The Orphan Drug Act and the
`Federal Government’s Orphan
`Products Development Program
`
`MARIONJ. FINKEL, MD
`
`
`
`Tearsheet requests to Marion J. Finkel, MD, Director, Office of
`Orphan Products Development, Food and Drug Administration,
`5600 Fishers Lane, Rm. 12-11, Rockville, Md. 20857.
`
`infrequently in the United States that there is no reason-
`able expectation that the cost of developing the drug and
`making it available will be recovered from sales in the
`United States. Examples of rare diseases given in the act
`include Huntington’s disease, amyotrophic lateral scle-
`rosis, Tourette syndrome, and muscular dystrophy.
`Among these examples,
`the disorder with the highest
`prevalence is Tourette syndrome, with an estimated prev-
`alence in the United States, for the full-blown syndrome,
`of 100,000 patients.
`The Orphan Drug Act provides four incentives for
`drug companies:
`
`May—June 1984, Vol. 99, No.3 313
`
`Darane THE PAST DECADE, a numberof independent
`groups in the executive and legislative branches of the
`Governmentandin the private sector examined the prob-
`lem of orphan drugs and made recommendationsforits
`amelioration.
`Orphandrugsare drugs with demonstratedor potential
`effectiveness in the diagnosis, prophylaxis, or treatment
`of an uncommondisease that remain unavailable because
`of lack of commercial
`interest on the part of phar-
`maceutical manufacturers. These drugs have been termed
`“orphans” not only because they are not available to
`most physicians and their patients but also because the
`research required to permit marketing approval
`is not
`conducted, due to lack of financial incentives for manu-
`facturers.
`The pharmaceutical industry has, over the years, pro-
`vided a considerable number of therapeutic and diag-
`nostic agents as a public service for patients with rare
`diseases.
`In many cases, all or most of the research
`leading to developmentof these agents was conducted by
`investigators under Governmentorprivate grants. This,
`of course, does not
`lessen the contributions of drug
`companies in seeking marketing licenses, developing
`finished dosage forms, and distributing the products. In
`somecases, drug companies have performeda consider-
`able amount of research themselves. Understandably,
`they cannot be expected to divert much oftheir resources
`away from the study of drugs for common diseases.
`Therefore, all groups that investigated the orphan drug
`problem concludedthat special incentives were needed to
`stimulate research on and development of these drugs.
`Such incentives are provided,
`to a considerable de-
`gree, by the Orphan Drug Act. The act was signed into
`law by the President on Jan. 4, 1983. An earlier version
`had been introduced in the Congress by former Repre-
`sentative Elizabeth Holtzman. The present act was
`passed largely through the efforts of Representative
`Henry A. Waxman, Chairman of the House Subcommit-
`tee on Health and the Environment.
`
`Provisions of the Orphan Drug Act
`
`1. A tax credit of 50 percent for the expenses of the
`clinical
`trials performed prior to marketing approval.
`This credit, together with the normal deduction for the
`remainderof the clinical expenses, amounts to about 73
`cents’ return per dollar spent. The tax credit is permitted
`only for clinical testing conducted in the United States
`unless there is an insufficient testing population in this
`country.
`2. A 7-year exclusive marketing license for unpaten-
`table drugs. During this period,
`the Food and Drug
`Administration (FDA) cannot approve another marketing
`application for the same drug for the same orphan use.
`The exclusivity applies only to the specific orphan indi-
`cation. If another firm develops the same drug for a
`common-disease indication or for a different orphan indi-
`cation, approval will also be granted to that firm.
`It
`should be noted that exclusivity continues only so long as
`the firm can supply the needs of the US. population with
`the orphan disease. Should a firm charge a high price
`unjustified by the costs of development, so that few
`patients can afford the drug, or, in the case of a complex
`biological, should a firm be unable to manufacture
`enough of the product, then approval will be granted to
`other manufacturers.
`3. Protocol assistance. Underthis provision, the FDA
`must provide, on request, written advice to a sponsor of
`an orphan drug on the studies (animal and clinical)
`needed for marketing approval.
`4. Grants and contracts. The act permits the Congress
`to appropriate $4 million per year for grants or contracts
`The act defines an orphan drug as a drug or biologic
`to support clinical trials of orphan drugs. The act author-
`intended for a disease or condition which occurs so
`(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)(cid:3)(cid:21)(cid:20)(cid:23)(cid:19)
`CELGENE 2140
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:89)(cid:17)(cid:3)(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)
`APOTEX v. CELGENE
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:22)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:21)
`IPR2023-00512
`
`

`

`izes such appropriations only for fiscal years 1983-85.
`The grants and contracts may be awarded to private
`entities or individuals.
`
`The Orphan Drug Act requires the establishment, in
`the Department of Health and HumanServices (HHS), of
`an Orphan Products Board comprising the Assistant Sec-
`retary for Health and representatives of the FDA, the
`National Institutes of Health,
`the Centers for Disease
`Control, and other Federal agencies that have activities
`relating to orphan drugs and orphan devices.
`Such a board was established by the HHS Secretary
`before passage of the Orphan Drug Act. In addition to
`representatives of the agencies just named,
`it includes
`representatives of the Alcohol, Drug Abuse, and Mental
`Health Administration; the Health Care Financing Ad-
`ministration; the Veterans Administration; and the De-
`partment of Defense. The board evaluates the activities
`of the represented agencies with respect to orphan prod-
`uct research and development and ensures appropriate
`coordination among Federal agencies, manufacturers,
`and organizations representing patients with rare dis-
`eases. The board also seeks investigators to perform
`research, seeks sponsors to complete developmentof and
`distribute orphan drugs, and recognizes the efforts of
`public and private entities and individuals to promote the
`availability of orphan drugs. The seeking of sponsorsis
`delegated to the FDA; the seeking of investigators is
`delegated toall of the grant- and contract-awarding agen-
`cies represented on the board. In addition, the board is a
`policy-making organization.
`
`Orphan Products Development Program
`
`Sinceits inception in
`The Orphan Products Board.
`March 1982, the board has developed a numberof pro-
`cedures and policies; has examined potential obstacles to
`product availability; and has opened communications
`with the drug industry, rare disease organizations, and
`investigators involved in the study of rare diseases and of
`drugs for those conditions. The board has reviewed the
`issue of liability and whetherit serves as a serious disin-
`centive to firms to study and market drugsoflittle or no
`commercial value, and it has concludedthat, in general,
`liability is not an obstacle.
`Two public meetings have been held by the board to
`listen to and act on the concernsof clinical investigators
`and patients with rare diseases. A majorinterest of these
`individuals is the establishment of a national clear-
`inghouse that would provide information to patients and
`physicians on rare diseases and on products under study
`or marketed for these conditions, and would maintain a
`registry of physicians whoare studying andtreating these
`diseases. The board is actively considering the desir-
`
`314 Public Health Reports
`
`ability of a clearinghouse, its nature, and methodsforits
`establishment.
`The board has also met with two pharmaceutical in-
`dustry organizations to determine how it and these en-
`tities can work together to help make orphan products
`available. (The organizations—the Pharmaceutical Man-
`ufacturers Association’s Commission on Drugs for Rare
`Diseases and the Generic Pharmaceutical Industry Asso-
`ciation’s Institute for Orphan Drugs—were formed
`within the last 2 years to consider the merits of specific
`orphan drugs and seek sponsors for them.) Indeed, sev-
`eral agencies represented on the board,
`including the
`FDA, have been liaison members of the Commission on
`Drugsfor Rare Diseasessince its inception, and the FDA
`has worked closely with the Institute for Orphan Drugs.
`The Board has monitored the progress toward avail-
`ability of more than 30 orphan products. It has consid-
`ered the types of research it will support under the
`appropriations provided by the Orphan Drug Act and has
`engaged in manyotheractivities, including development
`of a policy that will permit, when it
`is in the public
`interest, the granting of an exclusive license to a firm to
`complete development of and market an orphan product
`that has been developed almost entirely with Government
`funds.
`
`NIH and ADAMHA. Through their intramural and
`extramural programs,
`the National Institutes of Health
`and the Alcohol, Drug Abuse, and Mental Health Ad-
`ministration have provided considerable support over the
`years for research on orphan drugs, although such sup-
`port was not at
`the time thought of in “orphan” or
`“nonorphan”terms. The NIH, in order to underlineits
`commitmentto support of orphan product research, re-
`cently issued an announcement encouraging grant ap-
`plications for clinical testing of orphan products. These
`applications will undergo the usual peer review process.
`
`Centers for Disease Control. The CDC hasfor years
`distributed to physicians investigational orphan drugs
`and biologics. Approximately 30 such products have
`been distributed since 1965. CDC also collects data on
`adverse reactions to these drugs. Such data are useful
`when FDAfinds a sponsor to take over the drugs’ dis-
`tribution.
`
`Food and Drug Administration. The largest program
`in the Federal Governmentdirected specifically to or-
`phan products is that of the FDA. The FDA program,
`which has been in existence since May 1982, has a
`broader mandate than that encompassed by the Orphan
`Drug Act. The program’s scope includes orphan medical
`devices, medical foods, and veterinary products as well
`as drugs for humans. In addition, the program is directed
`
`

`

`not only to products for rare diseases but also to products
`for common diseases for which there is no commercial
`sponsor because the products are not patentable or the
`patents have expired or are about to expire. The program
`also addresses unlabeled uses for marketed drugs when
`such uses are for serious, uncommon diseases.
`FDAidentifies new products by meansof (a) continu-
`ous review of the published medical
`literature and of
`investigational applications submitted to the FDA by
`drug companies and academicians, and (b) communica-
`tions from professional organizations, voluntary disease
`associations, foreign and domestic drug companies, for-
`eign regulatory agencies, and clinical investigators.
`Manufacturers who will complete development of com-
`
`pounds of interest, submit marketing applications, and
`distribute the products are sought through notices pub-
`lished in the Federal Register, direct approach to com-
`panies with expertise in the manufacture of certain types
`of products, or request to the Commission on Drugsfor
`Rare Diseases or the Institute for Orphan Drugs.
`Through these mechanisms, during the period May
`1982 through December 1983, company sponsors were
`found for 24 unmarketed products and 4 new uses of
`marketed products. One of the sponsored products—
`hematin, for hepatic porphyria—was approved for mar-
`keting in July 1983, several others are under review, and
`marketing applications are scheduled to be submitted for
`the remainder in 1984 and 1985, depending upon the
`
`Drug
`
`Sponsor
`
`Intended use
`
`Date of commitment
`
`Examples of sponsor commitments for orphan products
`
`Trien (triethylene tetramine
`dihydrochloride)
`
`NP-59 (6-beta-19-iodonorcholesterol)
`
`Merck Sharp and
`Dohme
`
`Mallinckrodt
`
`Hematin
`
`Amiodarone
`
`Indium" Oxine
`
`Methacholine Cl
`
`Pimozide
`
`Bacitracin
`
`Hydroxy-ethyl starch
`
`L-5 hydroxy-tryptophan
`Vitamin E
`
`Pentamidine
`
`Carnitine
`
`Ethanolamine oleate
`
`Deprenyl
`
`Abbott
`
`Ives
`
`Amersham
`
`Roche
`
`McNeil
`
`A. L. Laboratories
`
`American Critical Care
`
`Bolar
`
`Roche
`
`Zenith
`
`McGaw
`
`Glaxo
`
`(’)
`
`I'*'-M-iodobenzyl-guanidine (I'*'-MIBG)
`
`Monooctanoin
`
`Citric acid, gluconic acid, magnesium hy-
`droxycarbonate, magnesium acid cit-
`rate, calcium carbonate solution
`
`Mallinckrodt
`
`Ascot
`
`Guardian Chemical
`
`Wilson's disease
`
`October 1982
`
`Adrenalcortical imaging
`
`Hepatic porphyria
`
`Cardiac arrhythmias
`Platelet imaging
`Diagnosis of occult
`bronchial asthma
`
`Tourette syndrome
`Pseudomembranous
`enterocolitis
`
`White bloodcell
`harvesting
`
`Postanoxic myoclonus
`Neuromuscular disorders
`secondary to cholestatic
`disease in vitamin E
`deficient patients
`
`P. carinii pneumonia
`Carnitine deficiency
`Bleeding esophageal
`varices
`
`Certain patients with
`Parkinson's disease
`
`Adrenal medullary imaging
`agent
`Cholesterol gallstone
`dissolution
`
`Dissolution of urinary tract
`calculi and prevention
`and treatment of en-
`crusted indwelling urin-
`ary tract catheters
`
`June 1982 (presen-
`tation to PMA
`commission’)
`
`May 1982 (licensed
`July 1983)
`October 1982
`
`December 1982
`
`March 1982
`
`November 1982
`
`August 1982
`
`August 1982
`
`June 1982
`
`October 1982
`
`November 1982
`
`July 1982
`December 1982
`
`January 1983
`
`March 1983
`
`July 1983
`
`November 1983
`
`1 Pharmaceutical Manufacturers Association's Commission on Drugs for Rare
`Diseases.
`
`2 Confidential.
`
`May—June 1984, Vol. 99, No.3 315
`
`

`

`is separate from that provided by the Orphan Drug Act.
`In fall 1983, FDA made 12 awards for clinical study of
`unmarketed orphan drugs and of new uses for marketed
`products.
`
`Summary
`
`amountof research to be completed. Examples of prod-
`ucts for which commitments have been made by spon-
`sors are presented in the table.
`FDAalso administers certain portions of the Orphan
`Drug Act previously described, namely, advice on stud-
`ies needed for marketing approval and the designation,
`when appropriate, of drugs as ‘‘orphans” so that
`tax
`credits can be claimed by sponsors and an exclusive
`marketing license obtained for nonpatentable drugs. In
`September 1983, FDA issued guidelines for sponsors,
`describing the information to be submitted in order to
`obtain orphan drug designation and protocol assistance.
`Regulations are expected to be issued in 1984.
`FDAhasreceived an appropriation from the Congress
`to support orphan products research. This appropriation
`
`
`Through the combined efforts of agencies and organ-
`izations in the public and private sector, drugs have been
`madeavailable that would not have been at hand without
`a specific focus on the orphan drugissue. It is anticipated
`that these cooperative efforts will continue beyond the
`first enthusiastic burst engendered by the inception of
`new andinteresting activities.
`
`The Population Attributable Risk
`of Hypertension from Heavy
`Alcohol Consumption
`
`E. B. LARBI, MD
`J. STAMLER, MD
`A. DYER, PhD
`R. COOPER, MD
`O. PAUL, MD
`R. B. SHEKELLE, PhD
`M. LEPPER, MD
`
`Dr. Larbi, Dr. Stamler, and Dr. Dyerare with the Department of
`Community Health and Preventive Medicine, Northwestern Uni-
`versity Medical School, Chicago. Dr. Cooper is with the Depart-
`ment of Cardiology, Cook County Hospital, Chicago. Dr. Paul
`is
`with the Department of Medicine, Harvard Medical School,
`Boston, Mass. Dr. Shekelle and Dr. Lepper are with the Depart-
`ment of Preventive Medicine, Rush-Presbyterian-St. Luke’s Medi-
`cal Center, Chicago.
`Tearsheet requests to Jeremiah Stamler, MD, Northwestern Uni-
`versity Medical School, 303 E. Chicago Ave., Chicago, II]. 60611.
`
`Synopsis ........... ins wseisa ni ce co
`
`ns
`
`wi anne a: wenn 6 bed
`
`The prevalence of hypertension among heavy drinkers
`was significantly higher than among those who did not
`drink heavily. Heavy drinking was defined as consump-
`tion offive or more drinks daily or four or more drinks
`daily. A total of 136 persons fulfilled the five drinks or
`more per day definition and 230,
`the four drinks daily
`definition.
`
`The population-attributable risk of hypertension con-
`tributed by heavy drinking, depending on the diagnostic
`criteria used to define each endpoint, variedfrom 3 to 12
`percent. There is reason to suspect that the contribution
`of alcohol to hypertension in the general population may
`be somewhathigher at the present time than in the late
`1950s when the study was conducted.
`
`in addition to
`Moderation of alcohol consumption,
`weight reduction and salt restriction,
`is another impor-
`tant nonpharmacological meansto control hypertension.
`
`The association between alcohol consumption and hy-
`pertension wasstudied in 11,899 men aged 40-55 years.
`
`
`Tie ASSOCIATION BETWEEN EXCESSIVE alcohol con-
`sumption and hypertension, first suggested at the turn of
`the century (/), has been found in several clinical and
`epidemiologic studies (2—/3). While some studies have
`showna linearrelationship, others indicate a U-shaped or
`threshold response. The association is independent of
`age, sex, race, smoking, coffee use, educational attain-
`
`ment, adiposity, social class, and physicial fitness. For-
`mer heavy drinking is not associated with high blood
`pressure; current consumption of alcohol seemsto be the
`essential factor.
`It has been suggested that 10—20 percent of essential
`hypertension in the United States and Australia (5—/4)
`may be due to alcohol use. Recent data from the Kaiser-
`
`316 Public Health Reports
`
`