics, narcotic antagonists, including naloxone (Blumberg et al, 1961), nalorphine (Eckenhoff et al, 1952), cyclazocine (Jaffe, 1967), and naltrexone (Julius and Renault, 1976) have been evaluated for potential clinical use. Naloxone was the first narcotic antagonist discovered that was virtually devoid of all agonistic activity (Foldes et al, 1969). It is reported to be a competitive antagonist at the mu, kappa, and sigma receptors. Foldes et al (1963) demonstrated naloxone to be an efficacious chemotherapeutic agent in man. Jasinski et al (1967) determined that when naloxone was administered chronically, and in large dosages, it did not produce physical dependence, further demonstrating its lack of agonist effects. Naloxone has limited clinical use as a less than chronic narcotic antagonist because of its relatively short half-life and the necessity for parenteral administration (Zaks et al, 1971). Naloxone, however, has become a standard pharmacologic agent for use to reverse the respiratory depression frequently associated with opioid overdose. Virtually all agonist effects induced by any opioid can be reversed by naloxone. Its ability to induce an immediate withdrawal syndrome makes naloxone particularly useful in the diagnosis of opioid dependence (Judson et al, 1980).

 

Cyclazocine (Resnick et al, 1970) was reported to be a promising longer acting antagonist. The duration of action of a 4 mg dose was reported to be as long as 24 hours. However, dysphoria and psychotomimetic effects were unacceptable concommitant reactions (Resnick et al, 1971). Although the development of tolerance to these side effects was clinically documented, cyclazocine was not well received by the volunteer addicts and subsequent clinical populations who were offered this chemotherapeutic agent.

 

Blumberg and Dayton (1973) reported that EN-1639A seemed to be a potent antagonist that did not produce either the dysphoria or other unpleasant side effects of cyclazocine. The reported duration of narcotic blockade following oral administration of 50 mg was 24 hours. Martin (Martin and Jasinski, 1973; Martin et al, 1973) and Resnick et al (1974a,b,c) suggested that naltrexone (EN-1639A), fulfilled the criteria of an optimal narcotic antagonist. In 1973, the NIDA initiated and funded a series of preclinical and clinical research studies to further elucidate the safety and efficacy of naltrexone. The preclinical studies were designed to meet the FDA requirements for the eventual approval of an NDA permitting clinical researchers to dispense naltrexone according to a reviewed and approved protocol. A number of studies were simultaneously undertaken, involving clinical researchers in more than a dozen clinics; however, not all researchers used the same protocol. Five clinics did participate in a double blind placebo controlled study of naltrexone conducted by the National Academy of Sciences (Committee on the Clinical Evaluation of Narcotic Antagonists, unpublished observations). Controlled and uncontrolled clinical trials were undertaken by Brahen et al (1976), Lewis (1975), O'Brien et al (1975), and others (Schecter, 1975; Taintor et al, 1975). Almost all investigators used a total weekly dose of 350 mg, liquid, on a three times weekly basis (100 mg Mondays, 100 mg Wednesdays, 150 mg Fridays) except Brahen who administers naltrexone twice weekly (150 mg Mondays, 200 mg Thursdays).

 

Some researchers terminated their use of naltrexone after the funding ceased. However, a number of researchers, including Brahen, Czertko, O'Brien, Resnick, and others continued to administer naltrexone to clients following the protocols developed for the Phase II study despite the lack of supplemental Federal research funds. Brahen (Nassau County Department of Drug and Alcohol Addiction Program) has, at this point, administered naltrexone to over 550 clients in a program with a voluntary Antagonist Treatment Unit and a prison Work-Release Unit.

 

THE DELAY, ITS CAUSES, AND ITS IMPLICATIONS

 

During the initial review of the early progress reports from the naltrexone carcinogenicity studies, some of the preliminary data suggested that naltrexone might have the potential of being carcinogenic. This occurred immediately prior to the commencement of the Phase III clinical studies. At this point, NIDA ordered that Phase III not commence until the animal studies were completed and the animal tissues reviewed by independent pathologists. Existing clients were permitted to continue on naltrexone, and new clients were permitted to be inducted and maintained on naltrexone. In both cases, clients were given an informed consent form which clearly stated that naltrexone might have the potential of being a carcinogen, but stated that the client had to consider the clinical benefits from the substance, and weigh them against the risks. It should be noted that the Drug Abuse Reporting Program (DARP) had established the death rate of clients continuing to use heroin or other opioids at approximately 1.5 percent per year (Watterson et al, 1974). This death rate, and it is assumed, comparably high morbidity rate, is at least ten times greater than the anticipated age specific rates.

 

The large scale clinical trials were to have been initiated two years ago. However, understandably, ENDO Laboratories, Inc., the pharmaceutical firm developing naltrexone, and the Government, were unwilling to continue extensive human testing until resolution of the carcinogenicity issue occurred. The final carcinogenicity reports were reviewed by outside independent consultants in September 1980 (Braude, 1980). Several independent review groups studied the findings and issued a statement which in essence indicated that, based on the Mason Research Institute (MRI) data, there was no evidence to conclude that naltrexone was a carcinogenic agent in the species of animals tested.

ENDO and the government were now in the position to initiate the Phase III studies. The decision on how to proceed was not as simple as it might have appeared. The contract to conduct the Phase III studies was in place, and the contractor was ready and eager to commence data collection. At this point, it was recognized that a number of researchers and clinicians had continued to collect data on clients maintained on naltrexone, and that the format of the data was the same as had been used in the earlier Phase II clinical studies and would be used in Phase III studies. Therefore, an initial exploration of these data was made to determine whether they were sufficient to provide the basis for an approvable NDA, thus obviating the necessity for carrying out the complete Phase III studies as initially conceived. The data that are presented below are based on the client records of the Nassau County Outpatient Drug Abuse Treatment Programs (Table 1). Over 550 clients were inducted on naltrexone without serious adverse sequelae. Almost all of the adverse drug reactions reported are related to gastrointestinal upset. It appears that these reactions are the result of a precipitated withdrawal in clients who have not been opiate-free for an adequate length of time. A tablet preparation will be available by late summer 1981; thus, the other subjective complaint, the bitter taste of the liquid preparation, hopefully will be obviated. The only other single adverse drug reaction was the development of a non-lifethreatening rash. There was equivocal evidence that the client in question had been concurrently taking unknown substances in addition to the naltrexone.

 

THE DATA

 

This data base represents clients that remained in treatment more than six consecutive weeks in either the voluntary Naltrexone Treatment Unit of the Nassau County Drug Abuse Treatment Program or the Work Release Treatment Unit of the Nassau County Jail. Six weeks was arbitrarily selected as the minimum time necessary for a patient to be considered to be engaged in treatment. During the period 1976 to April 1981, approximately 550 clients were inducted on naltrexone in both of these treatment units.

 

At least 287 clients have been identified as being on naltrexone for a minimum of one six week period, 16 percent had multiple treatment episode's (4.5 percent of all clients or 30 percent of those having a second treatment episode returned for a third). Approximately 200 of the clients in treatment for the minimum six week period have evidence in their records of at least two complete physical examinations and laboratory studies (at admission, and at termination from treatment), meeting the FDA reporting criteria to be considered a "case" in an NDA submission.

 

One hundred seventy two clients in this sample were from the work release program, 100 from the voluntary outpatient treatment program; an additional 14 clients were initially in the work release program and when they completed that program voluntarily transferred to the outpatient program; one client commenced naltrexone as a voluntary outpatient and continued it as a client of the work release program.

 

The client population was predominately male (93.4 percent), the mean age was 28 years. In the voluntary program, 79 percent of the clients were white, 20 percent Black and 1 percent Hispanic. In the work release program, 35.5 percent were White, 61 percent Black and 3.5 percent Hispanic.

 

Thirty-five percent of the voluntary naltrexone treatment unit clients and 37 percent of work release clients did not have a history of prior drug abuse treatment. In almost all cases heroin or another opioid was considered the primary drug of abuse at admission to treatment. Unlike clients entering drug free treatment programs for nonopioid related problems, these clients do not deny their drug related problems. What is worthy of note, in the work release program, is that 74 percent of these clients stated that they did not have a drug related problem in the month prior to entrance into the treatment program; all the clients were incarcerated during this period of time. Seventeen percent of the voluntary clients also stated that in the month before treatment their drug use was not a problem; a large proportion of these clients were also either incarcerated or under strict legal supervision during this period. It is, therefore, important to qualify answers which are related to access to drugs, and access to the community.

 

The results of the urine screening program were most provocative. Sixteen percent of the voluntary clients never had a positive urine for opioids, quinine, barbiturates, cocaine, or amphetamines, and half of all urines that were drug positive were so for only one substance. This does not appear to be a population of multiple substance abusers. Alcohol and marijuana are not considered in this discussion as these substances are relatively ubiquitous in similar age-specific populations not in treatment programs for opiate use.

 

The results of the urine testing program in the work release program were impressive. Slightly more than 40 percent (42.4 percent) never had a drug positive urine. More than half of the positive urines were for quinine alone. Morphine accounted for less than 10 percent of the positive urines. Whether the incidence of urines positive for quinine reflects heavy gin and tonic consumption, or the use of illicit heroin of poor quality heavily adulterated with quinine, is speculative.

 

Induction procedures are designed to stabilize clients on a maintenance dose of a chemotherapeutic agent while minimizing the possibility of adverse reactions. These procedures varied markedly between the work release and voluntary outpatient program. Immediate induction to 150 mg of naltrexone was the procedure of choice for the work release program (61 percent), with one week of 50 mg daily dose induction being used half as frequently (32 percent). Both clinics used a twice rather than a three times weekly standard regimen, with 150 mg being administered on Mondays and 200 mg being administered on Thursdays. In the voluntary program, 86 percent were inducted by the one day graduated procedure. Ten mg were given, and if no evidence of withdrawal was seen, additional amounts were given over several hours until a total of 150 mg was administered. Naloxone challenges infrequently were administered. The mean duration of treatment in the work release program was 11 weeks, and in the voluntary program 12 weeks. Ninety-seven percent of the work release clients did not have any lapses of naltrexone intake during their treatment experience; 52 percent of the voluntary clients did (of these 2/3, or 35 percent of the total number of voluntary clients, had only a single lapse). A lapse is defined as missing two consecutive doses of naltrexone, or one week of treatment. A client was considered to have dropped out of treatment after he or she missed eight successive doses of naltrexone, four weeks of treatment. Seven work release clients and 28 voluntary clients had two separate treatment experiences with naltrexone, and eleven voluntary clients (eleven of the 28) had three separate treatment experiences. It is noteworthy that in the voluntary program 15 percent of the clients remained in treatment more than 28 weeks, and that some who have terminated naltrexone continue to be "drug free" and attend the clinic for counseling.

 

It appears that both the work release clients and the clients in the voluntary program are appropriate candidates for naltrexone treatment. They appear to have had significant involvement with the criminal justice system and most of the clients have had prior treatment experiences. They appear to tolerate the naltrexone with a minimum of adverse side effects. Only four minor adverse reactions were reported in more than 50 patient-years experience provided by almost three hundred clients.

 

This single data base, fortuitously collected during administrative delays in the development of the NDA for naltrexone could be used as the basis for a limited NDA. These data and the data from other researchers should be sufficient to demonstrate to the FDA that naltrexone is a safe and efficacious drug for at least six weeks of treatment in males with a history of heroin or opioid abuse. Additional research, in the standard Phase III format, will be necessary to provide sufficient short-term data on women and long-term data on both men and women before anticipated unrestricted approval of the NDA by FDA will occur. These necessary studies will commence this year.

 

It is anticipated that when the FDA grants the limited NDA for naltrexone it will provide the clinician with the discretion of continuing clients on naltrexone for additional six week cycles. If this is not the case, then clinicians will need INDs to provide continuous naltrexone treatment for greater than the approved six week time period.

 

SUMMARY

 

This paper has attempted to outline the preclinical and clinical studies necessary to obtain approval of an NDA from the FDA. The particular substance discussed in this paper, EN-1639A, or naltrexone, has been determined to be both efficacious and safe as a chemotherapeutic agent in the treatment of clients with a history of heroin or opioid use and wishing to control their drug seeking behavior. However, because of a number of issues unrelated to the clinical studies, the NDA has been delayed for several years. Clinicians, believing in this drug, have continued to treat clients with it, under their own INDs. The data from one clinic were presented in this paper to indicate the magnitude of available data which may become part of an NDA. These data appear to be sufficient to justify an NDA for limited use (up to six weeks) in males until such time as additional data can be compiled on long term administration in both men and women.

 

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