List of Bulk Drug Substances for Which There Is a Clinical Need Under the Federal Food, Drug, and Cosmetic Act

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice.

SUMMARY:

The Food and Drug Administration (FDA or Agency) is developing a list of bulk drug substances (active pharmaceutical ingredients) for which there is a clinical need (the 503B Bulks List). Drug products that outsourcing facilities compound using bulk drug substances on the 503B Bulks List can qualify for certain exemptions from the Federal Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are met. This notice identifies one bulk drug substance that FDA has considered and proposes to include on the 503B Bulks List: Quinacrine hydrochloride (“quinacrine”). This notice identifies four bulk drug substances that FDA has considered and proposes not to include on the list: Bromfenac sodium, mitomycin-C, nepafenac, and hydroxychloroquine sulfate. Additional bulk drug substances nominated by the public for inclusion on this list are currently under consideration and may be the subject of future notices.

DATES:

Submit either electronic or written comments on the notice by May 24, 2021.

ADDRESSES:

You may submit comments as follows. Please note that late, untimely filed comments will not be considered. Electronic comments must be submitted on or before May 24, 2021. The https://www.regulations.gov electronic filing system will accept comments until 11:59 p.m. Eastern Time at the end of May 24, 2021. Comments received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are postmarked or the delivery service acceptance receipt is on or before that date.

Electronic Submissions

Submit electronic comments in the following way:

• Federal eRulemaking Portal: https://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https://www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov.
• If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”).

Written/Paper Submissions

Submit written/paper submissions as follows:

• Mail/Hand Delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in “Instructions.”

Instructions: All submissions received must include the Docket No. FDA-2018-N-3240 for “List of Bulk Drug Substances for Which There is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act.” Received comments, those filed in a timely manner (see ADDRESSES), will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.

• Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.

Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT:

Elizabeth Hankla, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5216, Silver Spring, MD 20993, 240-402-3359.

SUPPLEMENTARY INFORMATION:

I. Background

Section 503B of the FD&C Act (21 U.S.C. 353b) describes the conditions that must be satisfied for drug products compounded by an outsourcing facility to be exempt from section 505 (21 U.S.C. 355) (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)), section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate directions for use), and section 582 of the FD&C Act (21 U.S.C. 360eee-1) (concerning drug supply chain security requirements).

Drug products compounded that meet the conditions in section 503B are not exempt from current good manufacturing practice (CGMP) requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)). Outsourcing facilities are also subject to FDA inspections according to a risk-based schedule, specific adverse event reporting requirements, and other conditions that help to mitigate the risks of the drug products they compound. Outsourcing facilities may or may not obtain prescriptions for identified individual patients and can, therefore, distribute compounded drugs to healthcare practitioners for “office stock,” to hold in their offices in advance of patient need.

One of the conditions that must be met for a drug product compounded by an outsourcing facility to qualify for exemptions under section 503B of the FD&C Act is that the outsourcing facility may not compound a drug using a bulk drug substance unless: (1) The bulk drug substance appears on a list established by the Secretary of Health and Human Services identifying bulk drug substances for which there is a clinical need (the 503B Bulks List) or (2) the drug compounded from such bulk drug substances appears on the drug shortage list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing.

Section 503B of the FD&C Act directs FDA to establish the 503B Bulks List by: (1) Publishing a notice in the Federal Register proposing bulk drug substances to be included on the list, including the rationale for such proposal; (2) providing a period of not less than 60 calendar days for comment on the notice; and (3) publishing a notice in the Federal Register designating bulk drug substances for inclusion on the list.

FDA has published a series of Federal Register notices addressing bulk drug substances nominated for inclusion on the 503B Bulks List. This notice identifies one bulk drug substance that FDA has considered and proposes to include on the 503B Bulks List and four bulk drug substances that FDA has considered and proposes not to include on the 503B Bulks List.

For purposes of section 503B of the FD&C Act, bulk drug substance means an active pharmaceutical ingredient as defined in 21 CFR 207.1. Active pharmaceutical ingredient means any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body, but the term does not include intermediates used in the synthesis of the substance.

For further information about drug compounding and the background for the 503B Bulks List, see 83 FR 43877 (August 28, 2018).

II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

FDA requested nominations for specific bulk drug substances for the Agency to consider for inclusion on the 503B Bulks List in the Federal Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination process in the Federal Register of July 2, 2014 (79 FR 37747), and provided more detailed information on what FDA needs to evaluate nominations for the list. On October 27, 2015 (80 FR 65770), the Agency opened a new docket, FDA-2015-N-3469, to provide an opportunity for interested persons to submit new nominations of bulk drug substances or to renominate substances with sufficient information.

As FDA evaluates bulk drug substances, it intends to publish notices for public comment in the Federal Register that describe the FDA's proposed position on each substance along with the rationale for that position. After considering any comments on FDA's proposals regarding whether to include nominated substances on the 503B Bulks List, FDA intends to consider whether input from the Pharmacy Compounding Advisory Committee (PCAC) on the nominations would be helpful to the Agency in making its determination, and if so, it will seek PCAC input. Depending on its review of the docket comments and other relevant information before the Agency, FDA may finalize its proposed determination without change, or it may finalize a modification to its proposal to reflect new evidence or analysis regarding clinical need. FDA will then publish in the Federal Register a list identifying the bulk drug substances for which it has determined there is a clinical need and FDA's rationale in making that final determination. FDA will also publish in the Federal Register a list of those substances it considered but found that there is no clinical need to use in compounding and FDA's rationale in making this decision.

FDA intends to maintain a list of all bulk drug substances it has evaluated on its website, and separately identify bulk drug substances it has placed on the 503B Bulks List and those it has decided not to place on the 503B Bulks List. This list is available at https://www.fda.gov/media/120692/download. FDA will only place a bulk drug substance on the 503B Bulks List where it has determined there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance. If a clinical need to compound drug products using the bulk drug substance has not been demonstrated, based on the information submitted by the nominator and any other information considered by the Agency, FDA will not place a bulk drug substance on the 503B Bulks List.

FDA is evaluating bulk drug substances nominated for the 503B Bulks List on a rolling basis. FDA intends to evaluate and publish in the Federal Register its proposed and final determinations in groups of bulk drug substances until all nominated substances that were sufficiently supported have been evaluated and either placed on the 503B Bulks List or identified as bulk drug substances that were considered but determined not to be appropriate for inclusion on the 503B Bulks List (Ref. 1).

B. Analysis of Substances Nominated for the List

As noted above, the 503B Bulks List will include bulk drug substances for which there is a clinical need. The Agency is currently evaluating bulk drug substances that were nominated for inclusion on the 503B Bulks List, proceeding case by case, under the clinical need standard provided by the statute (Ref. 2). In applying this standard to develop the proposals in this notice, FDA is interpreting the phrase “bulk drug substances for which there is a clinical need” to mean that the 503B Bulks List may include a bulk drug substance if: (1) There is a clinical need for an outsourcing facility to compound the drug product and (2) the drug product must be compounded using the bulk drug substance. FDA is not interpreting supply issues, such as backorders, to be within the meaning of “clinical need” for compounding with a bulk drug substance. Section 503B separately provides for compounding from bulk drug substances under the exemptions from the FD&C Act discussed above if the drug product compounded from the bulk drug substance is on the FDA drug shortage list at the time of compounding, distribution, and dispensing. Additionally, we are not considering cost of the compounded drug product as compared with an FDA-approved drug product to be within the meaning of “clinical need.”

Some of the bulk drug substances that we are addressing in this notice are components of FDA-approved drug products, and we therefore began our evaluation of these bulk drug substances by asking one or both of the following questions:

(1) Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that: (a) An attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and (b) the drug product proposed to be compounded is intended to address that attribute?

(2) Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product?

The reason for question 1 is that unless an attribute of the FDA-approved drug is medically unsuitable for certain patients, and a drug product compounded using a bulk drug substance that is a component of the approved drug is intended to address that attribute, there is no clinical need to compound a drug product using that bulk drug substance. Rather, such compounding would unnecessarily expose patients to the risks associated with drug products that do not meet the standards applicable to FDA-approved drug products for safety, effectiveness, quality, and labeling and would undermine the drug approval process. The reason for question 2 is that to place a bulk drug substance on the 503B Bulks List, FDA must determine that there is a clinical need for outsourcing facilities to compound a drug product using the bulk drug substance rather than starting with an FDA-approved drug product.

If the answer to both of these questions is “yes,” there may be a clinical need for outsourcing facilities to compound using the bulk drug substance, and we would evaluate the substance further, applying the factors described below. If the answer to either of these questions is “no,” we generally would not include the bulk drug substance on the 503B Bulks List, because there would not be a basis to conclude that there may be a clinical need to compound drug products using the bulk drug substance instead of administering or compounding starting with an approved drug product. FDA did not answer “yes” to both of the threshold questions for the four bulk drug substances that are components of approved drug products that we are addressing in this notice. Accordingly, as explained further below, we did not proceed further in our evaluation of these substances and are proposing not to include them on the 503B Bulks List.

With respect to one bulk drug substance we are addressing in this notice that is not a component of an FDA-approved drug product, quinacrine, we are conducting a balancing test with four factors, considering each factor in the context of the others and balancing them to determine whether the statutory “clinical need” standard has been met. The balancing test includes the following factors:

• The physical and chemical characterization of the substance;
• any safety issues raised by the use of the substance in compounding;
• the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists; and
• current and historical use of the substance in compounded drug products, including information about the medical condition(s) that the substance has been used to treat and any references in peer-reviewed medical literature.

The discussion below reflects FDA's consideration of these four factors where they are applicable and describes how they were applied to develop FDA's proposal to include one bulk drug substance on the 503B Bulks List.

C. Inclusion of a Bulk Drug Substance on the 503B Bulks List

In preparing its proposal to include a substance on the 503B Bulks List, FDA considered whether the clinical need for the bulk drug substance in the compounded drug product is limited, by, for example, route of administration or dosage form. As appropriate, and as explained further below, the Agency tailored its proposed entry on the 503B Bulks List to reflect its findings related to clinical need for the bulk substance proposed for inclusion on the list. Specifically, the proposed entry would authorize use of this bulk drug substance to compound drug products for oral use only.

III. Substance Considered and Proposed for Inclusion on the 503B Bulks List

Because the substance in this section is not a component of an FDA-approved drug product, we applied the balancing test described above. The bulk drug substance that has been evaluated and that FDA is proposing to place on the 503B Bulks List is quinacrine HCl. The reasons for FDA's proposal is included below (Ref. 3).

Quinacrine

FDA nominated quinacrine as a bulk drug substance for the 503B Bulks List to compound drug products in oral dosage forms at strengths of 25-100 milligram (mg) for the treatment of cutaneous lupus erythematosus (CLE). The nominated bulk drug substance is not a component of an FDA-approved drug product. We evaluated quinacrine for potential inclusion on the 503B Bulks List under the clinical need standard in section 503B of the FD&C Act, considering data and information regarding the physical and chemical characterization of quinacrine, safety issues raised by use of this substance in compounding, available evidence of effectiveness or lack of effectiveness, and historical and current use in compounding (Ref. 3).

Quinacrine is well-characterized physically and chemically. Although there are concerns about its safety profile in certain patient populations, we believe these risks are well known within the rheumatology and dermatology specialties that most often treat CLE, and the known risks could be controlled with appropriate dosing and monitoring. Quinacrine has been used for several decades to treat systemic lupus erythematosus and CLE, and there is a significant body of experience, documented in the scientific literature, that quinacrine may be effective in the treatment of patients with cutaneous lupus, and patients who are not fully clinically responsive to, or are intolerant of, treatment with FDA approved products alone. These patients may respond to the addition of quinacrine to their existing therapy, or to the use of quinacrine alone. On balance, the physical and chemical characterization, safety, effectiveness, and historical and current use of quinacrine weigh in favor of including this substance on the 503B Bulks List. Accordingly, we propose adding quinacrine to the 503B Bulks List for oral use only. We have not identified sufficient evidence to support its use in other routes of administration.

Due to the safety risks referred to above, if quinacrine is placed on the 503B Bulks List, FDA intends to make safety information about the use of quinacrine available to prescribers, pharmacists, outsourcing facilities, and the public through information on FDA's website, in a safety guide, or through other mechanisms, as appropriate.

IV. Substances Evaluated and Not Proposed for Inclusion on the 503B Bulks List

Because the substances in this section are components of FDA-approved drug products, we considered one or both of the following questions: (1) Is there is a basis to conclude that an attribute of each FDA-approved drug product containing the bulk drug substance makes each one medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and the drug product proposed to be compounded is intended to address that attribute and (2) is there a basis to conclude that the drug product proposed to be compounded must be compounded using a bulk drug substance.

The four bulk drug substances that have been evaluated and that FDA is proposing not to place on the list are as follows: Bromfenac sodium, mitomycin-C, nepafenac, and hydroxychloroquine sulfate. The reasons for FDA's proposals are included below.

A. Bromfenac Sodium

Bromfenac sodium was nominated in combination with moxifloxacin hydrochloride and prednisolone for inclusion on the 503B Bulks List to compound drug products for postoperative inflammation and pain following cataract surgery. The proposed route of administration is ophthalmic, the proposed dosage forms are an ophthalmic injection and a topical ophthalmic solution, and the proposed compounded product is prednisolone-moxifloxacin-bromfenac (1-0>.5/0.4 percent). The nominated bulk drug substance, bromfenac sodium, is a component of FDA-approved drug products (e.g., ANDA 203395, NDA 206911, and NDA 203168). FDA has approved bromfenac sodium products as 0.07 percent, 0.075 percent, and 0.09 percent EQ acid ophthalmic solution. The nomination proposes to combine bromfenac sodium with two other bulk drug substances, moxifloxacin hydrochloride and prednisolone, both of which are components of FDA-approved products. Prednisolone acetate is a component of FDA-approved drug products (NDA 017469 and NDA 017011) and is available in a 1 milliliter (mL), 5 mL, 10 mL, and 15 mL suspension containing prednisolone acetate 1.0 percent. Moxifloxacin hydrochloride is a component of FDA-approved drug products (e.g., NDA 021598 and NDA 022428) and is available as an EQ 0.5 percent base ophthalmic solution.

1. Suitability of FDA-Approved Drug Product(s)

The nomination does not identify a medical unsuitability in any of the FDA-approved products that contain bromfenac, prednisolone, or moxifloxacin hydrochloride when these products are administered separately. Instead, it states that the single active-ingredient formulation of these products may make them unsuitable for co-administration after ocular surgeries. Specifically, the nomination states that “Compounded formulations may alleviate the need for multiple postoperative drops. Topical compounded formulations also may improve patient compliance and alleviate patient confusion because they typically require use of fewer drops.”

However, the labeling for the FDA-approved bromfenac sodium products (e.g., ANDA 203395) specifically warns against the use of bromfenac sodium with topical corticosteroids, which include prednisolone. This is because the use of bromfenac sodium with topical corticosteroids may increase the potential for healing problems. The nomination does not address this warning or provide support for the co-administration of these drug products. We decline to find that the approved drugs are medically unsuitable for some patients because they may be difficult to administer to patients under circumstances that are specifically warned against in the approved labeling.

Because co-administration of these products is the subject of a labeled warning, and therefore an inappropriate basis for a finding of clinical need, we do not evaluate the nomination's claims further. However, to help explain our thinking about this nomination and inform public comment, we address the nomination's statement that there is a clinical need to compound a drug containing multiple active ingredients because it may improve patient compliance relative to prescribing FDA-approved drugs that contain a single active ingredient. The nomination does not state that the approved drugs would be medically unsuitable for some patients for the conditions identified in the nomination, and it does not provide data or evidence to support that proposition. Reducing the number of drugs administered for the purpose of convenience is not “clinical need”; medical unsuitability of the approved drugs is required. While clinical need does not have to be fully established in FDA's analysis of questions 1 and 2, there must be a basis to conclude that such a need may exist before FDA will proceed to the more searching analysis conducted under the balancing test. No such basis is present here.

Accordingly, with respect to the bromfenac sodium drug products proposed to be compounded by the nominator, FDA finds no basis to conclude that there is an attribute of each of the FDA approved drug products that makes each one medically unsuitable to treat certain patients who undergo cataract surgery. There is therefore no attribute of the approved drug products that the proposed compounded drug products are intended to address.

2. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance

Because we have not identified a population for whom the approved products are medically unsuitable for the proposed uses under question 1, we are not considering whether there is a basis to conclude that the drug products proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product under question 2.

3. Additional Comments

For the reasons stated above, we are not evaluating this nomination under the balancing test. However, if this nomination for bromfenac sodium was to proceed to the balancing test, there would be some significant safety and effectiveness concerns to evaluate, which are not addressed in the nomination.

Each of the three ingredients proposed to be used in combination by the nomination is indicated for different medical conditions and has a different FDA-approved dosing regimen: Once daily for bromfenac sodium 0.09 percent, four times daily for prednisolone acetate and three times daily for moxifloxacin hydrochloride. The duration of treatment for each individual drug also differs.

The nomination also describes compounding drug products that include bromfenac sodium in a concentration (EQ 0.4 percent acid) that is more than four times higher than the FDA-approved product (the approved product is available at concentrations of EQ 0.07 percent acid, EQ 0.075 percent acid, and EQ 0.09 percent acid). The nomination does not provide any data or information supporting the need for a higher concentration than the approved drug.

Most of the bulk drug substance nominations FDA has evaluated to date have only proposed to compound drug products containing a single active ingredient. This nomination proposed to compound drug products containing more than one active ingredient. If FDA finalizes its proposal not to include bromfenac sodium on the 503B Bulks List, we intend to remove the substance from Category 1 for purposes of the Interim Policy, which would mean that ophthalmic solutions compounded using the bulk drug substance bromfenac sodium, including the proposed compounded products addressed in this notice, would fall outside the enforcement discretion described in the Interim Policy. We note that FDA's evaluation of bromfenac sodium for inclusion on the 503B Bulks List will not impact FDA's evaluation of any other bulk drug substances for inclusion on the 503B Bulks List, including prednisolone and moxifloxacin hydrochloride, because each bulk drug substance nominated for inclusion on the 503B Bulks List undergoes its own evaluation. We previously proposed not to include moxifloxacin hydrochloride on the 503B Bulks List (85 FR 46126), and we are currently reviewing comments on that nomination. Nominations for prednisolone, if they are not withdrawn, remain the subject of future evaluations. Finally, if FDA determines there is a clinical need for outsourcing facilities to use bulk drug substances to compound the proposed drug products, we would include each substance or combination of substances, as appropriate, on the 503B Bulks List at the time that final determination is made.

B. Mitomycin-C

Mitomycin-C was nominated for inclusion on the 503B Bulks List to compound drug products that treat stomach, pancreas, anal (nonmetastatic), bladder, cervical (recurrent or metastatic), esophageal, gastric, and non-small cell lung cancer. The proposed route of administration is injection and the proposed concentration is 20-40 mg. We evaluated the proposed products for both the intravenous and intravesical routes of administration because the nomination proposed that there is a need for a compounded mitomycin-C drug product for injection and we understand that mitomycin-C is used for both intravesical and intravenous administration in certain oncological conditions. The nominated bulk drug substance is a component of FDA-approved drug products (e.g., ANDA 064144, NDA 022572, and NDA 211728). FDA-approved mitomycin-C (e.g., ANDA 064114) is available as a 5, 20, and 40 mg/mL vial for intravenous administration. Mitomycin is also approved as a 0.2 mg vial, which when reconstituted with Sterile Water for Injection, provides a solution for application in glaucoma filtration surgery for use as an adjunct to ab externo glaucoma surgery (e.g., NDA 022572).

1. Suitability of FDA-Approved Drug Product(s)

Regarding the proposed use to treat bladder cancer, the nomination does not explain why an attribute of each of the FDA-approved 5, 20, and 40 mg vials of lyophilized powder for reconstituting into solution is medically unsuitable for the proposed use. For example, if there are patients for whom products for intravenous administration would be medically unsuitable, the nomination does not provide support or explain why the FDA-approved products, or products prepared using the FDA-approved products could not be used for intravesical administration. The nomination states that it may be necessary to compound a mitomycin-C drug product to attain a “higher, more efficacious dose,” but the nomination does not identify any specific higher concentrations that the nominator proposes to compound. The approved product is available as a lyophilized powder, which according to the approved labeling, is reconstituted to a final concentration of 0.5 mg/mL or below. While the nomination includes two articles which indicate that there could be a need for a product with a concentration above 0.5 mg/mL, the nomination does not identify an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients and that the proposed compounded drug products are intended to address. Further, the nomination proposes to “include excipients to prevent urine acidification,” but the nomination does not identify which excipients are proposed for the compounded product, nor does the nomination provide any data or information supporting how the proposed compounded drug products will address that concern.

Regarding the proposed use to treat stomach, pancreas, anal (nonmetastic), cervical (recurrent or metastic), esophageal, gastric, and non-small cell lung cancer, the nomination does not identify an attribute for each FDA-approved product that makes it medically unsuitable to treat certain patients for these conditions and that the proposed compounded products are intended to address.

Accordingly, with respect to the mitomycin products proposed to be compounded, FDA finds no basis to conclude that an attribute of the FDA-approved products makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that the proposed compounded drug products are intended to address.

2. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance

Because the nomination does not identify a population for whom the FDA-approved products are medically unsuitable for the proposed uses, FDA did not consider whether there is a basis to conclude that the drug products proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product under question 2.

C. Nepafenac

Nepafenac was nominated in combination with other bulk drug substances, including prednisolone and gatifloxacin, for inclusion on the 503B Bulks List to compound drug products for “post cataract surgery ocular complications related to pain, inflammation or bacterial conjunctivitis.” The proposed route of administration is topical ophthalmic, the proposed dosage forms are a preserved (multidose) and a preservative-free (unit dose) topical ophthalmic suspension, and the proposed compounded products are: (1) “Nepafenac 0.1%-Prednisolone 1%;” and (2) “Nepafenac 0.1%-Prednisolone 1%-Gatifloxacin 0.5%.” The nominated bulk drug substance, nepafenac, is a component of FDA-approved drug products (e.g., NDA 021862 and NDA 203491). FDA has approved nepafenac as 1.7 mL dropper bottle, and a 4 mL dropper bottle filled with 3 mL sterile ophthalmic suspension containing 0.1 percent (1 mg/mL) nepafenac and as a 4 mL bottle filled with 1.7 mL and 3 mL sterile ophthalmic suspension containing 0.3 percent (3 mg/mL) nepafenac for topical administration. The nomination proposes to combine nepafenac with two other bulk drug substances, prednisolone and gatifloxacin, both of which are components of FDA-approved products. Prednisolone acetate is a component of FDA-approved drug products (NDA 017469 and NDA 017011) and is available in a 1 mL, 5 mL, 10 mL, and 15 mL suspension containing prednisolone acetate 1.0 percent. Gatifloxacin is a component of FDA-approved drug products (e.g., NDA 022548), and is available in a 1 mL or 2.5 mL solution containing gatifloxacin .5 percent.

1. Suitability of FDA-Approved Drug Product(s)

The nomination does not identify a medical unsuitability in any of the FDA-approved products that contain nepafenac, prednisolone, or gatifloxacin when these products are administered separately. Instead, it states that the single active-ingredient formulation of these products may make them unsuitable for co-administration after ocular surgeries. Specifically, the nomination states that “[a]s a solution, fixed-dosage ophthalmic drug combinations of different pharmacological classes can be efficacious, reduce the side effects of each component and improve patient compliance.” However, the labeling for the FDA-approved nepafenac products (e.g., NDA 021862 and NDA 203491) specifically warns against the use of nepafenac with topical corticosteroids, which include prednisolone. This is because the use of nepafenac with topical corticosteroids may increase the potential for healing problems. The nomination does not address this warning or provide support for the co-administration of these drug products. We decline to find that the approved drugs are medically unsuitable for some patients because they may be difficult to administer to patients under circumstances that are specifically warned against in the approved labeling.

Because co-administration of these products is the subject of a labeled warning, and therefore an inappropriate basis for a finding of clinical need, we do not evaluate the nomination's claims further. However, to help explain our thinking about this nomination and inform public comment, we address the nomination's statement that there is a clinical need to compound a drug containing multiple active ingredients because it may improve patient compliance relative to prescribing FDA-approved drugs that contain a single active ingredient. The nomination does not state that the approved drugs would be medically unsuitable for some patients for the conditions identified in the nomination, and it does not provide data or evidence to support that proposition. Reducing the number of drugs administered for the purpose of convenience is not “clinical need”; medical unsuitability of the approved drugs is required. While clinical need does not have to be fully established in FDA's analysis of questions 1 and 2, there must be a basis to conclude that such a need may exist before FDA will proceed to the more searching analysis conducted under the balancing test. No such basis is present here.

Accordingly, with respect to the nepafenac drug products proposed to be compounded by the nominator, FDA finds no basis to conclude that there is an attribute of each of the approved drug products that makes each one medically unsuitable to treat certain patients who undergo cataract surgery. There is therefore no attribute of the approved drug products that the proposed compounded drug products are intended to address.

2. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance

Because the nominator has not identified a population for whom the approved products are medically unsuitable for the proposed uses under question 1, we are not considering whether there is a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product under question 2.

3. Additional Comments

Finally, if this nomination for nepafenac were to proceed to the balancing test, there would be some significant safety and effectiveness concerns to evaluate, which are not addressed in the nomination. Each of the three proposed ingredients intended to be compounded into a single drug product is indicated for different medical conditions and has different FDA-approved dosing regimens: One-time daily for nepafenac, four times daily for prednisolone, and two to eight times daily for gatifloxacin. The duration of treatment for each individual drug also differs, as do the approved indications.

Most of the bulk drug substance nominations FDA has evaluated to date have only proposed to compound drug products containing a single active ingredient. This nomination proposed to compound drug products containing more than one active ingredient. If FDA finalizes its proposal not to include nepafenac on the 503B Bulks List, we intend to remove the substance from Category 1 for purposes of the Interim Policy, which would mean that ophthalmic solutions compounded using the bulk drug substance nepafenac, including the proposed compounded products addressed in this notice, would fall outside the enforcement discretion described in the Interim Policy. We note that FDA's evaluation of nepafenac for inclusion on the 503B Bulks List will not impact FDA's evaluation of any other bulk drug substances for inclusion on the 503B Bulks List, including prednisolone and gatifloxacin, because each bulk drug substance nominated for inclusion on the 503B Bulks List undergoes its own evaluation. Nominations for prednisolone, if they are not withdrawn, remain the subject of future evaluations. Gatifloxacin has not been nominated for inclusion on the 503B Bulks List, and therefore has not been categorized under the Interim Policy; its status under the Interim Policy will not be affected if this proposal is finalized. Finally, if FDA determines there is a clinical need for outsourcing facilities to use bulk drug substances to compound the proposed drug products, we would include each substance or combination of substances, as appropriate, on the 503B Bulks List at the time that final determination is made.

D. Hydroxychloroquine Sulfate

Hydroxychloroquine sulfate was nominated for inclusion on the 503B Bulks List to compound drug products that treat rheumatoid arthritis and juvenile arthritis (also known as juvenile idiopathic arthritis). The proposed route of administration is oral, the proposed dosage forms are a capsule or suspension, and the proposed concentrations are 200-500 mg capsules and 100-200 mg/mL suspension. The nominated bulk drug substance is a component of FDA-approved drug products (e.g., NDA 009768, ANDA 040104, and ANDA 213342). FDA-approved hydroxychloroquine sulfate is available as 200 mg (equivalent to 155 mg of hydroxychloroquine base), film-coated tablets for oral administration.

1. Suitability of FDA-Approved Drug Product(s)

There is a basis to conclude that an attribute of the approved hydroxychloroquine sulfate tablets for oral administration makes them medically unsuitable for the treatment of some patients with rheumatoid arthritis and juvenile arthritis. The nomination suggests that the approved oral tablets, a solid oral dosage form, are medically unsuitable in pediatric patients who are unable to swallow tablets. We agree that there may be certain patients for whom the approved oral tablets are medically unsuitable and this would depend on a patient's clinical presentation and age, among other considerations. As a general matter, the drug product proposed to be compounded appears to be intended to address the potential unsuitability of a solid oral dosage form because the nominator proposes to compound a suspension of hydroxychloroquine sulfate for oral administration.

The nominator further states that “pediatric dosing is not standardized but weight-based, making getting the correct dose difficult with tablets.” We agree that an oral suspension could allow for more flexible dosing when compared to the approved tablets when following weight-based dosing recommendations, and that this also supports the proposition that the approved product may be unsuitable for certain patients.

In addition to the proposed suspension, the nominator also proposes to compound hydroxychloroquine sulfate 200-500 mg capsules for oral administration. The nomination does not explain how the proposed compounded capsule products are intended to address the medical unsuitability of the approved product. Similar to tablets, capsules are less flexible in dosing and would be difficult for patients to take if they are unable to swallow tablets. In addition, the nomination does not identify any data or information as to the need for compounded products with a higher concentration than the approved product.

The nomination also claims that some patients are “unable to tolerate excipients” in the approved product, but the nomination does not identify which excipients they are referring to, nor do they provide any data or information supporting how the proposed drug products will address that particular attribute.

2. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance

Because there is a basis to conclude that an attribute of the approved hydroxychloroquine sulfate tablets makes them medically unsuitable for some patients, and the proposed compounded oral suspension is intended to address that attribute, FDA next considers whether there is a basis to conclude that the proposed oral suspension must be made from a bulk drug substance rather than from an FDA-approved product. The approved hydroxychloroquine sulfate drug products are 200 mg immediate release tablets with film coating. Although the approved products are film-coated, the coating is not intended to change/control the release profile. FDA is not aware of issues with using the FDA-approved product as the starting material when the compounding process and equipment are appropriately selected. We also note that there is a draft USP monograph for the compounded suspension that uses an FDA-approved film-coated tablet as the starting material (Ref. 8). As with all suspensions, the particle size of the powder should be carefully controlled and the density of suspension vehicle should be selected appropriately in order to make the oral suspension uniform and stable, which can affect the dose administrated to the patients.

Because we do not find a basis to conclude that a bulk drug substance is needed to compound the proposed compounded hydroxychloroquine sulfate oral suspension, rather than starting with the FDA approved product, we do not find a need to include hydroxychloroquine sulfate on the 503B Bulks List under question 2.

V. Conclusion

For the reasons stated above, we tentatively conclude that there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance quinacrine for oral use, and we therefore propose to include it on the 503B Bulks List as described in this notice.

At this time, we find no basis to conclude that there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substances bromfenac sodium, mitomycin-C, nepafenac, and hydroxychloroquine sulfate. We therefore propose not to include these bulk drug substances on the 503B Bulks List.

VI. References

The following references marked with an asterisk (*) are on display at the Dockets Management Staff (see ADDRESSES) 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. References without asterisks are not on public display at https://www.regulations.gov because they have copyright restriction. Some may be available at the website address, if listed. References without asterisks are available for viewing only at the Dockets Management Staff. FDA has verified the website addresses, as of the date this document publishes in the Federal Register , but websites are subject to change over time.

*1. FDA, Guidance for Industry, “Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” January 2017 (available at https://www.fda.gov/media/94402/download ).

*2. FDA, Guidance for Industry, “Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” March 2019 (available at https://www.fda.gov/media/121315/download ).

*3. FDA Memorandum to File, “Clinical Need for Quinacrine Hydrochloride in Compounding Under Section 503B of the FD&C Act,” January 2021.

4. Colombo, R., L. Rocchini, N. Suardi, F. Benigni, et al., 2012, “Neoadjuvant Short-Term Intensive Intravesical Mitomycin C Regimen Compared with Weekly Schedule For Low-Grade Recurrent Non-Muscle-Invasive Bladder Cancer: Preliminary Results of a Randomised Phase 2 Study,” European Urology, 62: 797-802.

5. Au, J. L., R. A. Badalament, M. G. Wientjes, D. C. Young, et al., and International Mitomycin-C Consortium, 2001. “Methods to Improve Efficacy of Intravesical Mitomycin C: Results of a Randomized Phase III Trial,” Journal of the National Cancer Institute, 93: 597-604.

6. McHenry, A. R., M. F. Wempe, and P. J. Rice, 2017, “Stability of Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL Suspensions in Plastic Bottles and Syringes,” International Journal of Pharmaceutical Compounding, 21(3), 251-254 (APA). Retrieved from https://ijpc.com/Abstracts/Abstract.cfm?ABS=4322.

7. American Society of Hospital Pharmacists (ASHP 2020), ” Hydroxychloroquine Sulfate Suspension 25 mg/mL.” Retrieved from www.ashp.org.

8. USP 2020, “USP Draft Compounded Preparation Monograph for Hydroxychloroquine Sulfate Compounded Oral Suspension.” Published for public comment in Pharmacopeial Forum 46(2). Retrieved from https://go.usp.org/l/323321/2020-04-08/33wcg6.