New Drug Approval Approach
Boosts Fight Against Heroin Addiction
by Dixie Farley

     A new approach to bringing drugs to market won high marks last
year when the Food and Drug Administration approved levo-alpha-
acetyl-methadol (Orlaam, also known as LAAM) in record time. LAAM
is only the second synthetic narcotic medication approved to treat
heroin and other opioid addiction through outpatient narcotic
maintenance treatment programs. The other medication is methadone,
approved almost 25 years ago.
     Chronic and relapsing, heroin addiction controls its victims.
It wastes lives and addicts newborns along with their mothers. It
spreads infection with HIV, the virus that causes AIDS, and other
infectious diseases through the sharing of dirty needles. It is
connected with violent crime and casts a heavy economic burden upon
society.
     More than 586,000 Americans use heroin at least weekly, the
Office of National Drug Control Policy reports.
     LAAM was approved July 20, 1993, only 18 days after FDA
received the new drug application.
     The "new approach" that made this speedy approval possible
involved cooperation among FDA drug review and compliance staffs,
a new division of the National Institutes of Health's National
Institute on Drug Abuse (NIDA), the Drug Enforcement
Administration, and industry--in this case, Biometric Research
Institute Inc., of Arlington, Va.
     The cooperative clinical tests underpinning the approval took
just 18 months from protocol development to patient enrollment,
completion of the first phase of the study, and report to the
agency.
     NIDA's Medications Development Division (MDD) was established
in 1990 to encourage development of anti-addiction medications.
Although LAAM had been studied for many years, it was sitting on a
"back burner" at NIDA.
     About the same time MDD was created, FDA set up its Pilot Drug
Evaluation Staff to streamline drug approval. The agency assigned
review of anti-addiction medications to the new staff, and hired
experts in drug abuse issues, including senior scientist Michael
Klein, Ph.D.
     "In 1990, we advised NIDA," Klein says, "to reassemble the
data on LAAM submitted in the 1980s in two rejected new drug
applications, and give them back to us as an investigational new
drug application. The IND gave us a way to get involved in
development from step 1, and make recommendations for the eventual
submission of the NDA."
     Klein and others reviewed the IND and parceled out certain
older studies for review by FDA's Drug Abuse Advisory Committee.
     "We also wanted studies of the new population of patients,"
Klein says. "Many people abusing heroin today also use other drugs,
such as crack cocaine, which wasn't around in the early 1980s."
     MDD conferred with FDA to develop directions for using LAAM.
Researchers were to follow the directions, spot problems, and try
to correct them. To eliminate bias, FDA specified using only
clinics that had never studied LAAM.
     MDD contracted for the FDA-guided trials with 26 Department of
Veterans Affairs (VA) medical centers and university clinics.
According to MDD health scientist administrator Paul Coulis, Ph.D.,
"We worked with FDA all along, sharing our findings as they
developed."
     Klein says, "We got a very nice picture of the adequacy of the
labeling and potential problems today, which we could couple with
the old studies, some of which did show efficacy."

Maintenance Medications, Close Up
     Methadone and LAAM are oral narcotics that work in the body
much like morphine does. When taken for short periods by non-
addicts, they kill pain, sedate the central nervous system, and
relax smooth muscle tissues.
     Both medications can themselves produce dependence. But when
taken as part of a maintenance treatment program, they do not cause
euphoria. They in fact block the "highs" of other opioid narcotics,
such as heroin, and suppress the symptoms of withdrawal. These
symptoms include increased blood pressure and temperature, rapid
heartbeat, "goose-flesh" (piloerection), runny nose (rhinorrhea),
watery eyes (lacrimation), tremors, insomnia, vomiting, abdominal
cramps, restlessness, weakness, headache, hot or cold flashes, and
drug craving. Withdrawal from methadone or LAAM causes similar
symptoms, but starts more slowly, is less severe, and continues for
a longer time.
     LAAM's advantage is that it works for 48 to 72 hours after a
dose is taken, compared to 24 hours for methadone. With fewer
required visits, patients have the chance to lead a more normal
existence and clinics have the option to treat more patients.
     Methadone must be given every day, and take-home doses are
permitted in selected cases.
     LAAM is not approved for daily treatment because daily use of
the usual doses will lead to serious overdose. Evaluated only as an
in-clinic medication, LAAM is not allowed in take-home doses. In
extreme situations, however, certain LAAM patients may be
temporarily switched to methadone for a take-home dose when they
know in advance they can't come to the clinic for a scheduled LAAM
dose. Also, in-clinic dosing reduces the likelihood of patients'
diverting the medication to street sales. 
     Methadone and LAAM can interact adversely with tranquilizers,
tricyclic antidepressants, alcohol, and other drugs. They can
worsen low blood pressure and asthma. They can cause breathing
difficulty and impaired circulation. Less serious methadone side
effects include dizziness, vomiting, and sweating; LAAM can cause
flu-like symptoms, diarrhea, and muscle aches.

Maintenance Works
     "If your goal is to reduce drug abuse," says Nicholas Reuter,
a consumer safety officer in FDA's Office of Health Affairs, "a
properly administered maintenance program appears to be the most
effective treatment." Reuter is executive secretary of the federal
interagency review board that coordinates regulation of the
programs. Last year, the board reviewed U.S. and international
research on methadone--which has been studied extensively--
following media reports that questioned the safety of methadone
treatment.
     According to MDD's Coulis, effectiveness of maintenance
treatment can be measured by these outcomes: reduced heroin use,
staying in treatment, and perceptions by both patient and doctor of
improved well-being.
     Reuter adds that patients receiving maintenance treatment have
a death rate 10 times lower than untreated addicts and an incidence
of needle-sharing of 14 percent, compared to 47 percent before
treatment. In a recent Swiss study of people with HIV infection, he
says, 24 percent of maintenance program cases progressed to AIDS,
compared to 41 percent of untreated heroin abusers.
     "Retention in treatment is crucial," Reuter says. "In a direct
line with the time patients spend in treatment, their general
health and social productivity improve, and their drug abuse and
criminal activities diminish." He says some studies show that
patients stay in maintenance programs at a rate two-and-a-half
times that of patients in self-help residential programs, and five
times that of patients in drug-free outpatient programs. Of those
who stop treatment, more than 80 percent relapse within a year.
     "While maintenance treatment can't guarantee relapse
prevention even during treatment," Reuter says, "it is consistent
with medical management of chronic diseases such as diabetes, heart
disease, and arthritis."

Suspicion
     Despite more than two decades of documented success of
maintenance therapy, the idea of treating addiction with addictive
medications is often viewed by the public with suspicion.
     One source of this uneasiness is a misunderstanding of heroin
addiction, says Robert Lubran, chief of the Quality Assurance and
Evaluation Branch, Division of State Programs, in the Substance
Abuse and Mental Health Services Administration's (SAMHSA) Center
for Substance Abuse Treatment.
     "Many people," Lubran says, "don't realize that heroin addicts
must fight their addiction all their lives. Others equate patients
in maintenance programs with street addicts. In fact, the patients
are at some level of recovery, which benefits society as well as
the patient."
     Another source of suspicion is the ineffectiveness of some
programs, which Lubran attributes to poor medical or clinical
practices, such as inappropriate medication dosing to control
withdrawal, failure to properly screen and assess patients' needs
for counseling and support services, and lack of qualified
counseling staff. "Research indicates that a few patients may do
all right with minimum services," he says. "Most do not."

Strong Medicines, Strong Rules
     Narcotic maintenance treatment is regulated by FDA, the Drug
Enforcement Administration, and state authorities. FDA approves
only programs previously approved at the state level and registered
with DEA. Currently approved are 791 maintenance programs and 282
hospital programs (see map), serving some 115,000 patients. Of
these programs, 46 are approved to use LAAM. Maintenance
medications are unique in drug regulation, and this type of
regulation is unique in medical practice, says FDA  Associate
Commissioner for Health Affairs Stuart Nightingale, M.D., who
chairs the programs' interagency review board.
     "For no other class of drugs do we write and enforce rules
that directly affect how they're used in treatment," Nightingale
says. "With these medications, we specify rules for clinical
practice, such as requiring physicians to prepare and sign a
treatment plan for each patient and document all changes in dosing
regimens."
     Because of the implications for medical practice and other
broad societal concerns, Nightingale says, "the interagency
committee has been critical to the success of the federal
coordination." The committee includes representatives from FDA,
NIDA, SAMHSA, DEA, VA, the Office of the Secretary of Health and
Human Services, the Office of the Assistant Secretary for Health,
and the Office of National Drug Control Policy.
     Treatment clinics must register with DEA and meet security
rules because methadone and LAAM are controlled substances (drugs
regulated by the Federal Controlled Substances Acts). DEA requires
additional registration by the physicians who treat narcotic
addiction with narcotics.
     In light of the addictive potential and potential for
overdose, both FDA and state authorities require safety measures
and medication control rules in programs using methadone or LAAM.
The Department of Health and Human Services, FDA's parent agency,
must by law provide treatment standards for narcotics used to treat
narcotic dependence. These are minimum standards, currently in the
form of regulations. Individual states can, and some do, develop
stricter rules.
     Under FDA rules, programs may admit only current addicts with
at least a one-year history of addiction, although previously
addicted pregnant women at risk of returning to addiction may also
be admitted. Methadone maintenance, but not LAAM, is approved for
patients under 18 who have twice failed detoxification or other
drug-free treatment. A parent, guardian, or other designated
responsible adult must sign the consent form.
     Enrollment is voluntary. Patients must report to the same
program, except in an emergency.
     Among other agency requirements, comprehensive programs must
provide:
fl    medical services, counseling, vocational rehabilitation, and
treatment plans
fl    tuberculosis skin testing during the initial medical
evaluation
fl    HIV counseling
fl    information to women about drug risks to the fetus
fl    pregnancy tests for women of childbearing potential before
admission to LAAM maintenance, and monthly tests thereafter
fl    individualized dosage to control withdrawal symptoms without
causing sedation or other effects of intoxication, with the lowest
effective doses for pregnant women
fl    regular physician review of dosage levels
fl    observed dosing at the clinic (With methadone, visits are six
days a week to start but, with successful treatment, may be reduced
with use of take-home doses. With LAAM, visits are every other day
to start but eventually may be every third day.)
 fl   complete patient records, which physicians must sign and date
to document dosage changes and reasons for reducing visits
fl    frequent random urine tests for drugs of abuse--including an
initial screening test for prospective patients.
     Publicly funded treatment accounts for the vast majority of
patients in treatment, says FDA's Nightingale. These programs may
be free or have sliding scale fees. The cost of private programs
varies.
     In addition, FDA and SAMHSA in 1993 issued interim narcotic
maintenance program standards for heroin addicts who can't get into
a nearby comprehensive program within two weeks. The ADAMHA
Reorganization Act of 1992 required the standards to reduce the
AIDS threat posed by injection of illegal drugs--the major source
of new AIDS infection in the general population, according to NIDA.
States would guarantee patients' transfer to comprehensive
treatment no later than 120 days. Although no clinics have applied
to enroll patients in interim programs, any programs adopted would
be restricted to public, nonprofit clinics with federal- and state-
approved comprehensive programs.

Managing Compliance Problems
     FDA field staff inspect programs every two or three years,
reporting problems to the agency's regulatory management branch.
Follow-up visits are on a case-by-case basis. "If there are serious
violations and we send a warning letter," says compliance officer
Gerald Hajarian, "three to six months after the program responds
with its correction plan, the district inspects again to make sure
the violations no longer exist." (The facility must submit its
correction plan to FDA within 15 days of receiving the warning
letter.)
     DEA inspects programs on a routine cycle--or more frequently
if a program has a history of violations or pending allegations of
impropriety. DEA requires that programs follow all security and
record-keeping regulations. Violations may result in actions such
as an Investigative Warning or Letter of Admonition for less
serious violations, or an Administrative Hearing, Order to Show
Cause, or civil or criminal actions for serious violations.
     States inspect also.
     There is continuing concern about some patients selling their
take-home methadone doses on the street. In July 1990, FDA, DEA and
NIDA warned program sponsors and medical directors that federal and
state investigations confirmed increasing diversion of take-home
medications, pointing out that diversion was one reason FDA
requires frequent urine tests. (A negative test would indicate the
patient hadn't taken the take-home medication.) They warned that,
if necessary, they would revoke DEA registration or FDA approval.
     Indeed, FDA and DEA in 1991 allowed two New York programs to
stay open only after they presented evidence showing how they
intended to remedy their problems. FDA, DEA, and Texas authorities
in 1992 did close two Texas programs, with a third one closing
voluntarily. Last February, FDA closed a New Mexico program.

Improving the Programs
     Included among the Center for Substance Abuse Treatment's 
series of Treatment Improvement Protocols (or "TIPS") are several
that cover narcotic maintenance treatment. These are developed by
non-federal treatment experts.
     "We take the scientific research and expertise of leading
clinicians," the center's Lubran says, "and translate that into
practical guidance that can help states, maintenance programs, and
others improve the quality of services."
     Several TIPS--some of which are still under development--
provide recommendations about the most effective maintenance
treatment practices for such groups as pregnant women and infants
exposed to methadone, methadone patients who abuse stimulants
(especially cocaine), and patients on LAAM treatment.
     Technical assistance, training, and financial support to
states and communities are also available. For example, when the
state of Texas asked for assistance after media criticism of
maintenance programs in the state, the center arranged for state
and program representatives, treatment experts, and FDA and DEA
officials to meet in Texas. The conferees identified system-wide
problems and solutions and recommended improvement activities.
     The center helped the state of Arkansas open its first program
last December in Little Rock, which Lubran says reached three-
fourths of the target population within three months. "We enabled
them to gain invaluable exposure to quality treatment programs
around the country to see how they work, and provided guidance with
their state regulations," he says.
     Another project educates judges and court administrators on
how the programs can serve as alternative sentencing for people
convicted of crimes related to heroin use or other drug abuse.

Incentives
     As an incentive to firms to develop anti-addiction
medications, FDA permits this class of drugs fast-track review and
eligibility for orphan drug status, which confers tax credits and
research grants. Orphan drugs receive seven years of marketing
exclusivity. LAAM is a designated orphan drug.
     MDD encourages development of maintenance medications by
assisting firms with research. MDD deputy director Frank Vocci,
Ph.D., says his division is analyzing data from a study in 736
patients to evaluate the safety and effectiveness of an oral
sublingual (administered under the tongue) form of buprenorphine
(Buprenex) in blocking heroin's euphoria. The drug is approved as
an injectable narcotic analgesic.
     A buprenorphine-naloxone formulation also is being developed.
Although oral buprenorphine may block heroin's effects, the
injected form can produce euphoria. However, injected naloxone
(Narcan), approved to treat overdose, blocks the euphoria, inducing
withdrawal.
     "The idea," Vocci says, "is if the drug is taken as
prescribed, the naloxone won't kick in. But if patients abuse it by
injecting it, the naloxone effect will predominate."
     In another study, MDD tested a sustained-release naltrexone
formulation that blocked heroin euphoria up to 30 days. Dosage in
future trials will be based on the results of this study, Vocci
says. Naltrexone (Trexan) is approved for use with maintenance
medication, but not as a maintenance medication itself.
     These efforts, along with the new approach that brought LAAM
to market, offer hope for more safe and effective maintenance 
medications, possibly to treat other addictions as well.
     While there is no cure for heroin addiction, there is hope for
recovery through narcotic maintenance treatment programs. Using
legal oral synthetic narcotics, maintenance programs wean addicts
off heroin, the first step to stable, productive lives. 

Dixie Farley is a staff writer for FDA Consumer.

For More Information

The Center for Substance Abuse Treatment National Drug Hotline
(1-800) 662-HELP

The National Clearinghouse for Alcohol and Drug Information
P.O. Box 2345
Rockville, MD 20847-2345
(1-800) 729-6686
TDD: (1-800) 487-4889

American Methadone Treatment Association, Inc.
253-255 Third Ave.
New York, NY 10010

Changes on the Way?
     In 1992, the Public Health Service asked the Institute of
Medicine to study federal regulations on methadone maintenance
treatment. According to Richard Rettig, Ph.D., the study director,
"We examined evolution of the rules, their role in providing the
best treatment, and the role of complementary approaches, such as
clinical practice guidelines and formal quality control systems."
IOM will publish a report on the study late this year.
     IOM already released a report this year on development of
anti-addiction medications such as methadone and LAAM.
Recommendations included making the Treatment IND route and
parallel track mechanism available for anti-addiction medications,
and assigning priority to the development of anti-addiction
medications through an executive order issued by the president.
(The "parallel track" policy allows wider availability of promising
investigational drugs--currently, only for certain patients with
AIDS or other HIV-related conditions--through protocols without
control groups, which are conducted parallel to controlled clinical
trials necessary to establish safety and effectiveness.)
     In the report, IOM identified reasons why firms are reluctant
to develop anti-addiction medications. These included problems
related to the limited scientific knowledge about addiction, lack
of federal leadership, and an uncertain market environment with
issues such as pricing concerns, liability, and limited and
uncertain insurance coverage. Suggestions to resolve these and
other issues are slated for a later report.

--D.F.