
[Federal Register Volume 80, Number 148 (Monday, August 3, 2015)]
[Notices]
[Pages 45999-46005]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-18911]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-D-2138]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Guidance for Industry 
on Adverse Event Reporting for Outsourcing Facilities Under Section 
503B of the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by 
September 2, 2015.

[[Page 46000]]


ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-7285, or emailed to oira_submission@omb.eop.gov. All 
comments should be identified with the OMB control number 0910--NEW and 
title ``Guidance for Industry on Adverse Event Reporting for 
Outsourcing Facilities Under Section 503B of the Federal Food, Drug, 
and Cosmetic Act.'' Also include the FDA docket number found in 
brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of 
Operations,Food and Drug Administration, 8455 Colesville Rd., COLE-
14526, Silver Spring, MD 20993-0002, PRAStaff@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Guidance for Industry on Adverse Event Reporting for Outsourcing 
Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic 
Act OMB Control Number 0910--NEW

    In the Federal Register of February 19, 2015 (80 FR 8872), FDA 
announced the availability of a draft guidance for industry entitled 
``Adverse Event Reporting for Outsourcing Facilities Under Section 503B 
of the Federal Food, Drug, and Cosmetic Act.'' On November 27, 2013, 
President Obama signed the Drug Quality and Security Act (DQSA) into 
law (Pub. L. 113-54). The DQSA added a new section 503B to the FD&C Act 
(21 U.S.C. 353b). Under section 503B(b), a compounder can register as 
an outsourcing facility with FDA. If the conditions outlined in section 
503B(a) of the FD&C Act are satisfied, a drug compounded by or under 
the direct supervision of a licensed pharmacist in an outsourcing 
facility is exempt from certain sections of the FD&C Act, including 
section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of 
drugs with adequate directions for use) and section 505 (21 U.S.C. 355) 
(concerning the approval of human drug products under new drug 
applications (NDAs) or abbreviated new drug applications (ANDAs)). 
Drugs compounded in outsourcing facilities are not exempt from the 
requirements of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 
351(a)(2)(B)) (concerning current good manufacturing practice for 
drugs).
    Under section 503B(b)(5), an outsourcing facility must submit 
adverse event reports to FDA in accordance with the content and format 
requirements established through guidance or regulation under 21 CFR 
310.305 (or any successor regulations). This guidance explains 
electronic reporting of adverse events in accordance with Sec.  310.305 
with respect to outsourcing facilities.
    Under Sec.  310.305(c)(1), manufacturers, packers, and distributors 
of marketed prescription drug products that are not the subject of an 
approved new drug or abbreviated new drug application, including, as 
set forth in the guidance, outsourcing facilities must submit to FDA 
adverse event reports within 15 calendar days of receiving the 
information and must submit followup reports within 15 calendar days of 
receipt of new information about the adverse event, or as requested by 
FDA. Outsourcing facilities must submit the adverse event report in an 
electronic format that FDA can process, review, and archive (collection 
of information is approved by OMB control number 0910-0291). A copy of 
the current labeling of the compounded drug product must be provided.
    Under Sec.  310.305(f), entities subject to the regulation must 
maintain for 10 years the records of all adverse events required to be 
reported under Sec.  310.305. The outsourcing facility should also 
maintain records of its efforts to obtain the data elements described 
in the draft guidance for each adverse event report.
    In the Federal Register of February 19, 2015 (80 FR 8872), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. FDA received seven comments on the draft 
guidance, several of which raised issues pertaining to the information 
collection provisions in the draft guidance. The issues raised are 
addressed below.
    Issue One: Several individuals submitted comments related to the 
requirement described in the guidance that outsourcing facilities 
report adverse events that are both serious and unexpected and the 
recommendation in the guidance that outsourcing facilities report all 
serious adverse events, regardless of whether they are unexpected. 
Specifically:
     One commenter noted that the applicable regulation, Sec.  
310.305, defines an ``unexpected'' adverse drug experience as an 
adverse drug experience ``that is not listed in the current labeling 
for the drug product.'' The commenter indicated that this definition is 
not easily applied to unapproved drugs, as such products lack uniform 
FDA-reviewed language, meaning products with the same active ingredient 
may list different adverse events in the labeling, or no adverse events 
at all.
     One commenter indicated that instead of strongly 
recommending that outsourcing facilities report all serious adverse 
drug experiences to the FDA, the FDA should require such reporting.
     One commenter stated that reporting all serious adverse 
drug experiences (not just those that are both serious and unexpected) 
should be required, rather than ``strongly recommended,'' and because 
reporting all serious adverse events is not currently required under 
Sec.  310.305, FDA should amend this regulation.
     Several commenters noted that Sec.  310.305 only requires 
reporting of serious, unexpected adverse events, but the draft guidance 
suggests that outsourcing facilities should report all serious adverse 
events. They stated that FDA is reaching beyond what the regulations 
allow, and this suggestion will lead to confusion to what must be 
reported and what is suggested. FDA should narrow reporting to 
unexpected adverse events.
    FDA Response to Issue One: FDA responds as follows:
     FDA has clarified the guidance with regard to reporting 
adverse events that are considered ``unexpected.'' Specifically, the 
guidance now includes the following language to clarify the meaning of 
the term ``unexpected'' in the context of adverse events associated 
with compounded drugs: ``For example, if current labeling for a 
compounded drug product does not list any adverse drug experiences, all 
adverse drug experiences associated with the compounded drug product 
would be considered `unexpected.' ''
     With regard to the recommendation that outsourcing 
facilities be required to report all serious adverse events, rather 
than just those that are considered both serious and unexpected, Sec.  
310.305, the regulation applicable to reporting of adverse events by 
all manufacturers of unapproved drugs, does not require reporting of 
all serious adverse drug experiences to FDA. Therefore, requiring 
outsourcing facilities to report all serious adverse events would be 
inconsistent with Sec.  310.305.
     Amending the regulation Sec.  310.305 would require a 
separate rulemaking, which is beyond the scope of this guidance 
document.
     With regard to the concern about possible confusion caused 
by FDA's recommendation that outsourcing facilities report all serious 
adverse events, the draft guidance states the

[[Page 46001]]

regulations require reporting of all adverse events that are both 
serious and unexpected, and that FDA is recommending that outsourcing 
facilities report all serious adverse events. Specifically, the draft 
guidance states that ``FDA strongly recommends that outsourcing 
facilities submit all serious adverse drug experiences'' (lines 128-
131) and that ``the regulations require reporting of each adverse drug 
experience received or otherwise obtained that is both serious and 
unexpected . . . .'' (lines 103-104). FDA will further clarify this by 
adding the following italicized language: ``In addition, although they 
are not required to do so, FDA strongly recommends that outsourcing 
facilities report all serious adverse events. . . .''
    Issue Two: Several commenters noted that FDA encourages, as 
appropriate, the outsourcing facility to attach to the report: (1) 
Hospital discharge summaries, (2) autopsy reports/death certificates, 
(3) relevant laboratory data, and (4) other critical clinical data, and 
that in case of a death, an outsourcing facility should also provide 
any available information on the event(s) that led to the death. The 
commenters stated it is unlikely that an outsourcing facility will be 
given access to the elements voluntarily by the healthcare facility 
where the serious adverse event occurred without being legally 
compelled to do so. A commenter also asked how a manufacturer, 
distributor, and/or supplier can obtain this information under the 
Health Insurance Portability and Accountability Act (HIPAA).
    FDA Response to Issue Two: With regard to HIPAA, 45 CFR 164.512 
describes situations under which a covered entity, e.g., a healthcare 
provider, may use or disclose protected health information without the 
written authorization of the individual or the opportunity for the 
individual to agree or object. One of these situations is ``to collect 
or report adverse events'' to FDA (45 CFR 164.512(b)(1)(iii)(A)). 
However, although information about adverse events can be obtained 
under HIPAA, the guidance does not state that an outsourcing facility 
must obtain this information. Rather, the guidance states that 
attaching this information is encouraged. It should be provided if the 
outsourcing facility has the information, but the outsourcing facility 
is not specifically required to obtain this information. FDA has 
clarified in the guidance that the information should be provided to 
FDA if it is available. Specifically, the guidance now reads: ``In 
addition, as part of the adverse event report, we encourage, as 
appropriate, attachment of the following, if available: (1) Hospital 
discharge summaries, (2) autopsy reports/death certificates, (3) 
relevant laboratory data, and (4) other critical clinical data. In the 
case of a death, outsourcing facilities should also provide any 
available information on the event(s) that led to the death.''
    Issue Three: One commenter noted that the period of 15 calendar 
days to submit an initial report of an adverse event and the 15 
calendar days to submit a followup report is too long; that during this 
period illnesses, injuries, or deaths can result. The commenter also 
stated that this would likely also delay initiation of recall 
procedures, and that the time period for reporting should be no more 
than 48 or 72 hours, followed by an equally prompt followup and 
investigation period, and an immediate decision on a recall.
    FDA Response to Issue Three: The applicable regulation, Sec.  
310.305, provides a 15-day timeframe for reporting an adverse event and 
an additional 15-day timeframe to submit a followup report. This is the 
maximum amount of time permitted. The guidance states that the 
regulations require reporting ``as soon as possible, but in no case 
later than 15 calendar days . . . .'' The preamble to Sec.  310.305 
notes that the manufacturer must usually obtain additional information 
about the product (e.g., followup with the reporting physician or 
patient), and that reducing the time for submitting these reports would 
increase the number of incomplete reports. (51 FR 24478).
    Issue Four: FDA should immediately share all adverse events 
reported with the home State regulator, so the State agency is also 
aware of potential problems at one of its licensee's facilities.
    FDA Response to Issue Four: FDA intends to continue to work closely 
with its State partners on oversight of compounding, including 
improving and streamlining information sharing as much as possible. 
However, this recommendation is not relevant to this guidance document, 
which focuses on how outsourcing facilities should submit adverse event 
reports to FDA.
    Issue Five: Two commenters asked how the reporting requirements 
proposed by the draft guidance interplay with reporting requirements 
imposed by State boards of pharmacy. The commenters asked whether, in 
the event a State board of pharmacy has adverse event reporting 
requirements that apply to an outsourcing facility, satisfying the 
adverse event reporting requirements described by the draft guidance 
``preempt'' the requirement to comply with a State reporting 
requirement. They asked whether an outsourcing facility must report to 
both Federal and State regulators and noted that this could result in 
duplicate reporting.
    FDA Response to Issue Five: This guidance addresses requirements 
under the FD&C Act and FDA regulations. Outsourcing facilities may have 
independent responsibilities to report to State boards of pharmacy. FDA 
will clarify in the guidance that in addition to complying with federal 
adverse event reporting requirements, outsourcing facilities must 
comply with any applicable State adverse event reporting requirements. 
Specifically, FDA will add the following language: ``Certain state 
boards of pharmacy may also require outsourcing facilities licensed in 
their states to report adverse events. Outsourcing facilities must 
comply with any applicable state reporting requirements independent of 
and in addition to reporting adverse events as described in this 
guidance.''
    Issue Six: One commenter proposed language clarifying that the 
regulations described in the guidance apply to products without an 
ANDA.
    FDA Response to Issue Six: This additional language is unnecessary 
because the guidance cites the regulation Sec.  310.305 and makes clear 
that it applies to manufacturers of prescription drug products that are 
not the subject of an approved drug application.
    Issue Seven: With regard to the following statement in the draft 
guidance: ``Reports should be submitted as long as the outsourcing 
facility has information on at least the suspect drug and the adverse 
event'', one commenter recommended that FDA clarify that if a report 
lacks the four minimum data elements, the outsourcing facility should 
review the report for any potential safety issue.
    FDA Response to Issue Seven: FDA believes that the draft guidance 
is clear that if the report lacks the four data elements, the 
outsourcing facility should continue investigating. The guidance 
states, ``If the outsourcing facility was not able to include all four 
of the data elements in its initial report, it should exercise due 
diligence to obtain information about any of the remaining elements.''
    Issue Eight: One commenter suggested that FDA clarify that if an 
adverse event reporter does not identify a suspect drug, the 
outsourcing facility should submit a report that lists all drugs that 
the patient was taking as suspect.

[[Page 46002]]

    FDA Response to Issue Eight: FDA does not agree with this 
suggestion. The guidance states that for an adverse event to be 
reportable to FDA, the outsourcing facility must have information on at 
least two data elements: An adverse event and a suspect drug. A suspect 
drug product is one that the initial reporter suspected was associated 
with the adverse event. If the reporter does not identify a suspect 
drug, the adverse event is not reportable. The outsourcing facility 
should not submit a report that lists each of the drugs the patient was 
taking as suspect drugs, as the comment suggests, if none of the drugs 
was identified as suspect by the reporter. In most cases, we believe 
that a reporter that contacts an outsourcing facility will be able to 
identify the suspect drug. It is unlikely that the reporter would have 
notified the outsourcing facility of the adverse event if it did not 
believe the compounded drug manufactured by the outsourcing facility 
caused the adverse event.
    Issue Nine: Several commenters noted that under the draft guidance, 
when an adverse event cannot be directly determined to be associated 
with a specific drug, the outsourcing facility should identify and list 
all other medications to which the identified patient may have been 
exposed including information related to all compounded prescription 
preparations, brand and generic manufactured drug products, dietary 
supplements, and over-the counter medications that may have been taken 
by the patient. The commenters stated that requiring information on all 
drug products taken by a patient that may be ``suspect'' is unduly 
burdensome, especially when a compounded preparation is distributed to 
a medical center where multiple treatments and therapies are provided 
at any given time to an individual. An outsourcing facility may 
therefore have an incomplete picture of the circumstances under which 
the drug was administered. In addition, the outsourcing facility would 
also have no control over how a drug is administered, and improper 
administration may be material to the cause of the adverse event.
    FDA Response to Issue Nine: FDA will clarify that the outsourcing 
facility should only include information on suspect drug products that 
the outsourcing facility is aware of from the reporter and the 
outsourcing facility's due diligence to obtain additional information. 
The outsourcing facility is not expected to report information that it 
does not have. Specifically, FDA will add the italicized language: ``In 
all cases, including those where not all of the drug products were made 
by the outsourcing facility, the report should include information on 
all suspect drug products of which the outsourcing facility is aware.''
    FDA will also clarify that FDA will consider how the drug was 
administered, the patient's medical history, and any other relevant 
facts when investigating the adverse event. Specifically, FDA will add 
the following language: ``The outsourcing facility should include the 
information described in this guidance on suspect drug products and 
concomitant medications of which it is aware after exercising due 
diligence. For example, although an outsourcing facility should 
exercise due diligence to determine any concomitant medical products, 
FDA only expects that it report information about concomitant products 
that it is able to obtain from the reporter. Furthermore, as noted 
previously, the report or information submitted by an outsourcing 
facility issued in Sec.  310.305 (and any release by FDA of that report 
or information) does not necessarily reflect a conclusion that the 
report or information constitutes an admission that the drug caused or 
contributed to an adverse effect.\1\ When investigating the adverse 
event, FDA considers how the drug was administered, the patient's 
medical history, and any other relevant information.''
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    \1\ See Sec.  310.305(g).
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    Issue 10: Two commenters asked how, given that a compounded product 
contains more than one component, could an outsourcing facility or the 
healthcare provider know which component of the compounded product, or 
which component of which product, is suspect. Compounded products have 
a number of components and active pharmaceutical ingredients (API), so 
it may be difficult for an outsourcing facility to tie a serious, 
unexpected adverse event to a specific component or API. A commenter 
also noted that FDA should require that an adverse event report 
identify all the APIs contained in a compounded drug and the APIs' 
manufacturer(s).
    FDA Response to Issue 10: The guidance makes clear that the minimum 
data element for reporting is the suspect drug product, and not a 
suspect component. (See section III.B.3 of the draft guidance.) We 
agree with the suggestion that the outsourcing facility should identify 
in its adverse event report all of the APIs contained in a compounded 
drug and the APIs' manufacturer. The guidance states that all known 
components of a suspect drug product should be reported. It states 
that, ``[i]f the compounded drug product contains multiple components 
(e.g., excipients, drug substances, finished dosage forms), the 
outsourcing facility should list each component and its manufacturer. . 
.''
    Issue 11: One commenter noted that as indicated within the guidance 
document, FDA is not prepared nor has the necessary infrastructure in 
place to receive electronic reports of adverse events despite having 
such a system already available for other registered entities including 
manufacturers. The commenter asked that the FDA provide an 
implementation schedule to all currently registered outsourcing 
facilities outlining the anticipated date of an electronic adverse 
event reporting system as soon as possible.
    FDA Response to Issue 11: This final guidance describes the process 
for outsourcing facilities to report adverse events to FDA 
electronically. The electronic reporting system is ready for 
outsourcing facilities to use, and, therefore, the issue raised by this 
comment is now moot.
    Issue 12: Two commenters stated that this draft guidance imposes 
uneven reporting requirements on similarly-situated facilities (i.e., 
outsourcing facilities operating under section 503B and pharmacies 
operating under section 503A of the FD&C Act) engaging in the same 
activities. Because outsourcing facilities can compound drugs issued in 
individual prescriptions, they are permitted to do the same kind of 
activities as facilities compounding under section 503A of the FD&C 
Act. Holding facilities that engage in the same conduct to different 
standards is ``illogical and arbitrary and capricious.'' If FDA 
determines that section 503A facilities should not be required to 
adhere to the same adverse event reporting requirements as outsourcing 
facilities, an outsourcing facility that compounds issued in individual 
prescriptions should not have to report adverse events associated with 
individual preparations.
    FDA Response to Issue 12: FDA does not agree with this comment. The 
purpose of this guidance is to implement section 503B(b)(5) of the FD&C 
Act, which requires adverse event reporting for outsourcing facilities 
and does not address adverse reporting for compounding conducted under 
section 503A. Adverse event reporting for entities operating under 
section 503A of the FD&C Act is beyond the scope of this guidance. We 
also note that section 503B of the FD&C Act requires outsourcing 
facilities to report adverse events associated with all of their 
compounded drugs to FDA and does not

[[Page 46003]]

distinguish between patient specific and non-patient specific 
compounded products.
    Issue 13: One commenter noted that FDA may have written this 
guidance because it may be interested in knowing the sheer number of 
adverse events that occurred at each outsourcing facility. If this is 
the case, this kind of information could be collected by reporting the 
number of adverse events without the need for extensive detail about 
the affected patient or the components of the compounded product. This 
information could be collected through the recordkeeping and facility 
inspections that are already required of outsourcing facilities. 
Further, it may be more efficient to collect this information at 
regular intervals (e.g., quarterly or biannually) rather than in 
relation to when the adverse event occurred.
    FDA Response to Issue 13: FDA is not interested only in the number 
of adverse events associated with compounded drug products from a 
particular outsourcing facility, as the comment suggests. A single 
report of an adverse event can signal a serious public health concern, 
such as an outbreak resulting from drug contamination, or could signal 
serious quality problems at the outsourcing facility that if corrected 
promptly could prevent an outbreak. FDA evaluates each adverse event 
report to determine what followup action is appropriate. Collecting 
adverse events at longer intervals would conflict with the 15-calendar 
day submission timeline required under Sec.  310.305 and would not be 
sufficient for FDA's need to evaluate adverse event reports in a timely 
way. Whether to require additional reporting or collect additional 
information is beyond the scope of the current guidance.
    Issue 14: One commenter noted that an outsourcing facility would 
not necessarily know which patient received which drug, unless it was 
compounded issued in an individual prescription. Most outsourcing 
facilities make the majority of their preparations to be supplied to 
healthcare providers rather than issued in a prescription, so the only 
way an outsourcing facility would learn of the adverse event is if it 
is reported to the outsourcing facility by a patient or a healthcare 
provider. Healthcare providers are in a better position to know about 
the occurrence of adverse events. Therefore, it may be advantageous for 
FDA to seek to collect this information from healthcare providers with 
better access to the information, through submitting reports to FDA and 
supplying copies of those reports to the outsourcing facility. The 
outsourcing facility could then submit the adverse event report to FDA, 
reference the fact that the occurrence was already reported, and 
provide additional information about the product.
    FDA Response to Issue 14: Reporting by healthcare providers is not 
mandatory under the FD&C Act or its implementing regulations. Section 
503B of the FD&C Act requires outsourcing facilities, and not 
healthcare providers, to report adverse events to FDA. We agree with 
the comment that healthcare providers have useful information on a 
patient, and for this reason encourage outsourcing facilities to 
contact the healthcare provider to obtain additional information on the 
patient. The guidance makes clear that outsourcing facilities must 
report adverse events that they are aware of; if they do not learn of 
an adverse event, there would be nothing for them to report.
    Issue 15: Two commenters asked what the consequences are if a 
practitioner reports a serious, unexpected adverse event but the 
outsourcing facility did not because it was not aware of the adverse 
event. The commenters indicated that an outsourcing facility should be 
permitted to refer to a previously submitted adverse event report 
instead of being required to prepare a separate, duplicative report.
    FDA Response to Issue 15: Outsourcing facilities are required to 
report serious unexpected adverse events that they are aware of, 
regardless of whether anyone else voluntarily reported them. The 
guidance states that ``failure to report adverse events by an entity 
that is registered in accordance with section 503B(b) is a prohibited 
act under section 301(ccc)(3) of the FD&C Act. Violations relating to 
this provision are subject to regulatory and enforcement action.'' If 
an adverse event associated with an outsourcing facility's product is 
submitted to the FDA voluntarily by an entity other than the 
outsourcing facility (a healthcare provider), the outsourcing facility, 
under section 503B of the FD&C Act, is still required to submit an 
adverse event report if it also became aware of the same adverse event 
report and it is reportable. During the review and analysis of case 
reports from the FDA Adverse Event Reporting System, FDA reviewers 
identify duplicate cases and treat them as one case report in their 
evaluation.
    Issue 16: One commenter asked if there would be a consequence to an 
outsourcing facility that does not report an adverse event because 
another individual or entity reported it directly to FDA.
    FDA Response to Issue 16: The outsourcing facility is required to 
report any adverse events of which it becomes aware, regardless of 
whether anyone else voluntarily reported it. The guidance states that 
``failure to report adverse events by an entity that is registered in 
accordance with section 503B(b) is a prohibited act under section 
301(ccc)(3) of the FD&C Act. Violations relating to this provision are 
subject to regulatory and enforcement action.''
    Issue 17: Two commenters stated that the draft guidance fails to 
account for compounded drug products being used for off-label 
treatment. By failing to address this issue, the reporting requirements 
detailed in the draft guidance may not provide FDA with the information 
it seeks. Additionally, an outsourcing facility may not know how the 
compounded drug is to be used, thereby limiting its ability to provide 
a full and accurate accounting of the adverse event. The patient's 
healthcare provider may be in a better position to provide this 
information.
    FDA Response to Issue 17: FDA disagrees with this comment. The 
concept of ``off-label treatment'' is not applicable to compounded 
drugs because compounded drugs are not approved and do not have 
approved labeling. FDA evaluates adverse event reports associated with 
compounded drug products for quality issues. Furthermore, section 503B 
of the FD&C Act requires outsourcing facilities to report adverse 
events. Reporting by healthcare providers is voluntary and not the 
subject of this guidance.
    Issue 18: Two commenters asked if, after complying with the 
reporting requirement, FDA will require any additional information or 
followup activity by the outsourcing facility that submits the report. 
They asked if the outsourcing facility will be required to provide 
information about the adverse event to healthcare providers or others 
who purchased the same or similar product, and if the adverse event 
does not trigger reporting requirements imposed by the applicable State 
board of pharmacy, whether the outsourcing facility must notify the 
State board.
    FDA Response to Issue 18: The draft guidance describes the 
requirement under Sec.  310.305(c)(2) that all serious, unexpected 
adverse drug experiences shall be promptly investigated by the 
outsourcing facility and a followup report must be submitted within 15 
calendar days of receipt of new information ``or as requested by FDA.'' 
The guidance does not direct the outsourcing facility to provide 
information about adverse events to any other entities. Whether the 
outsourcing

[[Page 46004]]

facility must also notify the State is a question of State law. The 
guidance makes clear that the outsourcing facility must comply with any 
State requirements. As described above, for clarification, FDA added 
the following language to the guidance: ``Certain state boards of 
pharmacy may also require outsourcing facilities licensed in their 
states to report adverse events. Outsourcing facilities must comply 
with any applicable state reporting requirements independent of and in 
addition to reporting adverse events as described in this guidance.''
    Issue 19: Two commenters asked what action, if any, FDA will take 
following the reporting of an adverse event. They asked if such 
reporting will trigger inspections or additional scrutiny by FDA, 
whether the filing of an adverse event report automatically means FDA 
will undertake any kind of formal enforcement action or any other 
followup, and whether FDA will notify the State board, or otherwise 
disclose the adverse event to the public, healthcare providers, 
purchasers, or others. A commenter also noted that if the purpose of 
the guidance is to monitor and identify issues with particular 
outsourcing facilities, the disclosure requirements go too far because 
information such as patient information, a reporter, or drug 
information would not be needed by FDA and can be addressed through 
recordkeeping and inspections.
    FDA Response to Issue 19: When FDA receives a report of an adverse 
event associated with a compounded drug, FDA evaluates the report for 
appropriate action. In appropriate cases, FDA will contact the 
outsourcing facility or reporter for additional information, and if the 
report suggests a quality issue, FDA may initiate an inspection of the 
outsourcing facility and/or the reporter's facility, as appropriate. 
FDA may also contact such an outsourcing facility about initiating a 
recall or ceasing sterile operations if, for example, there is evidence 
that the firm may have released adulterated or misbranded drug products 
(e.g., contaminated drug products) that could cause patient harm, or 
pursue regulatory action. In other cases, FDA may be able to determine 
that the adverse event resulted from the patient's underlying 
condition, improper administration, or concomitant product and not from 
a drug product compounded by the outsourcing facility. In the guidance, 
FDA has provided additional information about the actions that it takes 
upon receiving an adverse event report and why adverse event reporting 
is important. Specifically, FDA added the following language:
    ``Adverse event reporting for drug products compounded by 
outsourcing facilities is a critical mechanism by which FDA identifies 
signals of potential quality problems that may be associated with a 
particular drug or drug component, and which may have been caused by 
substandard conditions or processes at a facility where the drug or its 
components were made or handled. FDA needs to distinguish such cases 
from cases of medication error, hospital or clinic procedural problems, 
or quality issues associated with ingredients such as active 
pharmaceutical ingredients (APIs) or excipients. For example, several 
reports of adverse events in patients who received compounded drug 
products from the same outsourcing facility may be a signal of a 
quality issue resulting from a deficiency in the outsourcing facility's 
manufacturing processes. However, if several different outsourcing 
facilities report adverse events in patients who received drug products 
that contained the same API, this may suggest a quality problem 
associated with the API used in the compounded drug product.
    An adverse event may be reported for reasons other than a quality 
problem. For example, it may be a side effect of taking the drug 
product, or may have resulted from lack of efficacy of the drug 
product, the patient's underlying medical condition, or use of a 
concomitant medication. To address the reported adverse event 
appropriately, FDA reviews information provided by the outsourcing 
facilities, such as the description of the circumstances associated 
with the adverse event such as the source of the drug and its 
ingredients, concomitant medications that the patient was taking, and 
relevant information reflected in hospital discharge summaries, autopsy 
reports/death certificates, relevant laboratory data, and other 
critical clinical data used to determine the cause of the adverse 
event.''
    Issue 20: One commenter noted that the draft guidance requires that 
outsourcing facilities maintain for 10 years the records of all adverse 
events required to be reported, including certain specific information. 
The commenter asked when this 10-year period begins: From the date of 
the occurrence of the adverse event, the date the adverse event is 
reported to FDA, or another date, whether there are any requirements 
concerning how or where these records must be maintained, and whether 
FDA expects to provide additional guidance on the maintenance of such 
records
    FDA Response to Issue 20: FDA clarified the guidance by adding the 
following language: ``The ten-year retention period for a particular 
record begins from the time that an outsourcing facility receives 
information (e.g., a document with information about one of the four 
data elements).'' FDA does not feel that additional recordkeeping 
guidance is necessary.
    Issue 21: One commenter requested clarification regarding the 
specific information that an outsourcing facility should keep in its 
records of an adverse event report. The commenter stated that if 
specific data are not available at the time of the report, FDA should 
specify that it is acceptable for those data to be missing from the 
record of the adverse event. In addition, FDA should clarify how 
outsourcing facilities should document their efforts to obtain the four 
data elements.
    FDA Response to Issue 21: FDA has clarified this in the guidance. 
Specifically, FDA added the following italicized language: ``If the 
outsourcing facility was not able to include all four of the data 
elements in its initial report, it should exercise due diligence to 
obtain information about any of the remaining elements and should keep 
records of its efforts to obtain this and other relevant information 
(e.g., dates of discussions with the reporter to determine how many 
patients experienced a particular adverse event or dates of discussions 
with a healthcare facility to obtain contact information for an 
identifiable person who purports to have knowledge about the patient, 
adverse event, or drug involved).''
    Issue 22: One commenter asked whether FDA anticipates requiring 
outsourcing facilities to adopt common standard operating procedures 
(SOPs) governing the reporting of adverse events. The commenter noted 
that having standardized SOPs issued by FDA may help ensure consistency 
in the frequency of reporting, the information reported, and how this 
information is provided. The commenter asked whether FDA will provide 
additional guidance or standards clarifying the ``written processes for 
the surveillance, receipt, evaluation, and reporting of adverse events 
for the drug products it compounds as described in 21 CFR 310.305(a) 
and 211.198'' that it anticipates reviewing during inspections of 
outsourcing facilities.
    FDA Response to Issue 22: Outsourcing facilities are required to 
develop and implement written procedures for the surveillance, receipt, 
evaluation, and reporting of postmarketing adverse drug experiences as 
described in Sec. Sec.  310.305(a) and

[[Page 46005]]

211.198. FDA will consider whether to provide additional guidance on 
SOPs, but outsourcing facilities are required to develop written 
procedures that enable them to fulfill their review, reporting, and 
recordkeeping obligations even if FDA does not provide such guidance.
    Issue 23: One commenter suggests using the MedWatch Form FDA 3500 
voluntary reporting instead of the mandatory Form FDA 3500A reporting 
form.
    FDA Response to Issue 23: FDA disagrees with this comment. Section 
503B of the FD&C Act requires that outsourcing facilities report 
adverse events. Therefore, voluntary reporting mechanisms such as the 
Form FDA 3500 would not be appropriate for outsourcing facility adverse 
event reporting.
    Issue 24: One commenter asked for clarification about the type of 
products about which adverse event reports must be submitted, noting 
that outsourcing facilities often do more than compounding. The 
commenter asked whether the reporting requirements apply to other 
activities such as repackaging.
    FDA Response to Issue 24: The guidance states that ``for purposes 
of reporting adverse drug experiences, the term prescription drug 
products includes any compounded drug product subject to the 
prescription requirements in section 503(b)(1) of the FD&C Act.'' 
Reporting for other activities such as repackaging will be addressed in 
separate guidance documents. For example, when finalized, FDA's draft 
guidance, ``Repackaging of Certain Human Drug Products by Pharmacies 
and Outsourcing Facilities,'' will describe adverse event reporting for 
drug products repackaged by outsourcing facilities, if they will be 
expected to report adverse events associated with their repackaged 
products, as contemplated by the draft guidance.
    Burden Estimates:
    The total estimated reporting and recordkeeping burdens for the 
guidance are as follows:
    We estimate that approximately 55 outsourcing facilities (``Number 
of Respondents'' and ``Total Annual Responses'' in table 1) will 
annually submit adverse event reports to FDA as specified in the 
guidance, and that preparing and submitting this information will take 
approximately 1.1 hours per registrant (``Average Burden per Response'' 
in table 1).
    We estimate that approximately 55 outsourcing facilities (``Number 
of Recordkeepers'' in table 2) will annually maintain records of 
adverse events as specified in the guidance, and that preparing and 
maintaining the records will take approximately 16 hours per registrant 
(``average burden per recordkeeping'' in table 2).
    FDA estimates the burden of this collection of information as 
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                               Number of
          Compounding outsourcing facility                 Number of         responses per       Total annual     Average burden per      Total hours
                                                          respondents         respondent           responses           response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Submission of adverse event reports including copy                   55                   1                  55                 1.1                  61
 of labeling and other information as described in
 the guidance.......................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                                   Table 2--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           Number of       Number of records     Total annual     Average burden per
                Type of recordkeeping                    recordkeepers     per recordkeeper         records          recordkeeping        Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Records of adverse events, including records of                      55                   1                  55                  16                 880
 efforts to obtain the data elements for each
 adverse event report...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


    Dated: July 28, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-18911 Filed 7-31-15; 8:45 am]
BILLING CODE 4164-01-P


