FDA Publishes Draft Guidance on What is “Essentially” a Copy of a Commercially Available Drug Under FDCA Sections 503A and 503B: Outsourcing Facilities

July 15, 2016

By Karla L. Palmer

FDA published for comment two non-binding draft guidance documents addressing compounding of commercially available drug products by traditional pharmacies under FDCA Section 503A and outsourcing facilities under Section 503B.  [Section 503A Draft Guidance is HERE, blogged separately] and Section 503B Guidance is [HERE].  These non-binding draft guidance documents reflect FDA’s latest attempt to restrict what may be compounded by narrowly construing what is and is not essentially a copy of a commercially available drug product.  If finalized, the Section 530B guidance would affect, by FDA’s estimates, approximately 40 outsourcing facilities.  The deadline for submitting comments on the draft guidance documents is October 11, 2016.

Section 503B Draft Guidance      

            Under Section 503B, outsourcing facilities may compound “essentially a copy of an approved drug” in limited circumstances.  Section 503B(d)(2).  Section 503B defines “essentially” copies somewhat differently than Section 503A, including referencing non-prescription marketed drugs, whether the compounded and commercially available substances are “identical,” and, if compounded from bulk substances, whether the compounded version produces a “clinical” difference for the patient (which FDA generally describes the same as the “significant” difference requirement under Section 503A).  FDA attaches to its draft Section503B guidance at Appendices A and B a very handy flow chart HERE to assist outsourcing facilities in determining whether a drug is essentially a copy of an approved drug.  Under the statute, and as depicted on FDA’s chart, essentially copies have two components: (1) A drug that is identical or nearly identical to an approved drug or an unapproved non-prescription drug is evaluated under Section 503B(d)(2)(A); and, (2) all other compounded drugs are evaluated under Section 503B(d)(2)(B).  FDA also defines “covered OTC drug products” in the draft guidance as a marketed drug not subject to Section 503(b) (prescription requirements) and not subject to approval under Section 505 to mean any non-prescription drug product marketed without an approved application; it includes monograph and non-monograph products as well. 

The draft guidance describes how FDA intends to apply its definition of “essentially a copy” of a compounded drug when applied to an approved drug (unless it appears on FDA’s shortage list) and how it intends to apply that definition when the compound is compared to a covered OTC product.  Some of the draft’s salient points are as follows:

Compounded drugs “nearly identical” to approved drugs: Referring to Box 1 of Appendix A, FDA will consider whether the compounded and approved drug have the same:  

(1) Active ingredients;

(2) Route of administration;

(3) Dosage form;

(4) Dosage strength; and

(5) Excipients (if excipients of the approved drug are known).   .    

If these characteristics between the two products are the same, then FDA will consider the products identical or nearly identical, and they may not be compounded.  Importantly, unlike in Section 503A, FDA will NOT exempt products from this restriction based on a determination by a prescriber that the compound produces a “clinical difference” for the patient (addressed below). However, in shortage situations, it expects compounds to be identical or nearly identical to the approved drug on FDA’s published shortage list. FDA does not intend to take action concerning compounding a shortage drug if it was on the list at the time the facility received the order, or within “60 days of … distributing or dispensing the drug.”  FDA notes there will be some regulatory flexibility, but if an outsourcing facility continues to fill orders more than 60 days after the drug is removed from the list, it may take regulatory action.   

If the compound differs in one or more of the above characteristics, then FDA would not consider it generally to be “identical or nearly identical.”  FDA would then turn to Section 503B(d)(2)(B) (see Appendix A) to determine whether the compound is appropriate. 

 Section 503B(d)(2)(B) states that a compounded drug is “essentially a copy” of an approved drug if a component of the compounded product is also a component of an approved drug, unless there is a change that produces a “clinical difference” for the patient as determined by the practitioner.  FDA further defines this section as follows:

Using the same bulk substance as the approved drug (Box 3):  FDA states that if the compounded bulk substance and approved drug products are the same, then the compound is essentially a copy, unless there is a determination of “clinical difference.” These provisions apply to a compound whether compounded from bulk substances or from drugs in finished form.    

Prescriber determination of clinical difference (Box 4):  To rely on a prescriber determination of “clinical difference,” the outsourcing facility should ensure that the determination is stated (in no particular format) on either the non-patient specific order or the patient specific prescription.  For non-patient specific orders, the facility should obtain a practitioner statement that specifies the change, and that the compound will only be provided to a patient “for whom the change produces a clinical difference.”  The facility may make the notation, if confirmed by the health care facility or prescriber (including date of the conversation).  FDA provides examples on pages 9-10 of the draft guidance, and elaborates on written statements that may suffice for non-patient specific orders:  

  • “Liquid form, compounded drug will be prescribed to patients who can’t swallow tablet” (if the comparable drug is a tablet)
  • “Dilution for infusion solution to be administered to patients who need this formulation during surgery” (if the comparable drug is not available at that concentration, pre-mixed with the particular diluent in an infusion bag)
  • “1 mg, pediatric patients need lower dose” (if the comparable drug is only available in 25 mg dose).

And for patient-specific prescriptions:

  • “No Dye X, patient allergy” (if the comparable drug contains the dye)
  • “Liquid form, patient can’t swallow tablet” (if the comparable drug is a tablet)
  • “150 mg drug X in 120 ml cherry-flavored Syrup USP, patient needs alcohol-free preparation (if the comparable drug is only available in formulations that contain alcohol)

An order or a prescription containing only a formulation will not suffice.  FDA adds that “lower price” is not sufficient to establish that the compound is not essentially a copy of the approved drug.  FDA does not intend to “question” the determinations of “clinical difference;” it will consider whether such determination is documented.

            Essentially a copy of one or more approved drug products:  FDA’s draft guidance also focuses on that statute’s statement that the compound must not be essentially a copy of “one or more” approved drug products.  FDA intends “to consider a compounded drug product that has bulk substances that are components of one or more approved drugs to be essentially a copy of an approved drug product” unless the change produces a “clinical difference.” 

            FDA’s application of the “essentially a copy” definition when the compounded drug is compared to a covered OTC product:  The Agency sets forth at Appendix B a flow chart for determining whether compounding copies of covered OTC drug products is appropriate. If the compounded drug is nearly identical to a covered OTC drug, FDA intends to apply the policy described above for “nearly identical” prescription drugs.  If it is not identical or nearly identical to the covered OTC drug, then

FDA will not permit compounding, if a component of the compounded drug is a bulk drug and is also a component of a covered OTC, unless there “is a change that produces for an individual patient a clinical difference,” as determined by the practitioner, between the compound and the comparable approved drug.  FDA leaves unanswered the result if there is no comparable “approved” drug (and what exactly is a “comparable approved drug to an OTC product).   FDA notes that a “clinical difference between the compounded drug and an unapproved drug (such as a covered OTC drug) does not exempt the compounded drug from the definition in section 503B(d)(2)(B).”  FDA should also clarify in final guidance whether this means that a compounder may not compound essentially copies of covered OTC drugs under any circumstance, or what documentation, if any would suffice to permit compounds of essentially copies of covered OTC drugs.  FDA also states that the statute does not provide an “essentially a copy” exemption for covered OTC drugs that may appear on FDA’s shortage list; thus copies of these OTC drugs may not be compounded in shortage situations. 

            Lastly, like with Section 503A’s draft guidance, FDA emphasizes that outsourcing facilities must keep good records to demonstrate compliance.