But I have been told that FDA has not even let a single contract to investigate methadone, and that the scanty reports forwarded so far are totally inconclusive as to its effects.

I think that the fact that the long term effects of methadone use have never been studied, nor have the side effects or the effects on expectant mothers and their offspring, would be basis enough to reject approval of any drug. The fact that methadone has the potential and the history of being lethal is an added factor and one which should also weigh heavily.

I do not accept the fact that methadone is a very useful drug for detoxification, and in some instances may be used for maintaining a hard

addict.

But for the Federal Government to give its official sanction to this drug as being safe and effective for curing addiction via and approved drug status, would cause great concern. And I have grave reservations about the Federal Government maintaining a portion of the population in a state of addiction.

Our concern over reported FDA approval of methadone for wider distribution does not rest only with the question of whether the drug is effective as a cure to heroin addiction. We know that, while methadone is safe if taken as prescribed, the overall question of safety is a shadowy area. Indeed, a few would contest this committee's findings during road hearings that the present means of controlling the distribution of methadone are wholly inadequate. Under present controls, methadone's potential for death is alarming. In New York State alone, between January 1970 and August 1971, 126 methadone related deaths were reported. Twenty were due to overdoses, six involved accidental poisonings of children.

It is not our intention to seek a total ban on the distribution of methadone, but to encourage only bona fide, well controlled methadone programs. It is our hope that the hearings today can serve as a vehicle to achieve this goal.

I know that the problem of distribution of methadone is of particular concern to our colleague on the committee, James Hastings, who has devoted considerable study to the problem nationally and to its impact on his home State of New York.

I might say that we have received a telegram, as I understand it. and I will be glad to yield at this time.

Mr. HASTINGS. Thank you, Mr. Chairman.

I would like for the record to indicate that as of October the New York Public Health Council sent a telegram to Dr. Edwards expressing their concern. I would like to read that for the record:

"New York State Public Health Council at monthly meeting today expressed serious concern over rumored removal of IND status of methadone. This would result in lack of control that would be possible for any one State to regulate and jeopardize successful programs."

I have received word that Governor Rockefeller has sent a telegram to you, Mr. Chairman, and I believe to Dr. Edwards and to Secretary Richardson, and the text of the telegram is:

"This is to support the action of New York State Public Health Council which recently expressed serious concern over present IND

status of methadone. Changing status will result in a lack of control, I would make regulation by any one State impossible, and jeopardize the present successful program.

So my State, the State of New York, expresses serious concern over the possible approval of the FDA on methadone. I personally feel there is a definite therapeutic need for methadone in the maintenance.

program.

My concern is one of control. I am sure that is a concern that is shared by all of us. I would hope that would be the purpose of this hearing.

Thank you, Mr. Chairman.

Mr. ROGERS. Without objection the telegrams from the Governor and the New York Public Health Council will be made a part of the record. (The telegrams follow :)

Hon. ELLIOT RICHARDSON,

[Telegram]

ALBANY, N.Y., November 8, 1971.

Secretary, Health, Education, and Welfare,

Washington, D.C.:

This is to support the action of the New York State Public Health Council which recently expressed its serious concern over removal of the present IND (investigational new drug) status of methadone. This change in status would result in a lack of control that would make regulation by any one State impossible and would jeopardize present successful programs.

(Cc: Mr. Paul G. Rogers, U.S. Representative.)

NELSON A. ROCKEFELLER.

Dr. CHARLES C. EDWARDS,

[Telegram]

ALBANY, NY., October 22, 1971.

Commissioner, Food and Drug Administration, Department of Health, Education and Welfare, Rockville, Md.:

New York State Public Health Council at its monthly meeting today expressed its serious concern over rumored removal of present IND status of methadone. This would result in lack of control that would be impossible for any one State to regulate and would jeopardize present successful programs,

NORMAN MOORE, M.D. Chairman,

Public Health Council, New York State Department of Health.

(Cc: President Nixon.) Mr. ROGERS. I should like to read from a letter from Dr. Neil Solo mon, secretary of health and mental hygiene of the State of Maryland. DEAR MR. ROGERS: It is my opinion that methadone should only be adminis tered under most rigidly controlled conditions. I believe there should be nation wide regulation similar to the ones proposed by the State of Maryland, which will make it unlawful for any physician to prescribe methadone except as part of controlled methadone maintenance programx or legitimate medical need. If this is not done, I predict a nationwide problem will develop with methadone that will be of the same magnitude as the one we now have with heroin. There were four deaths this year in the State of Maryland due to overdoses of methu done. These deaths could have all been avoided if we had stricter control over ths drug.

Our first witness this morning is Hon. Charles Edwards, Com missioner of the Food and Drug Administration.

We welcome you to the committee, and will be pleased to receive your testimony.

66-841 - 724-22

STATEMENT OF DR. CHARLES C. EDWARDS, COMMISSIONER, FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE; ACCOMPANIED BY DR. ELMER H. GARDNER, DIVISION OF NEUROPHARMACOLOGICAL DRUGS: PETER HUTT, GENERAL COUNSEL; AND DR. JOHN S. ZAPP, DEPUTY ASSISTANT SECRETARY FOR LEGISLATION (HEALTH), HEW

Dr. EDWARDS. Thank you, Mr. Chairman.

I would like to introduce on my left, Dr. Elmer Gardner, head of the Division of Neuropharmological Drugs.

On my right, Mr. Peter Hutt, General Counsel, and next to Mr. Hutt is Dr. John S. Zapp, Deputy Assistant Secretary for Legislation (Health).

Mr. ROGERS. We welcome you gentlemen to the committee.

Dr. EDWARDS. We appreciate this opportunity, Mr. Chairman. to discuss with you the background information leading to our current consideration of a new drug application submitted on June 28, 1971. by Eli Lilly & Co. for a Disket formulation of methadone hydrochloride to be used in the long-term treatment of heroin addiction. Until the submission of this data in this NDA, we could not take any position on the safety and efficacy of methadone in treating drug addiction. I wish to emphasize that this NDA is still under consideration. It has not yet been approved or disapproved. My remarks today, therefore, do not represent any final FDA or Department position.

I also want to emphasize that methadone is an addictive narcotic drug. It is certainly not a cure-all or panacea for the treatment of heroin addiction. We at FDA also are fully aware that its use must be very closely monitored and very closely controlled.

The extent of the drug abuse problem and heroin addiction, in particular, has been a cause of increasing public concern. A variety of non-drug-treatment approaches has been utilized over the past several years. They range from long-term hospitalization, to resi dential programs such as Synanon, to outpatient psychotherapeutic efforts. The time, manpower, and money required in all of these have resulted in only limited success. Accordingly, a chemical therapeutic agent has become an attractive alternative.

This has resulted in a search for an effective medication for addicts. Through such an agent, the addict might be freed of his crav ing for heroin.

The drug that has been most widely investigated and used for this purpose is methadone, a synthetic narcotic. Methadone has been approved and widely used as an effective analgesic since it was synthesized at the end of World War II. It has also been approved and widely used for more than a decade, in low oral doses, to allay opiate withdrawal symptoms. But not until 1963 was it first observed that this drug could possibly be of value in the treatment of heroin addiction.

Maintenance treatment of heroin addiction with methadone has since 1963, been in an investigational status. Thus, the drug is not yet approved for general use for maintenance therapy. The investigational

use of methadone under the IND regulations began on a national scale following a publication by Dole and Nyswander on the "Successful Treatment of 750 Criminal Addicts" with methadone in the Journal of the American Medical Association on December 16, 1968. A copy of that article is attached to this testimony (see p. 1502).

To collect the type of scientific data needed to support approval of any new drug, it is necessary that the programs using the drug follow proper protocols and keep adequate records. Moreover, investigational studies of methadone present problems not encountered in studies with other types of drugs because it is an addicting narcotic with a proven capacity for abuse.

Therefore, to protect the community from the hazards of diversion and abuse, and to assure the development of valid data, guidelines for methadone maintenance studies were developed through the cooperation of the National Institute of Mental Health, the Bureau of Narcotics and Dangerous Drugs, and the Food and Drug Administration. These guidelines were published in the Federal Register on April 2, 1971. A copy is attached to this testimony (see p. 1509).

Prior approval of both the Food and Drug Administration and the Bureau of Narcotics and Dangerous Drugs, Department of Justice, is required before any new IND program involving methadone can be initiated.

We have now approved approximately 298 IND sponsors for methadone maintenance programs-representing approximately 380 individual treatment units. New sponsors are sending in plans at the rate of more than one per day.

I would like to emphasize this; more than one per day.

Some sponsors, particularly NIMH and the Veterans' Administration, monitor 20 or more programs. Since publication of the April 2, 1971, regulations, each applicant for a methadone maintenance program has been subject to inspection by BNDD and must receive approval by both BNDD and FDA. Every applicant has been asked to correct any major deficiencies in his protocol before he can initiate this program. We have not approved applications unless BNDD and FDA are convinced that the sponsor can conduct an adequate study. Thus, few private practitioners have been granted IND's for methadone maintenance since April 2.

In considering the new drug application pending before us, and the obligations of the Secretary under section 4 of the Comprehensive Drug Abuse Act of 1970, we have consulted widely among the medical profession.

Among those with whom we have talked are the American Medical Association's Council on Mental Health, the National Research Council's Committee on Problems of Drug Dependence, the American Psychiatric Association's Commission on Drug Abuse a task force of the American Society of Pharmacology and Experimental Therapeutics, the Joint FDA/NIMH Psychotomimetic Advisory Committee, several other leading experts, and the FDA Drug Abuse Advisory Committee, chaired by Dr. D. Henry Brill.1

1 Committee members: Dr. William Bloom (Tulane University). Dr. Sidney Cohen (UCLA), Dr. Max Fink (New York Medical College), Dr. Daniel X. Freedman (University of Chicago), Dr. Robert Millman (Rockefeller University). Dr. Maurice Seevers (University of Michigan), Dr. Eddie L. Way (University of California, San Francisco).

We have met on numerous occasions with representatives of Dr. Jaffe's Special Action Office, the National Institute of Mental Health. and have maintained close liaison with the Bureau of Narcotics and Dangerous Drugs and all Federal agencies. Finally, we have discussed the matter thoroughly with the companies which presently produce and market methadone products.

As one would expect on any controversial subject, there is a wide diversity of opinion about this matter. There appears, however, to be a very strong consensus that the IND status of methadone is no longer defensible, an dthat an NDA is approvable as long as an acceptable control mechanism is available to make certain that the drug will not be misused.

As is true with some nonopiate drugs, the method of distribution and use is a very important factor in considering whether this drug will be safe under its conditions of use, and must therefore be considered in determining whether it can be approved for marketing under an NDA.

In the opinion of the best medical experts with whom we have consulted, including our advisory committee, and in the opinion of our own staff who have reviewed the data, there is currently substantial evidence that methadone is safe and effective for its pharmacologic effect.

Methadone, in contrast to heroin and many other narcotics, produces its pharmacologic action when taken orally as well as by injection. Oral methadone relieves the craving for injecting heroin for reasons that are not completely understood. When taken orally by the stabilized individual, methadone produces no euphoria or other mental effects and no impairment of functional capacity. Methadone is longer acting than heroin and has less severe withdrawal effects. The individual stabilized on methadone has little or no desire for heroin and, in contrast to the person needing intravenous heroin, is not on an emotional roller coaster which moves from euphoria to beginning withdrawal, and to drug seeking behavior, several times a day. In many instances, moreover, a patient stabilized on oral methadone who injects heroin does not experience the usual euphoria and thus may be dissuaded, therefore, from the use of heroin.

The question whether this will have a major impact in the rehabilitation of narcotic addicts, using various social criteria and indicators, is still open to debate and may not be resolved for some time to come. We have, therefore, been advised that, if the drug is to be approved, it should be approved only for its demonstrated pharmacological effect. This would follow the procedure we used when we approved antiacid drugs with indications for use in treating of symptomatic relief in peptic ulcer and other conditions for which control of gastric hyperacidity is required. Approval of methadone for its pharmacologic effect would therefore be consistent with normal FDA practice.

Some additional information on the safety of chronic use of methadone in animals and humans may be needed. Approval may therefore be conditioned upon development of such information, as well as further data on the type of patients who best respond to this drug. This is similar to our recent approval of an NDA for L-Dopa, where further studies have been required.