PCAC Meeting November 20, 2017:

IACP is in attendance at the Food & Drug Administration (FDA) Pharmacy Compounding Advisory Committee (PCAC) Meeting occurring today and tomorrow, November 20-21, 2017, in White Oak, Maryland, and will bring you live voting results!

PLEASE NOTE: These votes are NOT final. FDA must release final guidance for this to be FINAL. These are the Committee's votes on FDA's recommendations for the API Positive List. Please contact IACP with questions at [email protected] .

Please note that IACP and other pharmacy organizations previously let Congress know that these meetings should be webcast to the public and you can now watch the PCAC live webcast here . As IACP stated within its comments that you can read here , IACP is still very disappointed that while two PCAC members have been allowed to participate via conference call for this meeting, FDA denied all stakeholder participation via conference calls even during the public meeting sections.
Third Vote of the Day

We previously sent you the update that PCAC voted against FDA recommendation in a 6 - 5 Vote to ADD Pregnenolone to the API positive list! (See full vote and discussion below.)

For the Third Vote, PCAC Votes NOT to Include 7-Keto DHEA on 503A bulk List by 9-2 

7-Keto DHEA: Nominated for weight loss and for Raynaud's phenomena. 

FDA Presentation by Dr. Susan Johnson:
  • Not listed in USP in Britain, Japan, Europe
  • No clinical evidence for effectiveness in either indication
  • One adverse event said 7 fold testosterone increase but not attributable to 7-Keto
  • 7-year history in pharmacy compounding 
  • Available in DS in US
  • Four part balancing test weighs AGAINST inclusion on list
  • Q: is it possible it causes increase in testosterone. A: Predominant belief is no.
Nominator Presentation: Tom Wynn, RPh, Fagron
  • Easy to characterize as hormone
  • Safety- studies show healthy for men at doses up to 200mg/day for 4 weeks
  • Another study shows same results. Well tolerated
  • Commercial distribution- safety tied to limits on how much
  • Available over the counter
  • Efficacy- study shows potential to reduce body weight in rats
  • Raynaud's: study shows prevention in attacks
  • Tom has personal experience in this with patients as pharmacist
  • Physician prescribed 10mg/day for Raynaud's symptoms. Work with physician on appropriate dosage
  • Potency program necessary to check each product you are compounding with
  • Raynaud's - 10-15m patients, those with cardiac issues could benefit from 7-Keto
  • Conclusion: Safety in animals, characterized, DS status, weight loss and Raynaud's effective
  • Dosing issues in DS over the counter. What about suspension or different dose for kids if not allowed to compound?
  • Q: Effective in weight loss- any random placebo controlled trials? A: No only my own clinical experiences. 2 patients, 2 successes
  • Q: What is your sense of market? Weight loss or Raynaud's A: Only seen it for Raynaud's
  • Q: most common delivery? A: Capsules, although suspensions could be needed.
  • FDA: clinical study was on a different substance not 7-Keto. There are products called 7-Keto that are not but are related. No clinical study on 7-Keto
VOTE: FDA is proposing 7-Keto NOT be place on list. Should it be placed on list?

Yes: 2
No: 9
Abstain: 0
Not Voting: 0
Second Vote of the Day

We previously sent you the update the PCAC voted YES to ADD L-citrulline - oral administration only to the API Positive List (see full vote and discussion below).

For the Second vote, the PCAC voted against FDA recommendation in a 6 - 5 Vote to ADD Pregnenolone to the API positive list!

FDA presentation by Wafa Harrouk, PhD
  • Available as a DS in the US
  • Precursor for several steroidal hormones
  • Not toxiokinetic data for substance
  • Available data says oral absorption in humans in 5-35 hours
  • Transdermal absorption - no PK studies found
  • One study showed decrease in serum levels after topical application
  • FAERS adverse events- 7 reported, menopausal symptoms, dizziness, nausea and excessive hair
  • CAERS adverse events- 30 reported.
  • Causality not certain in either adverse event system as multiple substances involved
  • Clinical Trials- injection study led to oral recommendation. Weight gain, headache, reduced appetite, depression. No long term studies.
  • CA prohibits sale of steroid precursors without warning statement
  • Insufficient data to support safety of Pregnenolone. No long-term safety studies
  • Because it is pre-cursor steroid, long term safety concerns
  • Uses: Rheumatoid Arthritis: studies from 1950's show variable responses, could be caused by variations in RA. Another study shows no evidence of effectiveness.
  • Hypercholesterolemia: 2 uncontrolled chart reviews: lack of control groups preclude showing effectiveness.
  • Schizophrenia: 2 small exploratory studies: inadequate data
  • Bipolar Disorder: 2 small placebo controlled studies. Data inadequate.
  • Effectiveness Data does not support for RA or Hyper-c. Inadequate data for Schizo or Bipolar
  • Numerous FDA drug therapies for each
  • Historical Use in Compounding: used since 2003 for several indications
  • Not listed in any Pharmacopia (British, Japan, etc)
Nominator Presentation: AJ Day, PharmD, PCCA
  • Utilization of compounded pregnenolone: oral only. Highlights that none of the adverse events in studies are attributable to PregMarx review found no adverse events, AJ spoke to her about clinical trials, including ongoing 
  • Safety data from 2009 article by Marx 
  • 8 week trial under IND
  • 2011 article, only one adverse event
  • 4 studies in 2000s for psychiatric disorders. Safety data under IND 
  • Drop out rates: anti-psychotic drugs, placebo control designs effect rates, population is difficult
  • Compares FDA approval of Ziprasidone under 52 week placebo controlled study. Efficacy was based on short term trials, like Pregnenolone. No patent for Pregnenolone so no incentive to go through NDA
  • Also compares Quetiapine FDA approval and short term of trials under that NDA process
  • Claim of FDA approved products is not supported by data from studies on those drugs that show efficacy problems
  • Problem with FDA short notice of PCAC and several Psychiatrist that could not interrupt patient care to attend PCAC. AJ reads statement from Psychiatrist on urban patients addicted to multiple substances plus medications for illnesses like diabetes. Schizophrenia medications have their own risk, including metabolic risks. Clinical response is inadequate
  • Pregnenolone: no adverse events attributable to Pregnenolone in FDA data. 1.1% of US population with schizophrenia means lower data. High drop out rates on studies of other FDA approved drugs
  • FDA said no nominator presentations on phone, even though 3 PCAC voting members are on the phone
  • Article review on the lack of FDA approved anti-psychotic meds
  • PCCA gets it from cGMP compliant, FDA-inspected facilities only.
FDA Vote: (FDA recommends Pregnenolone NOT be placed on list): Should it be placed on list?:  
 
Yes: 6
No: 5
Abstaining:1
Not Voting: none
First Vote of the Morning

L-citrulline - oral administration only; FDA Recommendation is to ADD to the API Positive List.

L-citrulline- proposed for the treatment of urea cycle disorders (UCDs).  FDA presentation by Dr. Susan Johnson, Assoc Director at CDER. 
  • Produced by fermentation, soluble in water.  Likely to be stable as solid or liquid for oral dosage. 
  • Has been used to treat UCDs for 30 years
  • Available as a dietary supplement
  • Found in many foods, non-essential amino acid, antioxidant and vasodilator.
  • Data shows it passes to sheep fetus from placenta
  • Little toxicity at high doses
  • Adverse Events- 332 reports, 3 deaths but multiple supplements were used so not causality
  • Limited safety data, but decades of use shows little in safety concerns
  • Compounded and used in dietary supplements and is standard of care in certain UCDs
  • Published dosage recommendations.
  • Conclusion: It is effective in the treatment of certain UCDs
  • Recommendation:  Balance 4 evaluation criteria weighs in favor of adding to bulk drug substances list for 503A.
Nominator Presentation: AJ Day, PharmD, PCCA
  • Conflict statement: PCCA is bulk supplier of L-c
  • Source is FDA registered cGMP facility
  • Handful of pharmacies specialize in UCDs- relevance for MOU
  • Dr. Burn: Question- 500-750mg dosage depending on weight of patient.  (pharmacists provided data on range of dosage to AJ)
  • IV vs Oral: AJ not aware of any promotion of or use of IV for L-c
  • Q: Subpotent reports.  A: Quality control by wholesaler, previous to pharmacies receiving.  PCCA has process where every ingredient in quarantined and verified.
Open Public Hearing: None
Panel Discussion:
  • Q:  subpotent formulations, were they DS or compounds? A: Bulk substance was not L-c so it was the manufacturer's error.
  • Q: How many manufacturing sites for this product.  A: PCCA uses a Japanese co with US office
  • Q: Certificate of Analysis for subpotent product did it say it was L-c? A: 99.8% National Compounding Supplier.
  • Q: Impurities in fermentation? A: AJ: None other than in FDA presentation.
  • Comment: Certificate of Analysis is critical to compounder as they rely on bulk manufacturer.
  • With no USP Monograph, where does pharmacist get purity standards?
  • Guidance for best practices on compounders dealing with manufacturers.
  • AJ: Does independent analysis.
  • Q: Qualitative Analysis include identity testing?  A: Yes
  • Comment: relationship with Distributor also important to compounder.
  • Melting Point studied? Manufacturer chose not to.
  • Dietary supplements have been found to be subpotent or totally absent of L-c
VOTE:  For oral administration only - L-c on 503A Bulk List?

Yes:  12
No: 0
Abstain: 0
Not Voting 0

Comments: Reasons for yes votes: safety, efficacy, standard of care, only treatment, substance belongs in triad. 30 years of historical use.  Weight based dosing.  Important clinical uses, unusual that there are not long term studies.  
IACP Submits Comments for FDA's PCAC Meeting

The International Academy of Compounding Pharmacists (IACP) has submitted comments to the  Food & Drug Administration (FDA) for its  Pharmacy Compounding Advisory Committee meeting being held next week on November 20-21, 2017. 

IACP Members : Thank YOU for your input as we developed these comments! Your feedback was very helpful on the  a) Do Not Compound List and b) the Active Pharmaceutical Ingredients (APIs) Positive List  - which are both up for vote at next week's PCAC meeting. 

Make Sure Your Patients' Voices are Heard - Submit Comments!

Comment submission instructions, FDA Docket Number and meeting background are provided below to assist you in submitting comments!  Please note: FDA's comment submission deadline is TOMORROW - Friday, November 17, 2017. You are welcome and encouraged to use IACP's comments in your own submissions to PCAC.

View IACP's Comments Submitted to FDA for Assistance!

Please click here to view IACP's complete comments submitted to PCAC.

Here's How You Submit Comments!

Submit Comments : Please note while the meeting is November 20-21, comments are due November 17th. The docket number is FDA-2017-N-5818. The docket will close on November 17, 2017. Submit either electronic or written comments on this public meeting by November 17, 2017. Please note that late, untimely filed comments will not be considered. Electronic comments must be submitted on or before November 17, 2017. The  https://www.regulations.gov  electronic filing system will accept comments until midnight Eastern Time at the end of November 17, 2017. 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.

It's important that we make our voices heard on behalf of our patients! 

Stay Tuned Next Week for Live PCAC Meeting Reports

IACP will have a representative in attendance at the PCAC meeting being held next week on Monday & Tuesday, November 20th-21st. Please stay tuned to your email inbox and IACP's Breaking News Section on our website homepage for Member Alerts as we keep you updated on PCAC meeting news and voting results.

Patient access to compounded medications 
is a patient safety issue. 
UPDATE: FDA Releases PCAC Briefing Documents Ahead of November 20-21 Meeting Detailing FDA's Recommendations on API & Compound Nominations

The November 20-21, 2017 Pharmacy Compounding Advisory Committee (PCAC) meeting briefing document has been uploaded to the FDA website.

In addition, FDA has made updates to the PCAC meeting agenda and public participation details which can be found here.

These updates include: The Agenda portion has been changed for the November 20-21, 2017 meeting of the Pharmacy Compounding Advisory Committee. For L-citrulline, the uses reviewed have been updated from "Hyperammonaemia due to cycle disorders" to "Hyperammonaemia due to urea cycle disorders". In addition, "The committee also intends to discuss liposome drug products and drug products produced using hot melt extrusion technology" has been updated to "The committee also intends to discuss liposome drug products and drug products produced using hot melt extrusion."
The public participation information has been updated. The deadline for making formal oral presentation requests has been changed from Thursday, October 26, 2017 to Wednesday, November 8, 2017 and the contact person will now notify interested persons regarding their request to speak by Thursday, November 9, 2017. All other information remains the same.

Background - What you Need to Know!

The Food & Drug Administration (FDA) announced on October 25th that a Pharmacy Compounding Advisory Committee (PCAC) meeting would occur on November 20-21, 2017 during the week of the Thanksgiving holiday. PLEASE NOTE: The PCAC meeting will be open to the public, and you are encouraged to submit comments and attend the meeting.

The meeting will be held from 8:30 am to 5:00 pm on Monday, November 20th, and from 8:30 am to 11:30 am on Tuesday, November 21st at the FDA White Oak Campus, 10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room (Rm. 1503), Silver Spring, MD 20993-0002.

In the Agenda portion of the notice, the FDA announced that the nominators of the following substances and products will be invited to make a short presentation supporting the nomination: astragalus, L-citrulline, pregnenolone, 7-keto dehydroepiandrosterone (DHEA), epigallocatechin gallate (EGCg), and resveratrol.

There are Three Ways YOU Can Participate and Help:

(1) Submit Comments: Please note while the meeting is November 20-21, comments are due November 17th. Specifically, the invite states that all comments received on or before November 3, 2017 will be provided to the Committee for the meeting. The docket number is FDA-2017-N-5818. The docket will close on November 17, 2017. Submit either electronic or written comments on this public meeting by November 17, 2017. Please note that late, untimely filed comments will not be considered. Electronic comments must be submitted on or before November 17, 2017. The https://www.regulations.gov electronic filing system will accept comments until midnight Eastern Time at the end of November 17, 2017. 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.

(2) Help the Nominators Speak on these Compounds:

a. Do Not Compound List - The committee also intends to discuss liposome drug products and drug products produced using hot melt extrusion for inclusion on the Do Not Compound (Difficult to Compound) List.

b. APIs Positive List - FDA invited those that nominated and we need your help! We are looking for folks that will speak on the drugs nominated and for the uses nominated. Please note that the below APIs have been nominated and the FDA recommendation is out beside the bulk ingredient name

a.    L-citrulline for oral administration - Yes - to add to the Positive List
b.   Astragalus - No - to keep off the Positive List
c.   Pregnenolone - No - to keep off the Positive List
d.    7-keto dehydroepiandrosterone - No - to keep off the Positive List
e.   Epigallocatechin gallate - No - to keep off the Positive List
f.   Resveratrol - No - to keep off the Positive List

Drug
Uses Reviewed
Astragalus 
 Allergic rhinitis, asthma, diabetes, herpes simplex keratitis, wound healing 
L-citrulline "Hyperammonaemia due to urea cycle disorders
Pregnenolone Rheumatoid arthritis, hypercholesterolemia, manic and depressive symptoms of bipolar disorder and bipolar disorder with substance abuse (dual diagnosis), positive and negative symptoms of schizophrenia 
7-keto dehydroepiandrosterone Weight loss, Raynaud's phenomena 
Epigallocatechin gallate Treatment of obesity, wound healing, corneal neovascularization, nonalcoholic fatty liver disease, cardiac hypertrophy, diabetes (type 1 & 2),
Parkinson's disease

Resveratrol
Treatment of older adults with impaired glucose tolerance, pain   






























(3) You can Speak at the PCAC Meeting During the Public Session! Members may speak during the Public Portion of the PCAC Meeting: As a reminder, anyone can speak during the public portion of the meeting. There are designated public sections during every PCAC and sadly hardly anyone speaks due to the lack of knowledge by the public that they may speak during this section. The deadline for making formal oral presentation requests has been changed from Thursday, October 26, 2017 to Wednesday, November 8, 2017 and the contact person will now notify interested persons regarding their request to speak by Thursday, November 9, 2017. The public may speak at the following times: 

a. November 20th
i.     9:35 am - 9:45 am
ii.    10:55 am - 11:05 am
iii.   12:00 pm - 12:10 pm
iv.    2:05 pm - 2:15 pm
v.     3:25 pm - 3:35 pm
vi.    4:30 pm - 4:40 pm

b. November 21st
i.     9:40 am - 9:50 am
ii.    11:10 am - 11:20 am
View FDA Documents and Federal Register Public Meeting Notice

Please click here  to view FDA's official meeting notice and to obtain additional comment submission instructions. This information has been published in the Federal Register. 

Click here to view FDA's nominator letter sent to IACP.

Click here to view the 503A Substances and Nominators which will be discussed at the November 20-21, 2017 PCAC meeting. 

IACP was asked for comments by an  Inside Health Policy  reporter on FDA's announcement of the PCAC meeting, and we replied:

"IACP just became aware of this meeting, and we currently are reviewing the nominations. The FDA essentially has provided only a three-week notice for a meeting scheduled during the week of Thanksgiving. This timing does not indicate to us that they are encouraging or making stakeholder input a priority. Pharmacists, providers and patients need more than a three weeks' notice to make travel arrangements to attend and speak during the meeting. The fact that FDA has scheduled this during Thanksgiving week makes travel for these stakeholders even more difficult. Unfortunately, we believe FDA is showing once again that they are not serious about gathering stakeholder input."

IACP will keep our members updated on this November PCAC meeting. Please email us with questions at  [email protected] .

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