Naltrexone is a pure opioid antagonist originally marketed by DuPont as Trexan for the treatment of opioid dependence, and later as ReVia for the treatment of alcohol dependence. Naltrexone binds competitively to opioid receptors in the brain, and thus blocks the physiologically reinforcing euphoric effect of exogenous opioids like heroin. Naltrexone also plays a role in blocking the endogenous opioids associated with alcohol consumption, thereby blocking the euphoric effects of alcohol. Naltrexone works to help addicts control their craving for either heroin or alcohol by eliminating the euphoric effects. Naltrexone is typically distributed through treatment centers as part of comprehensive treatment programs for the treatment of opioid and alcohol dependence.
Estimates of the number of opioid addicts (primarily heroin) in the U.S. range from 500,000 to 1,000,000 (IOM 1990, Abt Associates 1995, Hammil and Cooley 1990). These estimates have remained fairly stable since the 1970s. In contrast, 15.3 million people in the U.S. are afflicted by alcohol abuse and dependence (Pink Sheet 1995, Scrip 1993). There were approximately 650,000 patients in alcohol treatment centers in 1992 (NDATUS 1993).
Key Issues from the Case Study
Naltrexone provides two related yet distinct pharmaceutical R&D and marketing lessons. Naltrexone's development encompasses over 30 years and reveals a wide range of government involvement in the drug development process, from conducting and funding clinical trials to creating novel regulatory approval incentives. For example, the impetus and vast majority of funding for clinical development came from the federal government through the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Interviewees emphasized that the development of naltrexone required a true public-private collaboration between the federal government and DuPont, the company that owned the rights to naltrexone. However, the story of naltrexone also reveals that despite significant government efforts and a willingness of DuPont to pursue naltrexone's development, a number of market barriers have prevented naltrexone from becoming successful. To date, sales of naltrexone for both the heroin treatment indication and the alcohol treatment indication have fallen far short of DuPont's original, modest expectations. In both cases, federal government support of naltrexone's clinical development was necessary but not sufficient to overcome some of the key market barriers.
A major market barrier with naltrexone is low patient compliance. There are several reasons patient compliance on naltrexone therapy is low, and there are several consequences. There is a large barrier to the initiation of naltrexone therapy because patients must be completely opioid free. Many addicts return to heroin use before detoxification because they are not able to cope with the physiological withdrawal effects of complete detoxification. State-level treatment centers for heroin addicts have not been able to afford the more intensive psychosocial support systems necessary to ensure patient compliance to Trexan. In addition, according to our interviewees, directors of federally funded clinics are often non-clinicians who do not understand how a non-addictive alternative to methadone can be effective for heroin treatment despite evidence from clinical trials which demonstrated that naltrexone was highly effective if taken. Low patient compliance also limited the marketing of naltrexone, as ReVia, to comprehensive alcohol treatment centers.
The following sections provide a more comprehensive overview of the research, development, and marketing experiences of naltrexone.
Product History and Development Timeline
Executive and legislative mandates of the 1970s provided the impetus for the development of naltrexone as a narcotic antagonist to treat the rapidly rising number of heroin addicts, both in the U.S. and in U.S. military personnel abroad. The timeline for the development of Trexan is presented in Figure 26 (below). The timeline for ReVia continues in Figure 27 (below). In June 1971, President Nixon created the Special Action Office for Drug Abuse Prevention (SAODAP), which consolidated all federal agencies that had resources devoted to drug abuse and addiction research. The SAODAP was first directed by Dr. Jerome Jaffe. By September, 1971, the Division of Narcotic Addiction and Drug Abuse (DNADA) of the National Institute of Mental Health (NIMH), in conjunction with SAODAP, had initiated a research plan to expedite the development of a narcotic antagonist, that could be used as a non-addicting pharmacotherapy for the treatment of opioid addiction. In March 1972, Congress passed the Drug Abuse Office and Treatment Act, with a particular interest in developing "long-lasting, non-addictive, blocking and antagonist drugs or other pharmacological substances for the treatment of heroin addiction." This Act provided financial support for research in this area. In 1973, DNDA separated from NIMH and became the National Institute on Drug Abuse (NIDA) (Julius 1976).
Figure 26: Timeline for the Development of Naltrexone as Trexan
Source: The Lewin Group
SAODAP and DNADA selected naltrexone for further development because, of the other drugs in early development at the time, naltrexone came the closest to meeting their 12 criteria for an ideal narcotic antagonist:
- ability to antagonize the euphoric high of opiates
- absent or low-agonistic effects, especially unpleasant ones
- does not cause physical dependence
- does not exhibit increasing tolerance to its antagonistic actions
- absence of serious side effects and toxicity even in chronic use
- easily administered, i.e., no surgery or painful procedure involved
- long-lasting or moderate duration of antagonist effects
- absent or low abuse potential
- reversible effects in case of medical emergency
- high potency to allow administration of small amounts in a biodegradable vehicle
- easily available and inexpensive
- therapeutic efficacy in treatment of narcotic addiction (Julius 1976).
SAODAP rejected several drugs in favor of naltrexone. For example, SAODAP rejected naloxone because of its high cost, difficult synthesis, poor oral absorption rate, and short duration of action (Julius 1976). It rejected cyclazocine because of its potential for strong agonist properties as well as other drugs that were considered to be too early in development.
Naltrexone was originally synthesized in 1963 and patented in 1967 as Endo 1639A (U.S. patent number 3332950) by Endo Laboratories, a small pharmaceutical company in Long Island, New York. Endo was a manufacturer of pain relief medications and had conducted substantial research on narcotic agents. Naltrexone was a cyclopropylmethyl analog of naloxone (used as an antidote for acute opiate overdose). In 1969, DuPont purchased Endo Laboratories to acquire a company with pharmaceutical marketing experience to help sell DuPont's Symmetrel, an antiviral compound. With the purchase of Endo, DuPont acquired the rights to several successful drugs, including: Coumadin (warfarin), an anticoagulant; Percodan, a prescription narcotic; Nubain, a combination agonist/antagonist analgesic; and Naloxone, for narcotic overdose. DuPont acquired the rights to naltrexone, still in the early development phase, as part of the overall purchase of Endo.
In 1972, SOADAP approached DuPont for permission to develop naltrexone for clinical use. At the time, it seemed unlikely that DuPont would develop naltrexone. First, DuPont thought naltrexone would have relatively low market potential. Second, the patent for naltrexone would most likely have expired before clinical development would have been completed. Third, thebaine, a chemical precursor to naltrexone, would have to be purchased from Mallinkrodt, the pharmaceutical company that isolated thebaine.
Ultimately, NIDA asked for DuPont's assistance in facilitating naltrexone's transit through the FDA regulatory process - in particular to identify the required clinical trials and to file the NDA. DuPont interviewees reported that a primary reason for helping the government to bring naltrexone to the market was the company's "public spirited" mission. DuPont agreed to assist NIDA with the development of naltrexone, particularly with filing the NDA, regardless of the economic returns. In return, NIDA agreed to pay for the bulk of clinical development costs.
The clinical trials for naltrexone as a treatment for heroin addiction began in 1973 (Schecter 1974, O'Brien 1978). The NDA for heroin treatment was approved in 1984, the same year the U.S. patent expired. On March 11, 1985, naltrexone was designated an orphan drug which provided 7 years of post-approval market exclusivity.
The impetus for the funding of clinical research to gain an alcohol indication for naltrexone also came from the federal government. Researchers at VA hospitals who had been using Trexan to treat heroin addicts noticed that treatment with Trexan reduced both heroin and alcohol use (O'Brien 1996, Volpicelli 1995, and O'Malley 1995).
Figure 27: Timeline for the Development of Naltrexone as ReVia
Source: The Lewin Group
The funding for the development of the alcohol indication for naltrexone was provided by the NIAAA. The SNDA for the alcohol treatment indication was approved in 1994, providing 3 additional years of market exclusivity for the alcohol indication (Pink Sheet 1994).
Clinical Development and Product Positioning Issues
A large amount of preclinical research on opioid receptors and narcotic antagonists had been underway prior to the development of naltrexone (Crabtree 1984), but naltrexone was the first narcotic antagonist to be clinically tested and developed for the treatment of heroin addiction (Schecter 1980).
Clinical Trial Results
The clinical trials showed a modest success in the reduction of heroin use. Factors that made treatment successful included: sustained therapy with naltrexone, participation in multidisciplinary programs, and good family and social support (Crabtree 1984). The early clinical trial results showed that compared with the methadone maintenance patients, those patients who were attracted to naltrexone therapy were relatively "more motivated and emotionally stable" (Schecter 1974). In 1974, Schecter and colleagues found that naltrexone successfully blocked the pharmacologic effects of heroin (Schecter 1974). Clinical trials by Martin et al. (1973) and Resnick et al. (1974) and the National Research Council Committee on Clinical Evaluation of Narcotic Antagonists (1978) showed that although naltrexone was an effective opiate blockade, clinical success, i.e., a reduction in heroin use, was limited to fully compliant patients. Similar results were found in clinical trials for alcoholism (O'Brien 1996). As a result of these findings and others, the labeling for naltrexone reads, "[Naltrexone], unlike methadone or LAAM (levo-alpha-acetylmethadol), does not reinforce medication compliance and is expected to have a therapeutic effect only when given under external conditions that support continued use of the medication" (naltrexone package insert).
Clinical Trials Obstacles
One unanticipated obstacle during the clinical development of naltrexone was the difficulty in patient accrual and compliance for the clinical trials, which resulted in much higher costs than initially anticipated. Dr. Arnold J. Schecter, who conducted many of the early safety and efficacy studies for naltrexone in the treatment of opioid addiction at the State University of New York, reported that patient recruitment was difficult because some patients feared a new drug, lacked a desire to become drug free, were unwilling to possibly receive a placebo, and disliked the rigid protocols associated with the clinical trials (Schecter 1980). In addition, patients had to remain opiate free for a minimum of 5 to 10 days prior to treatment because naltrexone would cause severe withdrawal symptoms in patients with opioids in their system (Schecter 1974). Many addicts were unable to remain opioid-free for the required amount of time because of the physiological withdrawal effects. Finally, unlike methadone treatment which helps to suppress craving, naltrexone had no effect until the addict attempted to use heroin. Some patients feared that when on naltrexone they would be more vulnerable to these heroin cravings and felt that methadone was more effective in controlling their cravings.
Many researchers also encountered suspicion in the community regarding treatment of patients with a new experimental drug. The methadone maintenance clinics were especially reluctant to refer patients for naltrexone therapy, partially because of their need to keep their own censuses high enough to receive funding (Schecter 1980). As a result of these difficulties recruiting patients, the naltrexone clinical researchers made no efforts to screen out patients who can be difficult to manage in clinical trials, e.g., patients who were poorly compliant, and this may have compromised the results of the clinical trials (Schecter 1980).
The methadone maintenance clinics felt that naltrexone therapy was less effective and more costly than methadone for two primary reasons. One reason was that heroin addicts would have to be completely opioid free prior to starting naltrexone therapy. This meant that, unlike methadone maintenance, heroin addicts undergoing naltrexone treatment would experience all of the physiological symptoms of opioid withdrawal creating a huge hurdle for initial compliance to therapy. Second, naltrexone therapy required more extensive psychosocial support services than methadone treatment, primarily because naltrexone was non-addictive and lacked the reinforcing effect of methadone. Schecter and colleagues (1974) estimated that total clinical treatment with naltrexone was almost twice as expensive as methadone treatment (an increase from methadone's annual per patient cost of $1200 - $1700 to a cost of $3500 per year) because of this need for more intensive psychosocial services. Naltrexone supporters argued that naltrexone therapy would be substantially more economical when compared with inpatient beds, jail facilities or other therapeutic communities (Schecter 1974). In addition to the difficulties of patient compliance, Dr. Schecter noted that the lack of adequate funding of the antagonist clinics, well below funding of methadone clinics, was another factor in the limited success of the early clinical trials (Schecter 1980).
Naltrexone had a few additional clinical side-effects or problems that concerned many treatment providers. First, naltrexone did not prevent addicts from using other drugs to experience a euphoric effect. Second, there was a danger of opioid overdose in those patients who tried to overcome the naltrexone blockade. Third, patients on naltrexone would have to use pain medications that did not rely on opiate action, and patients were encouraged to carry a card that indicated they were on naltrexone in the event of an emergency. Finally, some practitioners feared an increased chance of depression, although this was not clinically verified (Schecter 1980). These problems compounded the problem of low patient compliance and created significant barriers to the clinical acceptance of Trexan.
The clinical trials for alcohol treatment encountered similar problems with low patient compliance. Naltrexone did not perform significantly better than a placebo unless it was administered as part of a comprehensive, multidisciplinary treatment program (O'Malley 1995). As a result the labeling for ReVia included the following stipulation, "ReVia should be considered as only one of many factors determining the success of treatment of alcoholism." This labeling indication had a profound effect on product marketing strategy and sales by limiting marketing to comprehensive alcohol treatment programs.
Naltrexone researchers for both opioid and alcohol indications faced many barriers during the course of their research including difficulties with patient recruitment, patient compliance, the high cost of clinical support services, and the traditionally low funding of treatment centers. While the government funded and supported the clinical trials, the funding fell short of the amount necessary to provide the more intensive psychosocial support. Researchers also faced difficulties recruiting patients, which meant that all patients who agreed to participate in the clinical trials were accepted into the treatment program. The researchers did not "reject" any patients from the clinical trials. This may have negatively affected the results of the clinical trials by including a high proportion of high-risk patients, who may have been motivated more by payments for participating in the trial than addiction treatment which lead to poorer compliance and higher drop-out rates (Schecter 1980). These barriers had a significant impact on DuPont's marketing efforts after Trexan and ReVia were approved.
Product Marketing Strategy and Sales
DuPont did not expect Trexan or ReVia to become major revenue generators. Just prior to the launch of ReVia, Trexan sales were approximately $5-8 million annually, which represented approximately 15-25,000 patients per year, or less than 5% of the estimated number of heroin addicts (Scrip 1993). Trexan was marketed only through comprehensive treatment centers at a price of $3.80 per patient day (Scrip 1993). When Trexan's name was changed to ReVia and the alcohol treatment indication was added, DuPont expected U.S. sales of ReVia to rise to $15-25 million annually, which represented approximately 45-80,000 patients per year, or 1% of alcohol addicts and opioid addicts in the U.S. (Scrip 1993). For the treatment of alcoholism, the recommended dosage of ReVia is one 50mg tablet per day for up to 12 weeks. When it came on the market in 1995, ReVia was priced the same as Trexan at wholesale prices of $227.58 for 50 tablets at 50mg (Pink Sheet 1995).
As of October, 1996, DuPont Merck reported that sales of ReVia since market entry in January 1995 had been lower than expected. As of October, 1996, DuPont had not yet reached the FDA's threshold of 200,000 prescriptions that would have required them to conduct phase IV clinical trials (Pink Sheet 1996). The primary market barriers of patient compliance and the need for more intensive and expensive psychosocial support than other existing therapies significantly limit market penetration. Trexan has failed to penetrate the highly regulated federal treatment market for opioid addiction, and ReVia has failed to gain coverage under most private insurance plans. For both indications, DuPont sales representatives perceived that they had to manage provider and patient expectations by reminding them that naltrexone was not a "cure" for addiction. DuPont also had to convince providers that it was appropriate to treat a drug addiction with a pharmacotherapy. The marketing of naltrexone remains subject to significant barriers, and DuPont has not been successful in selling ReVia except in limited cases. (For example, the VA hospital system has widely adopted the use of naltrexone in the treatment of alcoholics.) These market barriers remain the most persistent and the most difficult to overcome.
Methadone maintenance clinics for the treatment of heroin addiction are subsidized by the federal government and highly regulated at both the federal and state levels, in part because methadone is a controlled substance. Naltrexone is not a controlled substance and does not fall under the same regulatory umbrella as methadone. However, funding for the treatment of heroin addicts was funneled primarily through methadone maintenance clinics at the state level. Thus DuPont's marketing strategy for Trexan focused on working with the methadone clinics, which were primarily controlled by state health care agencies such as the State of New York Division of Substance Abuse. Representatives from DuPont noted they also marketed to private hospitals or "white collar" treatment areas because patients in private hospitals tended to be more highly motivated and have a stronger support network, and would experience more favorable treatment outcomes.
DuPont's Marketing Strategy
DuPont had an extremely difficult time trying to convince methadone clinic personnel to use naltrexone once it was approved. One barrier was that clinics would have to implement more intensive psychosocial support programs to promote patient compliance. Most facilities could not afford to implement naltrexone therapy due to the combined price of the drug, the drug treatment program, and the additional time for counseling.
DuPont did not launch a targeted marketing campaign to physicians, primarily because non-physician administrators often made the crucial funding and regulatory decisions that affect the care given in the facility. DuPont marketed naltrexone as a non-addictive antagonist blocking therapy that would help rid patients of opioids completely. DuPont also stressed that the patients would have to be motivated to comply with the therapy. The DuPont sales force had a difficult time explaining the antagonistic mechanism of naltrexone and its benefits to a lay audience that was uninformed about the science underlying naltrexone and the drug's mechanism of action. The sales force reported that they were entering a consumer marketplace with inherent misunderstandings and negative perceptions. Pro-methadone treatment providers argued that because methadone was dependence-producing, it was easier to maintain a patient on methadone and thus more likely that treatment would be successful. One former member of the DuPont sales force said these misunderstandings continue to be a great barrier to the use of naltrexone.
After working around or within the methadone treatment camps, DuPont gave up trying to convert proponents of the "methadone philosophy" to the benefits of treatment with antagonists. These two treatment camps were very strongly divided. DuPont found a favorable audience in the private heroin treatment clinics. Specifically, the clinicians in the private clinics reportedly had a better understanding of the clinical benefits of naltrexone therapy. Also, private clinics could more easily afford the additional psychosocial therapy to help maintain patient compliance because some private insurers covered naltrexone treatment.
The publicity and stigma surrounding treatment of substance abuse was another market barrier for DuPont to negotiate. There was a negative public perception of methadone clinics as a "taxpayer-supported program that keeps junkies addicted." As a non-addictive blocking agent, naltrexone was perceived much more favorably than methadone. However, the favorable view of naltrexone raised expectations to the extent that naltrexone was being touted as the "cure of opioid addiction." Clinical trials results showed that naltrexone would not cure the addiction, but naltrexone would enhance the chances of a successful recovery if used as part of a comprehensive treatment process. Favorable expectations raised initially by the press could not be met. DuPont salesmen devoted considerable effort to managing these expectations and explaining the importance of naltrexone therapy in conjunction with a comprehensive treatment program.
Marketing Strategies for ReVia
The alcohol treatment market is very different than the opioid market. At the time ReVia entered the market, there were a few potential competitors with products that all demonstrated poor clinical results. For example, the market for disulfiram (marketed as Antabuse) was limited in its clinical effectiveness because of poor patient compliance. Other treatments that had been tried, including off-label use of antidepressants like fluoxetine, demonstrated poor results in treating alcohol abuse. ReVia was a significant improvement over disulfiram in its safety profile and potential for improved patient compliance and outcomes. In addition, because the treatment system was not as highly regulated as the heroin treatment system, DuPont had more flexibility in marketing directly to the clinics and treatment providers. Despite ReVia's clinical superiority over disulfiram and less restrictive distribution channels than for heroin treatment, DuPont's sales force encountered similar marketing problems.
Clinical trials with alcohol showed similar results to the clinical trials with opioids. In an outpatient setting, ReVia, administered via a prescription to the patient, was not much more effective than a placebo. However, in comprehensive alcohol treatment programs, ReVia was very successful in helping patients reduce their alcohol consumption (O'Malley 1995). Therefore, DuPont marketed naltrexone only through comprehensive inpatient and outpatient alcohol treatment centers, including the VA hospital system where the clinical trials were conducted.
While DuPont could have marketed its product directly to general practitioners, there were many reasons why it did not. DuPont did not want naltrexone to be falsely construed as a "miracle pill" that would "cure alcoholism," because it could not stop all alcoholics from drinking, especially without counseling from comprehensive treatment centers. Additionally, DuPont stressed that even a reduction in alcohol use was a desirable outcome (Behavioral Health Treatment 1996). As with Trexan, there is a strong camp of treatment providers who feel that alcoholism should not be treated by substituting one drug for another and that alcoholics were not cured unless they were abstinent. For these reasons, DuPont wanted to ensure that ReVia was marketed as a complementary, rather than stand-alone, therapy.
Interviewees reported that another barrier to market penetration is that ReVia has been unsuccessful in gaining formulary access with private insurance companies. For example, a chain of California treatment centers using naltrexone as the primary pharmacologic treatment suspended operations after only six months citing managed care companies' lack of desire to cover such treatment (Behavioral Health Treatment 1996). Managed care companies may be reluctant to cover naltrexone treatment because few cost-effectiveness studies on treatment with naltrexone have been done. However, employers are also responsible for limiting substance abuse treatment coverage in their employee's health plans (Buck 1997).
Policy Interaction in Product Development and Distribution
In addition to conducting and funding most of the clinical trials for Trexan and ReVia, the federal government implemented several policies to further promote the development and distribution of naltrexone.
The FDA gave Trexan orphan drug status, granting DuPont seven years of post-approval market exclusivity. When ReVia was approved, the FDA granted DuPont three additional years of market exclusivity for the alcoholism indication. These market exclusivity rulings protected DuPont from generic versions of the medication.
The FDA also added a novel step-wise regulatory incentive for phase IV clinical trials for ReVia. The FDA allowed DuPont to tailor the type of phase IV studies that had to be conducted based on the extent of use of the product, in a four-tiered system based on the number of annual prescriptions. If the number of prescriptions stayed below 200,000 per year, DuPont would be exempted from any phase IV requirements. If the number of prescriptions rose above 200,000 per year in the first three years, DuPont would conduct pharmacokinetic studies in patients with severe renal disease and severe hepatic disease. At each of 500,000 and 1,000,000 prescriptions per year, DuPont would conduct a series of additional phase IV trials including studies in older adults and children, patients with common co-morbid conditions, and larger patient populations. DuPont is also required to provide in its annual report to the FDA the amount of drug manufactured as well as the number of prescriptions (new or refill) filled annually based on IMS data. This ruling allowed the FDA to make the product available to a small number of patients without requiring DuPont to conduct expensive phase IV trials, while also ensuring that additional data would be collected if the product was used more widely (Pink Sheet 1995). (Note: DuPont and Merck & Co. formed a partnership in 1991 known as DuPont Merck, which owns the rights to Trexan and ReVia. DuPont Merck markets its products under the DuPont Pharma name.)
Likely Future of the Product
DuPont has essentially stopped actively marketing both Trexan and ReVia. The company still provides information to clinicians upon request and makes naltrexone available to clinicians for use with their patients on an as needed basis. Researchers have approached DuPont for permission to test naltrexone for use in a wide variety of other conditions including obesity, schizophrenia, and chronic obstructive pulmonary disease (Watson 1996). The FDA awarded orphan grants (research grants for treatments of rare conditions) for the use of naltrexone with a number of rare conditions, including childhood autism (FDA 1989). In addition, researchers have used derivatives of naltrexone in other conditions. For example, the FDA granted orphan drug status to methyl-naltrexone as a drug that blocks the side effects of morphine without interfering with pain relief in cancer treatment (Oncology 1996). However, because naltrexone is now completely off-patent, DuPont will most likely not pursue any other indication for naltrexone without a guarantee of market exclusivity post-approval.
Naltrexone held great clinical promise when it became an important figure in the federal government's efforts to combat heroin addiction in the 1970's. As a non-addicting antagonist of the euphoric high of opiates, naltrexone had certain characteristics of a drug that promised to revolutionize the treatment of heroin addiction. Naltrexone showed great promise in clinical trials by significantly reducing heroin use in patients. The federal government made the development of naltrexone a top priority, and created consolidated government divisions with the funding necessary to conduct the clinical research and development.
Orphan drug status and related provisions for market exclusivity, and the flexible phase IV trial requirements are all useful tools employed by the FDA to give DuPont more incentive to develop naltrexone. However, other barriers described above overshadowed the advantages gained from these regulatory incentives.
The federal government played a key role in eliminating many barriers to the development of naltrexone for both heroin and alcohol addiction. Several key barriers the government recognized and lowered, and their effect on DuPont's incentive to market the drug, are shown in Figure 28 (below).
|Market Barrier||Government Intervention||Effect|
|High expense of clinical development, with a low projected return||The federal government funded and conducted the vast majority of clinical trials||Lowered DuPont's initial development costs and made the initial research less risky financially|
|Difficulty of obtaining thebaine, a precursor to naltrexone||The NIH negotiated with Mallinkrodt to obtain thebaine||DuPont had easier access to an essential precursor material|
|Patent expiration||FDA granted orphan drug status and additional market exclusivity||"Protected" the market to increase DuPont's chances of gaining a return on their investment|
|High expense of post-marketing studies||FDA granted variable Phase IV research requirements||DuPont could bring the drug to the market without having to conduct costly Phase IV trials until the drug was widely used|
Despite the high level of government intervention, there were several barriers that DuPont and the federal government were unable to overcome. Estimates of naltrexone's sales suggest that naltrexone has reached less than 5% of heroin or alcohol addicts. As of October, 1996, sales of naltrexone had not reached the FDA's minimum threshold of 200,000 prescriptions per year to require phase IV research. As shown in Figure 29 (below), many of these barriers are related to issues of patient compliance.
|Market Barrier||Effect on DuPont's Marketing Success|
|Patient compliance||The non-addictive property of naltrexone, which was a high priority in choosing to develop naltrexone, makes patient compliance difficult. Clinical trials had shown that naltrexone was not effective without additional psychosocial therapy.|
|Need for intensive psychosocial therapy in addition to drug treatment||Limits the distribution of naltrexone through comprehensive patient treatment centers, and potentially misses another market segment that may seek care primarily through a general practitioner.|
|Higher cost for more intensive psychosocial therapy||State level treatment centers can not afford to implement the more intensive psychosocial support systems necessary to maintain patient compliance on naltrexone. In addition, there was no established reimbursement system for naltrexone treatment at the state level.|
|Federally controlled heroin treatment system||As a result of extensive regulations at the federal and state levels, DuPont had to market directly to individual state substance abuse directors, who often lacked clinical backgrounds.|
|Difficulties recruiting patients for clinical trials||The methadone maintenance clinics were reluctant to allow their patients to enter clinical trials for naltrexone either because they needed to protect their patient censuses, or they believed that a non-addictive alternative to methadone would not be effective.|
|Unrealistic patient and provider expectations||Naltrexone was not a "miracle pill" that would cure a patient of all addictions and DuPont sales representatives had to manage provider expectations and convince them that reducing consumption of opioids or alcohol was significant.|
|Lack of insurance coverage||Although some heroin addicts are covered under Medicaid, many private insurers are unwilling to cover naltrexone. In addition, managed care companies and employers offer limited insurance coverage for substance abuse.|
|Provider reluctance to use pharmacotherapies in the treatment of substance abuse||Many providers in the addiction world share a philosophy that substance abuse should not be treated with drugs, which further impeded DuPont's sales efforts.|