FDA responses on delayed CHOP study:
Dear Ms. Chittenden,
Thank you for writing the Division of Drug Information,in the FDA's Center for Drug Evaluation and Research.
Basic contract information on the Polyethylene Glycol Safety in Children (PGSC) study can be found here:https://www.usaspending.gov/award/CONT_AWD_75F40120C00061_7524_-NONE-_-NONE-.
The FDA promotes and protects public health by helping to ensure the availability of safe and effective drugs, promoting the safe use of marketed drugs, and helping to ensure the quality and integrity of marketed drug products. The FDA is committed to ensuring the medicines Americans take are safe and effective. FDA recognizes the importance of this study, and remains committed to its completion. If this study brings to light new evidence of a safety risk, the FDA will take appropriate regulatory action.
We appreciate and understand your concerns.
Thank you in advance for your patience, especially as FDA is currently engaged in significant and fast moving activities in response to the current public health emergency and is allocating our remaining available resources, as appropriate, among multiple competing priorities.
Best regards,
Kara Burke, PharmD
Team Leader
Division of Drug Information
Center for Drug Evaluation and Research
Tel: 855-543-DRUG (855-543-3784)
[email protected]
Follow us
This communication is consistent with 21 CFR 10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.
From: [email protected] <[email protected]>
Sent: Tuesday, February 2, 2021 2:38 PM
To: CDER DRUG INFO <[email protected]>
Subject: Re: Attn. Kara Burke - Fwd: PEG in Covid vaccine also being studied by FDA in Children Taking Laxatives, Letter from Empire State Consumer Project
Kara,
Thank you very much for forwarding our letter to the right people. We received their reply.
Can you please give me an update on our PEG 3350 children's study being conducted at Children's Hospital of Philadelphia and the due date for completion?
Regards,
Carol Chittenden
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com/
https://laxativekids.weebly.com/
---------- Forwarded message ---------
From: CDER DRUG INFO <[email protected]>
Date: Fri, Oct 23, 2020 at 3:18 PM
Subject: FW: PEG 3350 study update
To: [email protected] <[email protected]>
Dear Mr. Koehler,
Thank you for writing the Division of Drug Information,in the FDA's Center for Drug Evaluation and Research.
FDA recognizes the importance of the Polyethylene Glycol Safety in Children (PGSC) study and remains committed to ensuring its completion as well as minimizing risks to trial integrity that may result from the Coronavirus Disease 2019 (COVID-19) public health emergency. In September, 2020, FDA awarded CHOP a contract to complete the PGSC study, including funding to support additional sample collection and data analysis.
Thank you for contacting us. We appreciate and understand your concerns.
Best regards,
Kara Burke
Team Leader | Pharmacist
Division of Drug Information
Center for Drug Evaluation and Research
Tel: 855-543-DRUG (855-543-3784)
[email protected]
-----Original Message-----
From: Bernstein, Michael
To: cachitter
Sent: Tue, Nov 20, 2018 4:26 pm
Subject: RE: FOI Request Received, FDA-2012-P-0566
Dear Ms. Chittenden:
Because appropriately sensitive assays to detect PEG 3350 and the related metabolites to be measured in the study have taken much longer to develop than was anticipated, we understand the study will not be completed by the end of 2018. We are hopeful that the assay development will be concluded shortly, but given the challenges that have been encountered in developing assays to accurately and reliably measure PEG 3350 metabolites in pediatric plasma, it is difficult to provide any specific time estimates.
Michael Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
Tel 301/796-3478 Fax 301/847-8440
[email protected]
ESCP asks FDA again for an update on CHOP study:
-----Original Message-----
From: Bernstein, Michael
To: cachitter
Cc: Sipes, Grail
Sent: Fri, Aug 3, 2018 4:53 pm
Subject: RE: Second Request - Status of PEG 3350 Study at CHOP
Dear Ms. Chittenden:
Thank you for contacting us. I will need to look into the status of this and get back to you as soon as possible. Thanks.
Michael Bernstein
From: [email protected] [mailto:[email protected]]
Sent: Wednesday, August 01, 2018 11:54 AM
To: [email protected]; Bernstein, Michael <[email protected]>; Sipes, Grail <[email protected]>
Subject: Re: Second Request - Status of PEG 3350 Study at CHOP
Dear Mr. Bernstein and Ms. Sipes:
Would you please provide us with a completion date for this study? As it is now August, we are wondering how the year end deadline will be met with sufficient participant follow-up when the CHOP web page says they have not begun recruiting participants.
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com
-----Original Message-----
From: cachitter <[email protected]>
To: Michael.Bernstein <[email protected]>; Grail.Sipes <[email protected]>
Cc: mike <[email protected]>
Sent: Tue, Jun 5, 2018 6:44 pm
Subject: Re: Status of PEG 3350 Study at CHOP
Dear Mr. Bernstein and Ms. Sipes:
Yesterday, parent Mike Koehler spoke with Sara Baumgarten, Office Administrator for Referrals and Continuity at The Children's Hospital of Philadelphia. Ms. Baumgarten told him that our FDA funded study has been put on hold indefinitely due to a "main provider" leaving. We do not know if this means leaving her position or leaving the study and the status of the study.
Obviously, we are very concerned that, after all these years, the study is being put on hold yet again, for another reason, or may be dropped. Would you please tell us the meaning of the hold? We are hopeful that a change in personnel is not enough to derail the study. Are there other reasons the study was put on hold and will the FDA be issuing a Drug Safety Communication to doctors while the study is again delayed?
The Parents Against Miralax (PAM) Facebook page has grown to over 27,000 members since January of 2017, with parents all sharing the same tragic stories of neuropsychiatric and other harms to their children since taking Miralax and generic PEG laxatives. We are counting on the FDA to add this body of patient experience to the many harms to children
it acknowledged at its Drug Safety Oversight Board meeting in 2009, but felt that “no action was required” at that time:
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
This FDA document, updated in 2016 shows that the FDA acknowledged years ago that Miralax causes seizures:
(45th page): http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000OtherR.pdf
Although not all parents on PAM have filed adverse event reports, the FDA Adverse Event Reporting System (FAERS) shows over 22,000 adult and child adverse event reports attributed to PEG 3350, including 160 deaths. The number of reports rose from 2,257 in 2012, when our FDA Citizen petition was filed.
We strongly suspect that the chronic use of PEG laxatives is altering the gut microbiome and nutritient balance in dangerous ways that are affecting the nervous systems of children. It has been 9 years since the FDA Drug Safety Oversight Board claimed that no action was required to protect children from a drug that has never been approved for use in children. The time to take action is now.
Thank you.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com/
-----Original Message-----
From: Bernstein, Michael <[email protected]>
To: Carol Chittenden <[email protected]>
Sent: Wed, Nov 29, 2017 8:45 am
Subject: Status of PEG 3350 Study
Dear Ms. Chittenden:
This responds to your request for an update on the status of the CHOP study. As you know from my last email update (May 5, 2017), CHOP must develop assays for the relevant PEG 3350 metabolites and lower molecular weight polyethylene glycols of interest before it can complete the remaining study activities and analyze the results. Our science staff has reiterated, as stated in the initial grant document, that it is critical that the assays have proper sensitivity or the results will not be accurate or useful. While we understand your frustration with the slow pace of assay development, there is no point to proceeding to the testing phase of the study if the results will not be reliable and informative. Once the assays development is concluded, the testing phase should proceed relatively quickly, as obtaining the required samples should be fairly straightforward.
Although developing the assays has taken much longer and proven more difficult than anticipated, progress is being made. CHOP recently conducted clinical testing of several assays to determine the assays’ sensitivity at detecting PEG 3350 metabolites and lower molecular weight (MW) polyethylene glycols in blood. Specifically, the set-up and validation for ethylene glycol, diethylene glycol, triethylene glycol, glycolic acid, diglycolic acid has been completed. The validation of hydroxyethoxyacetic acid (HEAA) and oxalic acid (OA) is underway and should be finished before the end of this year. Finally, work to finalize the remaining assays to measure the 200 - 400 MW PEG is on-going and should be completed in early 2018.
CHOP has indicated that it will be able to complete the remaining study activities and analysis in 2018.
We share your desire to get this study completed as promptly as possible, and appreciate your patience in this matter.
Michael D. Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
Tel 301/796-3478 Fax 301/847-8440
[email protected]
From: Carol Chittenden [mailto:[email protected]]
Sent: Thursday, November 09, 2017 2:12 PM
To: Bernstein, Michael
Subject: Re: FDA-2016-P-0769 Response Received; Status of Study
Thank you.
Sent from my iPhone
On Nov 9, 2017, at 1:46 PM, Bernstein, Michael <[email protected]> wrote:
Dear Ms. Chittenden--
Dr. Woodcock has asked us to respond to your email requesting an update on the PEG study being conducted by Children’s Hospital of Philadelphia. We are following up on your inquiry and will provide you with a response as soon as possible. I appreciate your patience.
Michael D. Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
Tel 301/796-3478 Fax 301/847-8440
[email protected]
ESCP asks FDA again that a Safety Alert be issued to doctors:
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
February 6, 2018
Dr. Janet Woodcock, Director
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
[email protected]
FDA Safety Alerts for Human Medical Products, PEG 3350 Laxatives and Children
Dear Ms. Woodcock:
Since 2012, when we filed our petition to study PEG 3350 laxative safety in pediatric patients (FDA-2012-P-0566), we have been asking the FDA to issue a safety alert to doctors regarding adverse events associated with prescribing the drugs off-label to children. Our request was based on FDA’s 2009 Drug Safety Oversight Board acknowledgement of neuropsychiatric and other harms…
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
As subscribers to FDA’s newsletters, we regularly receive FDA Safety Alerts for Human Medical Products, many of which are issued before any type of study is done to prove a causal relationship between the product and potential harm. This warning just issued on a medical device states that 7 adverse events since 2012 prompted a warning to doctors: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm595476.htm. Adverse events related to PEG laxatives are now at 22,637, up from 2,257 in 2012. Although the FDA has a desire to protect the rights of industry, to the thousands of parents who say their children have been harmed, this suggests a bias in favor of the manufacturer of the best-selling PEG laxative, Miralax.
As we have expressed in past letters, the delay in finishing the study at Children’s Hospital of Philadelphia (CHOP) has caused 24,000 parents to seek information on the safety of PEG laxatives for children on the Parents Against Miralax (PAM) Facebook page, over 21,000 in the past year. There are obvious and serious adverse events related to these drugs, all of which have been acknowledged by the FDA Drug Safety Oversight Board, yet no warning is forthcoming, pending the completion of the CHOP study. Again, waiting another year for the expected completion of a study that was to have been completed in 2015 may result in harm to many thousands of children whose doctors are not made aware of problems with prescribing these unapproved products to children. We are also concerned that, due to the narrow scope of the study, if the study does not show that PEG breakdown alone is responsible for adverse events in children, all of the time that could have been used to also study PEG’s effects on the microbiome and nutrient absorption/depletion will have been wasted. Meanwhile, doctors have never been warned of skyrocketing adverse events and continue to prescribe without reservation. Don’t we owe it to the medical community as well as the children to end the widespread, careless off-label prescribing of these unapproved drugs?
We are requesting again that a Safety Alert be issued as soon as possible.
Thank you.
Sincerely,
Carol Chittenden
Empire State Consumer Project
[email protected]
Empire State Consumer Project, Inc. (ESCP) is a registered 501c3 Not-for-Profit Organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest. ESCP is represented by Joel Kupferman, Esq., NY Environmental Law & Justice Project, [email protected].
www.empirestateconsumerproject.blogspot.com
ESCP asks for information on Miralax children's studies:
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
December 5, 2017
Dr. Janet Woodcock, Director
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
[email protected]
Miralax PREA Deferment, Due October 6, 2016
Dear Ms. Woodcock:
This year, following television news reports that aired around the country, the Parents against Miralax Facebook group (PAM) grew from 3,000 to 23,000 members. Parents are joining daily with almost identical stories of serious behavior issues in their children following the start of polyethylene glycol laxatives. We urge you and your staff to sign on to the group and read the heartbreaking stories of harm parents are reporting. We post regularly asking parents to report symptoms to the FDA, but not all follow through. We are asking the FDA to reconsider issuing a warning to doctors while we wait for research – the Children’s Hospital of Philadelphia (CHOP) study or others - to explain what is happening. Another year is too long to allow doctors to continue the reckless off-label prescribing of PEG laxatives to children, especially when there are alternatives.
Further, the poison control document below published by CHOP lists PEG 3350 studies that have been conducted. Most say “no behavioral problems reported.”
http://media.chop.edu/data/files/pdfs/polyethyline-laxatives-fact-sheet.pdf
For these studies, would you please provide us with evidence that behavior changes were tracked and recorded by parents and documented by researchers? To our knowledge, the current CHOP study is the first that will study behavior changes in children on PEG 3350 laxatives. Prior to this study, parents would have no idea that PEG 3350 may cause behavior changes and would not have volunteered changes without being prompted to take daily notes about specific behaviors and report, unless asked to do so as part of a study. As we see over and over, doctors do not acknowledge the onset of behavior changes in children with PEG 3350 use and tell parents that the changes are typical for the age or another condition that happens to coincide with the start of PEG 3350 use.
Per the FDA…
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
Also, according to this letter to Braintree Laboratories dated 10/6/2006: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/022015s000ltr.pdf, it appears the Pediatric Research Equity Act (PREA) required the manufacturer (now Bayer) to have completed deferred pediatric studies (ages birth to 16) for Miralax by October 6, 2016. Would you please tell us whether the studies have been completed and when? If the studies have not been completed, would you please tell us when they will be completed or why they were not required?
If the tests were completed, the FDA would have been required to file the results with the Federal Register. We have searched Miralax and polyethylene glycol 3350 at the Federal Register; there are no documents regarding pediatric studies. The final report was to be attached to the NDA and there are no attachments. There are label changes attached to the Miralax NDA; per the approval letter there was supposed to have been an annual update regarding pediatric studies.
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=022015...
"If you are required by the FDA, or if you have entered into an agreement with the FDA, to conduct a postmarketing study concerning clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology, you are required to provide the Agency with an annual report on the status of the study until the FDA notifies you, in writing, that the Agency concurs with your determination that the study commitment has been fulfilled or that the study either is no longer feasible or would no longer provide useful information. This annual report must address the progress of the study or the reasons for your failure to conduct the study (21 U.S.C. 356b(a); 21 CFR 314.81(b)(2)(vii) and 601.70(b))."
"The FDA can require you to conduct a postmarketing study in certain situations. For example, the FDA can require you to conduct studies to verify and describe clinical benefit for a drug or biological product approved in accordance with the accelerated approval provisions (21 U.S.C. 356(b)(2)(A); 21 CFR 314.510 and 601.41). For a drug or biological product approved on the basis of animal efficacy data because human efficacy studies are not ethical or feasible, an applicant must conduct studies when ethical and feasible to verify and describe clinical benefit and to assess the product’s safety (21 CFR 314.610(b)(1) and 601.91(b)(1)). Section 2 of the Pediatric Research Equity Act of 2003 (PREA) authorized the FDA to require pediatric studies of marketed drugs that are not adequately labeled for children. These studies may be deferred if the drug is ready for approval in adults before pediatric studies are completed or because of concerns about the safety or effectiveness of the drug in pediatric populations (21 U.S.C. 355B(a); P.L. 108-155). The FDA may also issue an order or regulation requiring an applicant to provide a study report that is necessary and relevant to a determination concerning whether there is or may be grounds for revoking approval of an approved drug (21 U.S.C. 355(k)(1)). You must file 506B reports for all postmarketing study commitments that you are required to conduct provided that the study concerns a product’s clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology."
"Postmarketing Study Commitment: An agreement between you and the FDA, confirmed in writing, for you to conduct one or more 506B or CMC studies. Also includes 506B studies that are required by the FDA (e.g., accelerated approval clinical benefit studies, animal efficacy clinical benefit and safety studies, deferred pediatric studies under PREA)"
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project
[email protected]
Empire State Consumer Project, Inc. (ESCP) is a registered 501c3 Not-for-Profit Organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest. ESCP is represented by Joel Kupferman, Esq., NY Environmental Law & Justice Project, [email protected].
www.empirestateconsumerproject.blogspot.com
ESCP receives update on FDA study:
From: Bernstein, Michael
To: Carol Chittenden
Sent: Wed, Nov 29, 2017 8:45 am
Subject: Status of PEG 3350 Study
Dear Ms. Chittenden:
This responds to your request for an update on the status of the CHOP study. As you know from my last email update (May 5, 2017), CHOP must develop assays for the relevant PEG 3350 metabolites and lower molecular weight polyethylene glycols of interest before it can complete the remaining study activities and analyze the results. Our science staff has reiterated, as stated in the initial grant document, that it is critical that the assays have proper sensitivity or the results will not be accurate or useful. While we understand your frustration with the slow pace of assay development, there is no point to proceeding to the testing phase of the study if the results will not be reliable and informative. Once the assays development is concluded, the testing phase should proceed relatively quickly, as obtaining the required samples should be fairly straightforward.
Although developing the assays has taken much longer and proven more difficult than anticipated, progress is being made. CHOP recently conducted clinical testing of several assays to determine the assays’ sensitivity at detecting PEG 3350 metabolites and lower molecular weight (MW) polyethylene glycols in blood. Specifically, the set-up and validation for ethylene glycol, diethylene glycol, triethylene glycol, glycolic acid, diglycolic acid has been completed. The validation of hydroxyethoxyacetic acid (HEAA) and oxalic acid (OA) is underway and should be finished before the end of this year. Finally, work to finalize the remaining assays to measure the 200 - 400 MW PEG is on-going and should be completed in early 2018.
CHOP has indicated that it will be able to complete the remaining study activities and analysis in 2018.
We share your desire to get this study completed as promptly as possible, and appreciate your patience in this matter.
Michael D. Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
[email protected]
ESCP Asks FDA Again for Drug Safety Communication to Doctors:
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
January 27, 2017
Mr. Michael D. Bernstein, Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
FDA Citizen Petition FDA-2012-P-0566, Study and Drug Safety Communication
Dear Mr. Bernstein:
In 2012, Empire State Consumer Project (ESCP) filed an FDA Citizen Petition to study the safety of polyethylene glycol 3350 laxatives prescribed to children (FDA-2012-P-0566). The product safety concerns reported in the petition are symptoms similar to those of ethylene glycol toxicity. The petition grant includes an agreement by FDA to study the potential for PEG 3350 to degrade into ethylene glycol (EG) and diethylene glycol (DEG) and to study the long term effects of PEG 3350 products on pediatric patients. Ethylene glycol and diethylene glycol are chemicals used to make antifreeze. Both are toxic to the central nervous system, liver, and kidneys when ingested.
The ESCP petition was granted with a study awarded to Children’s Hospital of Philadelphia (CHOP), which was to have been completed by 9/9/2015. http://grantome.com/grant/NIH/R01-FD005312-01 As of this date, the FDA/CHOP study has not yet begun recruiting participants. Upon inquiring with the FDA on the status of the study, we have been advised to look for updates on the CHOP website. The website still states, “Researchers in CHOP’s Division of Gastroenterology who will be conducting the study have not begun enrolling children, but once enrollment begins, an announcement will be made.” http://heuckeroth.research.chop.edu/peg-3350-study
We are asking that the FDA issue an update on the status of this study and, given the delay in completing the study, to issue an FDA Drug Safety Communication regarding potential dangers in prescribing PEG 3350 drugs off-label to children. It has been almost five years since we filed our petition. As of this date, no study has been conducted on neuropsychiatric effects in children and no study has been done on the long term use of these products in children.
The FDA Adverse Event Reporting System (FAERS) now shows over 19,000 adult and child adverse event reports that include at least one PEG 3350 product (including a number of deaths), a small percentage of which have been reviewed by the FDA. The number of reports rose from 2,257 in 2012, when the FDA Citizen petition was filed.
In 2009, the FDA Drug Safety Oversight Board acknowledged neuropsychiatric, metabolic, gastrointestinal, and kidney events in children who took PEG 3350 laxatives, but felt that “no action was required” at that time:
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
This FDA document, updated in 2016 shows that the FDA acknowledged years ago that Miralax causes seizures (45th page): http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000OtherR.pdf
In addition to the ethylene glycol and diethylene glycol children may be exposed to through the degradation of PEG 3350, the FDA has tested 8 lots of polyethylene glycol 3350 and found ethylene glycol and diethylene glycol contaminants in the product itself… “To better understand the level of polyethylene glycol impurities in PEG, the FDA Chemistry and Manufacturing group evaluated PEG 3350. This analysis of eight lots of PEG 3350 confirmed the presence of small amounts of ethylene glycol and diethylene glycol in all lots tested. Based upon the recommended daily adult dose of 17g daily dose PEG 3350, the maximum daily exposure of ethylene glycol would be 0.005 mg/kg/day for a 60 kg patient, or 0.015 mg/kg/day for a 20 kg pediatric patient (approx 5 years of age). Other low molecular weight (LMW) PEGs were not included in this analysis. However, it is not known if any of these LMW species are absorbed and if so to what extent. Understanding the human absorption profile of LMW species is the first step needed in trying to understand the possible contribution of PEG 3350 use to the development of adverse events in children using this product chronically.”
The EPA recommends that children not be exposed to more than 20 mg/L or 20 parts per million (ppm) of ethylene glycol in drinking water per one day or 6 mg/L or 6 ppm per day over 10 days. The adult doses of PEG 3350 tested were found to contain 0.3 mg of ethylene glycol of daily exposure for a 44 lb. child. This exposure is in addition to any EG and DEG exposure that may be found to occur from PEG 3350 degradation of the laxative products. The health effects of long term exposure of children to PEG 3350 are not known, although risks from short term exposure to EG and DEG are well documented in humans.
In 2009, the FDA issued a warning about DEG in electronic cigarettes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm173222.htm
Empire State Consumer Project has since petitioned the FDA to issue a Drug Safety Communication regarding the finding of ethylene glycol and diethylene glycol in all lots of PEG 3350 it tested, so that parents of study participants and all parents can be made aware of the potential for PEG 3350 to contain ethylene glycol and diethylene glycol. This petition for a Drug Safety Communication was denied. Although one additional FDA test did not show EG and DEG, ESCP has asked that ongoing PEG 3350 product testing be conducted by the FDA, as one test is not a comprehensive study, nor an assurance of safety.
Doctors at the National Taiwan University Hospital in Taipei have also concluded “that bowel preparation with PEG lavage solution may be associated with severe renal complications, and that physicians should be aware of possible adverse effects when administering the agent.” http://www.ntuh.gov.tw/pmr/lists/list14/attachments/164/10253009-200903-37-1-45-50-a.pdf
Dosing
As stated in our petition, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) has created guidelines for off-label prescribing of PEG 3350 laxatives to children. These guidelines are not approved by the FDA. Parents report that many doctors are prescribing even higher doses. Children are often given multiple adult doses daily for months and years at a time.
Based on NASPGHAN dosing, one gram of PEG 3350 per kg of body weight is 10 grams of PEG for a 22 lb. child, or more than half of the 17 gram adult dose.
http://journals.lww.com/jpgn/fulltext/2006/09000/evaluation_and_treatment_of_constipation_in.28.aspx
In an example of a constipation treatment recommendation from a large children’s hospital in the US, dosing is 3 times per day for 3 days during the cleanout phase and a duration of 6-12 months or more for the maintenance phase. In this case, a 10 year old child would receive 3 adult daily doses per day for 3 days, then 1-2 adult daily doses per day for up to a year or more. Again, much younger children are also routinely given adult doses of PEG 3350 daily for months and years at a time… “As soon as they complete the first cleanout, give polyethylene glycol once daily at the following dosages. Mix in juice or water, not milk. It needs to be taken daily for at least 6-12 months and often longer. You can increase the dose slightly if needed.
Children 18 months to 5 years old – Give 2 teaspoons, mixed in 4 to 6 ounces of fluid
Children 5 to 10 years old – Give 1 capful (17 gms) mixed in 6-8 ounces of fluid
10 years old and older – Give 1 to 2 capfuls mixed in 8 ounces of fluid”
Selenium
In February 2016, Empire State Consumer Project entered another FDA Citizen Petition asking the FDA to test PEG 3350 products after finding high levels of selenium in the three PEG 3350 products ESCP tested (FDA-2016-P-0769). The FDA responded with an agreement to review and analyze the request, but we have not received any additional correspondence regarding FDA conducting its own testing.
The 2012 ESCP also called for a boxed warning on PEG 3350 products. The boxed warning was not granted, but the FDA has decided to update the labeling of prescription PEG 3350 bowel preparations with more stringent warnings and precautions for patients with certain health conditions. We feel it is crucial that, if a boxed warning is not forthcoming pending research, a Drug Safety Communication be issued. Also concerning is the FDA’s loosening of restrictions on off-label marketing and companies now creating food-based PEG 3350 products, which we fear will be marketed for children’s constipation before long.
Would you please provide us with an update on the FDA/CHOP study and an answer regarding a Drug Safety Communication. The thousands of parents who are members of PEG 3350 support groups are waiting for doctors to be informed of the potential dangers of these products before more children are harmed.
Sincerely,
Carol Chittenden
Empire State Consumer Project
[email protected]
www.empirestateconsumerproject.blogspot.com
Empire State Consumer Project, Inc. (ESCP) is a registered 501c3 not-for-profit organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest.
ESCP Asks FDA for Response on Freedom of Information Request:
Sent: Fri, Sep 18, 2015 11:08 am
Subject: FOIA 2014-6736 and FDA-2012-P-0566 from Carol Chittenden, Empire State Consumer Project
Dear Ms. Sipes,
Yesterday, I received a phone call from Michael Howard regarding the above FOIA. I had been told by Sharon Dodson on July 1, 2015 that she would forward our request to him to investigate why it had been sent to Food Additives when it was clearly a CEDR FOIA. I had begun the process by sending the request to you in January (see below) and I am hoping you can oversee the disposition of the request to ensure it goes to the correct person there. Would you please send me the name of the contact who will be responsible for processing the request, so I can follow up as needed?
I had also written to Michael Bernstein asking for an improvement in the 12-18 month timeline for an answer to this FOIA, as we are a not-for-profit consumer organization involved in public education and feel that this time frame is excessively long for a government agency response regarding current and serious medical issues being faced by children. We are now 9 months into that time period without any progress by FDA, as the request is being bumped to the wrong departments.
Also, I am in need of an update on the status of the study granted to Children's Hospital of Philadelphia related to our FDA petition, FDA-2012-P-0566. Would you please tell me if the study has begun recruiting participants, whether it will include an analysis of the effects of PEG 3350 on the gut microbiome and enteric nervous system (as we have requested), and when the study will be completed.
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
www.empirestateconsumerproject.blogspot.com
ESCP Asks FDA to Not Miss Critical Information in Study on Children
Ms. Grail Sipes
Director
Office of Regulatory Policy
Center for Drug Evaluation and Research
US Food and Drug Administration
FDA Petition FDA-2012-P-0566, Study at Children's Hospital of Philadelphia
Dear Ms. Sipes:
We understand from a press release issued by Children's Hospital of Philadelphia that participant recruiting for this study has not yet begun. We would like to take this opportunity to express our concern that the study be a comprehensive assessment of the effects of peg 3350 use in children. Rather than making the assumption that absorption alone is leading to neuropsychiatric symptoms in children, is it possible to include the following testing in FDA's research? We feel that if peg testing alone does not prove that EG or DEG are being absorbed, we have lost the opportunity to look for other factors that may be contributing to neuropsychiatric symptoms in children...
1. As we asked in our FDA petition, what are the effects of chronic laxative use on nutrient absorption and depletion in children? Many nutrients, including B vitamins and magnesium are related to neuropsychiatric health. If there is evidence that chronic laxative use blocks nutrient absorption or depletes nutrients, what key nutrients can be measured while blood is being drawn for PEG, EG, DEG. (See petition page 15,
absorption? http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-0566-0001).
2. Effects of chronic laxative use on the enteric nervous system and feedback to the central nervous system. As we asked in our petition, what effects does peg laxative use have on intestinal flora (FDA petition page 15)? How does this affect the nervous system in the intestines that would impact neuropsychiatric health? If it is true that 95% of seratonin is found in the bowels and that 90% of the fibers in the vagus nerve transmit information from the gut to the brain and not the other way around ( http://www.scientificamerican.com/article/gut-second-brain/ ), can we measure this effect in children on PEG 3350 through blood and stool testing.
3. Metabolic acidosis was acknowledged by the 2009 FDA Drug Safety Oversight Board as an adverse event related to PEG 3350 use in children. As metabolic acidosis is a cause of demylenation of nerves (as is B12 deficiency) and related neuropsychiatric symptoms, will metabolic acidosis be tested for in children being studied?
http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/multiple_sclerosis_ms_and_related_disorders/overview_of_demyelinating_disorders.html
http://www.nationalmssociety.org/For-Professionals/Clinical-Care/Diagnosing-MS/Signs-and-Symptoms-Consistent-with-Demyelinating-D#section-6
Thank you very much for your consideration of these issues as you study the effects of PEG 3350 laxatives in children.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
www.empirestateconsumerproject.blogspot.com
ESCP Submits Freedom of Information Request for Information on Toxics in PEG 3350 and Children's Study Protocol
January 20, 2015
Grail Sipes
Director
Office of Regulatory Policy
Center for Drug Evaluation and Research
US Food and Drug Administration
Re: Freedom of Information Act Request, FDA-2012-P-0566
Dear Ms. Sipes:
This is a request under the Freedom of Information Act. We request that a copy of the following records or documents containing the following information be provided to us.
I am requesting on behalf of Empire State Consumer Project, a registered 501c3 not-for-profit organization engaged in free consumer education services, for which this information will be used. We request a waiver of all fees for this request. Disclosure of the requested information to us is in the public interest because it is likely to contribute significantly to public understanding of the operations or activities of the government or a government funded study and is not related to a commercial interest. The information requested is related to Citizens Petition FDA-2012-P-0566 and is in response to your letter to Empire State Consumer Project dated November 12, 2014.
In that correspondence, we were advised to ask Children’s Hospital of Philadelphia (CHOP) for some of this information. We feel that, because this is an FDA funded study, the FDA should be providing us with this information, as CHOP is under no legal obligation to do so.
FDA-Funded Research at Children’s Hospital of Philadelphia
1. Records related to PEG 3350 potential health risks given to test participant parents/guardians, including the finding of EG and DEG in all lots of PEG 3350 FDA tested. We feel it is important for parents to understand the symptoms that have been reported to the FDA before they agree to participate.
2. Records related to the testing of PEG 3350 being used in the CHOP study for the presence of EG and DEG before being used on study participants. Although FDA tested again in 2013, this is not a thorough study of PEG 3350 products and we recommend ongoing testing for EG and DEG. A valid study of PEG 3350 absorption necessitates that EG and DEG-free products be used.
3. Records related to protocol for measuring baseline neuropsychiatric conditions of study participants taking PEG 3350 products before entering study, including data collection documents used to assess when PEG 3350 administration began, at what doses, for what duration, and when symptoms began. Children currently taking PEG 3350 may already be experiencing symptoms related to PEG 3350 use.
4. Records related to the length of time study participants will be evaluated for changes in neuropsychiatric behavior (including past the end of PEG 3350 administration). Parents report the continuation of symptoms long after discontinuation of PEG 3350 and some report an increase in severity of symptoms just after discontinuing.
5. Records related to protocol for measuring urinary/kidney changes in study participants and changes related to metabolic acidosis. These symptoms were part of the FDA’s Drug Safety Oversight Board meeting in 2009, but are not listed in CHOP’s study outline.
Relationship of Ethylene Glycol and Diethylene Glycol to PEG 3350 Adverse Events
“As part of the drug approval process, manufacturers must meet specifications for levels of impurities that exist in their products (see 21 CFR 211.84(d)(2)) for their products to be approved as safe and effective.”
1. Records related to the specifications for levels of ethylene glycol, diethylene glycol and their respective metabolites, glycolic acid, glyoxylic acid, glycoaldehyde, oxalic acid, 2-hydroxyethoxyacetic acid, 1,4-dioxane, ethylene oxide, and heavy metals that may be found in PEG 3350. If manufacturers must meet specifications, they must be published specifications available to the public.
2. Records related to amounts of these substances found in PEG 3350 FDA has tested and manufacturers have tested and submitted to FDA. These findings should not be misconstrued by manufacturers as possibly being related to manufacturer “trade secrets,” as mentioned in FDA’s last letter to us.
3. Records related to manufacturer information on potential for PEG 3350 to break down into EG or DEG in solution or in animal studies.
Adverse Event Reports
1. Records related to FDA’s or CHOP’s review of or plans to review PEG 3350 related adverse events added from August 6, 2012 to July 2014. Our records show 7,070 adverse events that include PEG 3350 are in the FAERS database through July 2014. Given the large number of adverse event reports that contain at least one PEG 3350 product, we think it is important for the FDA and CHOP to review all adverse event reports in designing and conducting a comprehensive study.
Would you please add this correspondence to online Docket No. FDA-2012-P-0566.
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project
www.empirestateconsumerproject.blogspot.com
ESCP Asks FDA to Research PEG in Covid Vaccines, Reactions, and Children
-----Original Message-----
From: [email protected]
To: [email protected] ; [email protected]
Cc: [email protected] ; [email protected] ; [email protected] ; [email protected]
Sent: Tue, Dec 15, 2020 9:26 am
Subject: PEG in Covid vaccine also being studied by FDA in Children Taking Laxatives, Letter from Empire State Consumer Project
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
December 15, 2020
Stephen M. Hahn M.D.
Commissioner of Food and Drugs - Food and Drug Administration
[email protected]
Peter Marks M.D., PhD.
Director - Center for Biologics Evaluation and Research (CBER)
[email protected]
cc: US Senator Kirsten Gillibrand, US Senator Chuck Schumer
Consumer Group Warns PEG Suspected in Pfizer Covid Vaccine Reactions is Same Chemical Harming Children Taking Laxatives, Being Studied by FDA
Dear Commissioner Hahn and Director Marks:
Empire State Consumer Project (ESCP) is a registered 501c3 not-for-profit organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest.
We want to bring to your attention that the ingredient suspected in the allergic reactions in two people who received the Pfizer Covid 19 vaccine, polyethylene glycol (PEG), is the same chemical causing neuropsychiatric and other adverse events in children taking polyethylene glycol laxatives. We ask that you please review ESCP’s FDA Citizen Petition on polyethylene glycol laxatives and risks to children and the resulting grant FDA issued to Children’s Hospital of Philadelphia to study PEG adverse events in children. ESCP’s website dedicated to this nonprofit consumer advocacy work is https://laxativekids.weebly.com/.
We understand that the British Medicines and Healthcare Products Regulatory Agency (MHRA) Chief Executive June Raine told lawmakers such allergic reactions had not been a feature of Pfizer’s clinical trials. Pfizer has said people with a history of severe adverse allergic reactions to vaccines or their ingredients were excluded from their late-stage trials. We see that the FDA will require Pfizer to increase its monitoring for anaphylaxis and submit data on anaphylaxis adverse events once the vaccine is distributed for use.
FDA reported adverse events related to PEG 3350 are over 36,000 and the parent Facebook group, Parents Against Miralax, Restoralax, Movicol is up to 43,000 members since we filed our petition in 2012. Our work has been receiving nationwide news coverage ever since, including two stories in the New York Times. Almost all parents report identical neuropsychiatric and other symptoms in their children while taking PEG 3350. The FDA has resumed the study (which had been delayed since 2015) with a new completion date of 2021.
PEG laxatives are not approved for use in children, nor in adults for more than 7 days, but are routinely prescribed to children by pediatricians in adult doses for long term use. Our research shows that PEG allergy and hypersensitivity are well known in humans, but have not been studied in children. Parents report that PEG allergy testing has not been made available to them when they report adverse events in their children taking the drug.
In light of the PEG adverse events acknowledged by the FDA in its Drug Safety Oversight Board meeting of June 18, 2009 (excerpts below), we think it is imperative that the FDA studies whether PEG as an ingredient in vaccines can be considered safe for children.
FDA Drug Safety Oversight Board Meeting June 18, 2009, Public Summary
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body’s acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings."
"There is a perception that PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known about whether absorption in children differs from adults, especially in children who are constipated, have underlying intestinal disease, or are very young."
"Children may be more susceptible to variations in PEG product quality."
"Effects of large doses of PEG given over a long duration (e.g weeks or longer) is not known.” "Children are receiving adult doses of PEG in some cases.”
Given the adverse events parents are reporting in children ingesting PEG, exposing children to PEG through injection should require FDA’s most thorough deliberation and research.
We look forward to your reply on this urgent drug safety and children’s health issue.
Sincerely,
Carol Chittenden, Director
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com/
https://laxativekids.weebly.com/
585-831-7124
Richards, Paul [email protected]Hide
To[email protected] [email protected]
Dear Ms. Chittenden,
This message is in response to our recent telephone conversation regarding your letter related to polyethylene glycol (PEG), one of the ingredients in the Pfizer-BioNTech and Moderna COVID-19 vaccines. The U.S. Food and Drug Administration (FDA) has authorized these vaccines for emergency use in the United States to prevent COVID-19.
The issuance of an Emergency Use Authorization (EUA) is different than an FDA approval of a vaccine, in that a vaccine available under an EUA is not approved. In determining whether to issue an EUA for a product, the FDA evaluates the available evidence to determine whether the product may be effective and also assesses any known or potential risks and any known or potential benefits. If the product meets the effectiveness standard and the benefit-risk assessment is favorable, the product is made available during the emergency.
For both vaccines, FDA has evaluated and analyzed the safety and effectiveness data from clinical trials conducted in tens of thousands of study participants and manufacturing information submitted by the companies. These clinical trials are being conducted according to the rigorous standards set forth by the FDA. FDA has determined that the totality of the available data provides clear evidence that both vaccines may be effective in preventing COVID-19 and support that the known and potential benefits outweigh the known and potential risks of the vaccine’s use in millions of people, including healthy individuals.
Within your letter you express concern about the risk of exposure to polyethylene glycol (PEG) in children. The Pfizer-BioNTech COVID-19 Vaccine is authorized for use for the prevention of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The Moderna COVID-19 Vaccine is authorized for use for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. Both manufacturers have publicly acknowledged that they intend to study their vaccines in adolescents, followed by studies in younger children.
Additionally, it is important to note that the Fact Sheets for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine explain that neither vaccine should be administered to individuals with a known history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine. The Fact Sheet for Healthcare Providers explains that appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration and references the Centers for Disease Control and Prevention (CDC) guidelines (https://www.cdc.gov/vaccines/covid-19/).
As of January 15, 2021, over 12 million individuals have received at least one dose of a COVID-19 vaccine, a disease that is causing vast numbers of hospitalizations and deaths in the United States each day and for which there are limited treatments available. Allergic reactions, some of which have been severe, have been reported in some individuals following administration of the Pfizer-BioNTech and Moderna COVID-19 vaccines. Information about these allergic reactions and their occurrence is available on CDC’s website (https://www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm?s_cid=mm7002e1_w).
The cause of the allergic reactions is unknown. However, further study is being planned for these vaccines with regard to risk of allergic reactions.
In addition, for both COVID-19 vaccines authorized under an EUA, ongoing clinical trials will continue to obtain additional safety and effectiveness information intended to support eventual approval. Also, as a condition of authorization for each of these COVID-19 vaccines, the manufacturer will conduct post-authorization observational study(ies) to evaluate the association between the vaccine and pre-specified adverse events of special interest, along with deaths and hospitalizations. Conditions of authorization also include requirements for the manufacturers and vaccination providers to report certain adverse events to the Vaccine Adverse Event Reporting System and for the manufacturers to submit periodic safety reports to FDA. Further, FDA, CDC, and other federal partners are using robust systems and data sources to conduct ongoing safety monitoring for COVID-19 vaccines authorized under an EUA.
The safety of vaccines is a high priority for FDA and pertinent information pertaining to COVID-19 vaccines will be communicated to the public as it becomes available.
On behalf of Dr. Janet Woodcock, acting commissioner of the FDA, and Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), I would like to thank you for your interest in this topic, as well as the opportunity to provide this information to you.
Sincerely,
Paul Richards
Chief, Consumer Affairs Branch
Center for Biologics Evaluation and Research
Office of Communication, Outreach and Development
U.S. Food and Drug Administration
Tel: 240-402-8153
[email protected]
This informal communication represents my best judgment at this time. It does not constitute an advisory opinion in accordance with 21 CFR 10.85, and does not necessarily represent the formal position of FDA or otherwise obligate the agency to the views expressed.
Dear Ms. Chittenden,
Thank you for writing the Division of Drug Information,in the FDA's Center for Drug Evaluation and Research.
Basic contract information on the Polyethylene Glycol Safety in Children (PGSC) study can be found here:https://www.usaspending.gov/award/CONT_AWD_75F40120C00061_7524_-NONE-_-NONE-.
The FDA promotes and protects public health by helping to ensure the availability of safe and effective drugs, promoting the safe use of marketed drugs, and helping to ensure the quality and integrity of marketed drug products. The FDA is committed to ensuring the medicines Americans take are safe and effective. FDA recognizes the importance of this study, and remains committed to its completion. If this study brings to light new evidence of a safety risk, the FDA will take appropriate regulatory action.
We appreciate and understand your concerns.
Thank you in advance for your patience, especially as FDA is currently engaged in significant and fast moving activities in response to the current public health emergency and is allocating our remaining available resources, as appropriate, among multiple competing priorities.
Best regards,
Kara Burke, PharmD
Team Leader
Division of Drug Information
Center for Drug Evaluation and Research
Tel: 855-543-DRUG (855-543-3784)
[email protected]
Follow us
This communication is consistent with 21 CFR 10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.
From: [email protected] <[email protected]>
Sent: Tuesday, February 2, 2021 2:38 PM
To: CDER DRUG INFO <[email protected]>
Subject: Re: Attn. Kara Burke - Fwd: PEG in Covid vaccine also being studied by FDA in Children Taking Laxatives, Letter from Empire State Consumer Project
Kara,
Thank you very much for forwarding our letter to the right people. We received their reply.
Can you please give me an update on our PEG 3350 children's study being conducted at Children's Hospital of Philadelphia and the due date for completion?
Regards,
Carol Chittenden
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com/
https://laxativekids.weebly.com/
---------- Forwarded message ---------
From: CDER DRUG INFO <[email protected]>
Date: Fri, Oct 23, 2020 at 3:18 PM
Subject: FW: PEG 3350 study update
To: [email protected] <[email protected]>
Dear Mr. Koehler,
Thank you for writing the Division of Drug Information,in the FDA's Center for Drug Evaluation and Research.
FDA recognizes the importance of the Polyethylene Glycol Safety in Children (PGSC) study and remains committed to ensuring its completion as well as minimizing risks to trial integrity that may result from the Coronavirus Disease 2019 (COVID-19) public health emergency. In September, 2020, FDA awarded CHOP a contract to complete the PGSC study, including funding to support additional sample collection and data analysis.
Thank you for contacting us. We appreciate and understand your concerns.
Best regards,
Kara Burke
Team Leader | Pharmacist
Division of Drug Information
Center for Drug Evaluation and Research
Tel: 855-543-DRUG (855-543-3784)
[email protected]
-----Original Message-----
From: Bernstein, Michael
To: cachitter
Sent: Tue, Nov 20, 2018 4:26 pm
Subject: RE: FOI Request Received, FDA-2012-P-0566
Dear Ms. Chittenden:
Because appropriately sensitive assays to detect PEG 3350 and the related metabolites to be measured in the study have taken much longer to develop than was anticipated, we understand the study will not be completed by the end of 2018. We are hopeful that the assay development will be concluded shortly, but given the challenges that have been encountered in developing assays to accurately and reliably measure PEG 3350 metabolites in pediatric plasma, it is difficult to provide any specific time estimates.
Michael Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
Tel 301/796-3478 Fax 301/847-8440
[email protected]
ESCP asks FDA again for an update on CHOP study:
-----Original Message-----
From: Bernstein, Michael
To: cachitter
Cc: Sipes, Grail
Sent: Fri, Aug 3, 2018 4:53 pm
Subject: RE: Second Request - Status of PEG 3350 Study at CHOP
Dear Ms. Chittenden:
Thank you for contacting us. I will need to look into the status of this and get back to you as soon as possible. Thanks.
Michael Bernstein
From: [email protected] [mailto:[email protected]]
Sent: Wednesday, August 01, 2018 11:54 AM
To: [email protected]; Bernstein, Michael <[email protected]>; Sipes, Grail <[email protected]>
Subject: Re: Second Request - Status of PEG 3350 Study at CHOP
Dear Mr. Bernstein and Ms. Sipes:
Would you please provide us with a completion date for this study? As it is now August, we are wondering how the year end deadline will be met with sufficient participant follow-up when the CHOP web page says they have not begun recruiting participants.
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com
-----Original Message-----
From: cachitter <[email protected]>
To: Michael.Bernstein <[email protected]>; Grail.Sipes <[email protected]>
Cc: mike <[email protected]>
Sent: Tue, Jun 5, 2018 6:44 pm
Subject: Re: Status of PEG 3350 Study at CHOP
Dear Mr. Bernstein and Ms. Sipes:
Yesterday, parent Mike Koehler spoke with Sara Baumgarten, Office Administrator for Referrals and Continuity at The Children's Hospital of Philadelphia. Ms. Baumgarten told him that our FDA funded study has been put on hold indefinitely due to a "main provider" leaving. We do not know if this means leaving her position or leaving the study and the status of the study.
Obviously, we are very concerned that, after all these years, the study is being put on hold yet again, for another reason, or may be dropped. Would you please tell us the meaning of the hold? We are hopeful that a change in personnel is not enough to derail the study. Are there other reasons the study was put on hold and will the FDA be issuing a Drug Safety Communication to doctors while the study is again delayed?
The Parents Against Miralax (PAM) Facebook page has grown to over 27,000 members since January of 2017, with parents all sharing the same tragic stories of neuropsychiatric and other harms to their children since taking Miralax and generic PEG laxatives. We are counting on the FDA to add this body of patient experience to the many harms to children
it acknowledged at its Drug Safety Oversight Board meeting in 2009, but felt that “no action was required” at that time:
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
This FDA document, updated in 2016 shows that the FDA acknowledged years ago that Miralax causes seizures:
(45th page): http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000OtherR.pdf
Although not all parents on PAM have filed adverse event reports, the FDA Adverse Event Reporting System (FAERS) shows over 22,000 adult and child adverse event reports attributed to PEG 3350, including 160 deaths. The number of reports rose from 2,257 in 2012, when our FDA Citizen petition was filed.
We strongly suspect that the chronic use of PEG laxatives is altering the gut microbiome and nutritient balance in dangerous ways that are affecting the nervous systems of children. It has been 9 years since the FDA Drug Safety Oversight Board claimed that no action was required to protect children from a drug that has never been approved for use in children. The time to take action is now.
Thank you.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com/
-----Original Message-----
From: Bernstein, Michael <[email protected]>
To: Carol Chittenden <[email protected]>
Sent: Wed, Nov 29, 2017 8:45 am
Subject: Status of PEG 3350 Study
Dear Ms. Chittenden:
This responds to your request for an update on the status of the CHOP study. As you know from my last email update (May 5, 2017), CHOP must develop assays for the relevant PEG 3350 metabolites and lower molecular weight polyethylene glycols of interest before it can complete the remaining study activities and analyze the results. Our science staff has reiterated, as stated in the initial grant document, that it is critical that the assays have proper sensitivity or the results will not be accurate or useful. While we understand your frustration with the slow pace of assay development, there is no point to proceeding to the testing phase of the study if the results will not be reliable and informative. Once the assays development is concluded, the testing phase should proceed relatively quickly, as obtaining the required samples should be fairly straightforward.
Although developing the assays has taken much longer and proven more difficult than anticipated, progress is being made. CHOP recently conducted clinical testing of several assays to determine the assays’ sensitivity at detecting PEG 3350 metabolites and lower molecular weight (MW) polyethylene glycols in blood. Specifically, the set-up and validation for ethylene glycol, diethylene glycol, triethylene glycol, glycolic acid, diglycolic acid has been completed. The validation of hydroxyethoxyacetic acid (HEAA) and oxalic acid (OA) is underway and should be finished before the end of this year. Finally, work to finalize the remaining assays to measure the 200 - 400 MW PEG is on-going and should be completed in early 2018.
CHOP has indicated that it will be able to complete the remaining study activities and analysis in 2018.
We share your desire to get this study completed as promptly as possible, and appreciate your patience in this matter.
Michael D. Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
Tel 301/796-3478 Fax 301/847-8440
[email protected]
From: Carol Chittenden [mailto:[email protected]]
Sent: Thursday, November 09, 2017 2:12 PM
To: Bernstein, Michael
Subject: Re: FDA-2016-P-0769 Response Received; Status of Study
Thank you.
Sent from my iPhone
On Nov 9, 2017, at 1:46 PM, Bernstein, Michael <[email protected]> wrote:
Dear Ms. Chittenden--
Dr. Woodcock has asked us to respond to your email requesting an update on the PEG study being conducted by Children’s Hospital of Philadelphia. We are following up on your inquiry and will provide you with a response as soon as possible. I appreciate your patience.
Michael D. Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
Tel 301/796-3478 Fax 301/847-8440
[email protected]
ESCP asks FDA again that a Safety Alert be issued to doctors:
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
February 6, 2018
Dr. Janet Woodcock, Director
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
[email protected]
FDA Safety Alerts for Human Medical Products, PEG 3350 Laxatives and Children
Dear Ms. Woodcock:
Since 2012, when we filed our petition to study PEG 3350 laxative safety in pediatric patients (FDA-2012-P-0566), we have been asking the FDA to issue a safety alert to doctors regarding adverse events associated with prescribing the drugs off-label to children. Our request was based on FDA’s 2009 Drug Safety Oversight Board acknowledgement of neuropsychiatric and other harms…
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
As subscribers to FDA’s newsletters, we regularly receive FDA Safety Alerts for Human Medical Products, many of which are issued before any type of study is done to prove a causal relationship between the product and potential harm. This warning just issued on a medical device states that 7 adverse events since 2012 prompted a warning to doctors: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm595476.htm. Adverse events related to PEG laxatives are now at 22,637, up from 2,257 in 2012. Although the FDA has a desire to protect the rights of industry, to the thousands of parents who say their children have been harmed, this suggests a bias in favor of the manufacturer of the best-selling PEG laxative, Miralax.
As we have expressed in past letters, the delay in finishing the study at Children’s Hospital of Philadelphia (CHOP) has caused 24,000 parents to seek information on the safety of PEG laxatives for children on the Parents Against Miralax (PAM) Facebook page, over 21,000 in the past year. There are obvious and serious adverse events related to these drugs, all of which have been acknowledged by the FDA Drug Safety Oversight Board, yet no warning is forthcoming, pending the completion of the CHOP study. Again, waiting another year for the expected completion of a study that was to have been completed in 2015 may result in harm to many thousands of children whose doctors are not made aware of problems with prescribing these unapproved products to children. We are also concerned that, due to the narrow scope of the study, if the study does not show that PEG breakdown alone is responsible for adverse events in children, all of the time that could have been used to also study PEG’s effects on the microbiome and nutrient absorption/depletion will have been wasted. Meanwhile, doctors have never been warned of skyrocketing adverse events and continue to prescribe without reservation. Don’t we owe it to the medical community as well as the children to end the widespread, careless off-label prescribing of these unapproved drugs?
We are requesting again that a Safety Alert be issued as soon as possible.
Thank you.
Sincerely,
Carol Chittenden
Empire State Consumer Project
[email protected]
Empire State Consumer Project, Inc. (ESCP) is a registered 501c3 Not-for-Profit Organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest. ESCP is represented by Joel Kupferman, Esq., NY Environmental Law & Justice Project, [email protected].
www.empirestateconsumerproject.blogspot.com
ESCP asks for information on Miralax children's studies:
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
December 5, 2017
Dr. Janet Woodcock, Director
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
[email protected]
Miralax PREA Deferment, Due October 6, 2016
Dear Ms. Woodcock:
This year, following television news reports that aired around the country, the Parents against Miralax Facebook group (PAM) grew from 3,000 to 23,000 members. Parents are joining daily with almost identical stories of serious behavior issues in their children following the start of polyethylene glycol laxatives. We urge you and your staff to sign on to the group and read the heartbreaking stories of harm parents are reporting. We post regularly asking parents to report symptoms to the FDA, but not all follow through. We are asking the FDA to reconsider issuing a warning to doctors while we wait for research – the Children’s Hospital of Philadelphia (CHOP) study or others - to explain what is happening. Another year is too long to allow doctors to continue the reckless off-label prescribing of PEG laxatives to children, especially when there are alternatives.
Further, the poison control document below published by CHOP lists PEG 3350 studies that have been conducted. Most say “no behavioral problems reported.”
http://media.chop.edu/data/files/pdfs/polyethyline-laxatives-fact-sheet.pdf
For these studies, would you please provide us with evidence that behavior changes were tracked and recorded by parents and documented by researchers? To our knowledge, the current CHOP study is the first that will study behavior changes in children on PEG 3350 laxatives. Prior to this study, parents would have no idea that PEG 3350 may cause behavior changes and would not have volunteered changes without being prompted to take daily notes about specific behaviors and report, unless asked to do so as part of a study. As we see over and over, doctors do not acknowledge the onset of behavior changes in children with PEG 3350 use and tell parents that the changes are typical for the age or another condition that happens to coincide with the start of PEG 3350 use.
Per the FDA…
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
Also, according to this letter to Braintree Laboratories dated 10/6/2006: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/022015s000ltr.pdf, it appears the Pediatric Research Equity Act (PREA) required the manufacturer (now Bayer) to have completed deferred pediatric studies (ages birth to 16) for Miralax by October 6, 2016. Would you please tell us whether the studies have been completed and when? If the studies have not been completed, would you please tell us when they will be completed or why they were not required?
If the tests were completed, the FDA would have been required to file the results with the Federal Register. We have searched Miralax and polyethylene glycol 3350 at the Federal Register; there are no documents regarding pediatric studies. The final report was to be attached to the NDA and there are no attachments. There are label changes attached to the Miralax NDA; per the approval letter there was supposed to have been an annual update regarding pediatric studies.
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=022015...
"If you are required by the FDA, or if you have entered into an agreement with the FDA, to conduct a postmarketing study concerning clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology, you are required to provide the Agency with an annual report on the status of the study until the FDA notifies you, in writing, that the Agency concurs with your determination that the study commitment has been fulfilled or that the study either is no longer feasible or would no longer provide useful information. This annual report must address the progress of the study or the reasons for your failure to conduct the study (21 U.S.C. 356b(a); 21 CFR 314.81(b)(2)(vii) and 601.70(b))."
"The FDA can require you to conduct a postmarketing study in certain situations. For example, the FDA can require you to conduct studies to verify and describe clinical benefit for a drug or biological product approved in accordance with the accelerated approval provisions (21 U.S.C. 356(b)(2)(A); 21 CFR 314.510 and 601.41). For a drug or biological product approved on the basis of animal efficacy data because human efficacy studies are not ethical or feasible, an applicant must conduct studies when ethical and feasible to verify and describe clinical benefit and to assess the product’s safety (21 CFR 314.610(b)(1) and 601.91(b)(1)). Section 2 of the Pediatric Research Equity Act of 2003 (PREA) authorized the FDA to require pediatric studies of marketed drugs that are not adequately labeled for children. These studies may be deferred if the drug is ready for approval in adults before pediatric studies are completed or because of concerns about the safety or effectiveness of the drug in pediatric populations (21 U.S.C. 355B(a); P.L. 108-155). The FDA may also issue an order or regulation requiring an applicant to provide a study report that is necessary and relevant to a determination concerning whether there is or may be grounds for revoking approval of an approved drug (21 U.S.C. 355(k)(1)). You must file 506B reports for all postmarketing study commitments that you are required to conduct provided that the study concerns a product’s clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology."
"Postmarketing Study Commitment: An agreement between you and the FDA, confirmed in writing, for you to conduct one or more 506B or CMC studies. Also includes 506B studies that are required by the FDA (e.g., accelerated approval clinical benefit studies, animal efficacy clinical benefit and safety studies, deferred pediatric studies under PREA)"
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project
[email protected]
Empire State Consumer Project, Inc. (ESCP) is a registered 501c3 Not-for-Profit Organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest. ESCP is represented by Joel Kupferman, Esq., NY Environmental Law & Justice Project, [email protected].
www.empirestateconsumerproject.blogspot.com
ESCP receives update on FDA study:
From: Bernstein, Michael
To: Carol Chittenden
Sent: Wed, Nov 29, 2017 8:45 am
Subject: Status of PEG 3350 Study
Dear Ms. Chittenden:
This responds to your request for an update on the status of the CHOP study. As you know from my last email update (May 5, 2017), CHOP must develop assays for the relevant PEG 3350 metabolites and lower molecular weight polyethylene glycols of interest before it can complete the remaining study activities and analyze the results. Our science staff has reiterated, as stated in the initial grant document, that it is critical that the assays have proper sensitivity or the results will not be accurate or useful. While we understand your frustration with the slow pace of assay development, there is no point to proceeding to the testing phase of the study if the results will not be reliable and informative. Once the assays development is concluded, the testing phase should proceed relatively quickly, as obtaining the required samples should be fairly straightforward.
Although developing the assays has taken much longer and proven more difficult than anticipated, progress is being made. CHOP recently conducted clinical testing of several assays to determine the assays’ sensitivity at detecting PEG 3350 metabolites and lower molecular weight (MW) polyethylene glycols in blood. Specifically, the set-up and validation for ethylene glycol, diethylene glycol, triethylene glycol, glycolic acid, diglycolic acid has been completed. The validation of hydroxyethoxyacetic acid (HEAA) and oxalic acid (OA) is underway and should be finished before the end of this year. Finally, work to finalize the remaining assays to measure the 200 - 400 MW PEG is on-going and should be completed in early 2018.
CHOP has indicated that it will be able to complete the remaining study activities and analysis in 2018.
We share your desire to get this study completed as promptly as possible, and appreciate your patience in this matter.
Michael D. Bernstein
Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
[email protected]
ESCP Asks FDA Again for Drug Safety Communication to Doctors:
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
January 27, 2017
Mr. Michael D. Bernstein, Director, DRP II
Office of Regulatory Policy
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6240
Silver Spring, MD 20993-0002
FDA Citizen Petition FDA-2012-P-0566, Study and Drug Safety Communication
Dear Mr. Bernstein:
In 2012, Empire State Consumer Project (ESCP) filed an FDA Citizen Petition to study the safety of polyethylene glycol 3350 laxatives prescribed to children (FDA-2012-P-0566). The product safety concerns reported in the petition are symptoms similar to those of ethylene glycol toxicity. The petition grant includes an agreement by FDA to study the potential for PEG 3350 to degrade into ethylene glycol (EG) and diethylene glycol (DEG) and to study the long term effects of PEG 3350 products on pediatric patients. Ethylene glycol and diethylene glycol are chemicals used to make antifreeze. Both are toxic to the central nervous system, liver, and kidneys when ingested.
The ESCP petition was granted with a study awarded to Children’s Hospital of Philadelphia (CHOP), which was to have been completed by 9/9/2015. http://grantome.com/grant/NIH/R01-FD005312-01 As of this date, the FDA/CHOP study has not yet begun recruiting participants. Upon inquiring with the FDA on the status of the study, we have been advised to look for updates on the CHOP website. The website still states, “Researchers in CHOP’s Division of Gastroenterology who will be conducting the study have not begun enrolling children, but once enrollment begins, an announcement will be made.” http://heuckeroth.research.chop.edu/peg-3350-study
We are asking that the FDA issue an update on the status of this study and, given the delay in completing the study, to issue an FDA Drug Safety Communication regarding potential dangers in prescribing PEG 3350 drugs off-label to children. It has been almost five years since we filed our petition. As of this date, no study has been conducted on neuropsychiatric effects in children and no study has been done on the long term use of these products in children.
The FDA Adverse Event Reporting System (FAERS) now shows over 19,000 adult and child adverse event reports that include at least one PEG 3350 product (including a number of deaths), a small percentage of which have been reviewed by the FDA. The number of reports rose from 2,257 in 2012, when the FDA Citizen petition was filed.
In 2009, the FDA Drug Safety Oversight Board acknowledged neuropsychiatric, metabolic, gastrointestinal, and kidney events in children who took PEG 3350 laxatives, but felt that “no action was required” at that time:
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body's acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.” “It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.”
This FDA document, updated in 2016 shows that the FDA acknowledged years ago that Miralax causes seizures (45th page): http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000OtherR.pdf
In addition to the ethylene glycol and diethylene glycol children may be exposed to through the degradation of PEG 3350, the FDA has tested 8 lots of polyethylene glycol 3350 and found ethylene glycol and diethylene glycol contaminants in the product itself… “To better understand the level of polyethylene glycol impurities in PEG, the FDA Chemistry and Manufacturing group evaluated PEG 3350. This analysis of eight lots of PEG 3350 confirmed the presence of small amounts of ethylene glycol and diethylene glycol in all lots tested. Based upon the recommended daily adult dose of 17g daily dose PEG 3350, the maximum daily exposure of ethylene glycol would be 0.005 mg/kg/day for a 60 kg patient, or 0.015 mg/kg/day for a 20 kg pediatric patient (approx 5 years of age). Other low molecular weight (LMW) PEGs were not included in this analysis. However, it is not known if any of these LMW species are absorbed and if so to what extent. Understanding the human absorption profile of LMW species is the first step needed in trying to understand the possible contribution of PEG 3350 use to the development of adverse events in children using this product chronically.”
The EPA recommends that children not be exposed to more than 20 mg/L or 20 parts per million (ppm) of ethylene glycol in drinking water per one day or 6 mg/L or 6 ppm per day over 10 days. The adult doses of PEG 3350 tested were found to contain 0.3 mg of ethylene glycol of daily exposure for a 44 lb. child. This exposure is in addition to any EG and DEG exposure that may be found to occur from PEG 3350 degradation of the laxative products. The health effects of long term exposure of children to PEG 3350 are not known, although risks from short term exposure to EG and DEG are well documented in humans.
In 2009, the FDA issued a warning about DEG in electronic cigarettes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm173222.htm
Empire State Consumer Project has since petitioned the FDA to issue a Drug Safety Communication regarding the finding of ethylene glycol and diethylene glycol in all lots of PEG 3350 it tested, so that parents of study participants and all parents can be made aware of the potential for PEG 3350 to contain ethylene glycol and diethylene glycol. This petition for a Drug Safety Communication was denied. Although one additional FDA test did not show EG and DEG, ESCP has asked that ongoing PEG 3350 product testing be conducted by the FDA, as one test is not a comprehensive study, nor an assurance of safety.
Doctors at the National Taiwan University Hospital in Taipei have also concluded “that bowel preparation with PEG lavage solution may be associated with severe renal complications, and that physicians should be aware of possible adverse effects when administering the agent.” http://www.ntuh.gov.tw/pmr/lists/list14/attachments/164/10253009-200903-37-1-45-50-a.pdf
Dosing
As stated in our petition, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) has created guidelines for off-label prescribing of PEG 3350 laxatives to children. These guidelines are not approved by the FDA. Parents report that many doctors are prescribing even higher doses. Children are often given multiple adult doses daily for months and years at a time.
Based on NASPGHAN dosing, one gram of PEG 3350 per kg of body weight is 10 grams of PEG for a 22 lb. child, or more than half of the 17 gram adult dose.
http://journals.lww.com/jpgn/fulltext/2006/09000/evaluation_and_treatment_of_constipation_in.28.aspx
In an example of a constipation treatment recommendation from a large children’s hospital in the US, dosing is 3 times per day for 3 days during the cleanout phase and a duration of 6-12 months or more for the maintenance phase. In this case, a 10 year old child would receive 3 adult daily doses per day for 3 days, then 1-2 adult daily doses per day for up to a year or more. Again, much younger children are also routinely given adult doses of PEG 3350 daily for months and years at a time… “As soon as they complete the first cleanout, give polyethylene glycol once daily at the following dosages. Mix in juice or water, not milk. It needs to be taken daily for at least 6-12 months and often longer. You can increase the dose slightly if needed.
Children 18 months to 5 years old – Give 2 teaspoons, mixed in 4 to 6 ounces of fluid
Children 5 to 10 years old – Give 1 capful (17 gms) mixed in 6-8 ounces of fluid
10 years old and older – Give 1 to 2 capfuls mixed in 8 ounces of fluid”
Selenium
In February 2016, Empire State Consumer Project entered another FDA Citizen Petition asking the FDA to test PEG 3350 products after finding high levels of selenium in the three PEG 3350 products ESCP tested (FDA-2016-P-0769). The FDA responded with an agreement to review and analyze the request, but we have not received any additional correspondence regarding FDA conducting its own testing.
The 2012 ESCP also called for a boxed warning on PEG 3350 products. The boxed warning was not granted, but the FDA has decided to update the labeling of prescription PEG 3350 bowel preparations with more stringent warnings and precautions for patients with certain health conditions. We feel it is crucial that, if a boxed warning is not forthcoming pending research, a Drug Safety Communication be issued. Also concerning is the FDA’s loosening of restrictions on off-label marketing and companies now creating food-based PEG 3350 products, which we fear will be marketed for children’s constipation before long.
Would you please provide us with an update on the FDA/CHOP study and an answer regarding a Drug Safety Communication. The thousands of parents who are members of PEG 3350 support groups are waiting for doctors to be informed of the potential dangers of these products before more children are harmed.
Sincerely,
Carol Chittenden
Empire State Consumer Project
[email protected]
www.empirestateconsumerproject.blogspot.com
Empire State Consumer Project, Inc. (ESCP) is a registered 501c3 not-for-profit organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest.
ESCP Asks FDA for Response on Freedom of Information Request:
Sent: Fri, Sep 18, 2015 11:08 am
Subject: FOIA 2014-6736 and FDA-2012-P-0566 from Carol Chittenden, Empire State Consumer Project
Dear Ms. Sipes,
Yesterday, I received a phone call from Michael Howard regarding the above FOIA. I had been told by Sharon Dodson on July 1, 2015 that she would forward our request to him to investigate why it had been sent to Food Additives when it was clearly a CEDR FOIA. I had begun the process by sending the request to you in January (see below) and I am hoping you can oversee the disposition of the request to ensure it goes to the correct person there. Would you please send me the name of the contact who will be responsible for processing the request, so I can follow up as needed?
I had also written to Michael Bernstein asking for an improvement in the 12-18 month timeline for an answer to this FOIA, as we are a not-for-profit consumer organization involved in public education and feel that this time frame is excessively long for a government agency response regarding current and serious medical issues being faced by children. We are now 9 months into that time period without any progress by FDA, as the request is being bumped to the wrong departments.
Also, I am in need of an update on the status of the study granted to Children's Hospital of Philadelphia related to our FDA petition, FDA-2012-P-0566. Would you please tell me if the study has begun recruiting participants, whether it will include an analysis of the effects of PEG 3350 on the gut microbiome and enteric nervous system (as we have requested), and when the study will be completed.
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
www.empirestateconsumerproject.blogspot.com
ESCP Asks FDA to Not Miss Critical Information in Study on Children
Ms. Grail Sipes
Director
Office of Regulatory Policy
Center for Drug Evaluation and Research
US Food and Drug Administration
FDA Petition FDA-2012-P-0566, Study at Children's Hospital of Philadelphia
Dear Ms. Sipes:
We understand from a press release issued by Children's Hospital of Philadelphia that participant recruiting for this study has not yet begun. We would like to take this opportunity to express our concern that the study be a comprehensive assessment of the effects of peg 3350 use in children. Rather than making the assumption that absorption alone is leading to neuropsychiatric symptoms in children, is it possible to include the following testing in FDA's research? We feel that if peg testing alone does not prove that EG or DEG are being absorbed, we have lost the opportunity to look for other factors that may be contributing to neuropsychiatric symptoms in children...
1. As we asked in our FDA petition, what are the effects of chronic laxative use on nutrient absorption and depletion in children? Many nutrients, including B vitamins and magnesium are related to neuropsychiatric health. If there is evidence that chronic laxative use blocks nutrient absorption or depletes nutrients, what key nutrients can be measured while blood is being drawn for PEG, EG, DEG. (See petition page 15,
absorption? http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-0566-0001).
2. Effects of chronic laxative use on the enteric nervous system and feedback to the central nervous system. As we asked in our petition, what effects does peg laxative use have on intestinal flora (FDA petition page 15)? How does this affect the nervous system in the intestines that would impact neuropsychiatric health? If it is true that 95% of seratonin is found in the bowels and that 90% of the fibers in the vagus nerve transmit information from the gut to the brain and not the other way around ( http://www.scientificamerican.com/article/gut-second-brain/ ), can we measure this effect in children on PEG 3350 through blood and stool testing.
3. Metabolic acidosis was acknowledged by the 2009 FDA Drug Safety Oversight Board as an adverse event related to PEG 3350 use in children. As metabolic acidosis is a cause of demylenation of nerves (as is B12 deficiency) and related neuropsychiatric symptoms, will metabolic acidosis be tested for in children being studied?
http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/multiple_sclerosis_ms_and_related_disorders/overview_of_demyelinating_disorders.html
http://www.nationalmssociety.org/For-Professionals/Clinical-Care/Diagnosing-MS/Signs-and-Symptoms-Consistent-with-Demyelinating-D#section-6
Thank you very much for your consideration of these issues as you study the effects of PEG 3350 laxatives in children.
Sincerely,
Carol Chittenden
Empire State Consumer Project, Inc.
www.empirestateconsumerproject.blogspot.com
ESCP Submits Freedom of Information Request for Information on Toxics in PEG 3350 and Children's Study Protocol
January 20, 2015
Grail Sipes
Director
Office of Regulatory Policy
Center for Drug Evaluation and Research
US Food and Drug Administration
Re: Freedom of Information Act Request, FDA-2012-P-0566
Dear Ms. Sipes:
This is a request under the Freedom of Information Act. We request that a copy of the following records or documents containing the following information be provided to us.
I am requesting on behalf of Empire State Consumer Project, a registered 501c3 not-for-profit organization engaged in free consumer education services, for which this information will be used. We request a waiver of all fees for this request. Disclosure of the requested information to us is in the public interest because it is likely to contribute significantly to public understanding of the operations or activities of the government or a government funded study and is not related to a commercial interest. The information requested is related to Citizens Petition FDA-2012-P-0566 and is in response to your letter to Empire State Consumer Project dated November 12, 2014.
In that correspondence, we were advised to ask Children’s Hospital of Philadelphia (CHOP) for some of this information. We feel that, because this is an FDA funded study, the FDA should be providing us with this information, as CHOP is under no legal obligation to do so.
FDA-Funded Research at Children’s Hospital of Philadelphia
1. Records related to PEG 3350 potential health risks given to test participant parents/guardians, including the finding of EG and DEG in all lots of PEG 3350 FDA tested. We feel it is important for parents to understand the symptoms that have been reported to the FDA before they agree to participate.
2. Records related to the testing of PEG 3350 being used in the CHOP study for the presence of EG and DEG before being used on study participants. Although FDA tested again in 2013, this is not a thorough study of PEG 3350 products and we recommend ongoing testing for EG and DEG. A valid study of PEG 3350 absorption necessitates that EG and DEG-free products be used.
3. Records related to protocol for measuring baseline neuropsychiatric conditions of study participants taking PEG 3350 products before entering study, including data collection documents used to assess when PEG 3350 administration began, at what doses, for what duration, and when symptoms began. Children currently taking PEG 3350 may already be experiencing symptoms related to PEG 3350 use.
4. Records related to the length of time study participants will be evaluated for changes in neuropsychiatric behavior (including past the end of PEG 3350 administration). Parents report the continuation of symptoms long after discontinuation of PEG 3350 and some report an increase in severity of symptoms just after discontinuing.
5. Records related to protocol for measuring urinary/kidney changes in study participants and changes related to metabolic acidosis. These symptoms were part of the FDA’s Drug Safety Oversight Board meeting in 2009, but are not listed in CHOP’s study outline.
Relationship of Ethylene Glycol and Diethylene Glycol to PEG 3350 Adverse Events
“As part of the drug approval process, manufacturers must meet specifications for levels of impurities that exist in their products (see 21 CFR 211.84(d)(2)) for their products to be approved as safe and effective.”
1. Records related to the specifications for levels of ethylene glycol, diethylene glycol and their respective metabolites, glycolic acid, glyoxylic acid, glycoaldehyde, oxalic acid, 2-hydroxyethoxyacetic acid, 1,4-dioxane, ethylene oxide, and heavy metals that may be found in PEG 3350. If manufacturers must meet specifications, they must be published specifications available to the public.
2. Records related to amounts of these substances found in PEG 3350 FDA has tested and manufacturers have tested and submitted to FDA. These findings should not be misconstrued by manufacturers as possibly being related to manufacturer “trade secrets,” as mentioned in FDA’s last letter to us.
3. Records related to manufacturer information on potential for PEG 3350 to break down into EG or DEG in solution or in animal studies.
Adverse Event Reports
1. Records related to FDA’s or CHOP’s review of or plans to review PEG 3350 related adverse events added from August 6, 2012 to July 2014. Our records show 7,070 adverse events that include PEG 3350 are in the FAERS database through July 2014. Given the large number of adverse event reports that contain at least one PEG 3350 product, we think it is important for the FDA and CHOP to review all adverse event reports in designing and conducting a comprehensive study.
Would you please add this correspondence to online Docket No. FDA-2012-P-0566.
Thank you very much.
Sincerely,
Carol Chittenden
Empire State Consumer Project
www.empirestateconsumerproject.blogspot.com
ESCP Asks FDA to Research PEG in Covid Vaccines, Reactions, and Children
-----Original Message-----
From: [email protected]
To: [email protected] ; [email protected]
Cc: [email protected] ; [email protected] ; [email protected] ; [email protected]
Sent: Tue, Dec 15, 2020 9:26 am
Subject: PEG in Covid vaccine also being studied by FDA in Children Taking Laxatives, Letter from Empire State Consumer Project
ESCP
Empire State Consumer Project, Inc.
Protecting children, consumers, and the environment since 1971.
December 15, 2020
Stephen M. Hahn M.D.
Commissioner of Food and Drugs - Food and Drug Administration
[email protected]
Peter Marks M.D., PhD.
Director - Center for Biologics Evaluation and Research (CBER)
[email protected]
cc: US Senator Kirsten Gillibrand, US Senator Chuck Schumer
Consumer Group Warns PEG Suspected in Pfizer Covid Vaccine Reactions is Same Chemical Harming Children Taking Laxatives, Being Studied by FDA
Dear Commissioner Hahn and Director Marks:
Empire State Consumer Project (ESCP) is a registered 501c3 not-for-profit organization dedicated to reducing the use of unsafe products and chemicals toxic to human and environmental health. We accomplish this by educating consumers and industry, conducting product testing and reporting, and by advocating for regulation where needed to protect the public interest.
We want to bring to your attention that the ingredient suspected in the allergic reactions in two people who received the Pfizer Covid 19 vaccine, polyethylene glycol (PEG), is the same chemical causing neuropsychiatric and other adverse events in children taking polyethylene glycol laxatives. We ask that you please review ESCP’s FDA Citizen Petition on polyethylene glycol laxatives and risks to children and the resulting grant FDA issued to Children’s Hospital of Philadelphia to study PEG adverse events in children. ESCP’s website dedicated to this nonprofit consumer advocacy work is https://laxativekids.weebly.com/.
We understand that the British Medicines and Healthcare Products Regulatory Agency (MHRA) Chief Executive June Raine told lawmakers such allergic reactions had not been a feature of Pfizer’s clinical trials. Pfizer has said people with a history of severe adverse allergic reactions to vaccines or their ingredients were excluded from their late-stage trials. We see that the FDA will require Pfizer to increase its monitoring for anaphylaxis and submit data on anaphylaxis adverse events once the vaccine is distributed for use.
FDA reported adverse events related to PEG 3350 are over 36,000 and the parent Facebook group, Parents Against Miralax, Restoralax, Movicol is up to 43,000 members since we filed our petition in 2012. Our work has been receiving nationwide news coverage ever since, including two stories in the New York Times. Almost all parents report identical neuropsychiatric and other symptoms in their children while taking PEG 3350. The FDA has resumed the study (which had been delayed since 2015) with a new completion date of 2021.
PEG laxatives are not approved for use in children, nor in adults for more than 7 days, but are routinely prescribed to children by pediatricians in adult doses for long term use. Our research shows that PEG allergy and hypersensitivity are well known in humans, but have not been studied in children. Parents report that PEG allergy testing has not been made available to them when they report adverse events in their children taking the drug.
In light of the PEG adverse events acknowledged by the FDA in its Drug Safety Oversight Board meeting of June 18, 2009 (excerpts below), we think it is imperative that the FDA studies whether PEG as an ingredient in vaccines can be considered safe for children.
FDA Drug Safety Oversight Board Meeting June 18, 2009, Public Summary
“The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body’s acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings."
"There is a perception that PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known about whether absorption in children differs from adults, especially in children who are constipated, have underlying intestinal disease, or are very young."
"Children may be more susceptible to variations in PEG product quality."
"Effects of large doses of PEG given over a long duration (e.g weeks or longer) is not known.” "Children are receiving adult doses of PEG in some cases.”
Given the adverse events parents are reporting in children ingesting PEG, exposing children to PEG through injection should require FDA’s most thorough deliberation and research.
We look forward to your reply on this urgent drug safety and children’s health issue.
Sincerely,
Carol Chittenden, Director
Empire State Consumer Project, Inc.
http://empirestateconsumerproject.blogspot.com/
https://laxativekids.weebly.com/
585-831-7124
Richards, Paul [email protected]Hide
To[email protected] [email protected]
Dear Ms. Chittenden,
This message is in response to our recent telephone conversation regarding your letter related to polyethylene glycol (PEG), one of the ingredients in the Pfizer-BioNTech and Moderna COVID-19 vaccines. The U.S. Food and Drug Administration (FDA) has authorized these vaccines for emergency use in the United States to prevent COVID-19.
The issuance of an Emergency Use Authorization (EUA) is different than an FDA approval of a vaccine, in that a vaccine available under an EUA is not approved. In determining whether to issue an EUA for a product, the FDA evaluates the available evidence to determine whether the product may be effective and also assesses any known or potential risks and any known or potential benefits. If the product meets the effectiveness standard and the benefit-risk assessment is favorable, the product is made available during the emergency.
For both vaccines, FDA has evaluated and analyzed the safety and effectiveness data from clinical trials conducted in tens of thousands of study participants and manufacturing information submitted by the companies. These clinical trials are being conducted according to the rigorous standards set forth by the FDA. FDA has determined that the totality of the available data provides clear evidence that both vaccines may be effective in preventing COVID-19 and support that the known and potential benefits outweigh the known and potential risks of the vaccine’s use in millions of people, including healthy individuals.
Within your letter you express concern about the risk of exposure to polyethylene glycol (PEG) in children. The Pfizer-BioNTech COVID-19 Vaccine is authorized for use for the prevention of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The Moderna COVID-19 Vaccine is authorized for use for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. Both manufacturers have publicly acknowledged that they intend to study their vaccines in adolescents, followed by studies in younger children.
Additionally, it is important to note that the Fact Sheets for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine explain that neither vaccine should be administered to individuals with a known history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine. The Fact Sheet for Healthcare Providers explains that appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration and references the Centers for Disease Control and Prevention (CDC) guidelines (https://www.cdc.gov/vaccines/covid-19/).
As of January 15, 2021, over 12 million individuals have received at least one dose of a COVID-19 vaccine, a disease that is causing vast numbers of hospitalizations and deaths in the United States each day and for which there are limited treatments available. Allergic reactions, some of which have been severe, have been reported in some individuals following administration of the Pfizer-BioNTech and Moderna COVID-19 vaccines. Information about these allergic reactions and their occurrence is available on CDC’s website (https://www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm?s_cid=mm7002e1_w).
The cause of the allergic reactions is unknown. However, further study is being planned for these vaccines with regard to risk of allergic reactions.
In addition, for both COVID-19 vaccines authorized under an EUA, ongoing clinical trials will continue to obtain additional safety and effectiveness information intended to support eventual approval. Also, as a condition of authorization for each of these COVID-19 vaccines, the manufacturer will conduct post-authorization observational study(ies) to evaluate the association between the vaccine and pre-specified adverse events of special interest, along with deaths and hospitalizations. Conditions of authorization also include requirements for the manufacturers and vaccination providers to report certain adverse events to the Vaccine Adverse Event Reporting System and for the manufacturers to submit periodic safety reports to FDA. Further, FDA, CDC, and other federal partners are using robust systems and data sources to conduct ongoing safety monitoring for COVID-19 vaccines authorized under an EUA.
The safety of vaccines is a high priority for FDA and pertinent information pertaining to COVID-19 vaccines will be communicated to the public as it becomes available.
On behalf of Dr. Janet Woodcock, acting commissioner of the FDA, and Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), I would like to thank you for your interest in this topic, as well as the opportunity to provide this information to you.
Sincerely,
Paul Richards
Chief, Consumer Affairs Branch
Center for Biologics Evaluation and Research
Office of Communication, Outreach and Development
U.S. Food and Drug Administration
Tel: 240-402-8153
[email protected]
This informal communication represents my best judgment at this time. It does not constitute an advisory opinion in accordance with 21 CFR 10.85, and does not necessarily represent the formal position of FDA or otherwise obligate the agency to the views expressed.