82 FR 7837 - Determination That ACTHAR GEL SYNTHETIC (Seractide Acetate) Injection, 80 Units/Milliliter and 40 Units/Milliliter, Was Withdrawn From Sale for Reasons of Safety or Effectiveness

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 82, Issue 13 (January 23, 2017)

The Food and Drug Administration (FDA or we) has determined that ACTHAR GEL SYNTHETIC (seractide acetate) injection, 80 units/ milliliter (mL) and 40 units/mL, was withdrawn from sale for reasons of safety or effectiveness. The Agency will not accept or approve abbreviated new drug applications (ANDAs) for seractide acetate injection, 80 units/mL and 40 units/mL.

[Federal Register Volume 82, Number 13 (Monday, January 23, 2017)]
[Notices]
[Pages 7837-7839]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2017-01249]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-P-0377]


Determination That ACTHAR GEL SYNTHETIC (Seractide Acetate) 
Injection, 80 Units/Milliliter and 40 Units/Milliliter, Was Withdrawn 
From Sale for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or we) has determined 
that ACTHAR GEL SYNTHETIC (seractide acetate) injection, 80 units/
milliliter (mL) and 40 units/mL, was withdrawn from sale for reasons of 
safety or effectiveness. The Agency will not accept or approve 
abbreviated new drug applications (ANDAs) for seractide acetate 
injection, 80 units/mL and 40 units/mL.

FOR FURTHER INFORMATION CONTACT: David E. Markert, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6222, Silver Spring, MD 20993-0002, 301-
796-0752.

SUPPLEMENTARY INFORMATION:

I. Background

    In 1984, Congress enacted the Drug Price Competition and Patent 
Term Restoration Act of 1984 (Pub. L. 98-417) (the 1984 amendments), 
which authorized the approval of duplicate versions of drug products 
under an ANDA procedure. ANDA applicants must, with certain exceptions, 
show that the drug for which they are seeking approval contains the 
same active ingredient in the same strength and dosage form as the 
``listed drug,'' which is a version of the drug that was previously 
approved. ANDA applicants do not have to repeat the extensive clinical 
testing otherwise necessary to gain approval of a new drug application 
(NDA).
    The 1984 amendments include what is now section 505(j)(7) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which 
requires FDA to publish a list of all approved drugs. FDA publishes 
this list as part of the ``Approved Drug Products With Therapeutic 
Equivalence Evaluations,'' which is known generally as the ``Orange 
Book.'' Under FDA regulations, drugs are removed from the list if the 
Agency withdraws or suspends approval of the drug's NDA or ANDA for 
reasons of safety or effectiveness or if FDA determines that the listed 
drug was withdrawn from sale for reasons of safety or effectiveness (21 
CFR 314.162).
    A person may petition the Agency to determine, or the Agency may 
determine on its own initiative, whether a listed drug was withdrawn 
from sale for reasons of safety or effectiveness. This determination 
may be made at any time after the drug has been withdrawn from sale, 
but must be made prior to approving an ANDA that refers to the listed 
drug (21 CFR 314.161). FDA may not approve an ANDA that does not refer 
to a listed drug.
    ACTHAR GEL SYNTHETIC (seractide acetate) injection, 80 units/mL and 
40 units/mL was the subject of NDA 017861, which was held by Armour 
Pharmaceutical Co. (Armour), and initially approved on February 21, 
1978. ACTHAR GEL SYNTHETIC is indicated for diagnostic testing of 
adrenocortical function. The labeling also provides that ACTHAR GEL 
SYNTHETIC may be employed in the following disorders:
    Endocrine Disorders: Nonsuppurative thyroiditis; Hypercalcemia 
associated with cancer.
    Nervous System Diseases: Acute exacerbations of multiple sclerosis.
    Rheumatic Disorders: As adjunctive therapy for short-term 
administration (to tide the patient over an acute episode or 
exacerbation) in: Psoriatic arthritis; rheumatoid arthritis, including 
juvenile

[[Page 7838]]

rheumatoid arthritis (selected cases may require low-dose maintenance 
therapy); ankylosing spondylitis; acute and subacute bursitis; acute 
non-specific tenosynovitis; acute gouty arthritis; post-traumatic 
arthritis; synovitis of osteoarthritis; epicondylitis.
    Collagen Diseases: During an exacerbation or as maintenance therapy 
in selected cases of: Systemic lupus erythematosus; systemic 
dermatomyositis (polymyositis); acute rheumatic carditis.
    Dermatologic Diseases: Pemphigus; bullous dermatitis herpetiformis; 
severe erythema multiforme (Stevens-Johnson syndrome); exfoliative 
dermatitis; severe psoriasis; severe seborrheic dermatitis; mycosis 
fungoides.
    Allergic States: Control of severe or incapacitating allergic 
conditions intractable to adequate trials of conventional treatment--
seasonal or perennial allergic rhinitis; bronchial asthma; contact 
dermatitis; atopic dermatitis; serum sickness.
    Ophthalmic Diseases: Severe acute and chronic allergic and 
inflammatory processes involving the eye and its adnexa such as: 
Allergic conjunctivitis; keratitis; herpes zoster ophthalmicus; iritis 
and iridocyclitis; diffuse posterior uveitis and choroiditis; optic 
neuritis; sympathetic ophthalmia; chorioretinitis; anterior segment 
inflammation; allergic corneal marginal ulcers.
    Respiratory Diseases: Symptomatic sarcoidosis; Loeffler's syndrome 
not manageable by other means; berylliosis; fulminating or disseminated 
pulmonary tuberculosis when used concurrently with anti-tuberculous 
chemotherapy; aspiration pneumonitis.
    Hematologic Disorders: Acquired (autoimmune) hemolytic anemia; 
secondary thrombocytopenia in adults; erythroblastopenia (RBC anemia); 
congenital (erythroid) hypoplastic anemia.
    Neoplastic Diseases: For palliative management of: Leukemias and 
lymphomas in adults; acute leukemia of childhood.
    Edematous State: To induce a diuresis or a remission of proteinuria 
in the nephrotic syndrome without uremia of the idiopathic type or that 
due to lupus erythematosus.
    Gastrointestinal Diseases: To tide the patient over a critical 
period of the disease in: Ulcerative colitis; regional enteritis.
    Miscellaneous: Tuberculous meningitis with subarachnoid block or 
impending block when concurrently accompanied by appropriate anti-
tuberculous chemotherapy; trichinosis with neurologic or myocardial 
involvement.
    Armour never marketed ACTHAR GEL SYNTHETIC (seractide acetate) 
injection, 80 units/mL and 40 units/mL. In previous instances (see, 
e.g., 72 FR 9763, March 5, 2007 and 61 FR 25497, May 21, 1996), the 
Agency has determined that for purposes of Sec. Sec.  314.161 and 
314.162, never marketing an approved drug product is equivalent to 
withdrawing the drug from sale. FDA withdrew approval of the NDA for 
ACTHAR GEL SYNTHETIC in 2014 because Armour had repeatedly failed to 
file annual reports for the application (79 FR 68454, November 17, 
2014).
    Hyman, Phelps & McNamara, P.C., submitted a citizen petition dated 
April 1, 2014 (Docket No. FDA-2014-P-0377), under 21 CFR 10.30, 
requesting that the Agency determine whether ACTHAR GEL SYNTHETIC 
(seractide acetate) injection, 80 units/mL and 40 units/mL, was 
withdrawn from sale for reasons of safety or effectiveness.

II. Response to Citizen Petition

    We have carefully reviewed the citizen petition (and comments 
submitted to the docket); our records for ACTHAR GEL SYNTHETIC 
(seractide acetate) injection, 80 units/mL and 40 units/mL; the 
scientific literature on seractide acetate; and other relevant 
information. Based on that review, and for the reasons set forth in 
this section, we have concluded that additional studies of safety would 
be necessary before ACTHAR GEL SYNTHETIC could be considered for 
introduction to the market today. Consequently, FDA has determined 
under Sec.  314.161 that ACTHAR GEL SYNTHETIC (seractide acetate) 
injection, 80 units/mL and 40 units/mL, was withdrawn for reasons of 
safety.\1\
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    \1\ In light of this conclusion, it is unnecessary for us to 
determine whether ACTHAR GEL SYNTHETIC was also withdrawn from sale 
for reasons of effectiveness. This notice does not address the 
effectiveness of ACTHAR GEL SYNTHETIC for its labeled indications.
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    The labeling for ACTHAR GEL SYNTHETIC describes the product as ``a 
highly purified synthetic polypeptide containing thirty-nine amino 
acids in the sequence described for human corticotropin by Lee, T.H.; 
Lerner, A.B.; and Buettner-Janusch, Vina (J. Biol Chem, 236:2970-2974, 
Nov. 1961)'' (Refs. 1 and 2). At the time of ACTHAR GEL SYNTHETIC's 
approval, FDA believed the amino acid sequence described by Lee et al. 
was the correct sequence for human corticotropin and, therefore, that 
ACTHAR GEL SYNTHETIC was identical to human corticotropin.\2\ However, 
since approval, the Agency has learned that ACTHAR GEL SYNTHETIC is not 
identical to the human corticotropin sequence. We now know that the 
amino acid sequence described by Lee et al. is a deamidated version of 
human corticotropin that differs from full length human corticotropin 
at four positions.\3\
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    \2\ The Agency's Institutional Summary of Basis of Approval 
(Ref. 3) describes ACTHAR GEL SYNTHETIC as ``a synthetic peptide of 
39 amino acids identical with that of natural human'' corticotropin.
    \3\ The record for human pro-opiomelanocortin preproprotein in 
the National Center for Biotechnology Information's ``Protein'' 
database (Reference Sequence NP_000930.1) contains the correct amino 
acid sequence for human corticotropin. The record is available at 
the following URL: https://www.ncbi.nlm.nih.gov/protein/NP_000930.1. 
The sequence described by Lee et al. differs from the correct 
sequence at positions 25-27 and 30.
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    The fact that ACTHAR GEL SYNTHETIC has a different amino acid 
sequence from human corticotropin raises significant safety concerns. 
Due to its different amino acid sequence, ACTHAR GEL SYNTHETIC might 
have a structure or function that is not recognized as endogenous by 
the immune system. ACTHAR GEL SYNTHETIC thus poses a higher risk of 
immunogenicity than a synthetic peptide product that is, in fact, 
identical to human corticotropin. The health consequences of 
immunogenicity range from subacute, minor reactions to severe, even 
deadly, reactions (e.g., anaphylaxis). In addition, frequent 
stimulation of the immune system could produce antibodies that cross-
react with human corticotropin and other closely related endogenous 
peptides, resulting in the loss of those peptides' physiological 
functions. Such an effect could last long after treatment with ACTHAR 
GEL SYNTHETIC has stopped.
    The safety concerns noted in this section have not been adequately 
investigated. ACTHAR GEL SYNTHETIC was studied in two clinical trials 
in 51 healthy adult men between 21 and 54 years old. Although no 
unusual adverse effects were reported during these trials, the trials 
did not assess the impact of immunogenicity on safety. Nor were they 
designed to assess immunogenicity. Moreover, because ACTHAR GEL 
SYNTHETIC was never marketed, the Agency has no postmarketing safety 
data or information confirming that the product is safe for human use, 
notwithstanding the differences between ACTHAR GEL SYNTHETIC's amino 
acid sequence and that of human corticotropin. Given the lack of any 
premarket or postmarket

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immunogenicity safety data, FDA cannot conclude that ACTHAR GEL 
SYNTHETIC would be safe for human use if it were introduced to the 
market today.
    Accordingly, the Agency will remove ACTHAR GEL SYNTHETIC (seractide 
acetate) injection, 80 units/mL and 40 units/mL, from the list of drug 
products published in the Orange Book. FDA will not accept or approve 
ANDAs that refer to this drug product.

III. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they are also available electronically at https://www.regulations.gov.

1. Armour Pharmaceutical Co., ``ACTHAR[supreg] Gel Synthetic 
(SERACTIDE ACETATE), Synthetic Corticotropin,'' Product Labeling, 
1979.
2. Lee, T. H., A. B. Lerner, and V. Buettner-Janusch, ``On the 
Structure of Human Corticotropin (Adrenocorticotropic Hormone),'' 
The Journal of Biological Chemistry, vol. 236, pp. 2970-2974, 1961.
3. FDA, ``Seractide Acetate: Institutional Summary of Basis of 
Approval,'' August 22, 1977.

    Dated: January 13, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-01249 Filed 1-19-17; 8:45 am]
 BILLING CODE 4164-01-P